| 1 | Behav Pharmacol 2000 Jun 11: 235-42 |
|---|---|
| PMID | 11103878 |
| Title | Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders. |
| Abstract | Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety-like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic-like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 2 | Mol. Psychiatry 2000 Sep 5: 558-62 |
| PMID | 11032392 |
| Title | Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. |
| Abstract | schizophrenia is a heterogeneous disease involving genetic and environmental factors. The frequency of structural brain abnormalities or physical anomalies supports a neurodevelopmental etiology, especially in early onset schizophrenia. Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems and interacts with the meso-limbic DA systems, involved in the therapeutic response to antipsychotic drugs and substance abuse. In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression. In a French Caucasian population, we found no statistical difference in allele or genotype distribution of the BDNF gene dinucleotide repeat polymorphism (166-174 bp) between the whole group of schizophrenic patients and controls. By contrast, an excess of the 172-176 bp alleles was found in patients with late onset, in neuroleptic-responding patients and in non-substance-abusing patients. BDNF gene variants thus appear to be associated with developmental features of schizophrenia. In addition, this association with good treatment responding was independent from the association found with the DRD3 Ball gene polymorphism in the same population. These results suggest an independent contribution of each gene to a treatment-sensitive form of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 3 | Mol. Psychiatry 2000 May 5: 293-300 |
| PMID | 10889532 |
| Title | Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. |
| Abstract | Previous neuropathological studies have revealed that the corticolimbic system of schizophrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we determined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influenced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. However, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither withdrawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 4 | Behav Pharmacol 2000 Jun 11: 235-42 |
| PMID | 11103878 |
| Title | Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders. |
| Abstract | Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety-like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic-like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 5 | Mol. Psychiatry 2000 Sep 5: 558-62 |
| PMID | 11032392 |
| Title | Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. |
| Abstract | schizophrenia is a heterogeneous disease involving genetic and environmental factors. The frequency of structural brain abnormalities or physical anomalies supports a neurodevelopmental etiology, especially in early onset schizophrenia. Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems and interacts with the meso-limbic DA systems, involved in the therapeutic response to antipsychotic drugs and substance abuse. In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression. In a French Caucasian population, we found no statistical difference in allele or genotype distribution of the BDNF gene dinucleotide repeat polymorphism (166-174 bp) between the whole group of schizophrenic patients and controls. By contrast, an excess of the 172-176 bp alleles was found in patients with late onset, in neuroleptic-responding patients and in non-substance-abusing patients. BDNF gene variants thus appear to be associated with developmental features of schizophrenia. In addition, this association with good treatment responding was independent from the association found with the DRD3 Ball gene polymorphism in the same population. These results suggest an independent contribution of each gene to a treatment-sensitive form of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 6 | Mol. Psychiatry 2000 May 5: 293-300 |
| PMID | 10889532 |
| Title | Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. |
| Abstract | Previous neuropathological studies have revealed that the corticolimbic system of schizophrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we determined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influenced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. However, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither withdrawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 7 | J. Neurosci. Res. 2000 Jun 60: 783-94 |
| PMID | 10861791 |
| Title | Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. |
| Abstract | The antipsychotics haloperidol and risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 8 | J. Neurosci. Res. 2000 Jun 60: 783-94 |
| PMID | 10861791 |
| Title | Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. |
| Abstract | The antipsychotics haloperidol and risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 9 | Biol. Psychiatry 2001 Aug 50: 260-5 |
| PMID | 11522260 |
| Title | Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. |
| Abstract | The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain. Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry. Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death. These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 10 | Eur. J. Neurosci. 2001 Jul 14: 135-44 |
| PMID | 11488957 |
| Title | BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. |
| Abstract | Brain-derived neurotrophic factor (BDNF) plays an important role in development, synapse remodelling and responses to stress and injury. Its abnormal expression has been implicated in schizophrenia, a neuropsychiatric disorder in which abnormal neural development of the hippocampus and prefrontal cortex has been postulated. To clarify the effects of antipsychotic drugs used in the therapy of schizophrenia on BDNF mRNA, we studied its expression in rats treated with clozapine and haloperidol and in rats with neonatal lesions of the ventral hippocampus, used as an animal model of schizophrenia. Both antipsychotic drugs reduced BDNF expression in the hippocampus of control rats, but did not significantly lower its expression in the prefrontal cortex. The neonatal hippocampal lesion itself suppressed BDNF mRNA expression in the dentate gyrus and tended to reduce its expression in the prefrontal cortex. These results indicate that, unlike antidepressants, antipsychotics down-regulate BDNF mRNA, and suggest that their therapeutic properties are not mediated by stimulation of this neurotrophin. To the extent that the lesioned rat models some pathophysiological aspects of schizophrenia, our data suggest that a neurodevelopmental insult might suppress expression of the neurotrophin in certain brain regions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 11 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2001 May 25: 691-707 |
| PMID | 11383973 |
| Title | Schizophrenia, a neurodegenerative disorder with neurodevelopmental antecedents. |
| Abstract | schizophrenia is a devastating disorder that has been referred to as youth's greatest disabler. Although a number of hypotheses have been proposed in an attempt to explain the pathophysiology of schizophrenia no single theory seems to account for all facets of the disease. Each hypothesis explains some of the phenomena associated with schizophrenia and it is probable that many variables described in these hypotheses interact to produce a disorder characterized by heterogeneous symptomatology, progression and prognosis. Compelling evidence suggests that the primary disturbance is a neurodevelopmental abnormality, possibly resulting from a genetic defect(s), resulting in a predisposition to schizophrenia. Events later in life may then lead to the presentation of symptoms and a subsequent progression of the disease. Recent evidence suggests that the progressive course of schizophrenia is associated with ongoing neurodegenerative processes. Changes in brain derived neurotrophic factor (BDNF) may explain the various changes observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 12 | Schizophr. Res. 2001 Apr 49: 65-71 |
| PMID | 11343865 |
| Title | Association study of schizophrenia with polymorphisms at six candidate genes. |
| Abstract | Clinical studies have shown that there is a genetic contribution to the pathogenesis of schizophrenia. The molecular mechanisms of effective antipsychotic drugs and recent advances in neural development suggest that several dopamine receptor, serotonin receptor and neurotrophic factor genes might be involved in the disorder. In this study, we assessed the associations between schizophrenia and polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3), the serotonin 2A receptor (5HTR2A), the brain-derived neurotrophic factor (BDNF), the ciliary neurotrophic factor (CNTF) and the neurotrophin-3 (NT-3) genes. Our results suggest that the polymorphisms at the DRD3, 5HTR2A, CNTF and BDNF gene loci are unlikely to make our sample more genetically susceptible to schizophrenia. However, we found significant differences in microsatellite allele frequencies between schizophrenic and control groups for DRD2 in the whole sample and for DRD2 and NT-3 only in women. Therefore, clinical differences in the presentation of schizophrenia between gender might be related to genetic factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 13 | Nature 2001 May 411: 86-9 |
| PMID | 11333982 |
| Title | BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. |
| Abstract | Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 14 | Schizophr. Res. 2001 Apr 49: 65-71 |
| PMID | 11343865 |
| Title | Association study of schizophrenia with polymorphisms at six candidate genes. |
| Abstract | Clinical studies have shown that there is a genetic contribution to the pathogenesis of schizophrenia. The molecular mechanisms of effective antipsychotic drugs and recent advances in neural development suggest that several dopamine receptor, serotonin receptor and neurotrophic factor genes might be involved in the disorder. In this study, we assessed the associations between schizophrenia and polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3), the serotonin 2A receptor (5HTR2A), the brain-derived neurotrophic factor (BDNF), the ciliary neurotrophic factor (CNTF) and the neurotrophin-3 (NT-3) genes. Our results suggest that the polymorphisms at the DRD3, 5HTR2A, CNTF and BDNF gene loci are unlikely to make our sample more genetically susceptible to schizophrenia. However, we found significant differences in microsatellite allele frequencies between schizophrenic and control groups for DRD2 in the whole sample and for DRD2 and NT-3 only in women. Therefore, clinical differences in the presentation of schizophrenia between gender might be related to genetic factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 15 | Schizophr. Res. 2001 Oct 52: 79-86 |
| PMID | 11595394 |
| Title | Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. |
| Abstract | Disturbed neural development has been postulated as a crucial factor in the pathophysiology of schizophrenic psychoses. The neurobiochemical basis for such changes of cytoarchitecture and changed neural plasticity could involve an alteration in the regulation of neurotrophic factors. In order to test this hypothesis, BDNF and NT-3 levels in post-mortem brain tissue from schizophrenic patients were determined by ELISA. There was a significant increase in BDNF concentrations in cortical areas and a significant decrease of this neurotrophin in hippocampus of patients when compared with controls. NT-3 concentrations of frontal and parietal cortical areas were significantly lower in patients than in controls. These findings lend further evidence to the neurotrophin hypothesis of schizophrenic psychoses which proposes that alterations in expression of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity, thus being an important event in the etiopathogenesis of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 16 | Rev Neurosci 2001 -1 12: 95-110 |
| PMID | 11392459 |
| Title | The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity. |
| Abstract | Several neurotrophic factors influence the development, maintenance and survival of dopaminergic neurons in the mammalian central nervous system (CNS), including neurotrophin-3 (NT-3), brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF) and glial derived neurotrophic factor (GDNF). This review focuses on the role of these neurotrophic factors in psychostimulant-induced behavioral sensitization, a form of dopamine-mediated neuronal plasticity that models aspects of paranoid schizophrenia as well as drug craving among psychostimulant addicts. Whereas NT-3, CNTF and bFGF appear to play a positive role in psychostimulant-induced behavioral sensitization, GDNF inhibits this form of behavioral plasticity. The role of BDNF in behavioral sensitization, however, remains elusive. While it has been shown that neurotrophic factors can influence the behavioral, structural and biochemical phenomena related to psychostimulant-induced neuronal plasticity, it is unclear which neurotrophic factors are important physiologically and which have purely pharmacological effects. In either case, examining the role of neurotrophic factors in behavioral sensitization may enhance our understanding of the mechanisms underlying the development of paranoid psychosis and drug craving and lead to the development of novel pharmacological treatments for these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 17 | Mol. Psychiatry 2001 May 6: 285-92 |
| PMID | 11326296 |
| Title | Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia. |
| Abstract | The neonatal (PND 7) lesion of the ventral hippocampus (VH) with ibotenic acid represents a well-established experimental paradigm that recapitulates many schizophrenia-like phenomena. In order to investigate molecular changes that could contribute to long lasting consequences on brain function, we have investigated the effects of the VH lesion on the expression for the trophic factors FGF-2 and BDNF. We used RNase protection assay to measure their mRNA levels in cortical regions of prepubertal (PND 35) and young adult (PND 56) animals, both under basal condition as well as in response to an acute restraint stress. The expression of BDNF was not altered by the VH lesion in prefrontal (PFC) and frontal cortex (FC) of PND 35 or PND 56 rats. An acute restraint stress at PND 35 produced a significant increase of the neurotrophin expression in PFC of sham as well as lesioned animals. However in young adult animals a significant elevation of BDNF expression was observed only in sham rats. We also found that the VH lesion produced a significant reduction of basal BDNF mRNA levels in the cingulate cortex of young adult, but not prepubertal rats. This effect was not accompanied by changes in the acute modulation of the neurotrophin, which was up-regulated by stress in both experimental groups. Conversely the expression of FGF-2 at PND 35 and PND 56 was not altered by early postnatal VH lesion, and there were no major differences between sham and lesioned animals in response to the acute stress. The changes in trophic factor expression may be relevant for the long-term effects of VH lesion on synaptic plasticity and may determine an increased vulnerability of the brain under challenging situations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 18 | Brain Res. 2002 Nov 956: 126-35 |
| PMID | 12426055 |
| Title | Brain-derived neurotrophic factor (BDNF) mRNA in rats with neonatal ibotenic acid lesions of the ventral hippocampus. |
| Abstract | Increasing evidence suggests that schizophrenia is a neurodevelopmental disorder with a progressive course characterized by worsening of symptoms and morphological alterations within the brain. This suggests that a neurodegenerative component may exist in schizophrenia. The role of brain-derived neurotrophic factor (BDNF) in neurodevelopment, cell viability and synaptic plasticity led to the investigation of BDNF as a potential candidate molecule in the pathophysiology of schizophrenia. BDNF mRNA was examined by in situ hybridization in the prefrontal cortex and hippocampus of animals with neonatal ibotenic acid lesions of the ventral hippocampus, a putative neurodevelopmental animal model of schizophrenia. Results demonstrate that animals with neonatal ibotenic acid lesions of the ventral hippocampus have reduced basal levels of BDNF mRNA. It is possible that alterations in this trophic factor render animals more susceptible to neurodegenerative insults. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 19 | Med. Hypotheses 2002 Aug 59: 154-8 |
| PMID | 12208201 |
| Title | Schizophrenia and other mental disorders require long-term adoptive immunotherapy. |
| Abstract | Many different microbial factors seem to contribute to the pathogenesis of schizophrenic and other psychiatric disorders. Activation of all T lymphocytes reactivates those downregulated by low-grade chronic infections and restores equilibrium in immune cell subpopulations. Different immune cell subpopulations express different neurotrophin receptors and produce different cytokines, particularly brain-derived neurotrophin (BDNF) and neurotrophin 3 (NT3) [M. Besser, R. Wank, J. Immunol. 162 (1998) 6303-6306] that appear to play a key role in schizophrenic and bipolar disorders [E. Jonsson, S. Brene, X.R. Zhang, et al., Acta Psychiatr. Scand. 95 (1997) 414-419; R.S. Duman, Arch. Gen. Psychiatry 54 (1997) 597-606; J.A. Siuciak, D.R. Lewis, S.J. Wiegand, R.M. Lindsay, Pharmacol. Biochem. Be 56 (1997) 131-137]. The hypothesis that adoptive immunotherapy is effective in psychiatric disorders will be supported by three case reports, in a patient with bipolar disorder, a patient with schizophrenia, and a patient with autism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 20 | Neurosci. Lett. 2002 Mar 321: 65-8 |
| PMID | 11872258 |
| Title | Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus. |
| Abstract | Quetiapine is a new atypical antipsychotic drug widely used in the treatment of schizophrenia and other psychotic disorders. This study examined the influence of quetiapine on the decrease of brain-derived neurotrophic factor (BDNF) expression, induced by chronic immobilization stress, in the hippocampus of the rat. Pretreatment with 10 mg/kg of quetiapine markedly attenuated the stress-induced decrease in levels of BDNF protein, as determined by Western blot analyses, and the reduction of BDNF immunoreactivity, in hippocampal pyramidal and dentate granular neurons. These results suggest that the chronic administration of quetiapine could be neuroprotective to hippocampal neurons in schizophrenia and this effect may be related to its antipsychotic effect in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 21 | Med. Hypotheses 2002 Aug 59: 154-8 |
| PMID | 12208201 |
| Title | Schizophrenia and other mental disorders require long-term adoptive immunotherapy. |
| Abstract | Many different microbial factors seem to contribute to the pathogenesis of schizophrenic and other psychiatric disorders. Activation of all T lymphocytes reactivates those downregulated by low-grade chronic infections and restores equilibrium in immune cell subpopulations. Different immune cell subpopulations express different neurotrophin receptors and produce different cytokines, particularly brain-derived neurotrophin (BDNF) and neurotrophin 3 (NT3) [M. Besser, R. Wank, J. Immunol. 162 (1998) 6303-6306] that appear to play a key role in schizophrenic and bipolar disorders [E. Jonsson, S. Brene, X.R. Zhang, et al., Acta Psychiatr. Scand. 95 (1997) 414-419; R.S. Duman, Arch. Gen. Psychiatry 54 (1997) 597-606; J.A. Siuciak, D.R. Lewis, S.J. Wiegand, R.M. Lindsay, Pharmacol. Biochem. Be 56 (1997) 131-137]. The hypothesis that adoptive immunotherapy is effective in psychiatric disorders will be supported by three case reports, in a patient with bipolar disorder, a patient with schizophrenia, and a patient with autism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 22 | Brain Res. 2002 Nov 954: 11-20 |
| PMID | 12393228 |
| Title | Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. |
| Abstract | Apart from their differential propensities to block dopamine D2 and serotonin 5-HT2 receptors, the molecular mechanisms underlying the clinical efficacy of typical and atypical antipsychotics in schizophrenia are largely unknown. Given recent interest in the effects of antipsychotics on neurotrophic and other growth related factors, the effects of antipsychotics on brain-derived neurotrophic factor (BDNF), a neurotrophin crucial to the structural integrity of adult neurons, were investigated in male Wistar rats. Chronic (19 day) but not acute (45 min) antipsychotic administration significantly altered levels of hippocampal BDNF mRNA. In addition, whereas chronic treatment with the strong D2 receptor-blocker haloperidol significantly downregulated hippocampal BDNF mRNA, the selective 5-HT2 receptor-blocker ritanserin significantly upregulated CA1 hippocampal BDNF mRNA in comparison to controls. Since high doses of risperidone and clozapine produce potent inhibition of both 5-HT2 and D2 receptors, while lower doses produce significantly greater 5-HT2 vs. D2 receptor blockade, a dose-response study was employed to determine whether low doses of these atypical antipsychotics would also upregulate hippocampal BDNF mRNA in the absence of significant D2 receptor blockade. Whereas chronic haloperidol and high-dose risperidone significantly downregulated hippocampal BDNF mRNA, intermediate and lower doses of risperidone and clozapine were, unlike ritanserin, without effect when compared to controls. Thus, although the long-term downregulation of hippocampal BDNF mRNA may underlie the different clinical profiles of certain antipsychotics, this effect seems to be associated with antipsychotic doses that not only cause significant D2 receptor inhibition, but are usually associated with side effects rather than therapeutic efficacies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 23 | Psychiatry Res 2002 Jul 110: 249-57 |
| PMID | 12127475 |
| Title | Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. |
| Abstract | Neurotrophic factors regulate neuronal development as well as synaptic plasticity, and their impairment is often implicated as a cause of schizophrenia. Among various neurotrophic molecules, brain-derived neurotrophic factor (BDNF) levels have been found to be increased in the corticolimbic regions of patients' brains. In the present study, we assessed peripheral BDNF levels in whole blood as well as in the serum of two independent groups of schizophrenic patients (n = 34 in each group) and healthy volunteers (n = 35 and n = 27, respectively). BDNF protein levels in fresh serum and blood of the patients and volunteers were measured using a two-site enzyme immunoassay and correlated with the number and decay of platelets. In addition to the studies of patients and volunteers, neuroleptic effects on BDNF levels were assessed by administering haloperidol to adult rats for 2 weeks or 5 months. The major findings were as follows: BDNF levels were significantly reduced in the serum of schizophrenic patients (P < 0.005, Mann-Whitney U-test) but not in their whole blood. Antipsychotic dose did not correlate with serum BDNF levels. Moreover, chronic administration of haloperidol failed to decrease serum BDNF levels in adult rats. Abnormal levels of BDNF are evident not only in the brain of schizophrenic patients, but also in their peripheral blood. The BDNF reduction in serum but not in whole blood suggests a potential deficit in neurotrophic factor release in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 24 | Pharmacol. Biochem. Behav. 2002 Sep 73: 317-26 |
| PMID | 12117585 |
| Title | Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. |
| Abstract | Previous studies have shown that 5-hydroxytryptamine(2A) (5-HT(2A)) receptor activation induces changes in the pattern of brain-derived neurotrophic factor (BDNF) mRNA expression in the neocortex and hippocampus, and that 5-HT(2A) receptor blockade interferes with the induction of BDNF mRNA by stress. Recent studies have also shown that activation of metabotropic glutamate group II (mGlu2/3) receptors suppresses 5-HT(2A) receptor-stimulated excitatory postsynaptic potentials/currents (EPSP/Cs) in pyramidal neurons in medial prefrontal cortex. Conversely, blockade of mGlu2/3 receptors enhances 5-HT-induced EPSCs. The current study examined the effects of the highly selective mGlu2/3 agonist (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and the mGlu2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) on BDNF mRNA expression in medial prefrontal cortex induced by the hallucinogen and 5-HT(2A/2B/2C) agonist 1-(2,5-dimethoxy-4-iodophenethyl)-2-aminopropane (DOI). LY354740 (0.1-10 mg/kg) dose-dependently suppressed DOI-induced BDNF mRNA levels in medial prefrontal cortex. In contrast, the mGlu2/3 antagonist LY341495 (1 mg/kg) enhanced DOI-induced BDNF mRNA levels. BDNF mRNA expression was not altered by administration of the mGlu agonist or the antagonist alone. These results are discussed with respect to a potential role for group II mGlu agonists in the treatment of depression and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 25 | Psychiatry Res 2002 Jul 110: 249-57 |
| PMID | 12127475 |
| Title | Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. |
| Abstract | Neurotrophic factors regulate neuronal development as well as synaptic plasticity, and their impairment is often implicated as a cause of schizophrenia. Among various neurotrophic molecules, brain-derived neurotrophic factor (BDNF) levels have been found to be increased in the corticolimbic regions of patients' brains. In the present study, we assessed peripheral BDNF levels in whole blood as well as in the serum of two independent groups of schizophrenic patients (n = 34 in each group) and healthy volunteers (n = 35 and n = 27, respectively). BDNF protein levels in fresh serum and blood of the patients and volunteers were measured using a two-site enzyme immunoassay and correlated with the number and decay of platelets. In addition to the studies of patients and volunteers, neuroleptic effects on BDNF levels were assessed by administering haloperidol to adult rats for 2 weeks or 5 months. The major findings were as follows: BDNF levels were significantly reduced in the serum of schizophrenic patients (P < 0.005, Mann-Whitney U-test) but not in their whole blood. Antipsychotic dose did not correlate with serum BDNF levels. Moreover, chronic administration of haloperidol failed to decrease serum BDNF levels in adult rats. Abnormal levels of BDNF are evident not only in the brain of schizophrenic patients, but also in their peripheral blood. The BDNF reduction in serum but not in whole blood suggests a potential deficit in neurotrophic factor release in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 26 | Mol. Psychiatry 2003 Feb 8: 146-7 |
| PMID | 12610646 |
| Title | Association between the BDNF gene and schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 27 | Schizophr. Res. 2003 Dec 65: 15-8 |
| PMID | 14623369 |
| Title | The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia. |
| Abstract | We investigated a novel polymorphism of single nucleotide substitution (C270T) of the brain-derived neurotrophic factor (BDNF) gene in schizophrenia patients (n=101) and in controls (n=68). The frequency of the C/T genotype and the T allele were significantly higher in the schizophrenia patients (25.7% and 13.9%, respectively) compared with the controls (5.9% and 2.9%). There were no significant differences in Positive and Negative Symptom Scale (PANSS) items and Global Assessment of Functioning (GAF) scores between the patients with C/C and C/T genotypes. Further studies are warranted to elucidate the significance of this finding in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 28 | Neurosci. Lett. 2003 Nov 351: 111-4 |
| PMID | 14583394 |
| Title | Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia are indistinguishable from controls. |
| Abstract | Our previous study showed that serum brain-derived neurotrophic factor (BDNF) was significantly decreased in the antidepressant-naive patients with major depressive disorders. However, it was still unclear whether serum BDNF level was altered in drug-naive patients with schizophrenia. Using ELISA, we measured serum BDNF levels in antipsychotic-naive (n=15) and medicated (n=25) patients with schizophrenia, and in age- and sex-matched normal controls (n=40). There were no significant differences in serum BDNF levels among antipsychotic-naive (n=15) and medicated (n=25) patients and normal controls (n=40). Possible factors such as duration of illness, age of onset, Brief Psychiatric Rating Scale scores, and chlorpromazine equivalent dosages of antipsychotics did not reveal any significant correlations with BDNF levels. Our results do not support the view that serum BDNF levels are associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 29 | Neurosci. Lett. 2003 Oct 349: 206-8 |
| PMID | 12951204 |
| Title | An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. |
| Abstract | A growing body of evidence suggests the involvement of brain-derived neurotrophic factor (BDNF) in both antipsychotic action and schizophrenia pathogenesis. The present study tested the hypothesis that the BDNF-gene Val66Met polymorphism is associated with schizophrenia and clozapine's therapeutic response. To identify any genetic predisposition to schizophrenia, we studied the BDNF-gene Val66Met polymorphism in 93 schizophrenic patients and 198 normal controls. Statistical analysis was used to test the association between this polymorphism and clozapine response the schizophrenic group. A trend (P=0.055) was demonstrated between genetic predisposition and Val66Met genotypes in 93 schizophrenic patients, especially for those with good response to clozapine (P=0.023). No significant difference in clozapine therapeutic response was demonstrated comparing the three Val66Met-genotype subgroups. Our finding suggests that this BDNF-gene Val66Met polymorphism may be related to schizophrenia pathogenesis in patients responsive to clozapine treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 30 | Mol. Psychiatry 2003 Jun 8: 592-610 |
| PMID | 12851636 |
| Title | Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. |
| Abstract | Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected a significant reduction in BDNF mRNA (mean=23%) and protein (mean=40%) in the DLPFC of patients with schizophrenia compared to normal individuals. At the cellular level, BDNF mRNA was expressed at varying intensities in pyramidal neurons throughout layers II, III, V, and VI of DLPFC. In patients with schizophrenia; neuronal BDNF expression was decreased in layers III, V and VI. Our study demonstrates a reduction in BDNF production and availability in the DLPFC of schizophrenics, and suggests that intrinsic cortical neurons, afferent neurons, and target neurons may receive less trophic support in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 31 | J. Neurosci. Res. 2003 Jun 72: 622-8 |
| PMID | 12749027 |
| Title | Effect of antipsychotic drugs on brain-derived neurotrophic factor expression under reduced N-methyl-D-aspartate receptor activity. |
| Abstract | Brain-derived neurotrophic factor (BDNF) promotes a variety of neuromodulatory processes during development as well as in adulthood. This neurotrophin has been associated with synaptic plasticity, suggesting that its regulation may represent one of the mechanisms through which psychotropic drugs alter brain function. Because reduced glutamatergic function represents a major feature of schizophrenia, we investigated the effects of the concomitant administration of haloperidol or olanzapine with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on BDNF expression. MK-801 reduces the hippocampal expression of the neurotrophin; this effect was exacerbated by haloperidol, but it was normalized by olanzapine. Our data reveal a fine tuning of BDNF biosynthesis and a differential modulation by antipsychotic drugs when NMDA-mediated transmission is reduced, suggesting that haloperidol and olanzapine can produce different effects on brain plasticity through the modulation of BDNF expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 32 | Nippon Rinsho 2003 Mar 61: 521-8 |
| PMID | 12701184 |
| Title | [Contribution of neurotrophic factors and cytokines to schizophrenia]. |
| Abstract | Abnormal development of the brain is implicated in the etiology and/or pathology of various psychiatric diseases, including schizophrenia. Current evidence indicates that neurotrophic factors can strongly influence neuronal phenotypic differentiation and subsequent neuronal function in synaptic plasticity. Among various neurotrophic factors, the expression of brain-derived neurotrophic factor(BDNF) and epidermal growth factor (EGF) is impaired in the brain as well as in the periphery of patients with schizophrenia. Based on this result, a novel animal model for schizophrenia has been established by perturbing the neurotrophic signaling during development. This review summarizes the latest progress of these studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 33 | Neurosci. Lett. 2003 Oct 349: 206-8 |
| PMID | 12951204 |
| Title | An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. |
| Abstract | A growing body of evidence suggests the involvement of brain-derived neurotrophic factor (BDNF) in both antipsychotic action and schizophrenia pathogenesis. The present study tested the hypothesis that the BDNF-gene Val66Met polymorphism is associated with schizophrenia and clozapine's therapeutic response. To identify any genetic predisposition to schizophrenia, we studied the BDNF-gene Val66Met polymorphism in 93 schizophrenic patients and 198 normal controls. Statistical analysis was used to test the association between this polymorphism and clozapine response the schizophrenic group. A trend (P=0.055) was demonstrated between genetic predisposition and Val66Met genotypes in 93 schizophrenic patients, especially for those with good response to clozapine (P=0.023). No significant difference in clozapine therapeutic response was demonstrated comparing the three Val66Met-genotype subgroups. Our finding suggests that this BDNF-gene Val66Met polymorphism may be related to schizophrenia pathogenesis in patients responsive to clozapine treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 34 | Mol. Psychiatry 2003 Jun 8: 592-610 |
| PMID | 12851636 |
| Title | Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. |
| Abstract | Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected a significant reduction in BDNF mRNA (mean=23%) and protein (mean=40%) in the DLPFC of patients with schizophrenia compared to normal individuals. At the cellular level, BDNF mRNA was expressed at varying intensities in pyramidal neurons throughout layers II, III, V, and VI of DLPFC. In patients with schizophrenia; neuronal BDNF expression was decreased in layers III, V and VI. Our study demonstrates a reduction in BDNF production and availability in the DLPFC of schizophrenics, and suggests that intrinsic cortical neurons, afferent neurons, and target neurons may receive less trophic support in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 35 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2003 Aug 27: 801-7 |
| PMID | 12921913 |
| Title | Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. |
| Abstract | Recently, the pathogenesis of schizophrenia has been investigated from the perspective of neurodevelopmental dysfunction theory. On the other hand, it has been indicated that neurotrophic factors, such as nerve growth factors, brain-derived neurotrophic factor (BDNF), and neurotrophin-3, are significantly involved in the development and functional differences of central nervous system (CNS). Some reports proposed that the dysfunction of these factors could explain the pathogenesis of schizophrenia possibly. In this study, the authors investigated immunohistochemically the distribution and/or morphology of BDNF and TrkB, its peculiar receptor, in the hippocampal formation of schizophrenic brain. As a result, BDNF-positive pyramidal cells in the CA2 and neurons in the CA3 and the field of the CA4 were intensely stained compared to those of normal control. Staining of TrkB-positive neurons showed a signet-ring like shape in the hippocampus of normal control brains. Such figures were not observed on staining of those neurons from schizophrenic brains. In the control cases, TrkB-immunopositive varicose fibers were frequently seen. Those observed differences between schizophrenic and normal cases may indicate the existence of dysfunction of BDNF and TrkB in schizophrenic brain, and this dysfunction may be one of the factors involved in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 36 | Biol. Psychiatry 2003 Jan 53: 39-47 |
| PMID | 12513943 |
| Title | MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients. |
| Abstract | schizophrenia, bipolar illness, and major depressive disorder have distinct presentations, but share some common symptoms. Hence, some common cellular and molecular abnormalities may be identifiable in these disorders. We examined cell-specific markers in the dorsolateral prefrontal cortex of brains from 18 patients with bipolar or major depressive disorder, and 18 matched controls, using in situ hybridization histochemistry and staining for nicotinamide-dinucleotide phosphate-diaphorase (NADPH). The distribution of NADPH-positive interstitial cells of the white matter and the expression of the mRNA for the 67 KD form of glutamic acid decarboxylase (GAD(67)) had previously been shown to be altered in prefrontal cortex of schizophrenics. Other markers identifying glutamatergic neuronal populations were alpha-type II calcium/calmodulin dependent protein kinase (CAMKII-alpha), brain derived neurotrophic factor, (BDNF) and the putative transcription factor, T-brain-1 (TBR1). Expression of GAD67 and the distribution of NADPH-positive cells in the white matter were not significantly altered in the dorsolateral prefrontal cortex of depressed subjects. Expression of CAMKII-alpha and TBR1 mRNAs was significantly increased in bipolar patients but not in major depressed patients, and there was a trend toward reduced BDNF expression in both groups. Abnormal patterns of gene expression and neuronal distribution in schizophrenics are markedly different from those in depressed patients. The findings that TBR1 and CAMKII-alpha expression is increased only in bipolar patients suggests abnormalities of specific genes related to a major cortical cell type and its connectivity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 37 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2003 Aug 27: 801-7 |
| PMID | 12921913 |
| Title | Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. |
| Abstract | Recently, the pathogenesis of schizophrenia has been investigated from the perspective of neurodevelopmental dysfunction theory. On the other hand, it has been indicated that neurotrophic factors, such as nerve growth factors, brain-derived neurotrophic factor (BDNF), and neurotrophin-3, are significantly involved in the development and functional differences of central nervous system (CNS). Some reports proposed that the dysfunction of these factors could explain the pathogenesis of schizophrenia possibly. In this study, the authors investigated immunohistochemically the distribution and/or morphology of BDNF and TrkB, its peculiar receptor, in the hippocampal formation of schizophrenic brain. As a result, BDNF-positive pyramidal cells in the CA2 and neurons in the CA3 and the field of the CA4 were intensely stained compared to those of normal control. Staining of TrkB-positive neurons showed a signet-ring like shape in the hippocampus of normal control brains. Such figures were not observed on staining of those neurons from schizophrenic brains. In the control cases, TrkB-immunopositive varicose fibers were frequently seen. Those observed differences between schizophrenic and normal cases may indicate the existence of dysfunction of BDNF and TrkB in schizophrenic brain, and this dysfunction may be one of the factors involved in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 38 | Biol. Psychiatry 2003 Jan 53: 39-47 |
| PMID | 12513943 |
| Title | MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients. |
| Abstract | schizophrenia, bipolar illness, and major depressive disorder have distinct presentations, but share some common symptoms. Hence, some common cellular and molecular abnormalities may be identifiable in these disorders. We examined cell-specific markers in the dorsolateral prefrontal cortex of brains from 18 patients with bipolar or major depressive disorder, and 18 matched controls, using in situ hybridization histochemistry and staining for nicotinamide-dinucleotide phosphate-diaphorase (NADPH). The distribution of NADPH-positive interstitial cells of the white matter and the expression of the mRNA for the 67 KD form of glutamic acid decarboxylase (GAD(67)) had previously been shown to be altered in prefrontal cortex of schizophrenics. Other markers identifying glutamatergic neuronal populations were alpha-type II calcium/calmodulin dependent protein kinase (CAMKII-alpha), brain derived neurotrophic factor, (BDNF) and the putative transcription factor, T-brain-1 (TBR1). Expression of GAD67 and the distribution of NADPH-positive cells in the white matter were not significantly altered in the dorsolateral prefrontal cortex of depressed subjects. Expression of CAMKII-alpha and TBR1 mRNAs was significantly increased in bipolar patients but not in major depressed patients, and there was a trend toward reduced BDNF expression in both groups. Abnormal patterns of gene expression and neuronal distribution in schizophrenics are markedly different from those in depressed patients. The findings that TBR1 and CAMKII-alpha expression is increased only in bipolar patients suggests abnormalities of specific genes related to a major cortical cell type and its connectivity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 39 | Neurosci. Lett. 2004 Nov 371: 79-83 |
| PMID | 15500971 |
| Title | Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are critically implicated in development and maintenance of function of neurons. Neurodevelopment is reported to be impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin, may be more harmful to schizophrenic brains than to non-schizophrenic brains when used chronically. And neurotoxic events may promote disease-onset and lead to exaggerated release of neurotrophins. We investigated 157 drug-naive first-episode schizophrenic patients and found significantly elevated BDNF serum concentrations (by up to 34%) in patients with chronic cannabis abuse (n = 35, p < 0.001) or multiple substance abuse (n = 20, p < 0.001) prior to disease onset. Drug-naive schizophrenic patients without cannabis consumption showed similar results to normal controls and cannabis controls without schizophrenia. Thus, raised BDNF serum levels are not related to schizophrenia and/or substance abuse itself but may reflect a cannabis-related idiosyncratic damage of the schizophrenic brain. In line with this hypothesis, disease onset was 5.2 years earlier in the cannabis-consuming group (p = 0.0111). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 40 | Brain Res. 2004 Oct 1025: 194-202 |
| PMID | 15464760 |
| Title | Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons: effect of chronic administration of olanzapine. |
| Abstract | In the present study, we used a repeated restraint stress animal model to observe the changes in the expression of brain-derived neurotrophic factor (BDNF) and B cell lymphoma protein-2 (Bcl-2) in hippocampal neurons of rats, monitored the time course of the expression over 3 weeks post-stress period, and examined the effects of the chronic administration of olanzapine on the time course. Olanzapine is an atypical antipsychotic drug that has been shown to be neuroprotective in previous in vitro studies. We found: (1) the repeated restraint stress decreases the levels of expression of BDNF and Bcl-2 in hippocampal neurons; (2) the stress-induced decreases spontaneously recover to their pre-stress levels in 3 weeks after the last stress exposure; (3) administration of olanzapine for 1 week returns the expression of Bcl-2 to its pre-stress level, and the administration for 3 weeks causes an excessive expression of BDNF in hippocampal neurons. In the context of the lower levels of BDNF and Bcl-2, and structural brain abnormalities observed in patients with schizophrenia, our findings suggest that BDNF and Bcl-2 may be involved in the pathophysiology of schizophrenia and in the therapeutic action of atypical antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 41 | Eur. J. Neurosci. 2004 Sep 20: 1348-54 |
| PMID | 15341606 |
| Title | Corticostriatal brain-derived neurotrophic factor dysregulation in adult rats following prenatal stress. |
| Abstract | Prenatal stress represents a well-established experimental protocol resembling some features of schizophrenia, including deficits in social interactions, disruption of prepulse inhibition and enhanced response to psychomotor stimulants. In order to evaluate molecular changes that could participate in long-lasting effects on brain function, we analysed the effects of prenatal stress on the expression of brain-derived neurotrophic factor (BDNF), an important molecular determinant of synaptic plasticity and cellular homeostasis, in adult male rats under basal conditions as well as in response to a chronic stress. The main finding is that BDNF expression is reduced in the prefrontal cortex and striatum of prenatally stressed rats. Furthermore, when exposed to chronic stress in adulthood, these rats display an altered regulation of BDNF expression in these brain structures, implying that adverse life events during gestation may interfere with the expression and function of this neurotrophin at adulthood in a region-specific manner. The dysregulation of corticostriatal BDNF expression might thus contribute to permanent alterations in brain functions leading to heightened susceptibility to psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 42 | Prostaglandins Leukot. Essent. Fatty Acids 2004 Apr 70: 417-22 |
| PMID | 15041037 |
| Title | Nutrition and schizophrenia: beyond omega-3 fatty acids. |
| Abstract | There are now five placebo-controlled trials of EPA in the treatment in schizophrenia, and four of these have given positive or partly positive findings. A cross-national ecological analysis of international variations in outcome of schizophrenia in relation to national dietary practices, showed that high consumption of sugar and of saturated fat is associated with a worse long-term outcome of schizophrenia. It is known that a high sugar, high fat diet leads to reduced brain expression of brain-derived neurotrophic factor (BDNF) which is responsible for maintaining the outgrowth of dendrites. Low brain BDNF levels also lead to insulin resistance which occurs in schizophrenia and is associated with diseases of the metabolic syndrome. It appears that the same dietary factors which are associated with the metabolic syndrome, including high saturated fat, high glycaemic load, and low omega-3 PUFA, may also be detrimental to the symptoms of schizophrenia, possibly through a common mechanism involving BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 43 | FASEB J. 2004 May 18: 863-5 |
| PMID | 15033926 |
| Title | Persistent, noncytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis. |
| Abstract | Infection of the central nervous system by Borna disease virus (BDV) provides a unique model to study the mechanisms whereby a persistent viral infection can impair neuronal function and cause behavioral diseases reminiscent of mood disorders, schizophrenia, or autism in humans. In the present work, we studied the effect of BDV infection on the response of hippocampal neurons, the main target for this virus, to the neurotrophin BDNF. We showed that persistent infection did not affect neuronal survival or morphology. However, it blocked BDNF-induced ERK 1/2 phosphorylation, despite normal expression of the TrkB BDNF receptor. In addition, BDNF-induced expression of synaptic vesicle proteins was abrogated, which resulted in severely impaired synaptogenesis and defects in synaptic organization. Thus, we provide the first evidence that a virus can interfere specifically with neurotrophin-regulated neuroplasticity, thereby hampering proper neuronal connectivity. These results may help to understand the behavioral disorders associated with BDV infection. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 44 | Mol. Psychiatry 2004 Jun 9: 609-20, 544 |
| PMID | 14708030 |
| Title | Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. |
| Abstract | Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2(A) and 5HT1(B) receptors, and dopamine D(5) receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 45 | Neurosci. Lett. 2004 Nov 371: 79-83 |
| PMID | 15500971 |
| Title | Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are critically implicated in development and maintenance of function of neurons. Neurodevelopment is reported to be impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin, may be more harmful to schizophrenic brains than to non-schizophrenic brains when used chronically. And neurotoxic events may promote disease-onset and lead to exaggerated release of neurotrophins. We investigated 157 drug-naive first-episode schizophrenic patients and found significantly elevated BDNF serum concentrations (by up to 34%) in patients with chronic cannabis abuse (n = 35, p < 0.001) or multiple substance abuse (n = 20, p < 0.001) prior to disease onset. Drug-naive schizophrenic patients without cannabis consumption showed similar results to normal controls and cannabis controls without schizophrenia. Thus, raised BDNF serum levels are not related to schizophrenia and/or substance abuse itself but may reflect a cannabis-related idiosyncratic damage of the schizophrenic brain. In line with this hypothesis, disease onset was 5.2 years earlier in the cannabis-consuming group (p = 0.0111). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 46 | World J. Biol. Psychiatry 2004 Oct 5: 215-20 |
| PMID | 15543516 |
| Title | Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar disorder. A functional polymorphism Val66Met of BDNF gene was studied in patients with schizophrenia (n=336), bipolar affective disorder (n=352) and healthy controls (n=375). Consensus diagnosis by at least two psychiatrists, according to DSM-IV and ICD-10 criteria, was made for each patient using a structured clinical interview for DSM-IV Axis I disorders (SCID). No association was found between the studied polymorphism and schizophrenia or bipolar affective disorder either for genotype or allele distribution (for genotype: p=0.210 in schizophrenia, p=0.400 in bipolar disorder; for alleles: p=0.260 in schizophrenia, p=0.406 in bipolar disorder). Results were also not significant when analysed by gender. For males genotype distribution and allele frequency were (respectively): p=0.480 and p=0.312 in schizophrenia, p=0.819 and p=0.673 in bipolar affective disorder. Genotype distribution and allele frequency observed in the female group were: p=0.258 for genotypes, p=0.482 for alleles in schizophrenia; p=0.432 for genotypes, p=0.464 for alleles in bipolar affective disorder. A subgroup of schizophrenic (n=62) and bipolar affective patients (n=28) with early age at onset (18 years or younger) was analysed (p=0.328 for genotypes, p=0.253 for alleles in schizophrenia; p=0.032 for genotypes, p=0.858 for alleles in bipolar affective disorder). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 47 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2004 Jul 28: 709-13 |
| PMID | 15276697 |
| Title | Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the etiology of schizophrenia. There is a line of evidence that disruption of neurotrophins could play a role in the etiology of schizophrenia, and antipsychotics show their effect by altering levels of neurotrophins. The aim of this study was to evaluate the effect of antipsychotics on serum BDNF levels and their relationship with the symptoms in patients with schizophrenia. Twenty-two schizophrenia patients were enrolled in the study. The control group consisted of 22 age- and sex-matched physically and mentally healthy volunteers (7 male, 15 female). Serum BDNF levels and the positive and negative syndrome scale (PANSS) scores were recorded at baseline and after 6 weeks of treatment. Serum BDNF levels were also recorded in the control group. schizophrenia patients who failed to meet 30% improvement in PANSS score were excluded from the study. The baseline serum BDNF levels of schizophrenia patients were lower than those of controls (t = 4.56; df = 21; p < 0.001). There was no correlation between serum BDNF levels and PANSS scores in patients with schizophrenia (p > 0.05). Although PANSS (for positive symptoms p < 0.001, for negative symptoms p < 0.001) and general psychopathology (t = 20.9; df = 22; p < 0.001) scores improved significantly after 6 weeks of antipsychotic treatment; there was no change in BDNF levels in patients' serum (p > 0.05). Our results support the view that BDNF would be associated with schizophrenia. However, we could not conclude that treatment with antipsychotics alters serum BDNF levels in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 48 | Curr Drug Targets CNS Neurol Disord 2004 Jun 3: 181-94 |
| PMID | 15180479 |
| Title | AMPA receptor potentiators for the treatment of CNS disorders. |
| Abstract | Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 49 | J Neural Transm (Vienna) 2004 Jun 111: 667-81 |
| PMID | 15168214 |
| Title | Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol. |
| Abstract | The neurotoxicity of conventional antipsychotic drugs has emerged as a potential pathogenic event in extrapyramidal side effects (EPS) and in their limited efficacy for negative-cognitive symptoms in schizophrenic patients. The atypical antipsychotics, recently developed, have superior therapeutic efficacy to treat not only positive symptoms but negative symptoms and cognitive dysfunctions with much lower potentials of side effects, although the influence of atypical antipsychotics on the regulation of neuronal survival has been less investigated. It is important to clarify the effects of typical and atypical antipsychotics on neuronal survival and their contributions to the therapeutic development and understanding of the pathophysiology of schizophrenia. We measured the neurotoxicity of two antipsychotic drug treatments, haloperidol and risperidone, in primary cultured rat cortical neurons. Immunoblotting and pharmacological agent analyses were used to determine the signal transduction changes implicated in the mechanisms of the neurotoxicity. Haloperidol induced apoptotic injury in cultured cortical neurons, but risperidone showed weak potential to injure the neurons. Treatment with haloperidol also led the reduction of phosphorylation levels of Akt, and activated caspase-3. The D2 agonist bromocriptine and 5-HT2A antagonist, ketanserin attenuated the haloperidol-induced neuronal toxicity. Moreover, brain-derived neurotrophic factor (BDNF) reduced the caspase-3 activity and protected neurons from haloperidol-induced apoptosis. BDNF also reversed the reduced levels of phosphorylation of Akt caused by treatment with haloperidol. Haloperidol but not risperidone induces caspase-dependent apoptosis by reducing cellular survival signaling, which possibly contributes to the differential clinical therapeutic efficacy and expression of side effects in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 50 | Psychopharmacology (Berl.) 2004 Sep 175: 196-205 |
| PMID | 14985924 |
| Title | Social withdrawal, neophobia, and stereotyped behavior in developing rats exposed to neonatal asphyxia. |
| Abstract | Perinatal asphyxia is a concern for public health and may promote subtle neuropsychiatric disorders. Anoxic insults to neonatal rats cause long-lasting neurobehavioral deficits. In the present study, we focussed on changes in emotional behaviors as a consequence of neonatal asphyxia in Wistar rats. Newborn pups (24 h after birth) underwent a single 30-min exposure to a 100% N2 atmosphere (or air). The offspring was tested for a) locomotor and exploratory activity with or without a d-amphetamine challenge (0, 1, or 2 mg/kg) on postnatal day (pnd) 15; b) social interactions and novelty seeking during adolescence; c) levels of the brain-derived neurotrophic factor (BDNF). In the open-field test (pnd 15), N2-exposed pups injected with the high (2 mg/kg) amphetamine dose exhibited reduced levels of locomotor hyperactivity, and a more marked involvement in stereotyped behaviors. Individual differences emerged in the locomotor response to the novelty-seeking test: two subgroups of rats (separated on the basis of the median value) showed either arousal/attraction or avoidance/inhibition in response to free-choice novelty. The N2-exposed group showed a more marked novelty-induced avoidance and inhibition. Time devoted to allogrooming and play-soliciting behaviors was reduced, whereas object exploration was increased. Levels of BDNF were reduced in the striatum of N2-exposed rats, suggesting poorer synaptic performance of dopamine pathways. In conclusion, these findings suggest an increased risk of developing social withdrawal, neophobia and behavioral stereotypies (common symptoms found in schizophrenia and autism) as a consequence of neonatal asphyxia in preterm humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 51 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Feb 125B: 69-78 |
| PMID | 14755448 |
| Title | Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. |
| Abstract | schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 52 | Prog. Brain Res. 2004 -1 146: 151-65 |
| PMID | 14699963 |
| Title | Neurotrophic factors and CNS disorders: findings in rodent models of depression and schizophrenia. |
| Abstract | Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system (CNS). Loss of neurons in specific brain regions has been found in depression and schizophrenia, and this chapter summarizes the findings of altered neurotrophins in animal models of those two disorders under baseline condition and following antidepressive and antipsychotic treatments. In a model of depression (Flinders sensitive line/Flinders resistant line; FSL/FRL rats), increased NGF and BDNF concentrations were found in frontal cortex of female, and in occipital cortex of male 'depressed' FSL compared to FRL control rats. Using the same model, the effects of electroconvulsive stimuli (ECS) and chronic lithium treatment on brain NGF, BDNF and glial cell line-derived neurotrophic factors were investigated. ECS and lithium altered the brain concentrations of neurotrophic factors in the hippocampus, frontal cortex, occipital cortex and striatum. ECS mimic the effects of electroconvulsive therapy (ECT) that is an effective treatment for depression and also schizophrenia. Since NGF and BDNF may also be changed in the CNS of animal models of schizophrenia, we investigated whether treatment with antipsychotic drugs (haloperidol, risperidone, and olanzapine) affects the constitutive levels of NGF and BDNF in the CNS. Both typical and atypical antipsychotic drugs altered the regional brain levels of NGF and BDNF. Other studies also demonstrated that these drugs differentially altered neurotrophin mRNAs. Overall, these studies indicate that alteration of brain level of NGF and BDNF could constitute part of the biochemical alterations induced by antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 53 | World J. Biol. Psychiatry 2004 Oct 5: 215-20 |
| PMID | 15543516 |
| Title | Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar disorder. A functional polymorphism Val66Met of BDNF gene was studied in patients with schizophrenia (n=336), bipolar affective disorder (n=352) and healthy controls (n=375). Consensus diagnosis by at least two psychiatrists, according to DSM-IV and ICD-10 criteria, was made for each patient using a structured clinical interview for DSM-IV Axis I disorders (SCID). No association was found between the studied polymorphism and schizophrenia or bipolar affective disorder either for genotype or allele distribution (for genotype: p=0.210 in schizophrenia, p=0.400 in bipolar disorder; for alleles: p=0.260 in schizophrenia, p=0.406 in bipolar disorder). Results were also not significant when analysed by gender. For males genotype distribution and allele frequency were (respectively): p=0.480 and p=0.312 in schizophrenia, p=0.819 and p=0.673 in bipolar affective disorder. Genotype distribution and allele frequency observed in the female group were: p=0.258 for genotypes, p=0.482 for alleles in schizophrenia; p=0.432 for genotypes, p=0.464 for alleles in bipolar affective disorder. A subgroup of schizophrenic (n=62) and bipolar affective patients (n=28) with early age at onset (18 years or younger) was analysed (p=0.328 for genotypes, p=0.253 for alleles in schizophrenia; p=0.032 for genotypes, p=0.858 for alleles in bipolar affective disorder). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 54 | J Neural Transm (Vienna) 2004 Jun 111: 667-81 |
| PMID | 15168214 |
| Title | Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol. |
| Abstract | The neurotoxicity of conventional antipsychotic drugs has emerged as a potential pathogenic event in extrapyramidal side effects (EPS) and in their limited efficacy for negative-cognitive symptoms in schizophrenic patients. The atypical antipsychotics, recently developed, have superior therapeutic efficacy to treat not only positive symptoms but negative symptoms and cognitive dysfunctions with much lower potentials of side effects, although the influence of atypical antipsychotics on the regulation of neuronal survival has been less investigated. It is important to clarify the effects of typical and atypical antipsychotics on neuronal survival and their contributions to the therapeutic development and understanding of the pathophysiology of schizophrenia. We measured the neurotoxicity of two antipsychotic drug treatments, haloperidol and risperidone, in primary cultured rat cortical neurons. Immunoblotting and pharmacological agent analyses were used to determine the signal transduction changes implicated in the mechanisms of the neurotoxicity. Haloperidol induced apoptotic injury in cultured cortical neurons, but risperidone showed weak potential to injure the neurons. Treatment with haloperidol also led the reduction of phosphorylation levels of Akt, and activated caspase-3. The D2 agonist bromocriptine and 5-HT2A antagonist, ketanserin attenuated the haloperidol-induced neuronal toxicity. Moreover, brain-derived neurotrophic factor (BDNF) reduced the caspase-3 activity and protected neurons from haloperidol-induced apoptosis. BDNF also reversed the reduced levels of phosphorylation of Akt caused by treatment with haloperidol. Haloperidol but not risperidone induces caspase-dependent apoptosis by reducing cellular survival signaling, which possibly contributes to the differential clinical therapeutic efficacy and expression of side effects in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 55 | Neuromolecular Med. 2004 -1 5: 243-51 |
| PMID | 15626824 |
| Title | Association analysis of the dopamine D3 receptor gene ser9gly and brain-derived neurotrophic factor gene val66met polymorphisms with antipsychotic-induced persistent tardive dyskinesia and clinical expression in Chinese schizophrenic patients. |
| Abstract | The association between the dopamine D3 receptor (DRD3) ser9gly genetic polymorphism and tardive dyskinesia (TD), a serious adverse motor disorder after long-term antipsychotic treatment, has been studied extensively in recent years. However, the existence of inconsistent reports makes the role of the DRD3 ser9gly polymorphism in TD development questionable. In rodent studies, the DRD3 expression could be controlled by the brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family. In this study, we examined the association between the DRD3 ser9gly and BDNF val66met genetic polymorphisms and TD occurrence in 216 schizophrenic patients (TD/non-TD = 102/114). In addition, we also studied the effects of the DRD3 ser9gly and BDNF val66met genotypes and their gene-gene interaction on the clinical expression of TD in these TD patients. We found that the TD patients who were heterozygous for the BDNF genotypes had significantly higher abnormal involuntary movement scale (AIMS) orofacial scores (corrected p = 0.021, Bonferroni correction), and a trend of higher AIMS total and limb-trunk scores than the combined homozygous analogs. The correlation between the DRD3 ser9gly genotypes and its interaction with the BDNF val66met polymorphism, and the three classes of AIMS scores were not statistically significant. Furthermore, neither the DRD3 nor the BDNF genotypes and alleles were demonstrated to be associated with TD occurrence. We concluded that the BDNF val66met genetic polymorphism may exert its effect on the clinically phenotypic variability after TD has occurred. Further replication studies with larger sample size and stringent definition for TD is necessary. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 56 | Schizophr. Res. 2005 Sep 77: 355-6 |
| PMID | 15913964 |
| Title | Effect of the BDNF Val66Met genotype on episodic memory in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 57 | Br. Med. Bull. 2005 -1 73-74: 107-22 |
| PMID | 16365481 |
| Title | Psychiatric genetics--the new era: genetic research and some clinical implications. |
| Abstract | Impressive advances in the last decade have been made in the genetics and neuroscience of neuropsychiatric illness. Synergies between complex genetics, elaboration of intermediate phenotypes (Egan et al. (2004) schizophrenia. London: Blackwell) and novel applications in neuroimaging (Bookheimer et al. (2000) N Engl J Med, 343, 450-456) are revealing the effects of positively associated disease alleles on aspects of neurological function. Genes such as NRG-1, DISC1, RGS4, COMT, PRODH, DTNBP1, G72, DAAO, GRM3 (Harrison and Weinberger (2005) Mol Psychiatry, 10, 40-68) and others have been implicated in schizophrenia along with 5-HTTPR (Ogilvie et al. (1996) Lancet, 347, 731-733; Caspi et al. (2003) Science, 301, 386-389) and BDNF (Geller et al. (2004) Am J Psychiatry, 161, 1698-1700) in affective disorders. As the genetics and complex neurocircuits of these and disorders are being untangled, parallel applications in pharmacogenomics and gene-based drug metabolism are shaping a drive for personalized medicine. Genetic research and pharmacogenomics suggest that the subcategorization of individuals based on various sets of susceptibility alleles will make the treatment of neuropsychiatric and other illnesses more predictable and effective. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 58 | Brain Res. 2005 Nov 1063: 32-9 |
| PMID | 16271709 |
| Title | Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress. |
| Abstract | Quetiapine is an atypical antipsychotic effective in treating the positive, negative, and cognitive symptoms of patients with schizophrenia. Our previous study has shown that chronic administration of quetiapine attenuates the decrease in levels of brain-derived neurotrophic factor (BDNF) in the hippocampi of rats subjected to chronic-restraint stress. In the present study, we investigated the effects of quetiapine on hippocampal neurogenesis that had been compromised in stressed rats. Newborn cells in the hippocampus were labeled by bromodeoxyuridine (BrdU), and immature neurons were detected immunohistochemically using an antibody against phosphorylated cAMP response element-binding protein (pCREB). The restrained rats (4 h/day for 7 days) showed lower levels of hippocampal neurogenesis indicated by decreased numbers of BrdU-labeled and pCREB-positive cells. Post-stress administration of quetiapine (10 mg/kg) for 7 or 21 days reversed the stress-induced suppression of hippocampal neurogenesis, evidenced in the numbers of BrdU-labeled and pCREB-positive cells that are comparable to those in non-stressed rats but higher than those in the vehicle-treated rats. The results may help us understand the therapeutic effects of quetiapine on cognitive deficits in patients with schizophrenia and depression, in which the structure and functions of the hippocampus are implicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 59 | Eur Arch Psychiatry Clin Neurosci 2005 Jun 255: 159-66 |
| PMID | 15995899 |
| Title | Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes? |
| Abstract | schizophrenia and affective disorder have been considered to be nosologically and etiologically distinct disorders. This postulate is challenged by progress in new biological research. Both disorders are strongly influenced by genetic factors; thus genetic research is a main contributor to this discussion. We review current evidence of the genetic relationship between schizophrenia and affective disorders, mainly bipolar disorder (the various genetic research methods have been particularly applied to bipolar disorder). Recent family and twin studies reveal a growing consistency in demonstrating cosegregation between both disorders which is difficult to detect with certainty given the low base rates. Systematic molecular genetic search for specific genes impacting on either disorder has now identified one gene which is apparently involved in both disorders (G72/G30); other candidate genes reveal some evidence to present as susceptibility genes with very modest effects for each of both disorders, although not consistently so (e. g., COMT, BDNF). There is room for speculation about other common susceptibility genes, given the overlap between candidate regions for schizophrenia and those for bipolar disorder emerging from linkage studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 60 | Schizophr. Res. 2005 Jul 76: 187-93 |
| PMID | 15949651 |
| Title | No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) regulates a variety of neuromodulatory processes during development, as well as in adulthood. It has been proposed as a risk factor for schizophrenia. We have investigated a possible association between schizophrenia and the C-270T polymorphism in the brain-derived neurotrophic factor (BDNF) gene in 397 schizophrenic patients and 380 control subjects. The diagnosis of schizophrenia was made for each patient by at least two psychiatrists, using DSM-IV and ICD-10 criteria in structured clinical interviews for DSM-IV Axis I disorders (SCID). No association was found between schizophrenia and the analyzed polymorphism, for either genotype or allele distribution (for genotype: p=0.513, for alleles: p=0.812). Differences were not statistically significant when analyzed separately by sex. For males, the differences for genotype distribution and allele frequency were p=0.078 and p=0.162 respectively and for females: p=0.441 and p=0.315. Thus, our data indicate that variations in the BDNF gene are unlikely to be an important factor in susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 61 | Biol. Psychiatry 2005 Apr 57: 932-4 |
| PMID | 15820715 |
| Title | Analysis of pyramidal neuron morphology in an inducible knockout of brain-derived neurotrophic factor. |
| Abstract | The messenger ribonucleic acid (mRNA) for brain-derived neurotrophic factor (BDNF), a regulator of pyramidal neuron dendritic spine density during development, is decreased in the prefrontal cortex of subjects with schizophrenia, and the level of BDNF mRNA expression is positively correlated with dendritic spine density in the same subjects. To determine whether reduced BDNF mRNA expression might account for decreased spine density in schizophrenia, a knockout of the BDNF gene was induced in mice during embryogenesis or at 12 weeks of age. Quantitative assessments were made of the dendritic arbor of Golgi-impregnated pyramidal neurons in the prelimbic and anterior cingulate cortices in adulthood. Despite an 80% reduction in BDNF mRNA levels in both knockouts, neither spine density nor other dendritic or somal measures were decreased compared with wild-type animals. A reduction in BDNF expression alone does not seem to be sufficient to alter pyramidal neuron morphology in mice. This finding suggests that other molecular abnormalities are also required to produce the pyramidal neuron dendritic spine abnormalities observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 62 | Eur Neuropsychopharmacol 2005 May 15: 319-29 |
| PMID | 15820422 |
| Title | The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. |
| Abstract | The pathogenesis of schizophrenia may be ascribed to early maldevelopment of brain tissue. Neurotrophins are a group of dimeric proteins that affect the development of the nervous system in all vertebrates' species. Since neurotrophins, as well as other growth factors, play a crucial role in neurodevelopment, they are plausible candidates of taking part in the pathophysiology of schizophrenia. In line with this hypothesis, accumulating preclinical and clinical data indicate that dysfunctions of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may contribute to impaired brain development, neuroplasticity and synaptic "dysconnectivity" leading to the schizophrenic syndrome, or at least some of its presentations. This article reviews the functions of neurotrophins in the complex process of normal brain development, and their possible relevance to the neuropathology and neuropharmacology of schizophrenia. Further research in this area may bring about novel pharmacological therapeutic strategies to this chronic debilitating disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 63 | J. Med. Genet. 2005 Mar 42: 193-204 |
| PMID | 15744031 |
| Title | The genetics of schizophrenia and bipolar disorder: dissecting psychosis. |
| Abstract | Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. Several well established linkages have emerged in schizophrenia. Strongly supported regions are 6p24-22, 1q21-22, and 13q32-34, while other promising regions include 8p21-22, 6q16-25, 22q11-12, 5q21-q33, 10p15-p11, and 1q42. Genomic regions of interest in bipolar disorder include 6q16-q22, 12q23-q24, and regions of 9p22-p21, 10q21-q22, 14q24-q32, 13q32-q34, 22q11-q22, and chromosome 18. Recently, specific genes or loci have been implicated in both disorders and, crucially, replicated. Current evidence supports NRG1, DTNBP1, DISC1, DAOA(G72), DAO, and RGS4 as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA(G72) and BDNF. Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1. Future identification of psychosis susceptibility genes will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 64 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 73-5 |
| PMID | 15719396 |
| Title | Association between BDNF val66 met genotype and episodic memory. |
| Abstract | The val66 met polymorphism of brain derived neurotrophic factor (BDNF) has been associated with variability in episodic memory [Egan et al., 2003]. In an attempt to replicate this finding, we genotyped 206 individuals (92 affected with schizophrenia or a related disorder and 114 unaffected relatives) from the Maudsley Family Study for the BDNF val66 met polymorphism. We analyzed the effect of this polymorphism on episodic memory using the Wechsler Memory Scale, revised version (WMS-R) by regression analysis between the WMS delayed score of logical memory and genotype (corrected for age, sex, and IQ). We found the met66 allele conferred a lower score on the WMS delayed measure (R2 = 0.014 P = 0.09), which was not significant. When cases and unaffected relatives were analyzed separately, met66 was associated with a lower score on the WMS delayed measure in the relatives only (R2 = 0.077 P = 0.01), which is consistent with previous findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 65 | Mol. Psychiatry 2005 Apr 10: 345-52 |
| PMID | 15655562 |
| Title | BDNF in schizophrenia, depression and corresponding animal models. |
| Abstract | Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 66 | Mol. Psychiatry 2005 Feb 10: 208-12 |
| PMID | 15630410 |
| Title | BDNF gene is a risk factor for schizophrenia in a Scottish population. |
| Abstract | schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P = 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (P < 1 x 10(-8)) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 67 | Schizophr. Res. 2005 Feb 73: 27-30 |
| PMID | 15567073 |
| Title | COMT Val(158)Met and BDNF C(270)T polymorphisms in schizophrenia: a case-control study. |
| Abstract | In a multicenter study involving 217 subjects of European ancestry [106 patients with schizophrenia and 111 healthy subjects], we tested the hypothesis that the catechol-O-methyl transferase (COMT) Val(158)Met and/or the brain-derived neurotrophic factor (BDNF) C(270)T gene polymorphisms are associated with schizophrenia. The COMT and BDNF genotype and their allele distribution did not differ between patients with schizophrenia and healthy comparison subjects. These results do not support the hypothesis that the COMT Val(158)Met or BDNF C(270)T gene polymorphisms are associated with liability to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 68 | J Neural Transm (Vienna) 2005 Jul 112: 885-90 |
| PMID | 15526143 |
| Title | Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics. |
| Abstract | Several studies have connected brain-derived neurotrophic factor (BDNF) with treatment response to neuroleptics. In recent studies, the BDNF expression was reduced by typical neuroleptics. We conducted a retrospective study on 94 patients with schizophrenia and 98 controls. The BDNF G196A and C270T polymorphisms are not associated with treatment response to typical neuroleptics or with age at first hospitalization. Moreover, these polymorphisms of the BDNF gene are not associated with the risk of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 69 | Schizophr. Res. 2005 Jul 76: 187-93 |
| PMID | 15949651 |
| Title | No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) regulates a variety of neuromodulatory processes during development, as well as in adulthood. It has been proposed as a risk factor for schizophrenia. We have investigated a possible association between schizophrenia and the C-270T polymorphism in the brain-derived neurotrophic factor (BDNF) gene in 397 schizophrenic patients and 380 control subjects. The diagnosis of schizophrenia was made for each patient by at least two psychiatrists, using DSM-IV and ICD-10 criteria in structured clinical interviews for DSM-IV Axis I disorders (SCID). No association was found between schizophrenia and the analyzed polymorphism, for either genotype or allele distribution (for genotype: p=0.513, for alleles: p=0.812). Differences were not statistically significant when analyzed separately by sex. For males, the differences for genotype distribution and allele frequency were p=0.078 and p=0.162 respectively and for females: p=0.441 and p=0.315. Thus, our data indicate that variations in the BDNF gene are unlikely to be an important factor in susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 70 | Eur Neuropsychopharmacol 2005 May 15: 319-29 |
| PMID | 15820422 |
| Title | The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. |
| Abstract | The pathogenesis of schizophrenia may be ascribed to early maldevelopment of brain tissue. Neurotrophins are a group of dimeric proteins that affect the development of the nervous system in all vertebrates' species. Since neurotrophins, as well as other growth factors, play a crucial role in neurodevelopment, they are plausible candidates of taking part in the pathophysiology of schizophrenia. In line with this hypothesis, accumulating preclinical and clinical data indicate that dysfunctions of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may contribute to impaired brain development, neuroplasticity and synaptic "dysconnectivity" leading to the schizophrenic syndrome, or at least some of its presentations. This article reviews the functions of neurotrophins in the complex process of normal brain development, and their possible relevance to the neuropathology and neuropharmacology of schizophrenia. Further research in this area may bring about novel pharmacological therapeutic strategies to this chronic debilitating disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 71 | Mol. Psychiatry 2005 Feb 10: 208-12 |
| PMID | 15630410 |
| Title | BDNF gene is a risk factor for schizophrenia in a Scottish population. |
| Abstract | schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P = 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (P < 1 x 10(-8)) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 72 | Bull. Acad. Natl. Med. 2005 May 189: 935-44; discussion 944-7 |
| PMID | 16433464 |
| Title | [Schizophrenic disorders: current etiologic and clinical knowledge]. |
| Abstract | Brain anomalies associated with schizophrenic disorders may be of a cognitive, neurophysiological or neurological nature [the latter being relatively minor and nonspecific]. Brain imaging has revealed early anomalies such as cortical-subcortical atrophy and abnormal gyration. These anomalies can also be present in relatives free of schizophrenic symptoms. This raises the question of what determines the transition from vulnerability to clinical onset. There is now evidence that schizophrenic disorders are true brain diseases. This is based on neuropathological studies, brain imaging and clinical findings such as "soft" neurological signs (pyramidal and extrapyramidal symptoms, coordination difficulties, etc.). Cognitive dysfunctions such as attention and memory disorders and abnormal verbal fluency have also been described. Oculomotor pursuit and auditive evoked potentials have identified specific neurophysiological disorders such as N300 and P50 wave modifications. schizophrenic disorders can also be associated with neuronal abnormalities, notably affecting factors involved in synaptic transmission and plasticity. For example, BDNF protein deficit is linked to certain late-onset forms of schizophrenia. Genetic studies are no longer focusing on a possible disease genotype but rather on phenotypic characteristics determined by simpler genotypes (P50 wave modulation, COMT and BDNF genes). The ultimate objective is to identify high-risk subjects, in order to shorten the treatment delay and thereby improve long-term outcome. The benefit of primary prophylaxis remains to be determined, however. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 73 | Neurosci. Lett. 2005 Dec 389: 173-7 |
| PMID | 16115734 |
| Title | Quetiapine and venlafaxine synergically regulate heme oxygenase-2 protein expression in the hippocampus of stressed rats. |
| Abstract | HO-2 is a constitutive isoform of heme oxygenase (HO), a microsomal enzyme that catalyzes the cleavage of the heme ring to form ferrous iron, carbon monoxide, and biliverdin. In contrast to HO-1, which is inducible, HO-2 is not responsive to stimuli tested to date except for prolonged exposure to the adrenal glucocorticoids (GCs). Previous studies have shown that high GC concentrations or stress damage or kill hippocampal neurons. In the present study, it was found that chronic restraint stress decreased HO-2 protein levels in hippocampal neurons, as demonstrated by immunohistochemistry and Western blot analysis. Moreover, our results showed that the combination of 2.5mg/kg of venlafaxine and 5mg/kg of quetiapine effectively prevented the HO-2 protein decrease in hippocampal neurons of stressed rats, whereas either of the drugs alone did not show any effect. At higher dose levels, both quetiapine (10mg/kg) and venlafaxine (5mg/kg) produced significant effects comparable to that of their combination. Quetiapine is an atypical antipsychotic and venlafaxine an antidepressant. In previous studies, these two drugs have been shown to prevent or protect against the stress-induced decrease in hippocampal neurogenesis and BDNF expression. These data suggest that both quetiapine and venlafaxine share the hippocampus as their common target by enhancing hippocampal resilience, which may be impaired in patients with schizophrenia or depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 74 | Biol. Psychiatry 2005 Aug 58: 307-14 |
| PMID | 16005437 |
| Title | Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. |
| Abstract | Previous genetic studies investigating a possible involvement of variations at the brain derived neurotrophic factor (BDNF) gene locus in major depressive disorder (MDD), bipolar affective disorder (BPAD), and schizophrenia have provided inconsistent results. We performed single-marker and haplotype analyses using three BDNF polymorphisms in 2,376 individuals (465 MDD, 281 BPAD, 533 schizophrenia, and 1,097 control subjects). Single-marker analysis did not provide strong evidence for association. Haplotype analysis of marker combination rs988748-(GT)n-rs6265 produced nominally significant associations for all investigated phenotypes (global p values: MDD p = .00006, BPAD p = .0057, schizophrenia p = .016). Association with MDD was the most robust finding and could be replicated in a second German sample of MDD patients and control subjects (p = .0092, uncorrected). Stratification of our schizophrenia sample according to the presence or absence of a lifetime history of depressive symptoms showed that our finding in schizophrenia might be attributable mainly to the presence of depressive symptoms. Association studies of genetic variants of the BDNF gene with various psychiatric disorders have been published with reports of associations and nonreplications. Our findings suggest that BDNF may be a susceptibility gene for MDD and schizophrenia-in particular, in a subgroup of patients with schizophrenia with a lifetime history of depressive symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 75 | Am J Pharmacogenomics 2005 -1 5: 149-60 |
| PMID | 15952869 |
| Title | Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. |
| Abstract | No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 76 | Mol. Psychiatry 2005 Jul 10: 637-50 |
| PMID | 15940304 |
| Title | Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. |
| Abstract | Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK+)-containing form of trkB and measured pan trkC mRNA in schizophrenics (N=14) and controls (N=15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkB(TK+) mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkB(TK+) mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkB(TK+) mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkB(TK+) was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 77 | Med. Hypotheses 2005 -1 65: 243-52 |
| PMID | 15922095 |
| Title | High risk of schizophrenia and other mental disorders associated with chlamydial infections: hypothesis to combine drug treatment and adoptive immunotherapy. |
| Abstract | Many microbial factors have been implicated as pathogenic factors in mental disorders. Occurrence of such microbial factors also in the mentally unaffected population raised skepticism against such findings, although each microbial factor may cause mental problems only in some individuals, depending on the individual's immunogenetic disposition. Skepticism against the role of infection in schizophrenia was also fostered by the low impact of antiinfections treatment on the course of disease progression in schizophrenia. We discovered previously that neurotrophins like neurotrophin3 (NT-3) and brain-derived neurotrophic factor (BDNF), involved in processes of neuroplasticity, are also secreted by immune cells, but only by subpopulations of immune cells. Therefore, infection of the immune cell subpopulation, specialized in secreting BDNF, or of another subpopulation, specialized in secreting NT-3, could distort communication of immune cells with the central nervous system (CNS). Chlamydiaceae could cause disbalancement of immune cell sub-populations and, in some individuals with a vulnerable disposition, symptoms of mental illness. Based on previous observations of persisting IgA titers in some patients with mental illness we hypothesize that the intracellular parasites Chlamydiaceae are main pathogenic factors in schizophrenia. We hypothesize furthermore that antiinfectious treatment has to be accompanied by adoptive immunotherapy because antibiotics alone will not restore the balance of immune subpopulations. Our hypothesis is supported by examination of patients with schizophrenia and other mental disorders. Using nested PCR we found a significant prevalence of the intracellular parasites Chlamydophila psittaci, C. pneumoniae and Chlamydia trachomatis (9/18, 50%), as compared to controls (8/115, 6.97%) (chi(2)=25.86, Fisher's exact p two-tailed=5x10(-5)). Treatment with in vitro-activated immune cells together with antibiotic modalities showed sustained mental improvements in patients that did not depend on treatment with antipsychotic drugs. Future controlled studies including sham treatment of patients have to be carried out to prove our hypotheses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 78 | Mol. Psychiatry 2005 Jul 10: 631-6 |
| PMID | 15768049 |
| Title | Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. |
| Abstract | Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 79 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 93-103 |
| PMID | 15666411 |
| Title | Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's Disease. |
| Abstract | Potential roles for variants in the human BDNF gene in human brain disorders are supported by findings that include: (a) influences that this trophic factor can exert on important neurons, brain regions, and neurotransmitter systems, (b) changes in BDNF expression that follow altered neuronal activity and drug treatments, and (c) linkages or associations between genetic markers in or near BDNF and human traits and disorders that include depression, schizophrenia, addictions, and Parkinson's disease. We now report assembly of more than 70 kb of BDNF genomic sequence, delineation of 7 noncoding and 1 coding human BDNF exons, elucidation of BDNF transcripts that are initiated at several alternative promoters, identification of BDNF mRNA splicing patterns, elucidation of novel sequences that could contribute to activity-dependent BDNF mRNA transcription, targeting and/or translation, elucidation of tissue-specific and brain-region-specific use of the alternative human BDNF promoters and splicing patterns, identification of single nucleotide polymorphism (SNP), and simple sequence length polymorphism (SSLP) BDNF genomic variants and identification of patterns of restricted haplotype diversity at the BDNF locus. We also identified type 2 BDNF-locus transcripts that are coded by a novel gene that is overlapped with type 1 BDNF gene and transcribed in reverse orientation with several alternative splicing isoforms. Association studies of BDNF variants reveal no associations with Parkinson's disease. Comparisons between substance abusers and controls reveal modest associations. These findings increase interest in this diverse human gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 80 | J. Neurosci. 2005 Jan 25: 372-83 |
| PMID | 15647480 |
| Title | Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. |
| Abstract | Dysfunction of inhibitory neurons in the prefrontal cortex (PFC), represented by decreased expression of GABA-related genes such as the 67 kDa isoform of glutamate decarboxylase (GAD67) and parvalbumin (PV), appears to contribute to cognitive deficits in subjects with schizophrenia. We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia. In 15 pairs of subjects with schizophrenia and matched control subjects, both BDNF and TrkB mRNA levels, as assessed by in situ hybridization, were significantly decreased in the PFC of the subjects with schizophrenia, whereas the levels of mRNA encoding the receptor tyrosine kinase for neurotrophin-3, TrkC, were unchanged. In this cohort, within-pair changes in TrkB mRNA levels were significantly correlated with those in both GAD67 and PV mRNA levels. Decreased BDNF, TrkB, and GAD67 mRNA levels were replicated in a second cohort of 12 subject pairs. In the combined cohorts, the correlation between within-pair changes in TrkB and GAD67 mRNA levels was significantly stronger than the correlation between the changes in BDNF and GAD67 mRNA levels. Neither BDNF nor TrkB mRNA levels were changed in the PFC of monkeys after a long-term exposure to haloperidol. Genetically introduced decreases in TrkB expression, but not in BDNF expression, also resulted in decreased GAD67 and PV mRNA levels in the PFC of adult mice; in addition, the cellular pattern of altered GAD67 mRNA expression paralleled that present in schizophrenia. Decreased TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 81 | Bull. Acad. Natl. Med. 2005 May 189: 935-44; discussion 944-7 |
| PMID | 16433464 |
| Title | [Schizophrenic disorders: current etiologic and clinical knowledge]. |
| Abstract | Brain anomalies associated with schizophrenic disorders may be of a cognitive, neurophysiological or neurological nature [the latter being relatively minor and nonspecific]. Brain imaging has revealed early anomalies such as cortical-subcortical atrophy and abnormal gyration. These anomalies can also be present in relatives free of schizophrenic symptoms. This raises the question of what determines the transition from vulnerability to clinical onset. There is now evidence that schizophrenic disorders are true brain diseases. This is based on neuropathological studies, brain imaging and clinical findings such as "soft" neurological signs (pyramidal and extrapyramidal symptoms, coordination difficulties, etc.). Cognitive dysfunctions such as attention and memory disorders and abnormal verbal fluency have also been described. Oculomotor pursuit and auditive evoked potentials have identified specific neurophysiological disorders such as N300 and P50 wave modifications. schizophrenic disorders can also be associated with neuronal abnormalities, notably affecting factors involved in synaptic transmission and plasticity. For example, BDNF protein deficit is linked to certain late-onset forms of schizophrenia. Genetic studies are no longer focusing on a possible disease genotype but rather on phenotypic characteristics determined by simpler genotypes (P50 wave modulation, COMT and BDNF genes). The ultimate objective is to identify high-risk subjects, in order to shorten the treatment delay and thereby improve long-term outcome. The benefit of primary prophylaxis remains to be determined, however. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 82 | Mol. Psychiatry 2005 Jul 10: 637-50 |
| PMID | 15940304 |
| Title | Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. |
| Abstract | Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK+)-containing form of trkB and measured pan trkC mRNA in schizophrenics (N=14) and controls (N=15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkB(TK+) mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkB(TK+) mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkB(TK+) mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkB(TK+) was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 83 | Schizophr. Res. 2005 May 74: 263-70 |
| PMID | 15722005 |
| Title | Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements. |
| Abstract | Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD). Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) plays a critical role in the maintenance of functional neurons. The present study was to examine plasma BDNF levels and the relationship among BDNF level, psychopathological and tardive dyskinesia symptoms in schizophrenic patients with TD. Eighty schizophrenic patients with TD were compared with 45 schizophrenic patients without TD, as well as with 45 age-, sex-matched normal controls. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). The psychopathology of patients was assessed by the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the patients with TD had lower plasma BDNF levels than those without TD, and than that of normal controls. In the patients with TD, plasma BDNF levels was inversely correlated with AIMS total score, and with PANSS negative subscore. Female patients had significantly lower plasma BDNF levels than male TD patients. Our results suggest that decreased BDNF may play an important role in the pathophysiology of TD. There may be a relationship between decreased BDNF levels and dyskinetic movements associated with TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 84 | Schizophr. Res. 2006 Sep 86: 321-2 |
| PMID | 16829047 |
| Title | Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 85 | Am J Psychiatry 2006 Oct 163: 1829-31 |
| PMID | 17012697 |
| Title | Increased expression of activity-dependent genes in cerebellar glutamatergic neurons of patients with schizophrenia. |
| Abstract | The purpose of this study was to evaluate the functional state of glutamatergic neurons in the cerebellar cortex of patients with schizophrenia. The authors measured messenger ribonucleic acid (mRNA) levels of three activity-dependent genes expressed by glutamatergic neurons in the cerebellar cortex (GAP-43, BDNF, and GABA OLE_LINK2>(A)-delta subunit) in the tissues of 14 patients with schizophrenia and 14 matched nonpsychiatric comparison subjects. Since its level of expression does not change in response to neuronal activity, gamma-aminobutyric acid(A)-alpha6 subunit mRNA was used as a control. The levels of GAP-43 and BDNF mRNAs were significantly elevated in patients with schizophrenia, and a similar finding was observed for GABA(A)-delta mRNA. In contrast, the levels of the GABA(A)-alpha6 subunit mRNA, which is expressed in cerebellar granule cells in an activity-independent manner, did not differ from comparison subjects. These results suggest that glutamatergic neurons may be hyperactive in the cerebellar cortices of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 86 | Schizophr. Res. 2006 Oct 87: 45-7 |
| PMID | 16854566 |
| Title | No evidence for an association between the BDNF Val66Met polymorphism and schizophrenia or personality traits. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family, which plays a critical role in neurodevelopment. Based on the neurodevelopmental hypothesis, the BDNF gene has been a candidate locus for schizophrenia. In Caucasians, recent studies identified an association with the Val66Met polymorphism, which has been suggested to affect episodic memory and hippocampal function in humans. However, in other populations, the association has not been replicated. In the present study, we investigated the association between the Val66Met polymorphism of the gene and schizophrenia in 401 Japanese patients with schizophrenia and 569 controls. As a result, we did not observe a significant difference in genotypic distribution or allele frequencies between the patients and controls (chi2=0.56, df=2, p=0.76 and chi2=0.39, df=1, p=0.53, respectively). We also investigated the association between the polymorphism and personality traits in the controls; however, no significant association was observed. Thus, the present study did not provide evidence for an association between the BDNF gene and schizophrenia or personality traits in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 87 | Schizophr. Res. 2006 Jul -1: -1 |
| PMID | 16846718 |
| Title | REMOVED: Association between the BDNF C270T polymorphism and negative symptoms of schizophrenia. |
| Abstract | This article has been removed, consistent with Elsevier Policy on Article Withdrawal. Please see http://www.elsevier.com/locate/withdrawalpolicy. The Publisher apologizes for any inconvenience this may cause. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 88 | Nat. Neurosci. 2006 Aug 9: 1009-18 |
| PMID | 16819522 |
| Title | BDNF-mediated neurotransmission relies upon a myosin VI motor complex. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been implicated in higher-order cognitive functions and in psychiatric disorders such as depression and schizophrenia. BDNF modulates synaptic transmission and plasticity primarily through the TrkB receptor, but the molecules involved in BDNF-mediated synaptic modulation are largely unknown. Myosin VI (Myo6) is a minus end-directed actin-based motor found in neurons that express Trk receptors. Here we report that Myo6 and a Myo6-binding protein, GIPC1, form a complex that can engage TrkB. Myo6 and GIPC1 were necessary for BDNF-TrkB-mediated facilitation of long-term potentiation in postnatal day 12-13 (P12-13) hippocampus. Moreover, BDNF-mediated enhancement of glutamate release from presynaptic terminals depended not only upon TrkB but also upon Myo6 and GIPC1. Similar defects in basal synaptic transmission as well as presynaptic properties were observed in Myo6 and GIPC1 mutant mice. Together, these results define an important role for the Myo6-GIPC1 motor complex in presynaptic function and in BDNF-TrkB-mediated synaptic plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 89 | Eur. J. Hum. Genet. 2006 Jun 14: 660-8 |
| PMID | 16721402 |
| Title | Genetics of affective (mood) disorders. |
| Abstract | The enormous public health importance of mood disorders, when considered alongside their substantial heritabilities, has stimulated much work, predominantly in bipolar disorder but increasingly in unipolar depression, aimed at identifying susceptibility genes using both positional and functional molecular genetic approaches. Several regions of interest have emerged in linkage studies and, recently, evidence implicating specific genes has been reported; the best supported include BDNF and DAOA but further replications are required and phenotypic relationships and biological mechanisms need investigation. The complexity of psychiatric phenotypes is demonstrated by (a) the evidence accumulating for an overlap in genetic susceptibility across the traditional classification systems that divide disorders into schizophrenia and mood disorders, and (b) evidence suggestive of gene-environment interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 90 | Neurosci. Lett. 2006 Jul 402: 25-9 |
| PMID | 16713676 |
| Title | Effects of quetiapine on the brain-derived neurotrophic factor expression in the hippocampus and neocortex of rats. |
| Abstract | The effects of antipsychotics on the brain-derived neurotrophic factor (BDNF) expression have been controversial. This study aimed to investigate the effects of chronic quetiapine administration on the BDNF mRNA expression in hippocampus and neocortex of rats with or without immobilization stress. The chronic administration (21 days) of quetiapine (10 mg/kg) significantly attenuated the decreased BDNF mRNA expression in the both hippocampal and cortical regions of rats caused by immobilization stress, and significantly increased the BDNF mRNA expression in the dentate gyrus of rats even without the immobilization stress. These results could add some theoretical bases to explain why quetiapine may improve cognitive symptoms of schizophrenia by stimulating BDNF mRNA expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 91 | Schizophr. Res. 2006 May 84: 29-35 |
| PMID | 16631352 |
| Title | No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population. |
| Abstract | Brain-derived neurotrophic factor (BDNF) plays important roles in the survival, maintenance and growth of neurons. Several studies have indicated that BDNF is likely to be related to the pathogenesis of schizophrenia. Recent genetic analyses have revealed that BDNF gene polymorphisms are associated with schizophrenia, although contradictory negative findings have also been reported. To assess whether three BDNF gene polymorphisms (rs988748, C132T and rs6265) could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (349 patients and 423 controls) in Japanese subjects. We found no association between these BDNF gene polymorphisms and schizophrenia using both single-marker and haplotype analyses. The results of the present study suggest that these three BDNF gene polymorphisms do not play major roles in conferring susceptibility to schizophrenia in a Japanese population. However, further studies assessing the associations between these BDNF gene polymorphisms and schizophrenia should be performed in several other ethnic populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 92 | CNS Neurol Disord Drug Targets 2006 Feb 5: 25-43 |
| PMID | 16613552 |
| Title | The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. |
| Abstract | The role of the D(3) receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D(3) receptor. The D(3) receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D(3) receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinson's disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D(3) receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D(3) receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 93 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2006 Jul 30: 924-33 |
| PMID | 16581172 |
| Title | Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study. |
| Abstract | Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene have been suggested to be associated with schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n=187) and control subjects (n=275) were assessed for four BDNF gene polymorphisms. There were no significantly different allele, genotype or haplotype frequencies between cases or controls. Neither were there any differences when schizophrenic patients were sub-divided with regard to a number of different clinical variables, although a small group of psychotic patients with prominent affective features displayed higher frequencies of the less common alleles of the Val66Met and 11757 G/C polymorphisms compared to controls. The present Swedish results do not verify previous associations between putative functional BDNF gene polymorphisms and schizophrenia. However, when combined with previous studies meta-analyses indicated that the BDNF 270 T-allele and the Val66Met homozygous state were associated with the disorder. Thus, the BDNF gene may confer susceptibility to schizophrenia. Additional studies are warranted to shed further light on this possibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 94 | Neurosci. Lett. 2006 Apr 397: 285-90 |
| PMID | 16406671 |
| Title | Association between the brain-derived neurotrophic factor (BDNF) gene and schizophrenia in the Chinese population. |
| Abstract | Brain-derived neurotrophic factor (BDNF) belongs to a family of the neurotrophin which plays important roles in the development of the brain. BDNF has been suggested as a factor that increases the risk of schizophrenia. In this study, we genotyped three single nucleotide polymorphisms (SNPs) in the BDNF gene using a set sample of Han Chinese subjects consisting of 560 schizophrenes and 576 controls. No significant differences were found for either the genotype or allele distribution of analyzed polymorphisms, nor was any gender-specific association found. Thus, our data suggest that the BDNF gene may not be an important factor in susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 95 | J Psychiatr Res 2006 Oct 40: 664-8 |
| PMID | 16386272 |
| Title | Associations between serum brain-derived neurotrophic factor levels and clinical phenotypes in schizophrenia patients. |
| Abstract | This study investigated serum brain-derived neurotrophic factor (BDNF) protein levels in schizophrenia patients and healthy control subjects and schizophrenia patients with various clinical phenotypes. During a 1-year period, 126 schizophrenic patients and 96 healthy control subjects were recruited. Serum BDNF protein levels were measured using an ELISA Kit. Psychiatric diagnoses were made according to DSM-IV criteria. One-way analysis of variance (ANOVA) showed no significant differences in serum BDNF protein levels between schizophrenia and healthy normals. Additionally, no significant differences existed in BDNF levels between schizophrenia patients for the following variables: with/without a suicide attempt; antipsychotic drug use, family tendency and disease onset before and after 25 years old. However, patients with catatonic schizophrenia had lower serum BDNF protein levels than patients with paranoid or residual schizophrenia. These analytical results suggested that BDNF might play an important role in the clinical subtypes of schizophrenia, but it needed further investigation in future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 96 | Nervenarzt 2006 May 77: 523-37 |
| PMID | 16078056 |
| Title | [Brain-derived neurotrophic factor: from nerve growth factor to modulator of brain plasticity in cognitive processes and psychiatric diseases]. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and plays an important role in neuronal survival and plasticity in the CNS. The proform of BDNF (pro-BDNF) is secreted and cleaved extracellularly by the serine protease plasmin to mature BDNF, which potentiates synaptic plasticity and long-term potentiation. Recent findings in animal models suggest an involvement of BDNF and its genetic functional single nucleotide polymorphism in the pathogenesis of different psychiatric diseases including depression, mania, schizophrenia, eating disorders, dementia, and Huntington's disease. In the brain and serum, BDNF is modulated by different factors. It is downregulated by stress and upregulated by learning processes, several antidepressive treatments, physical activity, and dietary restriction. Measurement of BDNF serum concentrations may be of diagnostic value. Additionally, the influence of different strategies for BDNF allocation seems to be relevant for the treatment and prevention of the above psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 97 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2006 Jul 30: 924-33 |
| PMID | 16581172 |
| Title | Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study. |
| Abstract | Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene have been suggested to be associated with schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n=187) and control subjects (n=275) were assessed for four BDNF gene polymorphisms. There were no significantly different allele, genotype or haplotype frequencies between cases or controls. Neither were there any differences when schizophrenic patients were sub-divided with regard to a number of different clinical variables, although a small group of psychotic patients with prominent affective features displayed higher frequencies of the less common alleles of the Val66Met and 11757 G/C polymorphisms compared to controls. The present Swedish results do not verify previous associations between putative functional BDNF gene polymorphisms and schizophrenia. However, when combined with previous studies meta-analyses indicated that the BDNF 270 T-allele and the Val66Met homozygous state were associated with the disorder. Thus, the BDNF gene may confer susceptibility to schizophrenia. Additional studies are warranted to shed further light on this possibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 98 | J Psychiatr Res 2006 Oct 40: 664-8 |
| PMID | 16386272 |
| Title | Associations between serum brain-derived neurotrophic factor levels and clinical phenotypes in schizophrenia patients. |
| Abstract | This study investigated serum brain-derived neurotrophic factor (BDNF) protein levels in schizophrenia patients and healthy control subjects and schizophrenia patients with various clinical phenotypes. During a 1-year period, 126 schizophrenic patients and 96 healthy control subjects were recruited. Serum BDNF protein levels were measured using an ELISA Kit. Psychiatric diagnoses were made according to DSM-IV criteria. One-way analysis of variance (ANOVA) showed no significant differences in serum BDNF protein levels between schizophrenia and healthy normals. Additionally, no significant differences existed in BDNF levels between schizophrenia patients for the following variables: with/without a suicide attempt; antipsychotic drug use, family tendency and disease onset before and after 25 years old. However, patients with catatonic schizophrenia had lower serum BDNF protein levels than patients with paranoid or residual schizophrenia. These analytical results suggested that BDNF might play an important role in the clinical subtypes of schizophrenia, but it needed further investigation in future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 99 | Psychiatr. Genet. 2006 Dec 16: 233-4 |
| PMID | 17106422 |
| Title | No association between genetic variants at the ASCT1 gene and schizophrenia or bipolar disorder in a German sample. |
| Abstract | Altered glutamatergic neurotransmission is considered a potential etiological factor of schizophrenia (SCZ) and affective disorders. The gene ASCT1 (SLC1A4) coding for a Na+-dependent neutral aminoacid transporter is a member of the glutamate transporter superfamily and is located on 2p13-14, a region showing linkage to both SCZ and bipolar disorder (BD). ASCT1 can thus be considered a candidate gene for both disorders. In a German sample, we tested for association between ASCT1 and both SCZ and BD. Allele and haplotype frequencies, however, did not differ between cases and controls. Recent findings on the associations between brainderived neurotrophic factor (BDNF) and SCZ and between G72/G30 and BD suggest that SCZ patients with a history of major depressive episodes (MDE) outside psychotic episodes and BD cases with a history of persecutory delusions constitute genetically distinct subgroups of these disorders. Thus, we hypothesized that restricting case definition to those 95 SCZ individuals with MDE and to those 107 BD patients with a history of persecutory delusions might clarify the relationship between BD, SCZ and ASCT1. However, these stratification approaches did not yield any significant association either. Allele and haplotype frequencies did not differ between cases and controls. Our results do not support an association of the ASCT1 gene with BD or SCZ in the German population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 100 | Eur. J. Hum. Genet. 2006 Sep 14: 1037-43 |
| PMID | 16736033 |
| Title | A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci. |
| Abstract | In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100,000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human-rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 101 | Schizophr. Res. 2006 Jun 84: 253-71 |
| PMID | 16632332 |
| Title | Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. |
| Abstract | Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 102 | J. Neurochem. 2006 Nov 99: 770-80 |
| PMID | 16903871 |
| Title | Sustained brain-derived neurotrophic factor up-regulation and sensorimotor gating abnormality induced by postnatal exposure to phencyclidine: comparison with adult treatment. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is involved in synaptic development and plasticity, and alterations in BDNF expression or signaling are implicated in drug addiction and psychiatric diseases, such as depression and schizophrenia. In this study, we administered phencyclidine to postnatal and adult rats with different time schedules, and determined the correlations between BDNF expression and the behavioral effects. Both single and repeated phencyclidine injections into adult rats induced BDNF up-regulation in the corticolimbic system and a decrease in prepulse inhibition, both of which were transient. In contrast, subchronic postnatal administration increased BDNF protein and mRNA levels in the hippocampus and entorhinal cortex, which were sustained until 8 weeks of age. In parallel, the postnatal rats treated with phencyclidine developed a persistent decrease in prepulse inhibition at the adult stage. The chronic BDNF increase appeared to contribute to the prepulse inhibition abnormality, as subchronic BDNF infusion into the hippocampus of normal rats mimicked the prepulse inhibition deficits. This study suggests that phencyclidine exposure during brain development induces sustained BDNF up-regulation in the limbic system with a biological link to sensorimotor gating deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 103 | Arch. Gen. Psychiatry 2006 Jul 63: 731-40 |
| PMID | 16818862 |
| Title | Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. |
| Abstract | Relatively little is known about genetic determinants of cognitive dysfunction in schizophrenia. Recent studies suggest that a brain-derived neurotrophic factor (BDNF) prodomain single nucleotide polymorphism resulting in a valine (Val)-to-methionine (Met) substitution is associated with impaired declarative memory in healthy volunteers and patients with schizophrenia. These studies indicate that the BDNF(Met) variant may mediate hippocampal cognitive functions by modulating intracellular trafficking and activity-dependent BDNF release. To our knowledge, the way in which this functional single nucleotide polymorphism affects other neurocognitive measures has not been examined. Its role in determining cognitive deficits in schizophrenia has also not been systematically studied. To characterize the neurocognitive and brain morphometric phenotypic correlates of the BDNF Val66Met polymorphism and to test the specificity of the BDNF(Met) variant on cognitive dysfunction in schizophrenia. A comprehensive battery of standardized neuropsychological tests was administered to 144 healthy volunteers and 293 patients with schizophrenia spectrum disorder at a tertiary care university hospital. Approximately two thirds of the sample also underwent high-resolution magnetic resonance imaging brain scans. Genotype effects (in Met allele carriers vs Val homozygotes) on 5 cognitive domain z scores and magnetic resonance imaging gray matter brain volume measures (Talairach atlas-based cerebral lobes and optimized voxel-based morphometry) were examined using general linear models. On verbal memory, there was a significant genotype effect but no genotype x diagnosis effects. In both patients with schizophrenia and healthy volunteers, Met allele carriers had poorer verbal memory performance than their Val-homozygous counterparts. On visuospatial abilities, there were significant genotype and genotype x diagnosis effects. Met allele-associated visuospatial impairment was specific to patients with schizophrenia but not healthy volunteers. There were significant genotype effects on gray matter volumes within brain regions known to subserve these 2 cognitive domains, with Met allele carriers having smaller temporal and occipital lobar gray matter volumes. Optimized voxel-based morphometry further suggests that parietal heteromodal cortical gray matter deficits may underlie visuospatial impairment in patients with schizophrenia carrying the Met allele. We replicated the association between the BDNF(Met) variant and poor medial temporal lobe-related memory performance. The consonance of our cognitive and brain morphology findings further suggests that the BDNF(Met) variant may have a specific role in conferring visuospatial dysfunction in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 104 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jul 141B: 513-23 |
| PMID | 16741916 |
| Title | BDNF gene variants and brain morphology in schizophrenia. |
| Abstract | The objective was to investigate putative associations between brain-derived neurotrophic factor gene (BDNF) polymorphisms and brain morphology in patients with schizophrenia and healthy control subjects. Four BDNF polymorphisms were genotyped and analyzed versus 39 brain volume measures in 96 patients with schizophrenia or schizoaffective disorder and 104 healthy subjects. In all subjects, quantitative data on segmented gray, white, and cerebrospinal fluid (CSF) tissue class volumes of total brain and major cerebral lobes including ventricular CSF were obtained using magnetic resonance imaging (MRI). In a randomly selected subset of this population (n = 101-122), MR volumes from cerebellar tonsil, hemispheres, and vermis subregions, striatal structures, hippocampus, and corpus callosum were also measured. The BDNF 11757 G/C polymorphism was highly significantly associated with frontal gray matter volume variation in patients alone and in patients and control subjects combined. In patients only, the 270 C/T polymorphism was associated with total caudate volume. Significant associations were demonstrated between the BDNF 11757 G/C and Val66Met polymorphisms and a global haplotype estimate of four BDNF polymorphisms and the posterior superior cerebellar vermis volume in the controls as well as in the combined group, but not in the patients. The 11757 G/C polymorphism was associated with cerebellar hemisphere white and gray matter volumes in the combined group. The BDNF -633 T/A polymorphism was associated with gray matter of the putamen in the controls. Trends for associations between several polymorphisms/haplotype estimates and MRI volumes were found. BDNF gene variation may influence brain morphology. The effects may be different in patients with schizophrenia and healthy subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 105 | Hippocampus 2006 -1 16: 551-9 |
| PMID | 16652337 |
| Title | Synergetic effects of quetiapine and venlafaxine in preventing the chronic restraint stress-induced decrease in cell proliferation and BDNF expression in rat hippocampus. |
| Abstract | Clinical studies show better response rates of patients with depression and schizophrenia to combinations of atypical antipsychotics and antidepressants, compared to responses to either type of drugs alone. Animal studies demonstrate that some antipsychotics and antidepressants increase neurogenesis and BDNF expression in the hippocampus, which is reduced in volume in patients with depression or schizophrenia. We hypothesized that the better therapeutic effects of combined treatment seen in schizophrenia and depression patients are related to the additive or synergistic effects of combined treatment on hippocampal neurogenesis and BDNF expression. To test this hypothesis, we investigated the effects of chronic administration of quetiapine, venlafaxine, and their combination, on hippocampal cell proliferation and BDNF expression in rats, when subjected to chronic restraint stress (CRS) during the last 2 weeks of a 3-week drug administration period. We found (1) CRS decreased hippocampal cell proliferation and BDNF expression; (2) chronic administration of quetiapine or venlafaxine dose-dependently prevented these decreases in hippocampal cell proliferation and BDNF expression caused by CRS (6 h/day for 14 days); (3) the combination of lower doses of quetiapine (5 mg/kg) and venlafaxine (2.5 mg/kg) increased hippocampal cell proliferation and prevented BDNF decrease in stressed rats, whereas each of the drugs exerted mild or no effects; (4) individual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/kg) exerted effects comparable to those produced by their combination. These results support our hypothesis and can lead to future studies to develop new therapeutic approaches for treatment-resistant depression and the negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 106 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jun 141B: 387-93 |
| PMID | 16649215 |
| Title | Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. |
| Abstract | Genetic variation at the locus encoding the brain derived neurotrophic factor (BDNF) has been implicated in some neuropsychiatric disorders such as Alzheimer's disease (AD), affective disorders (AFDs), schizophrenia, and substance dependence. We therefore performed a mutation scan of the BDNF gene to identify novel gene variants and examined the association between BDNF variants and several neuropsychiatric phenotypes in European American (EA) subjects and controls. Using denaturing high performance liquid chromatography (dHPLC), we identified a novel variant (G-712A) in the putative promoter region. This variant and two previously reported BDNF SNPs (C270T and Val66Met) were genotyped in 295 patients with AD, 108 with AFDs, 96 with posttraumatic stress disorder (PTSD), 84 with schizophrenia, 327 with alcohol and/or drug dependence, and 250 normal control subjects. No association was found between these three BDNF gene variants and AD, AFDs, PTSD, or schizophrenia. However, there was a nominally higher frequency of the G-712A G-allele and the G/G genotype in subjects with substance dependence than in controls (Allele: chi(2) = 4.080, df = 1, P = 0.043; Genotype: chi(2) = 7.225, df = 2, P = 0.027). Although after correction for multiple testing, the findings are not considered significant (threshold P-value was set at 0.020 by the program SNPSpD), logistic regression analyses confirmed the modest association between SNP G-712A and substance dependence, when the sex and age of subjects were taken into consideration. The negative results for AFDs, PTSD, and schizophrenia could be due to the low statistical power. Further study with larger samples is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 107 | J Clin Psychopharmacol 2006 Apr 26: 128-34 |
| PMID | 16633140 |
| Title | Risperidone-related weight gain: genetic and nongenetic predictors. |
| Abstract | A serious side effect of atypical antipsychotics is increased body weight, which leads to further morbidity and nonadherence to medication. It has been suggested that both genetic and nongenetic variables may influence antipsychotics-related weight gain. This study aimed to simultaneously explore the effects of multiple candidate genes and environment factors on body weight of schizophrenia patients who received risperidone, a commonly used atypical antipsychotic agent. One hundred twenty-three ethnically Han Chinese inpatients with acutely exacerbated schizophrenia were given risperidone monotherapy for up to 42 days. Body weight and clinical manifestations were assessed biweekly. Drug efficacy was measured by the Positive and Negative Syndrome Scale (PANSS), and safety was evaluated by the Extrapyramidal Symptom Rating Scale (ESRS) and the UKU Side Effect Rating Scale. We collected body weight as the response value. Potential prognostic factors were baseline body weight, age, sex, diagnosis subtypes, risperidone dosage, PANSS total scores, treatment duration (weeks 0-6), and 15 genetic variants [across 10 candidate genes: 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, D1, D2, D3, and alpha1-adrenergic receptors, brain-derived neurotrophic factor (BDNF), and cytochrome P450 2D6 (CYP2D6)]. Because there were repeated assessments, multiple linear regression with the generalized estimating equation (GEE) method was used to adjust the within-subject dependence. Of 15 genetic polymorphisms examined, 5-HT2A 102-T/C, 5-HT2C -759-C/T, 5-HT6 267-C/T, BDNF 66-Val/Met, and CYP2D6 188-C/T significantly influenced body weight, and so did baseline body weight, age, gender, schizophrenia subtype, and treatment duration and efficacy. These results suggest that numerous genetic and nongenetic factors affect antipsychotics-related weight gain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 108 | Med. Hypotheses 2006 -1 67: 354-8 |
| PMID | 16540254 |
| Title | Dopamine D3 receptor and schizophrenia: a widened scope for the immune hypothesis. |
| Abstract | schizophrenia may be related to immunity as is suggested by many findings of altered immune parameters in schizophrenic patients. How immune alterations might be involved in the emergence of psychosis is still unclear. Clearly, however, the dopamine hypothesis has been confirmed in recent studies, which implies a crucial role for dopamine and the dopamine D2 receptor (D2R) within the pathogenesis of schizophrenia. The Dopamine D3 receptor (D3R) is considered to have autoreceptor properties modulating the synthesis and release of dopamine, thereby possibly antagonizing the dopamine D2-receptor-mediated effects of dopamine and has been found reduced in schizophrenic patients during acute psychosis and increasing in the advent of negative schizophrenic symptoms. Immune parameters apparently influence the expression of dopamine receptors by means of their capability to induce regulatory factors involved in the expression of dopamine receptor subtypes, such as the neurotrophins, associations of which with psychosis have been reported repeatedly. Here, we propose a hypothesis of immune alterations that influence the production of distinct neurotrophins such as BDNF and NGF that, as animal studies suggest, influence the expression of dopamine receptor subtypes. This mechanism could result in a decrease of D3R and a consecutive relative preponderance of D2R and thereby connect immune alterations and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 109 | Neurosci. Lett. 2006 Jun 400: 262-6 |
| PMID | 16540246 |
| Title | Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 110 | Neurosci. Lett. 2006 Jun 401: 1-5 |
| PMID | 16533563 |
| Title | Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that promotes several functions of neurons and modulates neurotransmissions. It has been reported that there are alterations of BDNF levels in schizophrenic brains and that BDNF gene expressional changes would be responsible for the etiology of schizophrenia. Recent studies have shown that a variation of BDNF gene (Val66Met polymorphism) affects the function of neurons, and is associated with several neurological and psychiatrical disorders. We investigated the relationship between BDNF Val66Met polymorphism and the onset age as well as levels of clinical symptoms in 159 of chronic schizophrenia in-patients diagnosed by DSM-IV. The mean onset ages were 27.5+/-9.5 for BDNF Val/Val, 25.5+/-7.4 for BDNF Val/Met and 22.9+/-6.0 for BDNF Met/Met and this polymorphism was significantly associated with age at onset (P=0.023). The mean Brief Psychiatric Rating Scale scores (BPRS) were significantly different among those three groups (P=0.003). No significant differences were demonstrated comparing the BDNF genotype distributions of positive and negative family history (P=0.21). Our investigation indicates that the BDNF gene Val66Met polymorphism is related to the onset age of schizophrenia and the levels of clinical symptoms that remain after long-term antipsychotic treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 111 | Am J Psychiatry 2006 Mar 163: 534-7 |
| PMID | 16513879 |
| Title | BDNF Val66Met polymorphism and GAD67 mRNA expression in the prefrontal cortex of subjects with schizophrenia. |
| Abstract | In the prefrontal cortex of subjects with schizophrenia, decreased signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase (TrkB) appears to contribute to the reduced expression of mRNA encoding the 67-kilodalton isoform of glutamate decarboxylase (GAD(67)), an enzyme for GABA synthesis. The authors examined in subjects with schizophrenia the effect in the human BDNF gene of a single nucleotide polymorphism (Val66Met), which reduces the trafficking and secretion of BDNF protein, on the expression of GAD(67) mRNA. BDNF Val66Met genotyping was performed in 27 matched pairs of schizophrenia and comparison subjects. The impact of this polymorphism on prefrontal cortex GAD(67) mRNA expression in schizophrenia subjects was assessed by comparing within-pair differences in GAD(67) mRNA expression between schizophrenia subjects with versus without the Met66 allele after the level of BDNF mRNA expression was controlled. In contrast to expectations, the within-pair reduction in GAD(67) mRNA expression was not greater in schizophrenia subjects who were hetero- or homozygous for the Met66 allele. These subjects did tend to exhibit less marked within-pair reductions in both GAD(67) and BDNF mRNA expression compared with schizophrenia subjects homozygous for the Val allele. The presence of the BDNF Met66 allele does not contribute to the decreased level of GAD(67) mRNA expression in the prefrontal cortex of subjects with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 112 | Psychiatry Clin. Neurosci. 2006 Feb 60: 70-6 |
| PMID | 16472361 |
| Title | Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain-derived neurotrophic factor gene. |
| Abstract | The measures of prefrontal cognition have been used as endophenotype in molecular-genetic studies. Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive functions and in the pathogenesis of major psychoses. This study investigates the relationship between Val66Met polymorphisms of the BDNF gene and prefrontal cognitive function in 129 patients with schizophrenia and 111 patients with bipolar mood disorder. Cognitive tests included the Wisconsin Card Sorting Test (WCST), with such domains as number of perseverative errors, non-perseverative errors, completed corrected categories, conceptual level responses, and set to the first category, and the N-back test, where mean reaction time and percent of correct reactions were measured. Genotyping for Val66Met BDNF polymorphism was done by polymerase chain reaction method. In schizophrenia, no relationship between Val66Met polymorphism of the BDNF gene and the results of the WCST was observed. Patients with Val/Val genotype had a higher percentage of correct reactions in the N-back test than those with the remaining genotypes. Bipolar patients with Val/Val genotype obtained significantly better results on three of five domains of the WCST. No relationship between BDNF polymorphism and the results of the N-back test was found in this group. A limitation to the results could be variable psychopathological state and medication during cognitive testing and lack of Hardy-Weinberg equilibrium in schizophrenia group. Val66Met polymorphism of the BDNF gene may be associated with cognitive performance on the WCST in bipolar mood disorder but not in schizophrenia. An association of this polymorphism with performance on the N-back test in schizophrenia and not in bipolar illness may suggest that in schizophrenia, the BDNF system may be connected with early phases of information processing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 113 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Mar 141B: 135-8 |
| PMID | 16389585 |
| Title | The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with risk for psychosis: evidence from a family-based association study. |
| Abstract | schizophrenia (SZ) is a prevalent and severe mental disorder. One of the most favored hypotheses for the etiology of SZ is the neurodevelopmental hypothesis. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, promotes the development, regeneration, and survival of neurons and has been linked to the neuropathology of SZ. The present study tested, in a sample of 94 nuclear families, the hypothesis that the BDNF gene Val66Met polymorphism is associated to SZ and its psychopathologic phenotype using a multidimensional symptom approach. Furthermore, considering a reported reduction of BDNF in the frontal cortex of patients with SZ, we studied the relationship between this polymorphism and prefrontal function. The transmission disequilibrium test (TDT) showed a preferential transmission of allele Val from heterozygous parents to the affected offspring (P = 0.002), suggesting a possible role of this gene in the vulnerability to SZ spectrum disorders. The findings remained essentially unchanged when the analysis was restricted to the subgroup of patients with SZ (P = 0.009) and when a multidimensional approach to the diagnosis was used. Quantitative transmission disequilibrium test (QTDT) analyses did not demonstrate a significant association between the prefrontal tests assessed (Wisconsin Card Sorting Test and Trail Making Test) and the transmission of the BDNF alleles. Our finding suggests that the investigated BDNF polymorphism plays an important role in the phenotype of psychosis, but not in the performance of tests of prefrontal cognitive functions analyzed in these patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 114 | Schizophr Bull 2006 Jan 32: 9-16 |
| PMID | 16319375 |
| Title | Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. |
| Abstract | It has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories-including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. As psychosis susceptibility genes are identified and characterized over the next few years, this will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 115 | Med. Hypotheses 2006 -1 67: 354-8 |
| PMID | 16540254 |
| Title | Dopamine D3 receptor and schizophrenia: a widened scope for the immune hypothesis. |
| Abstract | schizophrenia may be related to immunity as is suggested by many findings of altered immune parameters in schizophrenic patients. How immune alterations might be involved in the emergence of psychosis is still unclear. Clearly, however, the dopamine hypothesis has been confirmed in recent studies, which implies a crucial role for dopamine and the dopamine D2 receptor (D2R) within the pathogenesis of schizophrenia. The Dopamine D3 receptor (D3R) is considered to have autoreceptor properties modulating the synthesis and release of dopamine, thereby possibly antagonizing the dopamine D2-receptor-mediated effects of dopamine and has been found reduced in schizophrenic patients during acute psychosis and increasing in the advent of negative schizophrenic symptoms. Immune parameters apparently influence the expression of dopamine receptors by means of their capability to induce regulatory factors involved in the expression of dopamine receptor subtypes, such as the neurotrophins, associations of which with psychosis have been reported repeatedly. Here, we propose a hypothesis of immune alterations that influence the production of distinct neurotrophins such as BDNF and NGF that, as animal studies suggest, influence the expression of dopamine receptor subtypes. This mechanism could result in a decrease of D3R and a consecutive relative preponderance of D2R and thereby connect immune alterations and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 116 | Neurosci. Lett. 2006 Jun 400: 262-6 |
| PMID | 16540246 |
| Title | Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 117 | Neurosci. Lett. 2006 Jun 400: 262-6 |
| PMID | 16540246 |
| Title | Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. |
| Abstract | Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 118 | Neurosci. Lett. 2006 Jun 401: 1-5 |
| PMID | 16533563 |
| Title | Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that promotes several functions of neurons and modulates neurotransmissions. It has been reported that there are alterations of BDNF levels in schizophrenic brains and that BDNF gene expressional changes would be responsible for the etiology of schizophrenia. Recent studies have shown that a variation of BDNF gene (Val66Met polymorphism) affects the function of neurons, and is associated with several neurological and psychiatrical disorders. We investigated the relationship between BDNF Val66Met polymorphism and the onset age as well as levels of clinical symptoms in 159 of chronic schizophrenia in-patients diagnosed by DSM-IV. The mean onset ages were 27.5+/-9.5 for BDNF Val/Val, 25.5+/-7.4 for BDNF Val/Met and 22.9+/-6.0 for BDNF Met/Met and this polymorphism was significantly associated with age at onset (P=0.023). The mean Brief Psychiatric Rating Scale scores (BPRS) were significantly different among those three groups (P=0.003). No significant differences were demonstrated comparing the BDNF genotype distributions of positive and negative family history (P=0.21). Our investigation indicates that the BDNF gene Val66Met polymorphism is related to the onset age of schizophrenia and the levels of clinical symptoms that remain after long-term antipsychotic treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 119 | Schizophr. Res. 2006 Feb 82: 95-106 |
| PMID | 16442781 |
| Title | Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. |
| Abstract | The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60-70% with HAL or CPZ, and by only 25-30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70-90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 120 | Encephale 2007 Nov 33: 870-2 |
| PMID | 18402360 |
| Title | [Drugs acting on D3 receptors in neuropsychiatric disorders: facts and prospects. Implication for schizophrenia and its treatment in the regulation of BDNF-dependence on D3 receptor expression]. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 121 | Mol. Psychiatry 2007 Dec 12: 1058-60 |
| PMID | 18043709 |
| Title | Multiple variants of the DRD3, but not BDNF gene, influence age-at-onset of schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 122 | Schizophr. Res. 2007 Dec 97: 297-8 |
| PMID | 17669628 |
| Title | Lack of association between the BDNF C270T polymorphism and schizophrenia in a Chinese Han population. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 123 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jun 144B: 578-9 |
| PMID | 17450558 |
| Title | Variance in facial recognition performance associated with BDNF in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 124 | Nippon Rinsho 2007 Sep 65: 1599-606 |
| PMID | 17876981 |
| Title | [Molecular biology of depressive disorders]. |
| Abstract | Heritability of major depression from twin studies is estimated as -40% that is relatively small as compared with -80% for schizophrenia and -90% for bipolar affective disorder. It suggests that genetic as well as environmental factors contribute to the aetiology of major depression. Approximately 800 association studies on candidate genes of depression have been published, and among them, several genes were confirmed as risk for vulnerability to major depression by meta-analyses. Recent investigations on pathophysiology of depression have focused on hippocampus as a modulator of Hypothalamus-Pituitary-Adrenal (HPA) glands axis. Molecular biological studies on the interaction between stress, hippocampus and HPA axis reveal glucocorticoid and brain-derived neurotrophic factor(BDNF) are key molecules developing and recovering from depressive disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 125 | Neurosci. Lett. 2007 Sep 425: 1-5 |
| PMID | 17720314 |
| Title | Genetic analysis of the TrkB gene and schizophrenia in the Japanese population: Juntendo University Schizophrenia Projects (JUSP). |
| Abstract | The presence of cognitive and social impairments during childhood and adolescence in patients with schizophrenia has lead to the widespread hypothesis that schizophrenia may be a neurodevelopmental disorder, which suggests that risk genes for schizophrenia may act through the disruption of normal neurodevelopmental processes. Moreover, recent studies indicate that TrkB, which is receptor of neurotrophins including BDNF, might be involved in schizophrenia. The aim of this study is to evaluate the role of sequence variation at the TrkB locus on schizophrenia. We genotyped 12 single nucleotide polymorphisms (SNPs) across TrkB in 276 subjects with schizophrenia and 274 control subjects from the Japanese population and assessed whether TrkB SNPs are associated with a diagnosis of schizophrenia. In addition, we also investigated if any association exists between the TrkB SNPs and the premorbid functioning as measured by M-PAS using 62 subjects with schizophrenia. The TrkB SNPs were not significantly associated with a diagnosis of schizophrenia. Although one TrkB SNP (rs920776) showed weak association with premorbid functioning (p=0.025), the significance did not remain after Bonferroni correction. Thus, these results do not support a significant role for TrkB sequence variation in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 126 | Aust N Z J Psychiatry 2007 Apr 41: 321-6 |
| PMID | 17464718 |
| Title | Changes in brain-derived neurotrophic factor following treatment with mifepristone in bipolar disorder and schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is stress-responsive and has been implicated in a number of disparate neuropsychiatric disorders. Glucocorticoid antagonists have been shown to have beneficial effects on mood and cognitive function in bipolar disorder but not in schizophrenia. The aim of the present study was to investigate BDNF levels in patients with bipolar disorder and schizophrenia before and after treatment with the glucocorticoid receptor antagonist mifepristone. Peripheral BDNF levels were measured in patients with bipolar disorder (n=20), schizophrenia (n=20) and 14 matched healthy controls following 7 days of adjunctive mifepristone (600 mg day(-1)) treatment in a double-blind, placebo-controlled crossover design study. Baseline BDNF values were similar in both patient groups and in healthy controls. Following treatment with mifepristone, cortisol levels were significantly increased and BDNF levels decreased in both schizophrenia and bipolar disorder. A significant correlation existed between change in cortisol level and change in BDNF levels following mifepristone treatment in schizophrenia, but not in bipolar disorder. Differing BDNF responses to increasing cortisol levels between patients with schizophrenia and with bipolar disorder may reflect underlying pathophysiological mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 127 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Jun 31: 1072-7 |
| PMID | 17459549 |
| Title | Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-hydroxypnenylglycol (MHPG) levels, but did not alter plasma brain-derived neurotrophic factor (BDNF) levels in schizophrenic patients. |
| Abstract | In the present study, we investigated the effects of risperidone treatment for 4 weeks on plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and brain-derived neurotrophic factor (BDNF) in 89 schizophrenic patients. We also compared the plasma levels of BDNF and MHPG between the schizophrenic group and 103 sex-and age-matched normal controls. In addition, we investigated the effects of two SNPs of the noradrenaline transporter (NAT) gene on plasma levels of MHPG, BDNF, and clinical improvement. The mean dose of risperidone was 3.8+/-1.4 mg/day. We demonstrated that treatment with risperidone increased plasma MHPG levels, and this increase was associated with an improvement of the negative symptoms of schizophrenia. In contrast, plasma BDNF did not change after 4 weeks of risperidone treatment, and the two SNPs in NAT did not influence the response to risperidone treatment or plasma MHPG and BDNF levels. These results suggest that the enhancement of noradrenergic neurons by risperidone, which occurs independently of the two SNPs of NAT, plays a role in the clinical efficacy of the drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 128 | Neurosci. Lett. 2007 Jun 420: 45-8 |
| PMID | 17442489 |
| Title | Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder. |
| Abstract | There is evidence that major psychiatric discords such as schizophrenia (SZ) and bipolar disorder (BD) are associated with dysregulation of synaptic plasticity with downstream alterations of neurotrophins. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and performs many biological functions such as promoting the survival, differentiation, and plasticity of neurons. Variants in the BDNF gene increase the risk of SZ and bipolar disorder. Chronic administration of drugs used to treat SZ and BD, such as lithium, valproate, quetiapine, clozapine, and olanzapine, increases BDNF expression in rat brain. To examine serum BDNF, three groups of chronically medicated DSM-IV SZ patients, on treatment with clozapine (n=27), typical (n=14), and other atypical antipsychotics (n=19), 30 euthymic BD patients, and 26 healthy control had 5 ml blood samples collected by venipuncture. Serum BDNF levels were significantly higher in SZ patients (p<0.001) when compared to either controls or euthymic BD patients. Increased BDNF in SZ patients might be related to the course of illness or to treatment variables. Prospective studies are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 129 | World J. Biol. Psychiatry 2007 -1 8: 12-22 |
| PMID | 17366345 |
| Title | Potential genetic variants in schizophrenia: a Bayesian analysis. |
| Abstract | A number of different gene polymorphisms have been found to dispose for the development of schizophrenia. However, no single gene polymorphism is sufficient for the precipitation of schizophrenia. Swedish psychosis patients (n=103) and control subjects (n=89) were analyzed for 36 single nucleotide polymorphisms in 30 candidate genes for schizophrenia. Evidence of association was analyzed with Bayesian statistical methods. Variants in the genes coding for dopamine-D2 receptor, brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), neuregulin 1, reelin and synapsin 3 showed association with schizophrenia, although few subjects were found in the minority allele for the two latter variants. The six gene variants, all with suspected connection to schizophrenia, were found to be risk factors when considered in combination, but not separately. The results indicate that the Bayesian statistical method gives additional possibilities in the search for risk factors for schizophrenia or other complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 130 | Int. Rev. Neurobiol. 2007 -1 78: 377-95 |
| PMID | 17349867 |
| Title | Brain-derived neurotrophic factor in schizophrenia and its relation with dopamine. |
| Abstract | The brain-derived neurotrophic factor (BDNF) belongs to the neurotrophins family and has a role in proliferation, differentiation of neurons but also as a neurotransmitter. This neurotrophin has received much attention during the last year in regard of the pathophysiology of schizophrenia. Results of genetic studies conducted in schizophrenia support a role for BDNF in schizophrenia and in brain function associated with the disorder. The changes of BDNF observed in the brain and in the plasma of patients with schizophrenia have generated results that can be interpreted either as a hallmark of the disease or a consequence of antipsychotic drugs. Antipsychotic drugs act by blocking the dopamine transmission at the dopamine D2-like receptors. BDNF controls the expression of one of these D2-like receptors, the dopamine D3 receptor. This raises the hypothesis of a link between cortical area, via BDNF, and the dopamine neurotransmission pathway in schizophrenia and its treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 131 | Biochem. Biophys. Res. Commun. 2007 Feb 353: 738-43 |
| PMID | 17196936 |
| Title | Brain-derived neurotrophic factor and risk of schizophrenia: an association study and meta-analysis. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and performs many biological functions such as neural survival, differentiation, and plasticity. Previous studies have suggested that variants in the BDNF gene increase the risk of schizophrenia. In this study, we genotyped one (GT)n dinucleotide repeat and three SNPs (rs6265, rs2030324, and rs2883187) in a Chinese sample (617 cases and 672 controls). In addition, we performed an updated meta-analysis based on 16 population-based case-control studies examining association between rs6265 and schizophrenia. In single-locus analysis, no significant association was found between BDNF polymorphisms and schizophrenia in our subjects. The meta-analysis based on Asian and Caucasian subjects did not give positive result that rs6265 is associated with schizophrenia. However, haplotype analysis found a common four-locus haplotype is protective against schizophrenia (Case 3.1% vs Control 7%, p=0.0011). Our data provides evidence that BDNF is a susceptibility gene for schizophrenia in Chinese subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 132 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Jun 31: 1072-7 |
| PMID | 17459549 |
| Title | Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-hydroxypnenylglycol (MHPG) levels, but did not alter plasma brain-derived neurotrophic factor (BDNF) levels in schizophrenic patients. |
| Abstract | In the present study, we investigated the effects of risperidone treatment for 4 weeks on plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and brain-derived neurotrophic factor (BDNF) in 89 schizophrenic patients. We also compared the plasma levels of BDNF and MHPG between the schizophrenic group and 103 sex-and age-matched normal controls. In addition, we investigated the effects of two SNPs of the noradrenaline transporter (NAT) gene on plasma levels of MHPG, BDNF, and clinical improvement. The mean dose of risperidone was 3.8+/-1.4 mg/day. We demonstrated that treatment with risperidone increased plasma MHPG levels, and this increase was associated with an improvement of the negative symptoms of schizophrenia. In contrast, plasma BDNF did not change after 4 weeks of risperidone treatment, and the two SNPs in NAT did not influence the response to risperidone treatment or plasma MHPG and BDNF levels. These results suggest that the enhancement of noradrenergic neurons by risperidone, which occurs independently of the two SNPs of NAT, plays a role in the clinical efficacy of the drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 133 | Schizophr Bull 2007 Nov 33: 1343-53 |
| PMID | 17329232 |
| Title | eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? |
| Abstract | Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 134 | Psychiatry Clin. Neurosci. 2007 Feb 61: 3-19 |
| PMID | 17239033 |
| Title | Molecular genetics of bipolar disorder and depression. |
| Abstract | In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 135 | Am J Psychiatry 2007 Dec 164: 1890-9 |
| PMID | 18056245 |
| Title | Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. |
| Abstract | Factors underlying progressive brain volume changes in schizophrenia remain poorly understood. The authors investigated whether a gene polymorphism influencing neuroplasticity may contribute to longitudinal brain volume alterations. High-resolution magnetic resonance (MR) images of the whole brain were obtained for 119 patients with recent-onset schizophrenia spectrum disorders. Changes in brain volumes over an average of 3 years were compared between brain-derived neurotrophic factor (BDNF) val66met genotype groupings. Exploratory analyses were conducted to examine relationships between antipsychotic treatment and brain volume changes as well as the effects of BDNF genotype on changes in cognition and symptoms. Significant genotype effects were observed on within-subject changes in volumes of frontal lobe gray matter, lateral ventricles, and sulcal CSF. Met allele carriers had significantly greater reductions in frontal gray matter volume, with reciprocal volume increases in the lateral ventricles and sulcal (especially frontal and temporal) CSF than Val homozygous patients. Independent of BDNF genotype, more antipsychotic exposure between MRI scans correlated with greater volume reductions in frontal gray matter, particularly among patients who were initially treatment naive. There were no statistically significant genotype effects on within-subject changes in cognition or symptoms. BDNF(Met) variant may be one of several factors affecting progressive brain volume changes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 136 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 137 | Psychiatry Clin. Neurosci. 2007 Oct 61: 509-14 |
| PMID | 17875029 |
| Title | Clinical effectiveness of the Kampo medicine kamishoyosan for adjunctive treatment of tardive dyskinesia in patients with schizophrenia: a 16-week open trial. |
| Abstract | The purpose of the present study was to evaluate the clinical effectiveness of kamishoyosan for antipsychotic-induced tardive dyskinesia, and to investigate the relationship between tardive dyskinesia and serum brain-derived neurotrophic factor (BDNF) levels. Sixty-nine schizophrenia patients were enrolled; of these, 49 presented with tardive dyskinesia while the remaining 20 patients showed no tardive dyskinesia. The tardive dyskinesia group was treated for 16 weeks with kamishoyosan and assessed using the abnormal involuntary movement scale. The abnormal involuntary movement scale scores in the tardive dyskinesia group were evaluated at baseline and after 4, 8, and 16 weeks of treatment. The BDNF levels of all subjects were measured at baseline in order to compare differences in serum BDNF levels between the tardive dyskinesia group and the non-tardive dyskinesia group, and to correlate the severity of tardive dyskinesia and serum BDNF in the tardive dyskinesia group. A meaningful reduction in total abnormal involuntary movement scale scores was observed in the tardive dyskinesia group treated with kamishoyosan at 4, 8, and 16 weeks of treatment (P < 0.01). No significant differences in serum BDNF levels were detected between the tardive dyskinesia group and the non-tardive dyskinesia group at baseline. Furthermore, no significant correlation was seen between the severity of tardive dyskinesia and serum BDNF levels. The present study suggests that kamishoyosan might be a promising adjunctive treatment for antipsychotic-induced tardive dyskinesia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 138 | J. Psychopharmacol. (Oxford) 2007 Nov 21: 820-5 |
| PMID | 17715210 |
| Title | Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor. |
| Abstract | Chronic cocaine and heroin users display a variety of central nervous system (CNS) dysfunctions including impaired attention, learning, memory, reaction time, cognitive flexibility, impulse control and selective processing. These findings suggest that these drugs may alter normal brain functions and possibly cause neurotoxicity. Neurotrophins are a class of proteins that serve as survival factors for CNS neurons. In particular, nerve growth factor (NGF) plays an important role in the survival and function of cholinergic neurons while brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity and in the maintenance of midbrain dopaminergic and cholinergic neurons. In the present study, we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF levels in serum of three groups of subjects: heroin-dependent patients, cocaine-dependent patients and healthy volunteers. Our goal was to identify possible change in serum neurotrophins in heroin and cocaine users. BDNF was decreased in heroin users whereas NGF was decreased in both heroin and cocaine users. These findings indicate that NGF and BDNF may play a role in the neurotoxicity and addiction induced by these drugs. In view of the neurotrophin hypothesis of schizophrenia the data also suggest that reduced level of neurotrophins may increase the risk of developing psychosis in drug users. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 139 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 140 | Curr Drug Targets 2007 May 8: 583-602 |
| PMID | 17504103 |
| Title | Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior. |
| Abstract | Ampakines are drugs structurally derived from aniracetam that potentiate currents mediated by AMPA type glutamate receptors. These drugs slow deactivation and attenuate desensitization of AMPA receptor currents, increase synaptic responses and enhance long-term potentiation. This review focuses mainly on recent physiological studies and on evidence for two distinct subfamilies. Type I compounds like CX546 are very effective in prolonging synaptic responses while type II compounds like CX516 mainly increase response amplitude. Type I and II drugs do not compete in binding assays and thus presumably act through separate sites. Their differences are likely to have consequences also for synaptic plasticity and behavior. Thus, while all ampakines facilitated long-term potentiation, only CX546 enhanced long-term depression. Further discussed are studies showing that ampakine effects vary substantially between neurons, with increases in EPSCs being larger in CA1 pyramidal cells than in thalamus and in hippocampal interneurons. In behavioral tests, ampakines facilitate learning in many paradigms including odor discrimination, spatial mazes, and conditioning, and they improved short-term memory in a non-matching-to-sample task. Positive results were also obtained in various psychological tests with human subjects. The drugs were effective in correcting behaviors in various animal models of schizophrenia and depression. Lastly, evidence is discussed that ampakines have few adverse effects at therapeutically relevant concentrations and that they protect neurons against neurotoxic insults, in part by mobilizing growth factors like BDNF. Type II drugs like CX516 in particular appear to be inherently safe since their ability to prolong responses is kinetically limited. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 141 | Vestn. Akad. Med. Nauk SSSR 2007 -1 -1: 3-8 |
| PMID | 17500207 |
| Title | [The molecular-genetic aspects of differentiation of schizoaffective psychosis and attack-like progressive schizophrenia]. |
| Abstract | To clarify nosologic differences between schizoaffective psychosis (SAP) and attack-like progressive schizophrenia at molecular-genetic level, the genetic polymorphism of serotonin receptor type 2A (5HTR2A), serotonin transporter (5-HTTLRP), and brain-derived neurotrophic factor (BDNF) was studied in 563 patients with schizophrenia (mean age 37.7+/-14.4 years, age at disease onset 26.7+/-11.4 years), and 171 patients with SAP (mean age 30.7+/-11.6 years, age at disease onset 24.9+/-8.5 years). The control group consisted of 536 psychiatrically well subjects. Clinical symptoms and personal features were evaluated as well. By comparison with schizophrenic patients, those with SAP were featured by subtle negative symptoms and personality changes that supported the evidence that SAP is a disorder with a favorable outcome. Molecular-genetic studies revealed higher frequencies of S allele and SS genotype (5-HTTLPR polymorphism), which are thought to be associated with depression and depressive symptoms, and higher frequency of BDNF genotypes, containing Met allele, in combination with 5-HTTLRP genotypes containing L allele, in patients with SAP as compared to the schizophrenic group. C allele and CC genotype (T102C 5-HTR2A polymorphism) frequencies were higher in both groups of patients vs. controls. In conclusion, the results confirm the concept considering SAP an independent nosologic category. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 142 | Eur Neuropsychopharmacol 2007 Dec 17: 756-62 |
| PMID | 17434716 |
| Title | Chronic amphetamine treatment reduces NGF and BDNF in the rat brain. |
| Abstract | Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 143 | Psychiatr. Genet. 2007 Jun 17: 165-70 |
| PMID | 17417060 |
| Title | Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder. |
| Abstract | A long-term controversy exists on whether or not major psychotic disorders can be discretely divided into two groups, for example, schizophrenia and bipolar disorder. Many genes and polymorphisms have been studied for a role in both disorders, including the Val66Met (also known as rs 6265 or G196A) variant of brain-derived neurotrophic factor (BDNF). Many case-control association studies have been performed to see if BDNF could serve as a useful clinical diagnostic biomarker for schizophrenia or bipolar disorder, but results have been equivocal. To determine, by meta-analysis, if the Val66Met polymorphism of BDNF influences risk for either schizophrenia, bipolar disorder, or both. We searched Pubmed, Medline, and PsycInfo using keywords including Val66Met, Rs6265, G196A, BDNF, schizophrenia, and bipolar disorder. A total of 13 studies for schizophrenia and 11 studies for bipolar disorder were combined by random-effects meta-analysis. The pooled results from the schizophrenia sample (2955 patients; 4035 controls) and the bipolar disorder sample (3143 patients; 6347 controls) indicated lack of significance with either of the two psychoses, with pooled odds ratios of 1.00 (P=0.944) and 0.95 (P=0.161), respectively. Although there are some limitations on the study, our results indicate there is a lack of association between the Val66Met polymorphism and either of the two psychoses. A larger sample size, and evaluation of more single-nucleotide polymorphisms are needed to obtain more robust and conclusive findings regarding the relationship between the BDNF gene and psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 144 | Schizophr. Res. 2007 Mar 91: 1-5 |
| PMID | 17306505 |
| Title | Brain derived neurotropic factor in first-episode psychosis. |
| Abstract | There is much interest, derived from current neurochemical, genetic, and therapeutic research, in the role of brain neurotrophins in schizophrenia. Neurotrophins play key roles in neuronal development and differentiation (i.e., promoting dendritogenesis and synaptogenesis), and in orchestrating the neuronal response to stress/noxious stimuli. Additionally, neurotrophins are modulators across monominergic (dopamine and serotonin), gabaergic and cholinergic systems. These roles focus on important areas of the etiopathophysiology of schizophrenia. Clinical studies show reductions in brain-derived neurotrophic factor (BDNF) and nerve growth factor (NFG) in schizophrenic patients as compared to normal control subjects, as well as differences in patients receiving first-generation antipsychotics (FGAs) or second-generation antipsychotics (SGAs). We now report on BDNF levels in subjects with first-episode psychosis in comparison with normal healthy controls. Compared to normal controls (N=14; 290.5+/-38.81 pg/ml), first-episode psychotic patients showed significant reduction (N=15; 135+/-21.77 pg/ml; P=0.001; f=12.873) in plasma BDNF. Additionally, plasma BDNF levels showed a significant negative correlation (N=13' r=0.584, P=0.0362) only with positive symptom scores at base line and no significant correlations were found with any of the cognitive performance test battery or motor function test scores. Low BDNF levels at the onset of psychosis suggest that it may contribute to the pathogenesis of schizophrenia and/or perhaps could be a helpful neurobiological marker for possible early treatment intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 145 | Schizophr. Res. 2007 Mar 91: 6-13 |
| PMID | 17289348 |
| Title | Brain-derived neurotrophic factor gene C-270T and Val66Met functional polymorphisms and risk of schizophrenia: a moderate-scale population-based study and meta-analysis. |
| Abstract | Lines of evidence have suggested that the brain-derived neurotrophic factor (BDNF) gene may be involved in the pathogenesis of schizophrenia. Two common functional polymorphisms C-270T and Val66Met within the BDNF gene were first reported by Kunugi et al. [Kunugi, H., Nanko, S., Hirasawa, H., Kato, N., Nabika, T., Kobayashi, S., 2003. Brain-derived neurotrophic factor gene and schizophrenia: polymorphism screening and association analysis. Schizophr. Res. 62, 281-283.] and pls expand this too: Hong et al. (2003) to be significantly associated with schizophrenia. However, subsequently several studies obtained conflicting results. We compared the allele/genotype frequencies of the C-270T and Val66Met polymorphisms and the haplotype frequencies at the two polymorphisms in a moderate independent patient-control sample from the Han Chinese population. Two systematic meta-analyses were performed to assess the collective evidence for association across studies for each of the two polymorphisms. No statistically significant differences were found in allele or genotype or haplotype frequencies between patient and normal control subjects for either of the two polymorphisms. On the other hand, the meta-analysis of all published population-based association studies showed statistically significant evidence for heterogeneity among each of the two polymorphisms. Stratification of the studies by ethnicity of the samples yielded no significant evidence for an association with the polymorphisms in the Caucasian population (for C-270T polymorphism: pooled OR(Caucasian)=0.736, 95% CI=0.476-1.139, p=0.169; for Val66Met polymorphism: pooled OR(Caucasian)=1.027, 95% CI=0.796-1.325, p=0.835), nor in the Asian population (for C-270T polymorphism: pooled OR(Asian)=0.445, 95% CI=0.144-1.373, p=0.159; for Val66Met polymorphism: pooled OR(Asian)=0.962, 95% CI=0.820-1.128, p=0.635). Our population-based study and meta-analysis demonstrate that the BDNF C-270T and Val66Met polymorphisms do not play major roles in the susceptibility to schizophrenia in either Caucasian or Asian populations. But we can not rule out the possibility that other polymorphisms with the BDNF gene are involved in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 146 | Neurosci. Lett. 2007 Mar 415: 108-12 |
| PMID | 17267117 |
| Title | No association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and schizophrenia in Asian populations: Evidence from a case-control study and meta-analysis. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that plays an important role in the development and maintenance of adult neurons and is important regulator of synaptic plasticity in human brain. It has been reported that there are alterations in BDNF levels in the brains of patients with schizophrenia. It has also been reported that transneuronal transfer of BDNF is dependent on neuronal activity, suggesting that BDNF plays an important role in neurotransmission. A single nucleotide polymorphism (SNP) in the BDNF gene that causes a valine to methionine substitution at codon 66 (Val66Met) has been demonstrated to affect human memory and hippocampal function. A possible positive association between the BDNF Val66Met polymorphism and schizophrenia has also been shown in Scottish and Spanish populations. Furthermore, the BDNF Val66Met polymorphism has been implicated in the age of onset of schizophrenia. In the present study, we attempted to replicate these findings in a Japanese case-control sample (211 patients with schizophrenia and 205 controls). We did not find an association between the BDNF Val66Met polymorphism and schizophrenia. An association between the Val66Met polymorphism and age of onset was not observed either. Furthermore, a meta-analysis including the present and previous Asian studies comparing 2059 patients with schizophrenia and 2765 controls also revealed no significant association between the BDNF Val66Met polymorphism and schizophrenia. Our results do not support a significant role for the BDNF Val66Met polymorphism in the development of schizophrenia in Asian populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 147 | J Psychiatr Res 2007 Dec 41: 979-90 |
| PMID | 17239400 |
| Title | Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. |
| Abstract | A number of lines of converging evidence suggest that brain-derived neurotrophic factor (BDNF) may play a role in the onset and treatment of bipolar disorder. We review pertinent data on BDNF from several different areas of preclinical and clinical investigation that suggest novel theoretical and treatment implications for the recurrent affective disorders. Data from several recent studies have also converged showing that the val66met allele of BDNF, a common single nucleotide polymorphism (SNP), is associated with selective minor deficits in cognitive functioning in subjects with schizophrenia, bipolar illness, and normal controls. Yet, paradoxically, the better functioning val66val allele of BDNF appears to be associated with an increased risk for bipolar disorder and perhaps early onset or rapid cycling. All the primary antidepressant modalities, as well as the mood stabilizers lithium and valproate, increase BDNF. Stressors decrease BDNF and this effect can be blocked by antidepressants. Serum BDNF is low in proportion to the severity of mania and depression and increases with clinical improvement. Assessment of the val66val BDNF allele and a range of other SNPs as potential vulnerability factors for bipolar illness and its early onset could facilitate studies of early intervention, help reduce long delays between the onset of first symptoms and the first treatment, and help in the prediction of individual patient's likelihood of responding to a given treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 148 | Biol. Psychiatry 2007 Apr 61: 911-22 |
| PMID | 17217930 |
| Title | Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. |
| Abstract | There is an increasing recognition that the pathophysiology of mental disorders could be the result of deregulation of synaptic plasticity with alterations of neurotrophins. The valine (Val)66-to-methionine (Met) variant, located in the pro brain-derived neurotrophic factor (BDNF) sequence, has been extensively studied through linkage and association approaches in several psychiatric disorders. We performed a meta-analysis restricted to individual case-control studies in different categories of mental disorders and BDNF Val66Met polymorphism. We included data from 39 case-control studies encompassing psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders, and schizophrenia, among others. The association of Val66Met was confined to three diagnoses: substance-related disorders, eating disorders, and schizophrenia. The Val/Met and the Met/Met genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. The homozygous carriers Met/Met showed a 19% increased risk of schizophrenia with respect to the heterozygous state. The study confirms the association of Val66Met to substance-related disorders, eating disorders, and schizophrenia. It remains to be determined if other variants in tight linkage disequilibrium with Val66Met could configure an extended functional haplotype that would explain observed discrepancies in risk estimations across studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 149 | Med. Hypotheses 2007 -1 69: 199-202 |
| PMID | 17166669 |
| Title | Therapeutic possibilities of cysteamine in the treatment of schizophrenia. |
| Abstract | schizophrenia has complicated pathogeneses that is not able to be explained by any one supposed hypothesis, although alterations in dopamine neurotransmission have been widely accepted as the most plausible mechanism. A transition from traditional typical antipsychotics to contemporary atypical antipsychotics which have significantly improved tolerability and enhanced specific efficacy has been also made based on this dopamine hypothesis. Cysteamine is a natural product of mammalian cells and found to be useful pharmacological alternative. A number of evidence suggests that cysteamine may control directly or indirectly dopamine neurotransmission in nucleus accumbens and other schizophrenia-related brain regions. Systemic cysteamine injection mitigated the apomorphine-induced stereotypy as well as decreasing motor stimulant effects of amphetamine, which favor cysteamine over animal models of schizophrenia relative to hyperactivity of dopaminergic pathway. In addition, cysteamine showed neuroprotective effects by way of enhancing central and serum brain derived neurotrophic factor (BDNF) that has been proved to be altered in patients with schizophrenia. Antipsychotic drugs exert their effect partly by modifying the synthesis and distribution of BDNF in selected brain region. Cysteamine was effective to reverse a disruption in prepulse inhibition, an endophenotypic marker of schizophrenia. Cysteamine can also stimulate the release of cortical dopamine, which is interesting in that decreased dopaminergic function in the cerebral cortex has been repeatedly demonstrated in patients with schizophrenia and associated with prominent depressive and negative symptoms. Cysteamine can also increase an important antioxidant, glutathione. Finally, cysteamine treatment was found to decrease weight gain, cataleptic behavior, and serum prolactin levels, which are the major beneficial properties of contemporary atypical antipsychotics. Hence, further explorations of therapeutic implication of cysteamine for schizophrenia in preclinical studies should be warranted in future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 150 | J Psychiatr Res 2007 Dec 41: 997-1004 |
| PMID | 17095017 |
| Title | Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics. |
| Abstract | Several lines of evidence suggest that central brain-derived neurotrophic factor (BDNF) modulates food intake, metabolism, and increases in body weight. Reports have also shown that serum BDNF is altered in schizophrenic patients treated with antipsychotics. This study aimed to determine if there was a relationship between BDNF and antipsychotic-induced weight gain in patients with chronic schizophrenia. Serum BDNF was measured in 124 schizophrenia patients chronically treated with clozapine (n=57), risperidone (n=23) or typical antipsychotics (n=44) and 50 healthy control subjects. To further assess group differences in serum BDNF, additional analyses were performed in a subset of patients and controls individually matched for body mass index (BMI). BDNF levels were lower in patients with schizophrenia than normal controls. However, this difference was not present when controlling for current BMI. In the individually BMI-matched sample, no differences in serum BDNF levels were observed in schizophrenic patients compared to BMI-matched healthy controls. BDNF levels negatively correlated with BMI gain in female but not in male patients when gender was considered. Antipsychotic class exerted differential effects over BDNF levels and BMI gain. Our findings suggest that decreased BDNF levels may be associated with weight gain in female schizophrenic patients on long-term antipsychotic treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 151 | J Neural Transm (Vienna) 2007 Feb 114: 255-9 |
| PMID | 16897602 |
| Title | Interaction between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in age at onset and clinical symptoms in schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) gene is one of the candidate genes for schizophrenia because it codes an enzyme that participates in the metabolic inactivation of dopamine and noradrenaline and a limiting factor of dopamine metabolism in the prefrontal cortex. COMT gene lies on chromosome 22q11.2, which has been associated with schizophrenia susceptibility. A single-nucleotide polymorphism of COMT gene at position 108/158 results in an amino acid substitution from valine (val) to methionine (met), which modifies its enzymatic activity and may change the brain morphology and expressional behaviors. On the other hand, brain-derived neurotrophic factor (BDNF) plays a critical role in the development of mesolimbic dopaminergic- related systems. BDNF also contains a functional single-nucleotide polymorphism at codon 66 (Val66Met) of its prodomain and this polymorphism is responsible for schizophrenia susceptibility. In this study, we first investigated the relationship between COMT Val108/158Met polymorphism and age at onset as well as levels of clinical symptoms in 158 of chronic schizophrenia inpatients and then we investigated the gene-by-gene interaction between COMT Val108/158Met polymorphism and BDNF Val66Met polymorphism with age- and sex-matched control subjects (n = 318). We concluded that the COMT Val108/158Met polymorphism was not related to either the onset at age or the levels of clinical symptoms after long-term antipsychotic treatment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 152 | Med. Hypotheses 2007 -1 68: 180-3 |
| PMID | 16890384 |
| Title | The P11, tPA/plasminogen system and brain-derived neurotrophic factor: Implications for the pathogenesis of major depression and the therapeutic mechanism of antidepressants. |
| Abstract | Major depressive disorder (MDD) is a common disabling psychiatric illness with an unknown etiology. Evidence from animal and human studies suggests that a disturbance in serotonergic (5-HT) activity and/or brain-derived neurotrophic factor (BDNF) signaling may be implicated in the pathogenesis of MDD. Recently, a protein, p11, has been found to increase the number of 5-HT(1B) receptors on the surface of cells and enhance 5-HT(1B) receptor function. Furthermore, mice over-expressing p11 acted as if they were undergoing treatment with antidepressants and p11 knockout mice exhibit a depression-like phenotype and reduced behavioural reactions to an antidepressant. As tissue-type plasminogen activator (tPA)/plasminogen proteolytic cascade is implicated in the cleavage of proBDNF to BDNF, and p11, a component of the Annexin II, which can greatly enhance the activation of plasmin by tPA, it is proposed that p11 may act through the tPA/plasminogen/BDNF pathway to achieve its antidepressant effect. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention for this disorder. In addition, BDNF is also implicated in several psychiatric diseases such as schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder and Alzheimer's disease; whether p11 and other components related to the tPA/plasminogen pathway may be related to the pathogenesis of these diseases needs further exploration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 153 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 154 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 155 | Psychiatry Res 2007 Sep 153: 7-15 |
| PMID | 17604122 |
| Title | A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. |
| Abstract | Previous studies have suggested that catechol-O-methyltransferase (COMT), proline dehydrogenase (PRODH), and brain-derived neurotrophic factor (BDNF) genes are possible susceptibility genes for schizophrenia. We hypothesized that these genes are also associated with schizotypal traits, which are heritable and related to schizophrenia. We genotyped five single nucleotide polymorphism (SNPs) from the COMT, PRODH and BDNF genes, and performed a series of association analyses between alleles, genotypes or haplotypes, and quantitative schizotypal trait scores derived from the schizotypal Personality Questionnaire (SPQ), in 465 Chinese healthy subjects. We found that 'years of education' was a major influence on seven out of nine schizotypal components, three schizotypal factors and the total SPQ scores. Molecular genetic analysis of COMT, PRODH and BDNF genes showed no significant effects of any variants on schizotypal components or factors of SPQ after correction for multiple testing, although there were weak association between COMT Val158Met (rs4680G/A) and the odd speech subscale (allele-wise, P=0.04; genotype-wise, P=0.049), between COMT Val158Met (rs4680G/A) and the suspiciousness subscale (genotype-wise, P=0.024), and between BDNF Val66Met and the Factor 2 interpersonal measure (genotype-wise, P=0.027) before correction. Furthermore, we found SNP Val158Met (rs4680) of the COMT gene significantly influenced the scores of some of schizotypal traits including total SPQ score, the disorganization factor and the constricted affect subscale in male subjects only. However, the effect was in the opposite direction of an earlier association with the SPQ reported by Avramopoulos et al. [Avramopoulos, D., Stefanis, N.C., Hantoumi, I., Smyrnis, N., Evdokimidis, I., Stefanis, C.N., 2002. Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. Molecular Psychiatry 7, 706-711]. We conclude that SNP Val158Met (rs4680) in the COMT gene may be associated with some schizotypal traits in male subjects, but our results are not conclusive. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 156 | Vestn. Akad. Med. Nauk SSSR 2007 -1 -1: 3-8 |
| PMID | 17500207 |
| Title | [The molecular-genetic aspects of differentiation of schizoaffective psychosis and attack-like progressive schizophrenia]. |
| Abstract | To clarify nosologic differences between schizoaffective psychosis (SAP) and attack-like progressive schizophrenia at molecular-genetic level, the genetic polymorphism of serotonin receptor type 2A (5HTR2A), serotonin transporter (5-HTTLRP), and brain-derived neurotrophic factor (BDNF) was studied in 563 patients with schizophrenia (mean age 37.7+/-14.4 years, age at disease onset 26.7+/-11.4 years), and 171 patients with SAP (mean age 30.7+/-11.6 years, age at disease onset 24.9+/-8.5 years). The control group consisted of 536 psychiatrically well subjects. Clinical symptoms and personal features were evaluated as well. By comparison with schizophrenic patients, those with SAP were featured by subtle negative symptoms and personality changes that supported the evidence that SAP is a disorder with a favorable outcome. Molecular-genetic studies revealed higher frequencies of S allele and SS genotype (5-HTTLPR polymorphism), which are thought to be associated with depression and depressive symptoms, and higher frequency of BDNF genotypes, containing Met allele, in combination with 5-HTTLRP genotypes containing L allele, in patients with SAP as compared to the schizophrenic group. C allele and CC genotype (T102C 5-HTR2A polymorphism) frequencies were higher in both groups of patients vs. controls. In conclusion, the results confirm the concept considering SAP an independent nosologic category. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 157 | Schizophr. Res. 2007 Mar 91: 1-5 |
| PMID | 17306505 |
| Title | Brain derived neurotropic factor in first-episode psychosis. |
| Abstract | There is much interest, derived from current neurochemical, genetic, and therapeutic research, in the role of brain neurotrophins in schizophrenia. Neurotrophins play key roles in neuronal development and differentiation (i.e., promoting dendritogenesis and synaptogenesis), and in orchestrating the neuronal response to stress/noxious stimuli. Additionally, neurotrophins are modulators across monominergic (dopamine and serotonin), gabaergic and cholinergic systems. These roles focus on important areas of the etiopathophysiology of schizophrenia. Clinical studies show reductions in brain-derived neurotrophic factor (BDNF) and nerve growth factor (NFG) in schizophrenic patients as compared to normal control subjects, as well as differences in patients receiving first-generation antipsychotics (FGAs) or second-generation antipsychotics (SGAs). We now report on BDNF levels in subjects with first-episode psychosis in comparison with normal healthy controls. Compared to normal controls (N=14; 290.5+/-38.81 pg/ml), first-episode psychotic patients showed significant reduction (N=15; 135+/-21.77 pg/ml; P=0.001; f=12.873) in plasma BDNF. Additionally, plasma BDNF levels showed a significant negative correlation (N=13' r=0.584, P=0.0362) only with positive symptom scores at base line and no significant correlations were found with any of the cognitive performance test battery or motor function test scores. Low BDNF levels at the onset of psychosis suggest that it may contribute to the pathogenesis of schizophrenia and/or perhaps could be a helpful neurobiological marker for possible early treatment intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 158 | J Psychiatr Res 2007 Dec 41: 997-1004 |
| PMID | 17095017 |
| Title | Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics. |
| Abstract | Several lines of evidence suggest that central brain-derived neurotrophic factor (BDNF) modulates food intake, metabolism, and increases in body weight. Reports have also shown that serum BDNF is altered in schizophrenic patients treated with antipsychotics. This study aimed to determine if there was a relationship between BDNF and antipsychotic-induced weight gain in patients with chronic schizophrenia. Serum BDNF was measured in 124 schizophrenia patients chronically treated with clozapine (n=57), risperidone (n=23) or typical antipsychotics (n=44) and 50 healthy control subjects. To further assess group differences in serum BDNF, additional analyses were performed in a subset of patients and controls individually matched for body mass index (BMI). BDNF levels were lower in patients with schizophrenia than normal controls. However, this difference was not present when controlling for current BMI. In the individually BMI-matched sample, no differences in serum BDNF levels were observed in schizophrenic patients compared to BMI-matched healthy controls. BDNF levels negatively correlated with BMI gain in female but not in male patients when gender was considered. Antipsychotic class exerted differential effects over BDNF levels and BMI gain. Our findings suggest that decreased BDNF levels may be associated with weight gain in female schizophrenic patients on long-term antipsychotic treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 159 | Mol. Psychiatry 2008 Sep 13: 873-7 |
| PMID | 18195713 |
| Title | Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. |
| Abstract | The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 160 | Rev Bras Psiquiatr 2008 Dec 30: 341-5 |
| PMID | 19142409 |
| Title | Molecular genetic case-control women investigation from the first Brazilian high-risk study on functional psychosis. |
| Abstract | Data from epidemiological studies have demonstrated that genetics is an important risk factor for psychosis. The present study is part of a larger project, pioneer in Brazil, which has been conducted by other researchers who intend to follow a high-risk population (children) for the development of schizophrenia and bipolar disorder. In this first phase of the project, the objective was to investigate the distribution of four candidate genetic polymorphisms for functional psychosis (Ser9Gly DRD3, 5HTTLPR, the VNTR 3'-UTR SLC6A3 and Val66Met BDNF) in a case-control sample. A total of 105 women (58 with schizophrenia and 47 with bipolar disorder) and 62 gender-matched controls were investigated. Allele and genotype distributions of all identified functional polymorphisms did not differ statistically between cases and controls. These results suggest that the investigated polymorphisms were not related to susceptibility to functional psychoses in our Brazilian sample. These findings need to be validated in larger and independent studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 161 | Pharmacogenomics 2008 Nov 9: 1589-93 |
| PMID | 19018714 |
| Title | BDNF gene: functional Val66Met polymorphism in mood disorders and schizophrenia. |
| Abstract | The brain-derived neurotrophic factor (BDNF) gene has become a candidate gene for molecular-genetic studies of mood disorders and schizophrenia, and also for pharmacogenomics of drugs used in the treatment of these conditions, such as mood-stabilizers in bipolar mood disorder, antidepressants in depression, and antipsychotics in schizophrenia. It has been demonstrated that the functional Val66Met polymorphism of the gene can be associated with a number of clinical and pharmacological phenomena in these illnesses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 162 | Neurosci. Lett. 2008 Sep 442: 100-3 |
| PMID | 18638525 |
| Title | Distinct regulation of brain-derived neurotrophic factor and noradrenaline in S100B knockout mice. |
| Abstract | The mainly glia-derived protein S100B has been shown to be involved in the pathophysiology of diseases such as neurodegenerative diseases, schizophrenia or depression. These diseases go along with distinct changes of cerebral neurotransmitters and neurotrophic factors. Few and partly inconsistent data exist on the influence of cerebral S100B protein levels on different neurotransmitters. Therefore we investigated levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), dopamine (DA), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus, frontal cortex and residual neocortex in S100B knock out (S100B KO) mice compared to wildtype controls. There was a significant increase of hippocampal BDNF (+53%) and a decrease of hippocampal (-12%) and residual neocortical (-15%) NA in 10-month-old S100B KO mice compared to wildtype mice whereas the other mediators investigated did not show genotype-dependent changes. The increased hippocampal BDNF may represent an endogenous attempt to compensate trophic effects of S100B protein especially on serotonergic neurons, which have been shown to be unaffected in S100B KO mice previously. As referred to changes in NA levels functional studies are warranted to elucidate the link between S100B protein and the noradrenergic metabolism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 163 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1545-8 |
| PMID | 18602732 |
| Title | No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and tardive dyskinesia in schizophrenic patients. |
| Abstract | This study investigated whether the brain-derived neurotrophic factor (BDNF) gene Val66Met single-nucleotide polymorphism (SNP) is associated with antipsychotic-induced tardive dyskinesia (TD) in schizophrenia. Genotyping was performed for the BDNF gene Val66Met SNP in Korean schizophrenic patients with (n=83) and without TD (n=126) who were matched for antipsychotic drug exposure and other relevant variables. The frequencies of genotypes (chi2=2.37, p=0.306) and alleles (chi2=0.03, p=0.867) did not differ significantly between these two groups. These findings suggest that the BDNF polymorphism does not play a major role in the susceptibility to TD in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 164 | Neuroreport 2008 Jul 19: 1155-8 |
| PMID | 18596619 |
| Title | Effects of brain-derived neurotrophic factor-catecholamine-O-methyltransferase gene interaction on schizophrenic symptoms. |
| Abstract | The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O-methyltransferase (COMT L) is associated with a deficit in attention and aggravation of delusions in schizophrenia. We hypothesized that the BDNF-COMT gene interaction would affect the symptoms and cognition in schizophrenia. Ninety-six schizophrenic patients and 79 control participants were recruited. The patients who were BDNF met/met x COMT L carriers had the highest scores of delusion of Positive Symptoms and the Scale for Assessment of Negative Symptoms, word reading of the color word test, and trail-making test B time, compared with the other three genotype interactions. The current results suggest that patients with the BDNF met/met x COMT L allele had more delusional symptoms and poorer cognitive flexibility, compared with the other three genotype interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 165 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1595-8 |
| PMID | 18582525 |
| Title | Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet. |
| Abstract | Dietary factors influence BDNF in animal studies, but there is no comparable data in clinical populations. We examined the effect of a dietary intervention on BDNF serum levels in 67 DSM-IV schizophrenic outpatients (51 males and 16 females). Two groups were assessed in a cross-sectional study: one on a hypocaloric diet (HD) and the other not on a hypocaloric diet. Weight, height and BMI data were collected concurrently with 5-ml blood sampling of each subject. BDNF levels were measured with a sandwich-ELISA. The blood sample was obtained a minimum of one month after the exposure to dietary intervention. Serum BDNF levels were significantly higher in patients on the HD (p=0.023). Additional research examining the interaction among patterns of nutritional food behavior and underlying physiopathology may result in insights upon which evidence-based decisions regarding dietary interventions can be made in people identified with major psychiatric disorders, such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 166 | Neurosci. Lett. 2008 Jul 439: 157-9 |
| PMID | 18514407 |
| Title | Increased serum levels of brain-derived neurotrophic factor in chronic institutionalized patients with schizophrenia. |
| Abstract | There is a growing body of evidence implicating the neurotrophin brain-derived neurotrophic factor (BDNF) in the pathogenesis of schizophrenia. As circulating BDNF levels may reflect the BDNF levels in the brain, we assessed serum BDNF in 40 institutionalized schizophrenic patients and 20 healthy controls. Serum BNDF levels were significantly increased in schizophrenic patients when compared to control subjects (p<0.001). Interestingly, serum BDNF correlated positively with the clinical scores at the negative subscale of the positive and negative syndrome scale (PANSS) (r=0.41; p<0.01). Our results confirm the emergent literature on the involvement of BDNF in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 167 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Jul 32: 1308-11 |
| PMID | 18502013 |
| Title | Investigation of serum BDNF levels in drug-naive patients with schizophrenia. |
| Abstract | The role of brain-derived neurotrophic factor (BDNF) is to promote and modulate the neuronal responses across neurotransmitter systems in the brain. Therefore, abnormal BDNF signaling may be associated with the pathophysiology of schizophrenia. Decreased BDNF levels in the brain and the serum of patients with psychotic disorders have been reported. In the present study, we assessed serum BDNF levels in a group of 14 drug-naive first-episode patients with schizophrenia (FEP), compared to 15 healthy controls. The serum BDNF levels in the sample of FEP patients was significantly reduced compared to normal controls (23.92+/-5.99 ng/ml vs. 30.0+/-8.43 ng/ml, F=5.01, df=1, p=.034). Negative correlations were shown between serum BDNF levels of the patients and the PANSS Positive and Negative subscale scores. Our findings indicate that BDNF levels at the onset of schizophrenia may reflect associated pathophysiological processes as well as the severity of positive and negative psychotic symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 168 | Novartis Found. Symp. 2008 -1 289: 119-29; discussion 129-35, 193-5 |
| PMID | 18497099 |
| Title | Cell biology of BDNF and its relevance to schizophrenia. |
| Abstract | BDNF is a key regulator of synaptic plasticity and hence is thought to be uniquely important for various cognitive functions. While correlations of schizophrenia with polymorphisms in the BDNF gene and changes in BDNF mRNA levels have been reported, specific links remain to be established. Cell biology studies may provide clues as to how BDNF signalling impacts schizophrenia aetiology and pathogenesis: (1) the Val-Met polymorphism in the pro-domain affects activity-dependent BDNF secretion and short-term, hippocampus-mediated episodic memory. (2) pro-BDNF and mBDNF, by interacting with their respective p75(NTR) and TrkB receptors, facilitate long-term depression (LTD) and long-term potentiation (LTP), two common forms of synaptic plasticity working in opposing directions. (3) BDNF transcription is controlled by four promoters, which drive expression of four BDNF-encoding transcripts in different brain regions, cell types and subcellular compartments (dendrites, cell body, etc.), and each is regulated by different genetic and environmental factors. A role for BDNF in early- and late-phase LTP and short- and long-term, hippocampal-dependent memory has been firmly established. Extending these studies to synaptic plasticity in other areas of the brain may help us to better understand how altered BDNF signalling could contribute to intermediate phenotypes associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 169 | Metab Brain Dis 2008 Jun 23: 213-9 |
| PMID | 18496748 |
| Title | Lack of effect of antipsychotics on BNDF and NGF levels in hippocampus of Wistar rats. |
| Abstract | schizophrenia is a common and serious mental disorder, in which the majority of patients require long-term antipsychotic treatment. Several studies have suggested that schizophrenia is associated with decreased neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Investigation of the mechanisms of pharmacological agents that are used in the treatment of schizophrenia has been used to better understand the basis of the pathology associated with this mental illness. The present study aims to investigate the effect of chronic treatment with antipsychotics, named haloperidol (HAL), clozapine (CLO), olanzapine (OLZ) or aripiprazole (ARI) on BDNF and NGF levels in rat hippocampus. Adult male Wistar rats received daily injections of HAL (1.5 mg/kg), CLO (25 mg/kg), OLZ (2.5, 5 or 10 mg/kg) or ARI (2, 10 or 20 mg/kg), whereas control animals were given vehicle. BDNF and NGF levels were measured in rat hippocampus by sandwich-ELISA. The results showed that chronic administration of antipsychotics did not modify BDNF and NGF levels in rat hippocampus, suggesting that their therapeutic properties are not mediated by stimulation of these neurotrophins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 170 | Med Chem 2008 May 4: 256-63 |
| PMID | 18473918 |
| Title | Expression of mRNA of neurotrophic factors and their receptors are significantly altered after subchronic ketamine treatment. |
| Abstract | The neurotrophic factors play an important role in the maintenance of neurone viability and neuronal communication which are considered to be altered in schizophrenia. Subchronic application of ketamine (Ket) was found to be a useful model in schizophrenia research. To further validate this model the mRNA levels of neurotrophic factors NGF, NT-3, and BDNF and their receptors TrkA, TrkB, and TrkC, respectively, were measured in different brain areas in Ket-pretreated rats subchronically dosed with the atypical antipsychotic drug risperidone (Ris). With the exception of NGF in the frontal cortex, Ket pretreatment did change NGF, NT-3, and BDNF mRNA levels in the frontal cortex, the hippocampus, the striatum, the thalamus/hypothalamus region, and in the cerebellum. These changes correspond with changes at their tyrosine kinase receptors. Ris treatment normalised altered NT-3 levels in the hippocampus and balanced BDNF levels in the same structure. It was concluded that the Ket model might reflect distinct alterations in neurotrophic factor activity as found in schizophrenic patients and, moreover, that Ris treatment rebalances disturbed neurotrophic factor activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 171 | Neurosci. Lett. 2008 Apr 435: 34-9 |
| PMID | 18325670 |
| Title | Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons. |
| Abstract | Magnetic resonance imaging was used to investigate the relation between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and volumetric measurements for the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) and prefrontal sub-regions (the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, ventral medial prefrontal cortex, orbitofrontal cortex, and straight gyrus) in a Japanese sample of 33 schizophrenia patients and 29 healthy subjects. For the controls, the Met carriers had significantly smaller parahippocampal and left superior frontal gyri than the Val homozygotes. The schizophrenia patients carrying the Met allele had a significantly smaller right parahippocampal gyrus than those with the Val/Val genotype, but the genotype did not affect the prefrontal regions in schizophrenia patients. These findings might reflect different genotypic effects of BDNF on brain morphology in schizophrenia patients and healthy controls, implicating the possible role of the brain morphology as an endophenotype for future genetic studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 172 | J Child Adolesc Psychopharmacol 2008 Feb 18: 25-9 |
| PMID | 18294085 |
| Title | GAD1 single nucleotide polymorphism is in linkage disequilibrium with a child bipolar I disorder phenotype. |
| Abstract | Pediatric bipolar I disorder (BP-I) and childhood schizophrenia (SZ) share certain symptoms (e.g., psychosis, aggression/irritability [A/I]), and the psychotic and A/I features are treated with neuroleptics in both disorders. Thus, it is of interest to examine the association of GAD1 to child BP-I because of its recently reported association to childhood SZ. Child BP-I probands were obtained by consecutive new case ascertainment, and the phenotype was defined as current DSM-IV BP-I (manic or mixed phase) with at least one of the cardinal symptoms of mania (i.e., elation and/or grandiosity) and a Children's Global Assessment Scale score < or =60 (clinical impairment). These child BP-I probands are part of a large, ongoing, longitudinal study in which the phenotype has been validated by unique symptoms, longitudinal stability, and 7-8 times greater family loading than adult BP-I probands. Genotyping was performed using a TaqMan Validated SNP Genotyping Assay, and FBAT was used for analysis. There were 48 families. The rs2241165 A allele was preferentially transmitted (FBAT chi(2) = 5.2, df = 1, p = 0.022). No interaction between this GAD1 SNP and the Val66 BDNF allele was found. These data are consistent with some shared genetic vulnerability between child BP-I and SZ, which may be related to similar treatments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 173 | Schizophr. Res. 2008 Apr 101: 58-66 |
| PMID | 18289832 |
| Title | Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia. |
| Abstract | Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N=74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N=87). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21-59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r=-0.387, P=0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 174 | Neurosignals 2008 -1 16: 183-93 |
| PMID | 18253057 |
| Title | Brain-derived neurotropic factor/TrkB signaling in the pathogenesis and novel pharmacotherapy of schizophrenia. |
| Abstract | The role of neurotropins, predominantly brain-derived neurotropic factor (BDNF), has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Both human and rodent studies indicate that the beneficial effects of antipsychotic drugs are mediated, at least in part, through BDNF and its receptor, TrkB. This review will discuss the available data on the levels of BDNF and TrkB in subjects with schizophrenia and in animals with and without conventional antipsychotics. The data concerning the impact of the antipsychotic drugs on BDNF/TrkB signaling will also be discussed. More importantly, this review will provide future perspective on BDNF/TrkB signaling as a novel molecular target to correct the pathogenesis and improve the long-term clinical outcome by treatments with conventional and adjunctive drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 175 | J. Psychopharmacol. (Oxford) 2008 Jul 22: 536-42 |
| PMID | 18208916 |
| Title | Differential expression of IEG mRNA in rat brain following acute treatment with clozapine or haloperidol: a semi-quantitative RT-PCR study. |
| Abstract | Antipsychotic drugs have been shown to modulate immediate early gene (IEG) expression in rat brain regions that are associated with schizophrenia, which may be directly linked to their immediate therapeutic benefit. In this study, we analysed the expression profile of a series of IEGs (c-fos, c-jun, fra-1, Krox-20, Krox-24, arc, sgk-1, BDNF and NARP) in six rat brain regions (prefrontal cortex, hippocampus, striatum, nucleus accumbens, thalamus and cerebellum). Rats (n=5) were administered either clozapine (20 mg/kg i.p.), haloperidol (1 mg/kg i.p.) or the appropriate vehicle with pre-treatment times of 1, 6 and 24 h. IEG expression was analysed in these regions by Taqman RT-PCR. The spatial and temporal profile of IEG induction following antipsychotic drug treatment correlates with regions associated with the efficacy and side effect profile of each drug. In particular, sgk-1 expression levels after antipsychotic drug treatment may have predictive value when investigating the profile of a novel antipsychotic drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 176 | Neuropsychopharmacology 2008 Aug 33: 2200-5 |
| PMID | 17987059 |
| Title | BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. |
| Abstract | Recent evidence suggests that centrally released brain-derived neurotrophic factor (BDNF) modulates eating behavior and metabolism that is responsible for body weight fluctuation. BDNF also may play an important role in the therapeutic action of antipsychotic medications. We investigated whether the Val66Met polymorphism of the BDNF gene affected weight gain after long-term antipsychotic treatment in schizophrenia. The polymorphism was genotyped in 196 Chinese patients with schizophrenia on long-term antipsychotic medication. Serum BDNF was measured in all patients and 50 normal controls. Mean body mass index (BMI) change was evaluated retrospectively by means of clinical records. The results showed that there was a significant relationship between the three BDNF Val/Met genotypes and mean BMI gain, with genotype having a strong effect on BMI gain in male but not female patients. BDNF levels were significantly lower in patients than normal controls, and negatively correlated with BMI gain in female but not male patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment, and decreased BDNF levels may be associated with weight gain in females. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 177 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jun 147B: 505-6 |
| PMID | 17894414 |
| Title | BDNF Val66Met variant and age of onset in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been advanced as a candidate gene for schizophrenia by virtue of its effects on neurotransmitter systems that are dysregulated in psychiatric disorder and its involvement in the response to antipsychotic drugs. The extensively examined BDNF gene Val66Met (or rs6265) variant has been associated with schizophrenia, and studies have linked this polymorphism to brain morphology, cognitive function, and psychiatric symptoms in schizophrenia. Moreover the BDNF Val66Met variant has been reported to be associated with age of onset in schizophrenia. Genotyping of African-American subjects with schizophrenia for five BDNF coding region single nucleotide polymorphisms revealed variance only at the Val66Met allele. The results of statistical analyses indicate a relationship between the BDNF Val66Met genotype and the ages of first psychiatric hospitalization and first schizophrenia symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 178 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1545-8 |
| PMID | 18602732 |
| Title | No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and tardive dyskinesia in schizophrenic patients. |
| Abstract | This study investigated whether the brain-derived neurotrophic factor (BDNF) gene Val66Met single-nucleotide polymorphism (SNP) is associated with antipsychotic-induced tardive dyskinesia (TD) in schizophrenia. Genotyping was performed for the BDNF gene Val66Met SNP in Korean schizophrenic patients with (n=83) and without TD (n=126) who were matched for antipsychotic drug exposure and other relevant variables. The frequencies of genotypes (chi2=2.37, p=0.306) and alleles (chi2=0.03, p=0.867) did not differ significantly between these two groups. These findings suggest that the BDNF polymorphism does not play a major role in the susceptibility to TD in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 179 | Neuroreport 2008 Jul 19: 1155-8 |
| PMID | 18596619 |
| Title | Effects of brain-derived neurotrophic factor-catecholamine-O-methyltransferase gene interaction on schizophrenic symptoms. |
| Abstract | The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O-methyltransferase (COMT L) is associated with a deficit in attention and aggravation of delusions in schizophrenia. We hypothesized that the BDNF-COMT gene interaction would affect the symptoms and cognition in schizophrenia. Ninety-six schizophrenic patients and 79 control participants were recruited. The patients who were BDNF met/met x COMT L carriers had the highest scores of delusion of Positive Symptoms and the Scale for Assessment of Negative Symptoms, word reading of the color word test, and trail-making test B time, compared with the other three genotype interactions. The current results suggest that patients with the BDNF met/met x COMT L allele had more delusional symptoms and poorer cognitive flexibility, compared with the other three genotype interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 180 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1595-8 |
| PMID | 18582525 |
| Title | Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet. |
| Abstract | Dietary factors influence BDNF in animal studies, but there is no comparable data in clinical populations. We examined the effect of a dietary intervention on BDNF serum levels in 67 DSM-IV schizophrenic outpatients (51 males and 16 females). Two groups were assessed in a cross-sectional study: one on a hypocaloric diet (HD) and the other not on a hypocaloric diet. Weight, height and BMI data were collected concurrently with 5-ml blood sampling of each subject. BDNF levels were measured with a sandwich-ELISA. The blood sample was obtained a minimum of one month after the exposure to dietary intervention. Serum BDNF levels were significantly higher in patients on the HD (p=0.023). Additional research examining the interaction among patterns of nutritional food behavior and underlying physiopathology may result in insights upon which evidence-based decisions regarding dietary interventions can be made in people identified with major psychiatric disorders, such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 181 | Neurosci. Lett. 2008 Jul 439: 157-9 |
| PMID | 18514407 |
| Title | Increased serum levels of brain-derived neurotrophic factor in chronic institutionalized patients with schizophrenia. |
| Abstract | There is a growing body of evidence implicating the neurotrophin brain-derived neurotrophic factor (BDNF) in the pathogenesis of schizophrenia. As circulating BDNF levels may reflect the BDNF levels in the brain, we assessed serum BDNF in 40 institutionalized schizophrenic patients and 20 healthy controls. Serum BNDF levels were significantly increased in schizophrenic patients when compared to control subjects (p<0.001). Interestingly, serum BDNF correlated positively with the clinical scores at the negative subscale of the positive and negative syndrome scale (PANSS) (r=0.41; p<0.01). Our results confirm the emergent literature on the involvement of BDNF in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 182 | Med Chem 2008 May 4: 256-63 |
| PMID | 18473918 |
| Title | Expression of mRNA of neurotrophic factors and their receptors are significantly altered after subchronic ketamine treatment. |
| Abstract | The neurotrophic factors play an important role in the maintenance of neurone viability and neuronal communication which are considered to be altered in schizophrenia. Subchronic application of ketamine (Ket) was found to be a useful model in schizophrenia research. To further validate this model the mRNA levels of neurotrophic factors NGF, NT-3, and BDNF and their receptors TrkA, TrkB, and TrkC, respectively, were measured in different brain areas in Ket-pretreated rats subchronically dosed with the atypical antipsychotic drug risperidone (Ris). With the exception of NGF in the frontal cortex, Ket pretreatment did change NGF, NT-3, and BDNF mRNA levels in the frontal cortex, the hippocampus, the striatum, the thalamus/hypothalamus region, and in the cerebellum. These changes correspond with changes at their tyrosine kinase receptors. Ris treatment normalised altered NT-3 levels in the hippocampus and balanced BDNF levels in the same structure. It was concluded that the Ket model might reflect distinct alterations in neurotrophic factor activity as found in schizophrenic patients and, moreover, that Ris treatment rebalances disturbed neurotrophic factor activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 183 | Ann. Ist. Super. Sanita 2008 -1 44: 167-77 |
| PMID | 18660566 |
| Title | Clozapine or Haloperidol in rats prenatally exposed to methylazoxymethanol, a compound inducing entorhinal-hippocampal deficits, alter brain and blood neurotrophins' concentrations. |
| Abstract | Rats exposed during prenatal life to methylazoxymethanol (MAM) display in postnatal age structural and behavioral deficits resembling those observed in schizophrenic patients. These deficits are associated with significant changes in brain nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), particularly in the hippocampus and entorhinal cortex. In the present study, we used the MAM model to investigate in young rats the effect of antipsychotics, Clozapine and Haloperidol, on brain and blood NGF and BDNF presence. Young animals were used because administration of antipsychotics during adolescence is a common feature of intervention. The results showed that administration of Clozapine and Haloperidol causes significant changes in the concentration of NGF and BDNF in the brain and bloodstream of MAM-treated rats. These findings indicate that these drugs may affect the synthesis and release of neurotrophins in the central nervous system and in the blood circulation. In addition, the MAM model can be a useful tool to investigate the biochemical and molecular mechanisms regarding the effects of antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 184 | Biol. Psychiatry 2008 Dec 64: 1077-87 |
| PMID | 18973876 |
| Title | Insulin, IGF-1, and muscarinic agonists modulate schizophrenia-associated genes in human neuroblastoma cells. |
| Abstract | Genes associated with energy metabolism are decreased in schizophrenia brain and human and rodent diabetic skeletal muscle. These and other similarities between diabetes and schizophrenia suggest that an insulin signaling deficit may underlie schizophrenia. We determined with human SH-SY5Y neuroblastoma and astrocyte cell lines whether insulin or other molecules could modulate genes opposite to their change reported in schizophrenia brain. Both cell lines were treated with insulin, insulin-like growth factor (IGF)-1, IGF-2, or brain-derived neurotrophic factor (BDNF). Genes whose expression was found with microarrays to be changed by insulin in a reciprocal manner to their change in schizophrenia were used in a 16-gene miniarray to identify small molecules that might mimic insulin. Insulin phosphorylated its receptor in the neuroblastoma cells but not in astrocytes and, like IGF-1, increased ERK1/2 and Akt phosphorylation. Insulin and IGF-1 increased the expression of genes decreased in schizophrenia, including those involved in mitochondrial functions, glucose and energy metabolism, hydrogen ion transport, and synaptic function. These gene effects were confirmed and shown to be dose related with the 16-gene miniarrays. Most of 1940 pharmacologically unique compounds failed to alter gene expression, with the exception of muscarinic agonists, which mimicked insulin and IGF-1, and which were blocked by the muscarinic antagonists atropine and telenzepine. Stimulation of muscarinic and insulin/IGF-1 receptors alter genes associated with metabolic and synaptic functions in a manner reciprocal to their changes in schizophrenia. Pharmacologic activation of these receptors may normalize genomic alterations in schizophrenia and better address root causes of this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 185 | Psychiatr. Genet. 2008 Oct 18: 219-25 |
| PMID | 18797396 |
| Title | Association study of candidate variants from brain-derived neurotrophic factor and dystrobrevin-binding protein 1 with neuroticism, anxiety, and depression. |
| Abstract | Association of the valine/methionine variant at codon 66 (Val66Met) of brain derived neurotrophic factor (BDNF) has been reported inconsistently across a spectrum of psychiatric disorders. Haplotypes of six tagging single nucleotide polymorphisms (SNPs) of a 37-kb region of dystrobrevin-binding protein 1 (DTNBP1) were found to be associated with schizophrenia. These haplotypes have not been studied extensively for other psychiatric disorders but are plausible candidates for anxiety and depression disorders. Here, association between variants of BDNF and DTNBP1, and multiple anxiety and depression phenotypes is explored. Study participants were selected as sibling pairs that were either concordant or discordant for extreme neuroticism scores from a total sample of 18 742 Australian twin individuals and their siblings. All participants completed detailed Composite International Diagnostic Interview from which diagnoses of Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV depression and anxiety disorders were determined. Six hundred and seventy-four participants had a diagnosis of anxiety and/or depression from 492 families. The BDNF Val66Met and six DTNBP1 (rs3213207, rs1011313, rs2619528, rs760761, rs1018381, rs2619538) SNPs were genotyped on samples from study participants (n=2045 from 987 families) and, where possible, their parents (n=787). Family-based association tests were conducted between the individual SNPs and the DTNBP1 six SNP haplotypes and anxiety, depression, and neuroticism. We found no convincing evidence for association between any of the variants studied and anxiety, depression, or neuroticism. This study sample is relatively large but our results do not support an association between BDNF Val66Met and anxiety, depression, or neuroticisim. DTNBP1 haplotypes, which have been found to be risk factors for schizophrenia, are unlikely to be risk factors for anxiety and depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 186 | J. Neurochem. 2008 Nov 107: 941-51 |
| PMID | 18786174 |
| Title | Cystamine prevents haloperidol-induced decrease of BDNF/TrkB signaling in mouse frontal cortex. |
| Abstract | The role of brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Rodent studies indicate that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. Earlier studies from our laboratory have indicated that long-term treatment with haloperidol (HAL) decreases BDNF, reduced GSH and anti-apoptotic marker, Bcl-xl protein levels and increases the expression of pro-apoptotic proteins in rat frontal cortex. Furthermore, findings from human as well as rodent studies suggest that treatment of schizophrenia must involve the neuroprotective strategies to improve the neuropathology and thereby clinical outcome. In the present study, we investigated the potential of cystamine (CYS), an anti-oxidant and anti-apoptotic compound, to prevent HAL-induced reduction in BDNF, GSH, and Bcl-xl protein levels in mice and the signaling mechanism(s) involved in the beneficial effects of CYS. The results indicated that CYS as well as cysteamine (the FDA-approved precursor of CYS) increased BDNF protein levels in mouse frontal cortex 7 days after treatment. CYS co-treatment prevented chronic HAL treatment-induced reduction in BDNF, GSH, and Bcl-xl protein levels. CYS treatment enhanced TrkB-tyrosine phosphorylation and activated Akt and extracellular signal-regulated kinase (ERK)1/2, downstream molecules of TrkB signaling. In addition, in vitro experiments with mouse cortical neurons showed that CYS prevented the HAL-induced reduction in neuronal cell viability and BDNF protein levels, and increase in apoptosis. BDNF-neutralizing antibody as well as K252a, a selective inhibitor of neurotrophin signaling blocked the CYS-mediated neuroprotection. Moreover, CYS-mediated neuroprotection is also blocked by LY294002, a phosphatidylinositol 3-kinase inhibitor or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. Thus, CYS protects cortical neurons through a mechanism involving TrkB receptor activation, and a signaling pathway involving phosphatidylinositol 3-kinase and MAPK. The findings from the present study may be helpful for the development of novel neuroprotective strategies to improve the treatment outcome of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 187 | J Am Acad Child Adolesc Psychiatry 2008 Sep 47: 1077-85 |
| PMID | 18664999 |
| Title | Brain-derived neurotrophic factor gene expression in pediatric bipolar disorder: effects of treatment and clinical response. |
| Abstract | Pediatric bipolar disorder (PBD) is a major public health concern; however, little is known about the cellular and genetic factors that are involved in the pathophysiology of this illness. The observed structural abnormality in the brains of patients with mood disorders has been related to abnormal brain-derived neurotrophic factor (BDNF) function, suggesting an important role for BDNF in these disorders. We determined the gene expression of BDNF in lymphocytes obtained from 26 PBD subjects during a drug-free baseline period and during the eighth week of treatment (n = 19) and from 21 medication-free normal control subjects. We also determined the protein levels of BDNF in platelets of patients with PBD and normal control subjects. Subjects were diagnosed according to DSM-IV diagnostic criteria using the Washington University at St. Louis Schedule for Affective Disorders and schizophrenia. The mRNA levels of BDNF in lymphocytes of PBD subjects were significantly decreased compared with those of normal control subjects and were significantly higher in 19 subjects after 8 weeks of treatment than the pretreatment drug-free baseline levels and similar to those of normal controls. Similarly, protein levels of BDNF were decreased in platelets of patients with PBD. These studies suggest that BDNF levels may be a potential biomarker for PBD. BDNF levels may also serve as a potential treatment predictor and prognostic indicator in PBD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 188 | Psychiatr. Genet. 2008 Aug 18: 177-83 |
| PMID | 18628679 |
| Title | Brain-derived neurotrophic factor polymorphisms and frontal cortex morphology in schizophrenia. |
| Abstract | To investigate associations between brain-derived neurotrophic factor (BDNF) gene polymorphisms and regional frontal cortical thickness and volume in patients with schizophrenia and healthy control participants. BDNF genotyping was performed using polymerase chain reaction and pyrosequencing techniques in 96 patients with schizophrenia or schizoaffective disorder and 104 healthy control participants. Cortical morphology was analyzed by processing magnetic resonance brain images with the FreeSurfer software package. General linear model analysis was used to study associations between BDNF variants and cortical thickness in patients and controls, respectively. Regional frontal cortical volumes were defined from automatic cortical parcellations. For patients with schizophrenia, there was an association between the BDNF -633 T/A polymorphism and thickness and volume of distinct subregions of the prefrontal cortex. Data indicated trends toward genotypic associations between the BDNF 270 C/T and 11757 G/C polymorphisms and the volume of specific frontal lobe regions in patients with schizophrenia. Among controls, there were no significant associations between BDNF polymorphisms and cortical thickness. Trends toward genotypic associations between BDNF polymorphisms and volumes of some frontal lobe regions for control participants were observed, although these differences did not reach statistical significance. Polymorphisms in the BDNF gene may be associated with variation in frontal lobe morphology. Associations seem to be stronger in patients with schizophrenia than in healthy controls. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 189 | Expert Rev Neurother 2008 Jul 8: 1101-13 |
| PMID | 18590480 |
| Title | Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder. |
| Abstract | Initial descriptions of bipolar disorder (BD) emphasized that patients returned to a baseline condition after acute episodes. Such definitions were operational in teasing bipolar disorder apart from schizophrenia, where patients were described to be permanently impaired after the initial episodes. However, this view of BD as a disorder where cognition and overall functioning was spared has been changing after the scrutiny of new research. Currently, the cognitive impairment and neuroanatomical changes related to cumulative mood episodes, particularly manic episodes, are well described. In terms of neuropathological findings, recent data suggest that changes in neuronal plasticity, particularly in cell resilience and connectivity, are the main findings in BD. Data from differential lines of research converge to BDNF as an important contributor to the pathophysiology of BD. Serum BDNF levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. Moreover, factors that negatively influence the course of BD, such as life stress and trauma, have been shown to be associated with a decrease in serum BDNF levels among bipolar patients. These findings suggest that BDNF plays a central role in the transduction of psychosocial stress and recurrent episodes into the neurobiology of bipolar disorder. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 190 | Biol. Psychiatry 2008 Nov 64: 797-802 |
| PMID | 18486103 |
| Title | Decreased neurotrophic response to birth hypoxia in the etiology of schizophrenia. |
| Abstract | Obstetric complications, particularly fetal hypoxia, are associated with increased risk for schizophrenia later in life. Such factors are also related to increased severity of certain neuropathological features of schizophrenia, including hippocampal and cortical gray matter reduction, among individuals with a genetic susceptibility to the disorder. However, the molecular mechanisms underlying these associations are unknown. Here, we sought to determine whether neurotrophic factors, which are stimulated as part of a neuroprotective response to fetal distress, are differentially expressed in cord blood samples at the time of birth following fetal hypoxia, maternal hypertension/small for gestational age status, and/or prematurity among individuals who developed schizophrenia as adults, as compared with control subjects. One hundred eleven cases with psychotic disorders (70 with schizophrenia) and 333 control subjects matched for gender, race, and date of birth were drawn from the Philadelphia cohort of the National Collaborative Perinatal Project in a nested case-control study. Brain-derived neurotrophic factor (BDNF) was assayed from cord and maternal blood samples taken at delivery and stored at -20 degrees C for 45 to 50 years. Among control subjects, birth hypoxia was associated with a significant (10%) increase in BDNF in cord samples, while among cases, hypoxia was associated with a significant (20%) decrease in BDNF. This differential response to fetal hypoxia was specific to schizophrenia and was not explained by other obstetric complications or by the BDNF valine (val) to methionine (met) polymorphism at codon 66 (val66met). These findings provide serologically based prospective evidence of disrupted neurotrophic signaling in response to birth hypoxia in the molecular pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 191 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Jul 32: 1236-42 |
| PMID | 18472202 |
| Title | The association of genotypic combination of the DRD3 and BDNF polymorphisms on the adhesio interthalamica and medial temporal lobe structures. |
| Abstract | Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI), as well as in the medial temporal lobe structures has been implicated in schizophrenia, while its genetic mechanism is unknown. This magnetic resonance imaging study investigated the effect of the genotypic combination of the dopamine D3 receptor (DRD3) Ser9Gly and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms on the AI length and volumetric measures of the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) in 33 schizophrenia patients and 29 healthy controls. The subjects with a combination of the Ser/Ser genotype of DRD3 and Met-containing genotypes of BDNF (high-risk combination) had a shorter AI than those without it in the healthy controls, but not in the schizophrenia patients. The subjects carrying the high-risk combination had a smaller posterior hippocampus than those without it for both diagnostic groups. These genotypic combination effects on brain morphology were not explained by the independent effect of each polymorphism. These findings suggest the effect of gene-gene interaction between the DRD3 and BDNF variations on brain morphology in midline and medial temporal lobe structures, but do not support its specific role in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 192 | Zh Nevrol Psikhiatr Im S S Korsakova 2008 -1 108: 62-9 |
| PMID | 18454098 |
| Title | [Investigation of association of the brain-derived neurotrophic factor (BDNF) and a serotonin receptor 2A (5-HTR2A) genes with voluntary and involuntary attention in schizophrenia]. |
| Abstract | To investigate the effect of Val66Met BDNF and 5-HTR2A T102C polymorphisms on the characteristics of voluntary and involuntary visual attention, 89 patients with schizophrenia, 91 their well relatives and 163 controls have been studied. Attention was assessed using a modified version of the Munsterberg test. The significant interaction effect of the BDNF, 5-HTR2A and diagnosis on attention characteristics was found (p=0,04). Carriers of the Val/Val genotype demonstrated higher scores of both voluntary and involuntary attention and those with the A1 (T) allele needed more time for the performance of the test. The combination of the A1 allele with a Met BDNF allele was associated with lower scores of voluntary attention and higher scores of involuntary attention. The study confirmed the impairment of selective attention in patients with schizophrenia and their relatives while any pathological changes in involuntary attention were not observed. The effect of genotypes was presented irrespective of diagnostic group studied. The data obtained suggest that carriers of the Val/Val genotype are able to allocate more attentional resources to process external stimuli. At the same time, the possibility that this polymorphism is likely associated with specific visual-spatial abilities than with attention as such or general cognitive resources can not be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 193 | Brain Res. 2008 May 1211: 37-43 |
| PMID | 18433734 |
| Title | Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. |
| Abstract | Antidepressant treatments have been proposed to produce their therapeutic effects, in part, through increasing neurotrophin levels in the brain. The current experiments investigated the effects of acute and chronic treatment with different pharmacologic and somatic antidepressant treatments on protein levels of BDNF in several brain regions associated with depression in the rat. Repeated applications (10 days) of electroconvulsive shock (ECS), but not a single treatment (1 day), produced 40-100% increases of BDNF protein in the hippocampus, frontal cortex, amygdala, and brainstem. Chronic (21 days), but not acute (1 day), treatment with the tricyclic antidepressant (TCA) desipramine (10 mg/kg), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg), and the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg) increased BDNF protein levels in the frontal cortex (10-30%), but not in the hippocampus, amygdala, olfactory bulb, and brain stem. To determine whether the regulation of BDNF was unique to antidepressant treatments, drugs used to treat schizophrenia and anxiety were also studied. Chronic administration of the typical antipsychotic haloperidol (1 mg/kg) and the atypical antipsychotic clozapine (20 mg/kg) increased BDNF levels by only 8-10% in the frontal cortex. Haloperidol also elevated BDNF levels in the amygdala, while clozapine decreased BDNF in the olfactory bulb. Acute or chronic treatment with the benzodiazepine chlordiazepoxide (10 mg/kg) did not alter BDNF levels. These results suggest that diverse pharmacologic and somatic antidepressant treatments, as well as antipsychotics, increase levels of BDNF protein in the frontal cortex, even though they have different mechanisms of action at neurotransmitter systems. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 194 | Pharmacogenet. Genomics 2008 Jun 18: 449-57 |
| PMID | 18408624 |
| Title | BDNF gene is a genetic risk factor for schizophrenia and is related to the chlorpromazine-induced extrapyramidal syndrome in the Chinese population. |
| Abstract | Brain-derived neurotrophic factor (BDNF) belongs to a family of the neurotrophin, which plays important roles in the neurodevelopment of dopaminergic-related systems and interacts with meso-limbic dopaminergic systems involved in the therapeutic response to antipsychotics. Functional experiments have suggested that BDNF may be involved in the etiology of schizophrenia. In this study, we genotyped two important functional polymorphisms in the BDNF gene using a sample of Han Chinese patients consisting of 340 schizophrenic patients and 343 healthy controls. We found a statistical difference in the 232-bp allele distribution of the BDNF gene (GT)n dinucleotide repeat polymorphism between the schizophrenic patients and controls. In early onset patients, the 234-bp allele had a risk role. For the chlorpromazine-induced extrapyramidal syndrome, the 230-bp allele and the 234-bp allele acted in opposite directions, that is, patients with the 230-bp allele of the (GT)n polymorphism exhibited a lower degree of induced extrapyramidal syndrome. Haplotype-based analysis also revealed a very important risk haplotype (P=0.0000226546). These findings suggest that BDNF plays an important role in the susceptibility to schizophrenia and that the (GT)n repeat polymorphism of the BDNF gene may be an independent contributor to the chlorpromazine treatment-sensitive form of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 195 | Hippocampus 2008 -1 18: 655-67 |
| PMID | 18398848 |
| Title | Combined neonatal stress and young-adult glucocorticoid stimulation in rats reduce BDNF expression in hippocampus: effects on learning and memory. |
| Abstract | Epidemiological studies suggest that multiple developmental disruptions are involved in the etiology of psychiatric illnesses including schizophrenia. In addition, altered expression of brain-derived neurotrophic factor (BDNF) has been implicated in these illnesses. In the present study, we examined the combined long-term effect of an early stress, in the form of maternal deprivation, and a later stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone, on BDNF expression in the hippocampus of rats. To assess whether there were behavioral effects, which may correlate with the BDNF changes, learning and memory was tested in the Y-maze test for short term spatial memory, the Morris water maze for long-term spatial memory, and the T-maze test for working memory. Four groups of rats received either no stress, maternal deprivation, corticosterone treatment, or both. Dorsal hippocampus sections obtained from parallel groups were used for BDNF mRNA in situ hybridization. Rats which had undergone both maternal deprivation and corticosterone treatment displayed a unique and significant 25-35% reduction of BDNF expression in the dentate gyrus (DG), and similar trends in the CA1 and CA3 regions of the hippocampus. These "two-hit" animals exhibited a learning delay in the Morris water maze test, a marked deficit in the Y-maze, but little change in the T-maze test. However, some aspects of cognition were also altered in rats with either maternal deprivation or corticosterone treatment. This study demonstrates a persistent effect of two developmental disruptions on BDNF expression in the hippocampus, with parallel, but not completely correlative changes in learning and memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 196 | Methods Mol. Biol. 2008 -1 448: 187-212 |
| PMID | 18370235 |
| Title | Epigenetic alterations of the dopaminergic system in major psychiatric disorders. |
| Abstract | Although there is evidence to link schizophrenia (SCZ) and bipolar disorder (BD) to genetic and environmental factors, specific individual or groups of genes/factors causative of the disease have been elusive to the research community. An understanding of the molecular aberrations that cause these mental illnesses requires comprehensive approaches that examine both genetic and epigenetic factors. Because of the overwhelming evidence for the role of environmental factors in the disease presentation, our initial approach involved deciphering how epigenetic changes resulting from promoter DNA methylation affect gene expression in SCZ and BD. Apparently, the central reversible but covalent epigenetic modification to DNA is derived from methylation of the cytosine residues that is potentially heritable and can affect gene expression and downstream activities. Environmental factors can influence DNA methylation patterns and hence alter gene expression. Such changes can be especially problematic in individuals with genetic susceptibilities to specific diseases. Recent reports from our laboratory provided compelling evidence that both hyper- and hypo-DNA methylation changes of the regulatory regions play critical roles in defining the altered functionality of genes in major psychiatric disorders such as SCZ and BD. In this chapter, we outline the technical details of the methods that could help to expand this line of research to assist with compiling the differential methylation-mediated epigenetic alterations that are responsible for the pathogenesis of SCZ, BD, and other mental diseases. We use the genes of the extended dopaminergic (DAergic) system such as membrane-bound catechol-O-methyltransferase (MB-COMT), monoamine oxidase A (MAOA), dopamine transporter 1 (DAT1), tyrosine hydroxylase (TH), dopamine (DA) receptors1 and 2 (DRD1/2), and related genes (e.g., reelin [RELN] and brain-derived neurotrophic factor [BDNF]) to illustrate the associations between differential promoter DNA methylations and disease phenotype. It is our hope that comprehensive analyses of the DAergic system as the prototype could provide the impetus and molecular basis to uncover early markers for diagnosis, help in the understanding of differences in disease severity in individuals with similar or identical genetic makeup, and assist with the identification of novel targets for therapeutic applications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 197 | PLoS ONE 2008 -1 3: e1784 |
| PMID | 18335055 |
| Title | Decreased expression of Sprouty2 in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder: a correlation with BDNF expression. |
| Abstract | Current theories on the pathophysiology of schizophrenia suggest altered brain plasticity such as decreased neural proliferation and migration, delayed myelination, and abnormal synaptic modeling, in the brain of subjects with schizophrenia. Though functional alterations in BDNF, which plays important role in neuroplasticity, are implicated in many abnormalities found in schizophrenia, the regulatory mechanism(s) involved in the abnormal signaling of BDNF in schizophrenia is not clear. The present study investigated whether Sprouty2, a regulator of growth factor signaling, is abnormally expressed in schizophrenia, and is associated with the changes in BDNF mRNA in this disorder. The potential effect of antipsychotic drugs on Sprouty2 expression was tested in adult rats. Sprouty2 and BDNF gene expression were analyzed in dorsolateral prefrontal cortex samples from the Stanley Array Collection. Quantitative real-time PCR analysis of RNA in 100 individuals (35 with schizophrenia, 31 with bipolar disorder, and 34 psychiatrically normal controls) showed significantly decreased expression of Sprouty2 and BDNF in both schizophrenia and bipolar disorder. Moreover, a significant correlation between these two genes existed in control, schizophrenia and bipolar subjects. Long-term treatment with antipsychotic drugs, haloperidol and olanzapine, showed differential effects on both Sprouty2 and BDNF mRNA and protein levels in the frontal cortex of rats. These findings demonstrating decreased expression of Sprouty2 associated with changes in BDNF, suggest the possibility that these decreases are secondary to treatment rather than to factors that are significant in the disease process of either schizophrenia and/or bipolar disorder. Further exploration of Sprouty2-related signal transduction pathways may be helpful to design novel treatment strategies for these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 198 | Curr Opin Psychiatry 2008 Mar 21: 161-7 |
| PMID | 18332664 |
| Title | Genes and structural brain imaging in schizophrenia. |
| Abstract | schizophrenia is a complex genetic disorder, caused by multiple genetic and environmental factors. Recently, studies have focused on testing specific genetic markers in a known candidate gene for association with endophenotypes. These are measurable characteristics of a disorder that are assumed to be closer to the action of the gene, resulting in higher genetic signal-to-noise ratios. Structural brain parameters have been shown to be useful endophenotypes for studies in psychiatric illnesses. After reviewing the available studies on the influence of genotype on brain volume in schizophrenia, it is evident that the BDNF and COMT genes are clearly favourites for genetic imaging studies. Results from these studies seem to be quite consistent, with the same associated alleles and direction of brain volume changes. The most frequently investigated polymorphisms suggest that sample sizes of approximately 50-100 patients are sufficient to report consistent findings. Considering the ongoing discussion about the sample size necessary to detect significant associations, however, larger sample sizes are needed. There is sufficient evidence to defend the use of structural neuroimaging as an endophenotype to investigate a complex phenotype such as schizophrenia despite the notion that, so far, no single causal pathway emerges from these studies. Replication studies and larger numbers of patients are essential in this respect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 199 | Am. J. Hum. Genet. 2008 Mar 82: 696-711 |
| PMID | 18319075 |
| Title | Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. |
| Abstract | Epigenetic misregulation is consistent with various non-Mendelian features of schizophrenia and bipolar disorder. To date, however, few studies have investigated the role of DNA methylation in major psychosis, and none have taken a genome-wide epigenomic approach. In this study we used CpG-island microarrays to identify DNA-methylation changes in the frontal cortex and germline associated with schizophrenia and bipolar disorder. In the frontal cortex we find evidence for psychosis-associated DNA-methylation differences in numerous loci, including several involved in glutamatergic and GABAergic neurotransmission, brain development, and other processes functionally linked to disease etiology. DNA-methylation changes in a significant proportion of these loci correspond to reported changes of steady-state mRNA level associated with psychosis. Gene-ontology analysis highlighted epigenetic disruption to loci involved in mitochondrial function, brain development, and stress response. Methylome network analysis uncovered decreased epigenetic modularity in both the brain and the germline of affected individuals, suggesting that systemic epigenetic dysfunction may be associated with major psychosis. We also report evidence for a strong correlation between DNA methylation in the MEK1 gene promoter region and lifetime antipsychotic use in schizophrenia patients. Finally, we observe that frontal-cortex DNA methylation in the BDNF gene is correlated with genotype at a nearby nonsynonymous SNP that has been previously associated with major psychosis. Our data are consistent with the epigenetic theory of major psychosis and suggest that DNA-methylation changes are important to the etiology of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 200 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Sep 147B: 814-21 |
| PMID | 18205169 |
| Title | Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis. |
| Abstract | Depression is common and a major cause of morbidity and mortality and is also known to have serious effects on quality of life. Both clinical and pharmacologic studies have implicated the role of brain-derived neurotrophic factor (BDNF) as a susceptibility locus for the development of mental illness, including depression, bipolar disorder, and schizophrenia. Population-based genetic studies have examined the association between BDNF and a variety of depression outcomes, but the results have not clearly established the role of BDNF in the development of this complex disorder. The aim of this study was to test for associations between two genetic variants in BDNF, Val66Met (rs6265) and -270 C > T, and depression measured in two independent samples. In this analysis we included 3,548 participants from British Women's Heart and Health Study (BWHHS) and 6,836 mothers from Avon Longitudinal Study of Parents and Children (ALSPAC) who had complete data on genotype and depression outcomes. We did not detect any strong evidence of associations between any of the two polymorphisms and indicators of depression in either BWHHS or ALSPAC samples. Further, we carried out a systematic review and meta-analysis of all association studies of these two BDNF polymorphisms and depression. The meta-analysis of Val66Met in depression obtained an overall summary OR of 1.06 (95% CI: 0.89-1.26, P = 0.537) comparing MM with VV genotypes and an OR of 0.97 (95% CI: 0.89-1.05, P = 0.403) comparing MV with VV genotypes. Our findings suggest that BDNF genotype does not exert a major influence on the development of depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 201 | Schizophr. Res. 2008 Mar 100: 325-33 |
| PMID | 18187310 |
| Title | Increased truncated TrkB receptor expression and decreased BDNF/TrkB signaling in the frontal cortex of reeler mouse model of schizophrenia. |
| Abstract | Heterozygous reeler mouse has been used as an animal model for schizophrenia based on several neuropathological and behavioral abnormalities homologous to schizophrenia. Since some of these abnormalities are primarily associated with altered BDNF signaling we investigated BDNF signaling in the frontal cortex of reeler mice in order to shed some light on the neuropathology and treatment of schizophrenia. BDNF, TrkB receptor isoforms (full-length and truncated), reelin, GAD67, GAD65, p75NTR, and NRH-2 levels were measured in the frontal cortex samples from reeler (B6C3Fe a/a-Reln rl/+) and wild-type (WT) mice. BDNF protein levels were significantly higher in reeler compared to WT. The protein levels of full-length TrkB were not altered in reeler mice, but both mRNA and protein levels of truncated TrkB were significantly higher. Protein analysis showed that TrkB activity, as indicated by the levels of tyrosine-phosphorylated TrkB, was lower in reeler mice. We did not find any significant change in the levels of p75NTR and NRH-2, regulatory proteins of TrkB signaling, in the reeler mice. Furthermore, we found significant reduction in reelin and GAD67 expressions, but not GAD65 expression in reeler compared to WT mice. In summary, molecular processes associated with defective BDNF signaling in reeler mice provide new therapeutic targets for neuroprotective pharmacotherapy for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 202 | Neuropsychopharmacology 2008 Jul 33: 1942-51 |
| PMID | 17805306 |
| Title | Erythropoietin prevents haloperidol treatment-induced neuronal apoptosis through regulation of BDNF. |
| Abstract | Functional alterations in the neurotrophin, brain-derived neurotrophic factor (BDNF) have recently been implicated in the pathophysiology of schizophrenia. Furthermore, animal studies have indicated that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. For example, our previous studies in rats indicated that chronic treatment with the conventional antipsychotic, haloperidol, was associated with decreases in BDNF (and other neurotrophins) in the brain as well as deficits in cognitive function (an especially important consideration for the therapeutics of schizophrenia). Additional studies indicate that haloperidol has other deleterious effects on the brain (eg increased apoptosis). Despite such limitations, haloperidol remains one of the more commonly prescribed antipsychotic agents worldwide due to its efficacy for the positive symptoms of schizophrenia and its low cost. Interestingly, the hematopoietic hormone, erythropoietin, in its recombinant human form rhEPO has been reported to increase the expression of BDNF in neuronal tissues and to have neuroprotective effects. Such observations provided the impetus for us to investigate in the present study whether co-treatment of rhEPO with haloperidol could sustain the normal levels of BDNF in vivo in rats and in vitro in cortical neuronal cultures and further, whether BDNF could prevent haloperidol-induced apoptosis through the regulation of key apoptotic/antiapoptotic markers. The results indicated that rhEPO prevented the haloperidol-induced reduction in BDNF in both in vivo and in vitro experimental conditions. The sustained levels of BDNF in rats with rhEPO prevented the haloperidol-induced increase in caspase-3 (p<0.05) and decrease in Bcl-xl (p<0.01) protein levels. Similarly, in vitro experiments showed that rhEPO prevented (p<0.001) the haloperidol-induced neuronal cell death as well as the decrease in Bcl-xl levels (p<0.01). These findings may have significant implications for the development of neuroprotective strategies to improve clinical outcomes when antipsychotic drugs are used chronically. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 203 | Pharmacogenet. Genomics 2008 Jun 18: 449-57 |
| PMID | 18408624 |
| Title | BDNF gene is a genetic risk factor for schizophrenia and is related to the chlorpromazine-induced extrapyramidal syndrome in the Chinese population. |
| Abstract | Brain-derived neurotrophic factor (BDNF) belongs to a family of the neurotrophin, which plays important roles in the neurodevelopment of dopaminergic-related systems and interacts with meso-limbic dopaminergic systems involved in the therapeutic response to antipsychotics. Functional experiments have suggested that BDNF may be involved in the etiology of schizophrenia. In this study, we genotyped two important functional polymorphisms in the BDNF gene using a sample of Han Chinese patients consisting of 340 schizophrenic patients and 343 healthy controls. We found a statistical difference in the 232-bp allele distribution of the BDNF gene (GT)n dinucleotide repeat polymorphism between the schizophrenic patients and controls. In early onset patients, the 234-bp allele had a risk role. For the chlorpromazine-induced extrapyramidal syndrome, the 230-bp allele and the 234-bp allele acted in opposite directions, that is, patients with the 230-bp allele of the (GT)n polymorphism exhibited a lower degree of induced extrapyramidal syndrome. Haplotype-based analysis also revealed a very important risk haplotype (P=0.0000226546). These findings suggest that BDNF plays an important role in the susceptibility to schizophrenia and that the (GT)n repeat polymorphism of the BDNF gene may be an independent contributor to the chlorpromazine treatment-sensitive form of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 204 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Apr 150B: 441-2 |
| PMID | 18535997 |
| Title | Semantic but not phonological verbal fluency associated with BDNF Val66Met polymorphism in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 205 | Zh Nevrol Psikhiatr Im S S Korsakova 2009 -1 109: 50-4 |
| PMID | 20037522 |
| Title | [The role of genotype-environment interactions in the development of symptoms of anxiety and depression related to the disease burden for family]. |
| Abstract | The association of 5-HTTLPR and Val66Met BDNF genotypes with symptoms of anxiety and depression related to stress caused by severe chronic psychiatric disease of a family member has been studied. Genotyping has been conducted in the group of 214 unaffected parents of patients with schizophrenia and 100 healthy age-matched controls. The diplotype Met*ss was associated with higher scores of depressive symptoms as assessed by MMPI in the group of parents but not in the control group. The most marked differences were seen in the subgroup of parents whose children had the greatest severity of symptoms. The results suggest that the interaction of 5-HTT and BDNF genes may moderate the association between objective and subjective burden of disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 206 | Hum Psychopharmacol 2009 Dec 24: 639-45 |
| PMID | 19946939 |
| Title | Associations between plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and negative symptoms or cognitive impairments in early-stage schizophrenia. |
| Abstract | schizophrenic patients demonstrate a variety of cognitive deficits, including attention, executive functions, and working memory, even in the early stage of disease. In the present study, we examined the association between blood levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), or brain-derived neurotrophic factor (BDNF) and scores on the Wisconsin Card Sorting Test (WCST) in patients with early-stage schizophrenia. We also investigated the association between frontal GABA levels using 1H-magnetic resonance spectroscopy (MRS) at 3T and scores on the WCST in the same patients. Blood levels of BDNF and catecholamine metabolites and brain GABA levels using 1H-MRS were measured in 18 schizophrenic patients (nine males, nine females; age range 13-52 year). A significantly positive correlation was observed between plasma MHPG levels and %PEM (rho = -0.686, p = 0.0047). A trend toward negative correlation was found between frontal lobe GABA levels and the per cent of preservation error (%PEM) in the early stage of schizophrenia (rho = -0.420, p = 0.0836). These results suggest that noradrenergic neurons might be involved in neuropsychological functions in early-stage of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 207 | Ann Pharm Fr 2009 Jul 67: 251-5 |
| PMID | 19596098 |
| Title | [Schizophrenia, a neurodevelopmental illness]. |
| Abstract | Developmental anomalies have been identified as risk factors for a future schizophrenic illness: low weight at birth, congenital malformations, delayed motor and social learning. Cognitive deficits and neurological soft signs belong to the indices of the schizophrenic spectrum. Neuroimaging has visualized various structural abnormalities present from the very beginning of schizophrenia. These structural changes may represent an exacerbation of normal neurodevelopmental processes. Moreover, vulnerability genes for schizophrenia are involved at different stages of neurodevelopment: the best studied associations are dysfunctional variants of DISC-1 and neuroregulin-1 genes, the role of other genes (dysbindin, BDNF, reelin...) remaining more widely debated. Lastly, the observation of structural chromosomal anomalies in 15% of patients suffering from schizophrenia (versus 5% of controls), more frequent in early onset schizophrenia (32% of cases) suggests a neurodevelopmental cause. Such a dynamic understanding of schizophrenia is consistent with what we know about cerebral plasticity along the life span. This does not preclude the search for cues of degenerative mechanisms. The issue now is a better characterization of the vulnerable phenotype for screening procedures to be implemented prior to disease onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 208 | J Neuropsychiatry Clin Neurosci 2009 -1 21: 30-7 |
| PMID | 19359449 |
| Title | Brain-derived neurotrophic factor Val66Met polymorphism: association with psychopathological symptoms of schizophrenia? |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been proposed as a risk factor for schizophrenia, but no consistent association between BDNF Val66Met polymorphism and schizophrenia has been established. Therefore, analyses with larger sample sizes and better methodology are needed. To examine whether BDNF Val66Met polymorphism is associated with schizophrenia, schizophrenia patients (n=251) and healthy volunteers (n=284) were recruited for a case-control analysis. Pretreatment psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 125 hospitalized schizophrenia patients who were drug-free or drug-naive. Genotyping was performed using polymerase chain reaction, restriction fragment length polymorphism (RFLP), and direct screening techniques. With the exception of nominally significant associations between BDNF Val66Met variation and PANSS total, negative, or general scores, no association between the BDNF Val66Met polymorphism and schizophrenia was found. However, this polymorphism may reduce psychopathology, in particular negative symptoms, in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 209 | Br J Psychiatry 2009 Apr 194: 313-8 |
| PMID | 19336781 |
| Title | Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes. |
| Abstract | Allelic variation in the gene encoding brain-derived neurotrophic factor (BDNF) has been associated with affective disorders, but generally not schizophrenia. Brain-derived neurotrophic factor variants may help clarify the status of schizoaffective disorder. To test the hypothesis that BDNF haplotypes are associated with psychiatric illness marked by a prominent affective component. Frequencies of a 5-marker BDNF haplotype were examined in 600 White participants across four diagnostic categories and healthy controls. Individuals with schizoaffective disorder and other affective disorders were significantly more likely to carry two copies of the most common BDNF haplotype (containing the valine allele of the Val66Met polymorphism) compared with healthy volunteers. Moreover, when compared with people with schizophrenia, individuals with schizoaffective disorder were significantly more likely to carry two copies of the common haplotype. To our knowledge, this is the first candidate gene study to demonstrate association with schizoaffective disorder but not schizophrenia. Variation in the BDNF gene may be associated with the clinical phenotype of affective dysregulation across several DSM-IV diagnostic categories. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 210 | Proc. Natl. Acad. Sci. U.S.A. 2009 Apr 106: 5942-7 |
| PMID | 19293383 |
| Title | Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex. |
| Abstract | Transcription of BDNF is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the BDNF exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated BDNF expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven BDNF transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent BDNF transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 211 | Eur Neuropsychopharmacol 2009 May 19: 317-28 |
| PMID | 19217756 |
| Title | Genetic study of BDNF, DRD3, and their interaction in tardive dyskinesia. |
| Abstract | Tardive dyskinesia (TD) is a neuroleptic-induced movement disorder. Its pathophysiology is unclear. The most consistent genetic findings have shown an association with the Ser9Gly polymorphism of the DRD3 gene. However, only few polymorphisms within DRD3 has been tested, and a comprehensive examination of DRD3 in TD is still lacking. Further, brain-derived neurotrophic factor (BDNF), a neuronal growth and survival peptide, regulates DRD3 expression and may be involved in the neuronal degeneration observed in TD. In the present study, we investigated 15 tag DRD3 polymorphisms and four tag BDNF polymorphisms for association with TD in our sample of Caucasian schizophrenia patients (N=171). While BDNF markers showed no association, a haplotype containing rs3732782, rs905568, and rs7620754 in the 5' region of DRD3 was associated with TD diagnosis (p[10,000 permutations]=0.007). We also found evidence of interaction between BDNF and DRD3 polymorphisms. Further studies are needed to confirm these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 212 | J Psychiatr Res 2009 Jan 43: 274-81 |
| PMID | 18656896 |
| Title | Differential effects of ziprasidone and haloperidol on immobilization stress-induced mRNA BDNF expression in the hippocampus and neocortex of rats. |
| Abstract | Recent in vivo and in vitro experiments have demonstrated that second-generation antipsychotic drugs (SGAs) might have neuroprotective effects. Ziprasidone is a SGA that is efficacious in the treatment of schizophrenia. In this study, we sought to analyze the effects of ziprasidone on the expression of the neuroprotective protein brain-derived neurotrophic factor (BDNF) in the rat hippocampus and neocortex, with or without immobilization stress. The effect of ziprasidone (2.5mg/kg) on the expression of BDNF mRNA was determined by in situ hybridization in tissue sections from the rat hippocampus and neocortex. Haloperidol (1.0mg/kg) was used for comparison. Haloperidol strongly decreased the expression of BDNF mRNA in both the hippocampal and cortical regions, with or without immobilization stress (p<0.01). In contrast, the administration of ziprasidone significantly attenuated the immobilization stress-induced decrease in BDNF mRNA expression in the rat hippocampus and neocortex (p<0.01). Ziprasidone exhibited differential effects on BDNF mRNA expression in the rat hippocampus and neocortex. These results suggest that ziprasidone might have a neuroprotective effect by recovering stress-induced decreases in BDNF mRNA expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 213 | Hum Psychopharmacol 2009 Dec 24: 639-45 |
| PMID | 19946939 |
| Title | Associations between plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and negative symptoms or cognitive impairments in early-stage schizophrenia. |
| Abstract | schizophrenic patients demonstrate a variety of cognitive deficits, including attention, executive functions, and working memory, even in the early stage of disease. In the present study, we examined the association between blood levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), or brain-derived neurotrophic factor (BDNF) and scores on the Wisconsin Card Sorting Test (WCST) in patients with early-stage schizophrenia. We also investigated the association between frontal GABA levels using 1H-magnetic resonance spectroscopy (MRS) at 3T and scores on the WCST in the same patients. Blood levels of BDNF and catecholamine metabolites and brain GABA levels using 1H-MRS were measured in 18 schizophrenic patients (nine males, nine females; age range 13-52 year). A significantly positive correlation was observed between plasma MHPG levels and %PEM (rho = -0.686, p = 0.0047). A trend toward negative correlation was found between frontal lobe GABA levels and the per cent of preservation error (%PEM) in the early stage of schizophrenia (rho = -0.420, p = 0.0836). These results suggest that noradrenergic neurons might be involved in neuropsychological functions in early-stage of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 214 | Ann Pharm Fr 2009 Jul 67: 251-5 |
| PMID | 19596098 |
| Title | [Schizophrenia, a neurodevelopmental illness]. |
| Abstract | Developmental anomalies have been identified as risk factors for a future schizophrenic illness: low weight at birth, congenital malformations, delayed motor and social learning. Cognitive deficits and neurological soft signs belong to the indices of the schizophrenic spectrum. Neuroimaging has visualized various structural abnormalities present from the very beginning of schizophrenia. These structural changes may represent an exacerbation of normal neurodevelopmental processes. Moreover, vulnerability genes for schizophrenia are involved at different stages of neurodevelopment: the best studied associations are dysfunctional variants of DISC-1 and neuroregulin-1 genes, the role of other genes (dysbindin, BDNF, reelin...) remaining more widely debated. Lastly, the observation of structural chromosomal anomalies in 15% of patients suffering from schizophrenia (versus 5% of controls), more frequent in early onset schizophrenia (32% of cases) suggests a neurodevelopmental cause. Such a dynamic understanding of schizophrenia is consistent with what we know about cerebral plasticity along the life span. This does not preclude the search for cues of degenerative mechanisms. The issue now is a better characterization of the vulnerable phenotype for screening procedures to be implemented prior to disease onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 215 | Acta Neuropsychiatr 2009 Jun 21: 109-20 |
| PMID | 26953749 |
| Title | Schizophrenia: genetics, prevention and rehabilitation. |
| Abstract | Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Medline search of relevant studies published between 1990 and 2008. In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 216 | Neuroscience 2009 Nov 164: 331-43 |
| PMID | 19358880 |
| Title | The genetics of bipolar disorder. |
| Abstract | Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 217 | Proc. Natl. Acad. Sci. U.S.A. 2009 Dec 106: 21377-82 |
| PMID | 19948956 |
| Title | Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth. |
| Abstract | Although the perturbation of either the dopaminergic system or brain-derived neurotrophic factor (BDNF) levels has been linked to important neurological and neuropsychiatric disorders, there is no known signaling pathway linking these two major players. We found that the exclusive stimulation of the dopamine D1-D2 receptor heteromer, which we identified in striatal neurons and adult rat brain by using confocal FRET, led to the activation of a signaling cascade that links dopamine signaling to BDNF production and neuronal growth through a cascade of four steps: (i) mobilization of intracellular calcium through Gq, phospholipase C, and inositol trisphosphate, (ii) rapid activation of cytosolic and nuclear calcium/calmodulin-dependent kinase IIalpha, (iii) increased BDNF expression, and (iv) accelerated morphological maturation and differentiation of striatal neurons, marked by increased microtubule-associated protein 2 production. These effects, although robust in striatal neurons from D5(-/-) mice, were absent in neurons from D1(-/-) mice. We also demonstrated that this signaling cascade was activated in adult rat brain, although with regional specificity, being largely limited to the nucleus accumbens. This dopaminergic pathway regulating neuronal growth and maturation through BDNF may have considerable significance in disorders such as drug addiction, schizophrenia, and depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 218 | Psychiatriki 2009 Oct 20: 297-304 |
| PMID | 22218230 |
| Title | Association of serum BDNF and val66met polymorphism of the brain-derived neurotrophic factor in a sample of first psychotic episode patients. |
| Abstract | Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene have been indicated to be associated with schizophrenia. Previous studies have suggested that val66met polymorphism may increase the risk for schizophrenia, although other studies have not confirmed this association. Decreased BDNF levels in the brain and the serum of patients with psychotic disorders have been reported in first episode psychotic (FEP) patients. In our study we investigated the potential genetic association of this polymorphism with schizophrenia in a sample of 38 FEP patients with schizophrenia compared with a sample of 21 normal controls. Furthermore, we assessed serum BDNF levels and investigated whether there was an association between this polymorphism and alterations of serum BDNF levels between the investigated groups. There was a significant difference in genotyped frequencies between cases and controls (p=0.030). The homozygous carriers Met/Met were over-represented in the schizophrenia group (13/31, 41.9%), compared to controls (2/19, 10.5%). The serum BDNF levels in the sample of FEP patients was significantly reduced compared to controls (18.87±8.23 ng/mL vs 29.2±7.73ng/mL, U=140, p=0.0). No association was found between alterations of serum BDNF levels and Val66Met polymorphism in the group of patients (p=0.198). Negative correlations were shown between serum BDNF levels of the patients and the PANSS Negative subscale scores (p=0.015). There was found no significant difference between genotypes and memory scores in the sample of patients. Our findings indicate that serum BDNF levels at the onset of schizophrenia and BDNF Val66Met variant may be susceptibility risk factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 219 | Psychopharmacology (Berl.) 2009 Dec 207: 375-80 |
| PMID | 19787338 |
| Title | Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes. |
| Abstract | There is accumulating evidence that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of patients with schizophrenia. Clinical studies show reductions in BDNF in schizophrenic patients treated with first generation antipsychotics or second generation antipsychotics. However, there have been few systematic studies to examine the relationship between BDNF levels and psychopathology in first-episode and drug-naïve patients with schizophrenia. Serum BDNF levels were determined using enzyme-linked-immunosorbent assay (ELISA) in the serum of 88 never-medicated first-episode and 90 healthy controls subjects matched for age and gender. The schizophrenia symptomatology and the depressive symptoms were assessed by the positive and negative syndrome scale (PANSS) and the Hamilton rating (HAMD) scale for depression. The results showed that BDNF levels were significantly lower in first-episode patients with schizophrenia than in healthy control subjects (9.0 +/- 4.2 ng/ml vs 12.1 +/- 2.2 ng/ml; F = 37.6; df = 1, 176; p < 0.0001). A significant positive correlation between BDNF levels and PANSS positive subscore was observed (r = 0.29; df = 88; p = 0.008). Furthermore, higher BDNF levels were observed in patients with paranoid subtype of schizophrenia. However, no significant correlation between BDNF and HAMD total score was found. Low BDNF levels at the onset of psychosis suggest that it may contribute to the pathogenesis of schizophrenia and perhaps, could be a candidate biological marker for positive symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 220 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Nov 33: 1508-12 |
| PMID | 19720106 |
| Title | Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics. |
| Abstract | Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Decreased BDNF levels have been found in the serum of schizophrenic patients with mixed results. In the present study, we assessed serum BDNF levels in a large group of 364 schizophrenic patients (157 on clozapine, 89 on risperidone and 118 on typical antipsychotics), compared to 323 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were significantly lower in chronic patients with schizophrenia than in healthy control subjects (9.9+/-2.0 ng/ml vs.11.9+/-2.3 ng/ml, p<0.0001). Lower BDNF levels were observed in patients treated with risperidone (9.3+/-2.3 ng/ml) compared to those with clozapine (10.2+/-2.0 ng/ml, p<0.001) and typical antipsychotics (10.0+/-2.1 ng/ml, p<0.01). Furthermore, a stepwise multiple regression analysis identified types of antipsychotic drugs (beta=-0.37, t=-3.15, p=0.001) and BDNF levels (beta=-0.26, t=-2.51, p=0.014) as the influencing factor for the positive symptom subscore of PANSS. In addition, there was a sex difference in BDNF levels in patients with schizophrenia (9.7+/-1.9 ng/ml for males vs.10.4+/-2.1 ng/ml for female, p<0.005), but not in normal controls. Our findings indicated decreased BDNF serum levels in chronic patients with schizophrenia, which may be related to clinical phenotypes, including gender, antipsychotic treatment and the severity of psychotic symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 221 | Psychol Med 2009 Nov 39: 1783-97 |
| PMID | 19573260 |
| Title | The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis. |
| Abstract | Morphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis. A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family. The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes. Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 222 | Pharmacogenomics 2009 Jun 10: 989-95 |
| PMID | 19530966 |
| Title | Development of a new genotyping assay for detection of the BDNF Val66Met polymorphism using melting-curve analysis. |
| Abstract | Brain-derived neurotrophic factor (BDNF) plays a critical role in the growth, differentiation and survival of neurons in the CNS. Recent research has suggested that BDNF may be implicated in the etiology of mood disorders and schizophrenia, as well as in the therapeutic action of some drugs, such as antidepressants and antipsychotics. This study aimed to develop a simple, fast and accurate new method for detecting the Val66Met polymorphism of the BDNF gene in schizophrenia patients using melting-curve analysis and a DNA-specific dye, SYBR Green I. A group of 30 schizophrenia patients were analyzed to detect the BDNF Val66Met polymorphism (rs6265) using the new genotyping method based on the analysis of fluorescence melting curves of PCR products that were labeled with SYBR Green I. The genotype results were confirmed for all 30 samples using the specific BDNF TaqMan allele discrimination assay. This new method allows the analysis of both alleles in the same reaction tube using SYBR Green I, with no need for additional steps. The addition of a GC clamp makes this method universally applicable, since the melting temperature of one allele can be adjusted as necessary to give the distinctive separation of melting curves. Therefore, this new method is simple, fast and accurate for determining the presence of the BDNF Val66Met polymorphism. It may also be useful for the analysis of other SNPs in pharmacogenetic studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 223 | Turk Psikiyatri Derg 2009 -1 20: 175-82 |
| PMID | 19504368 |
| Title | [New pharmacological approaches to the treatment of schizophrenia]. |
| Abstract | schizophrenia is a serious mental disorder with a challenging rational pharmacotherapy. Neurochemical transmission in the dopaminergic system, especially via D2 receptors, and related changes in postsynaptic signal transduction are very important in both the formation of schizophrenia and current pharmacotherapeutic treatment with antipsychotic drugs. Blocking the serotonergic 5-HT2A and 5-HT2C receptors is growing growing importance with regard to the action mechanisms of new generation antipsychotic medications. Recent preclinical and clinical data show that dysfunction of central neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurophin-3 (NT-3) might contribute to impaired brain development and neuroplasticity, leading to schizophrenia. In addition, some recent studies suggest that there is an important relationship between alcohol and substance addiction, and schizophrenia. There is also some preclinical data indicating that the central nitrergic system and agmatine(3/4)a biologically active agent produced after decarboxylation of arginine(3/4)might be interesting and important targets for understanding the etiopathogenesis of schizophrenia and for development of new drugs. Selective dopamine D3 receptor antagonists, specific agonists for metabotropic and NMDA receptors of the glutamatergic system, and nicotinic alpha-7 receptor agonists were reported in preclinical and a limited number of clinical studies as potential new targets for schizophrenia treatment. In this review, new advances in the pharmacotherapy of schizophrenia and possible new targets are discussed in the light of the current literature. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 224 | Basic Clin. Pharmacol. Toxicol. 2009 Aug 105: 113-9 |
| PMID | 19486334 |
| Title | Effects of 4-week treatment with lithium and olanzapine on levels of brain-derived neurotrophic factor, B-cell CLL/lymphoma 2 and phosphorylated cyclic adenosine monophosphate response element-binding protein in the sub-regions of the hippocampus. |
| Abstract | A large body of evidence indicates that lithium, the prototype mood stabilizer in the treatment of bipolar disorder, has diverse neuroprotective and neurotrophic actions, and the actions are associated with its efficacy in treating bipolar disorder. It has been suggested that up-regulation of neurotrophic and neuroprotective factors including brain-derived neurotrophic factor (BDNF) and B-cell CLL/lymphoma 2 (Bcl-2) may underlie these neuroplastic actions of the drug. Olanzapine, an atypical anti-psychotic drug, has been shown to be an effective mood stabilizer. Olanzapine also has neurotrophic and neuroprotective actions, and these actions may underlie the efficacy of the drug for bipolar disorder and schizophrenia. However, the molecular mechanism by which the drug produces the neuroplastic actions is poorly understood. To understand a common molecular mechanism underlying the neuroplastic actions of lithium and olanzapine, we assessed the effect of 4-week lithium and olanzapine treatment on the levels of BDNF, Bcl-2 and cyclic adenosine monophosphate response element-binding protein (CREB), a transcription factor involved in expression of BDNF and Bcl-2, in the dentate gyrus and hippocampal area CA1. Our results show that 4-week treatment with both olanzapine and lithium increases the levels of Bcl-2 and CREB in the dentate gyrus and hippocampal area CA1. Four-week lithium treatment up-regulates BDNF in the dentate gyrus, and 4-week olanzapine treatment marginally did so. Neither drug altered BDNF levels in area CA1. These results suggest that the up-regulation of Bcl-2 and CREB may underlie the neuroplastic actions of olanzapine and lithium. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 225 | Psychiatry Clin. Neurosci. 2009 Aug 63: 433-9 |
| PMID | 19457211 |
| Title | Genetic association of BDNF val66met and GSK-3beta-50T/C polymorphisms with tardive dyskinesia. |
| Abstract | Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD), and a growing body of evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in both the antipsychotic effects and the pathogenesis of TD. BDNF and glycogen synthase kinase (GSK)-3beta are important in neuronal survival, and thus abnormal regulation of BDNF and GSK-3beta may contribute to TD pathophysiology. This study investigated the relationship between two polymorphisms, val66met in the BDNF coding region and -50T/C in the GSK-3beta promoter, and susceptibility to TD among a matched sample of patients having schizophrenia with TD (n = 83), patients with schizophrenia without TD (n = 78), and normal control subjects (n = 93). All subjects were Korean. The BDNF val66met and GSK-3beta-50T/C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses. Polymerase chain reaction analysis revealed no significant difference in the occurrence of the polymorphisms among the TD, non-TD, and control subjects, but a significant interaction was observed among the groups possessing BDNF val allele in compound genotypes (P = 0.001). We found that the schizophrenic subjects with the C/C GSK-3beta genotype, who carry the val allele of the BDNF gene, are expected to have a decreased risk of developing neuroleptic-induced tardive dyskinesia (P < 0.001). Our results demonstrate that the GSK-3beta C/C genotype with the BDNF val allele is associated with patients having schizophrenia without TD. This study also suggests that the BDNF and GSK-3beta gene polymorphisms work in combination, but not individually, in predisposing patients with schizophrenia to TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 226 | Schizophr. Res. 2009 Jul 112: 72-9 |
| PMID | 19406621 |
| Title | BDNF is not associated with schizophrenia: data from a Japanese population study and meta-analysis. |
| Abstract | A variety of evidence suggests brain-derived neurotrophic factor (BDNF) as a candidate gene for schizophrenia, and several genetic studies have shown a significant association between the disease and certain SNPs within BDNF (specifically, Val66Met and C270T). According to a recent study, the functional microsatellite marker BDNF-LCPR (BDNF-linked complex polymorphic region), which affects the expression level of BDNF, is associated with bipolar disorder. The goals of our current study were to 1) evaluate the quality of HapMap-based linkage disequilibrium (LD) tagging of BDNF-LCPR, 2) examine whether these tagging SNPs are associated with schizophrenia in a Japanese population, and 3) conduct a meta-analysis of the two most extensively studied polymorphisms: Val66Met and C270T. We genotyped eight tagging SNPs, including Val66Met and C270T. Our LD evaluation showed that BDNF-LCPR could be represented by these tagging SNPs in controls (with 73.5% allelic coverage). However, the functional A1 allele was not captured due to its low minor allele frequency (2.2%). In a case-control study (1117 schizophrenics and 1102 controls), no association was found in single-marker or multimarker analysis. Moreover, in a meta-analysis, the Val66Met polymorphism was not associated with schizophrenia, whereas C270T showed a trend for association in a fixed model (p=0.036), but not in a random model (p=0.053). From these findings, we conclude that if BDNF is indeed associated with schizophrenia, the A1 allele in BDNF-LCPR would be the most promising candidate. Further LD evaluation, as well as an association study in which BDNF-LCPR is genotyped directly, would be required for a more conclusive result. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 227 | J Psychiatr Res 2009 Sep 43: 1175-84 |
| PMID | 19376528 |
| Title | Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains. |
| Abstract | Several lines of evidence implicate BDNF in the pathophysiology of psychiatric illness. BDNF polymorphisms have also been associated with the risk of schizophrenia and mood disorders. We therefore investigated whether levels of (pro)BDNF and receptor proteins, TrkB and p75, are altered in hippocampus in schizophrenia and mood disorder and whether polymorphisms in each gene influenced protein expression. Formalin-fixed paraffin-embedded hippocampal sections from subjects with schizophrenia, major depressive disorder (MDD), bipolar disorder (BPD) and non-psychiatric controls were obtained from the Stanley Foundation Neuropathology Consortium. (pro)BDNF, TrkB(T1) and p75 protein densities were quantified by immunoautoradiography and DNA extracted from each subject was used to determine the effect of genotype on protein expression. In MDD, reductions in (pro)BDNF were seen in all layers of the right but not the left hippocampus with no changes in the dentate gyrus. The pattern was similar but less marked for BPD. In addition, BPD but not MDD patients, had bilateral reductions in p75 in hippocampal layers but not in dentate gyrus. No changes in TrkB(T1) density were seen in any diagnosis. These findings suggest MDD and BPD may share impairment in (pro)BDNF expression. However, BPD may involve impairments of both (pro)BDNF and p75 receptor, whereas MDD may involve impaired (pro)BDNF alone. Moreover, the lateralisation of changes may indicate a role of asymmetry in vulnerability to MDD. Hippocampal (pro)BDNF and receptor levels were also affected by genotype, suggesting that allelic variations are important in the hippocampal abnormalities seen in these psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 228 | Biol. Psychiatry 2009 Sep 66: 549-53 |
| PMID | 19368899 |
| Title | Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? |
| Abstract | Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and plasticity; decreased BDNF functioning may contribute to the pathogenesis of schizophrenia. However, BDNF levels are not static; in animal experiments, brain BDNF increases during spatial learning, and in clinical depression, successful antidepressant treatment raises serum BDNF. We asked: would neuroplasticity-based cognitive training in schizophrenia result in increased serum BDNF? Fifty-six schizophrenia outpatients and 16 matched healthy comparison subjects were assessed on baseline cognitive performance and serum BDNF. schizophrenia subjects were randomly assigned to either 50 hours (10 weeks) of computerized auditory training or a computer game control condition, followed by reassessment of cognition and serum BDNF. At baseline, schizophrenia participants had significantly lower-than-normal serum BDNF. schizophrenia subjects who engaged in computerized cognitive training designed to improve auditory processing showed significant cognitive gains and a significant increase in serum BDNF compared with subjects who played computer games. This increase was evident after 2 weeks of training, and after 10 weeks in the active condition, subjects "normalized" their mean serum BDNF levels, whereas the control group showed no change. In the active condition, change in BDNF was significantly associated with improved quality of life. Serum BDNF levels are significantly increased in clinically stable, chronically ill schizophrenia subjects after neuroplasticity-based cognitive training, but not after computer games. Serum BDNF levels may serve as a peripheral biomarker for the effects of intensive cognitive training and may provide a useful tool for the evaluation of cognitive enhancement methods in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 229 | Neuroimage 2009 Aug 47: 213-9 |
| PMID | 19341802 |
| Title | Local and covariate-modulated false discovery rates applied in neuroimaging. |
| Abstract | False discovery rate (FDR) control has become a standard technique in neuroimaging. Recent work has shown that a finer grained estimate of the FDR is obtained by estimating, at a specific value of the test statistic, the scaled ratio of the null density to the observed density of the test statistic. The method can be extended by allowing an external covariate, also measured on the points where the hypothesis was tested, to modulate estimation of this local FDR. The current work, in addition to demonstrating these methods by re-analyzing results from two previously published investigations of cortical thickness, presents a method to test if the covariate modulation differs significantly from chance. The first study compared schizophrenia patients to healthy controls and the second compared genotypes of the -633 T/A polymorphism of the gene coding the brain derived neurotrophic factor (BDNF) protein in a subset of the subjects from the case/control study. Local FDR estimates increased findings over FDR in both studies. Using p-values from the case/control study to modulate local FDR estimation in the BDNF study further increased findings. The relationship between case/control related and BDNF related cortical thickness variation was found to be highly significant, providing support for this gene's involvement in the etiology of the disease. The increased statistical precision from more accurate models of the distribution of the test statistic demonstrates the potential of these methods for neuroimaging and suggests the possibility to test novel hypothesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 230 | Neuropsychobiology 2009 -1 59: 51-8 |
| PMID | 19270464 |
| Title | Increased plasma brain-derived neurotropic factor, not nerve growth factor-Beta, in schizophrenia patients with better response to risperidone treatment. |
| Abstract | Some neurotropins, including brain-derived neurotropic factor (BDNF) or nerve growth factor-beta (beta-NGF), play important roles in neurodevelopment and neuroprotection. We examined the plasma levels of these 2 factors in schizophrenia patients at the time of admission and after 6 weeks of treatment with risperidone. Plasma BDNF and beta-NGF levels were measured in 36 schizophrenia patients and 36 healthy controls. All the patients underwent 6 weeks of treatment with risperidone. The severity of schizophrenia and response to treatment were assessed with the positive and negative syndrome scale (PANSS). We compared plasma BDNF and beta-NGF levels among much-improved (n = 13, 36.1%, > or =50% PANSS score reduction), minimal-improved (n = 15, 41.7%, > or =25% and <50% PANSS score reduction) and nonresponse patients (n = 8, 22.2%, <25% PANSS score reduction). At baseline, plasma BDNF had no significant difference between schizophrenia patients and controls, but beta-NGF levels were significantly lower in schizophrenia patients than controls (p = 0.037). Plasma BDNF and beta-NGF in all schizophrenia patients had no significant changes between pre- and posttreatment. Baseline BDNF levels were significantly lower in nonresponse patients than others (p = 0.038). After treatment, much-improved patients had significantly higher plasma BDNF than nonresponse patients (p = 0.023). However, beta-NGF levels had no significant differences between them. Our data suggest that higher plasma BDNF levels might be associated with better response to risperidone treatment, while plasma beta-NGF levels might have no effect on the clinical response in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 231 | Pharmacogenomics 2009 Feb 10: 277-91 |
| PMID | 19207030 |
| Title | Genetic susceptibility to schizophrenia: role of dopaminergic pathway gene polymorphisms. |
| Abstract | We investigated 16 polymorphisms from three genes, dopamine receptor D2 (DRD2), catechol-O-methyl transferase (COMT) and brain derived neurotrophic factor (BDNF), which are involved in the dopaminergic pathways, and have been reported to be associated with susceptibility to schizophrenia and response to antipsychotic therapy. Single-locus association analyses of these polymorphisms were carried out in 254 patients with schizophrenia and 225 controls, all of southern Indian origin. Additionally, multifactor-dimensionality reduction analysis was performed in 422 samples (243 cases and 179 controls) to examine the gene-gene interactions and to identify combinations of multilocus genotypes associated with either high or low risk for the disease. Our results demonstrated initial significant associations of two SNPs for DRD2 (rs11608185, genotype: chi(2) = 6.29, p-value = 0.043; rs6275, genotype: chi(2) = 8.91, p-value = 0.011), and one SNP in the COMT gene (rs4680, genotype: chi(2) = 6.67, p-value = 0.035 and allele: chi(2) = 4.75, p-value = 0.029; odds ratio: 1.33, 95% confidence interval: 1.02-1.73), but not after correction for multiple comparisons indicating a weak association of individual markers of DRD2 and COMT with schizophrenia. Multifactor-dimensionality reduction analysis suggested a two locus model (rs6275/DRD2 and rs4680/COMT) as the best model for gene-gene interaction with 90% cross-validation consistency and 42.42% prediction error in predicting disease risk among schizophrenia patients. The present study thus emphasizes the need for multigene interaction studies in complex disorders such as schizophrenia and to understand response to drug treatment, which could lead to a targeted and more effective treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 232 | Eur Neuropsychopharmacol 2009 May 19: 356-62 |
| PMID | 19196496 |
| Title | Differential effects of aripiprazole and haloperidol on BDNF-mediated signal changes in SH-SY5Y cells. |
| Abstract | Recent studies have suggested that first and second generation antipsychotics (FGAs and SGAs) have different neuroprotective effects. However, the molecular mechanisms of SGAs are not fully understood, and investigations into changes in intracellular signaling related to their neuroprotective effects remain scarce. In the present study, we compared the SGA aripiprazole with the FGA haloperidol in SH-SY5Y human neuroblastoma cells via brain-derived neurotrophic factor (BDNF)-mediated signaling, notably BDNF, glycogen synthase kinase-3beta (GSK-3beta), and B cell lymphoma protein-2 (Bcl-2). We examined the effects of aripiprazole (five and 10 microM) and haloperidol (one and 10 microM) on BDNF gene promoter activity in SH-SY5Y cells transfected with a rat BDNF promoter fragment (-108 to +340) linked to the luciferase reporter gene. The changes in BDNF, p-GSK-3beta, and Bcl-2 levels were measured by Western blot analysis. The haloperidol was not associated with a significant difference in BDNF promoter activity. In contrast, aripiprazole was associated with increased BDNF promoter activity only with a dose of 10 microM (93%, p<0.01). Treatment with aripiprazole at 10 microM increased the levels of BDNF by 85%, compared with control levels (p<0.01), whereas haloperidol had no effect. Moreover, cells treated with aripirazole effectively increased the levels of GSK-3beta phosphorylation and Bcl-2 at doses of five and 10 microM (30% and 58% and 31% and 80%, respectively, p<0.05 or p<0.01). However, haloperidol had no effects on p-GSK-3 beta and Bcl-2 expression. This study showed that aripiprazole, but not haloperidol, appeared to offer neuroprotective effects on human neuronal cells. The actions of signaling systems associated with BDNF may represent key targets for both aripiprazole and haloperidol, but the latter may be associated with distinct effects. These differences might be related to the different therapeutic effects of FGAs and SGAs in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 233 | Biol. Psychiatry 2009 Jun 65: 1006-14 |
| PMID | 19121517 |
| Title | Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. |
| Abstract | Prefrontal deficits in gamma-aminobutyric acid (GABA)ergic gene expression, including neuropeptide Y (NPY), somatostatin (SST), and parvalbumin (PV) messenger RNAs (mRNAs), have been reported for multiple schizophrenia cohorts. Preclinical models suggest that a subset of these GABAergic markers (NPY/SST) is regulated by brain-derived neurotrophic factor (BDNF), which in turn is under the inhibitory influence of small noncoding RNAs. However, it remains unclear if these mechanisms are important determinants for dysregulated NPY and SST expression in prefrontal cortex (PFC) of subjects with schizophrenia. Using a postmortem case-control design, the association between BDNF protein, NPY/SST/PV mRNAs, and two BDNF-regulating microRNAs (miR-195 and miR-30a-5p) was determined in samples from the PFC of 20 schizophrenia and 20 control subjects. Complementary studies were conducted in cerebral cortex of mice subjected to antipsychotic treatment or a brain-specific ablation of the BDNF gene. Subjects with schizophrenia showed deficits in NPY and PV mRNAs. Within-pair differences in BDNF protein levels showed strong positive correlations with NPY and SST and a robust inverse association with miR-195 levels, which in turn were not affected by antipsychotic treatment or genetic ablation of BDNF. Taken together, these results suggest that prefrontal deficits in a subset of GABAergic mRNAs, including NPY, are dependent on the regional supply of BDNF, which in turn is fine-tuned through a microRNA (miRNA)-mediated mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 234 | Pharmacol. Ther. 2009 Jan 121: 115-22 |
| PMID | 19046988 |
| Title | Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia. |
| Abstract | In recent years evidence has accumulated that the activity of the signaling cascades of Neuregulin-1, Wnt, TGF-beta, BDNF-p75 and DISC1 is different between control subjects and patients with schizophrenia. These pathways are involved in embryonic and adult neurogenesis and neuronal maturation. A review of the clinical data indicates that in schizophrenia the Wnt pathway is most likely hypoactive, whereas the Nrg1-ErbB4, the TGF-beta- and the BDNF-p75-pathways are hyperactive. Haplo-insuffiency of the DISC1 gene is currently the best established schizophrenia risk factor. Preclinical experiments indicate that suppression of DISC1 signaling leads to accelerated dendrite development in neuronal stem cells, accelerated migration and aberrant integration into the neuronal network. Other preclinical experiments show that increasing NRG1-, BDNF- and TGF-beta signaling and decreasing Wnt signaling, also promotes adult neuronal differentiation and migration. Thus deviations in these pathways detected in schizophrenia could contribute to premature neuronal differentiation, accelerated migration and inappropriate insertion into the neuronal network. Initial clinical findings are confirmatory: neuronal stem cells isolated from nasal biopsies from schizophrenia patients display signs of accelerated development, whilst increased erosion of telomeres and bone age provide further support for accelerated cell maturation in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 235 | Neuropsychopharmacology 2009 Jan 34: 18-54 |
| PMID | 18923405 |
| Title | Target identification for CNS diseases by transcriptional profiling. |
| Abstract | Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to tau, amyloid-beta precursor protein, and amyloid-beta peptides (Abeta), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 236 | Psychopharmacology (Berl.) 2009 Mar 202: 569-78 |
| PMID | 18807247 |
| Title | Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. |
| Abstract | Acute and chronic exposure to cannabinoids has been associated with cognitive deficits, a higher risk for schizophrenia and other drug abuse. However, the precise mechanism underlying such effects is not known. Preclinical studies suggest that cannabinoids modulate brain-derived neurotrophic factor (BDNF). Accordingly, we hypothesized that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the principal active component of cannabis, would alter BDNF levels in humans. Healthy control subjects (n = 14) and light users of cannabis (n = 9) received intravenous administration of (0.0286 mg/kg) Delta(9)-THC in a double-blind, fixed order, placebo-controlled, laboratory study. Serum sampled at baseline, after placebo administration, and after Delta(9)-THC administration was assayed for BDNF using ELISA. Delta(9)-THC increased serum BDNF levels in healthy controls but not light users of cannabis. Further, light users of cannabis had lower basal BDNF levels. Delta(9)-THC produced psychotomimetic effects, perceptual alterations, and "high" and spatial memory impairments. The effects of socially relevant doses of cannabinoids on BDNF suggest a possible mechanism underlying the consequences of exposure to cannabis. This may be of particular importance for the developing brain and also in disorders believed to involve altered neurodevelopment such as schizophrenia. Larger studies to investigate the effects of cannabinoids on BDNF and other neurotrophins are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 237 | Psychopharmacology (Berl.) 2009 Jan 202: 343-54 |
| PMID | 18795266 |
| Title | Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat. |
| Abstract | Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment. The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration. CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05). Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 238 | Acta Neuropsychiatr 2009 Jun 21: 109-20 |
| PMID | 26953749 |
| Title | Schizophrenia: genetics, prevention and rehabilitation. |
| Abstract | Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Medline search of relevant studies published between 1990 and 2008. In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 239 | Psychopharmacology (Berl.) 2009 Dec 207: 375-80 |
| PMID | 19787338 |
| Title | Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes. |
| Abstract | There is accumulating evidence that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of patients with schizophrenia. Clinical studies show reductions in BDNF in schizophrenic patients treated with first generation antipsychotics or second generation antipsychotics. However, there have been few systematic studies to examine the relationship between BDNF levels and psychopathology in first-episode and drug-naïve patients with schizophrenia. Serum BDNF levels were determined using enzyme-linked-immunosorbent assay (ELISA) in the serum of 88 never-medicated first-episode and 90 healthy controls subjects matched for age and gender. The schizophrenia symptomatology and the depressive symptoms were assessed by the positive and negative syndrome scale (PANSS) and the Hamilton rating (HAMD) scale for depression. The results showed that BDNF levels were significantly lower in first-episode patients with schizophrenia than in healthy control subjects (9.0 +/- 4.2 ng/ml vs 12.1 +/- 2.2 ng/ml; F = 37.6; df = 1, 176; p < 0.0001). A significant positive correlation between BDNF levels and PANSS positive subscore was observed (r = 0.29; df = 88; p = 0.008). Furthermore, higher BDNF levels were observed in patients with paranoid subtype of schizophrenia. However, no significant correlation between BDNF and HAMD total score was found. Low BDNF levels at the onset of psychosis suggest that it may contribute to the pathogenesis of schizophrenia and perhaps, could be a candidate biological marker for positive symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 240 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Nov 33: 1508-12 |
| PMID | 19720106 |
| Title | Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics. |
| Abstract | Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Decreased BDNF levels have been found in the serum of schizophrenic patients with mixed results. In the present study, we assessed serum BDNF levels in a large group of 364 schizophrenic patients (157 on clozapine, 89 on risperidone and 118 on typical antipsychotics), compared to 323 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were significantly lower in chronic patients with schizophrenia than in healthy control subjects (9.9+/-2.0 ng/ml vs.11.9+/-2.3 ng/ml, p<0.0001). Lower BDNF levels were observed in patients treated with risperidone (9.3+/-2.3 ng/ml) compared to those with clozapine (10.2+/-2.0 ng/ml, p<0.001) and typical antipsychotics (10.0+/-2.1 ng/ml, p<0.01). Furthermore, a stepwise multiple regression analysis identified types of antipsychotic drugs (beta=-0.37, t=-3.15, p=0.001) and BDNF levels (beta=-0.26, t=-2.51, p=0.014) as the influencing factor for the positive symptom subscore of PANSS. In addition, there was a sex difference in BDNF levels in patients with schizophrenia (9.7+/-1.9 ng/ml for males vs.10.4+/-2.1 ng/ml for female, p<0.005), but not in normal controls. Our findings indicated decreased BDNF serum levels in chronic patients with schizophrenia, which may be related to clinical phenotypes, including gender, antipsychotic treatment and the severity of psychotic symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 241 | Psychiatry Clin. Neurosci. 2009 Aug 63: 433-9 |
| PMID | 19457211 |
| Title | Genetic association of BDNF val66met and GSK-3beta-50T/C polymorphisms with tardive dyskinesia. |
| Abstract | Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD), and a growing body of evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in both the antipsychotic effects and the pathogenesis of TD. BDNF and glycogen synthase kinase (GSK)-3beta are important in neuronal survival, and thus abnormal regulation of BDNF and GSK-3beta may contribute to TD pathophysiology. This study investigated the relationship between two polymorphisms, val66met in the BDNF coding region and -50T/C in the GSK-3beta promoter, and susceptibility to TD among a matched sample of patients having schizophrenia with TD (n = 83), patients with schizophrenia without TD (n = 78), and normal control subjects (n = 93). All subjects were Korean. The BDNF val66met and GSK-3beta-50T/C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses. Polymerase chain reaction analysis revealed no significant difference in the occurrence of the polymorphisms among the TD, non-TD, and control subjects, but a significant interaction was observed among the groups possessing BDNF val allele in compound genotypes (P = 0.001). We found that the schizophrenic subjects with the C/C GSK-3beta genotype, who carry the val allele of the BDNF gene, are expected to have a decreased risk of developing neuroleptic-induced tardive dyskinesia (P < 0.001). Our results demonstrate that the GSK-3beta C/C genotype with the BDNF val allele is associated with patients having schizophrenia without TD. This study also suggests that the BDNF and GSK-3beta gene polymorphisms work in combination, but not individually, in predisposing patients with schizophrenia to TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 242 | Schizophr. Res. 2009 Jul 112: 72-9 |
| PMID | 19406621 |
| Title | BDNF is not associated with schizophrenia: data from a Japanese population study and meta-analysis. |
| Abstract | A variety of evidence suggests brain-derived neurotrophic factor (BDNF) as a candidate gene for schizophrenia, and several genetic studies have shown a significant association between the disease and certain SNPs within BDNF (specifically, Val66Met and C270T). According to a recent study, the functional microsatellite marker BDNF-LCPR (BDNF-linked complex polymorphic region), which affects the expression level of BDNF, is associated with bipolar disorder. The goals of our current study were to 1) evaluate the quality of HapMap-based linkage disequilibrium (LD) tagging of BDNF-LCPR, 2) examine whether these tagging SNPs are associated with schizophrenia in a Japanese population, and 3) conduct a meta-analysis of the two most extensively studied polymorphisms: Val66Met and C270T. We genotyped eight tagging SNPs, including Val66Met and C270T. Our LD evaluation showed that BDNF-LCPR could be represented by these tagging SNPs in controls (with 73.5% allelic coverage). However, the functional A1 allele was not captured due to its low minor allele frequency (2.2%). In a case-control study (1117 schizophrenics and 1102 controls), no association was found in single-marker or multimarker analysis. Moreover, in a meta-analysis, the Val66Met polymorphism was not associated with schizophrenia, whereas C270T showed a trend for association in a fixed model (p=0.036), but not in a random model (p=0.053). From these findings, we conclude that if BDNF is indeed associated with schizophrenia, the A1 allele in BDNF-LCPR would be the most promising candidate. Further LD evaluation, as well as an association study in which BDNF-LCPR is genotyped directly, would be required for a more conclusive result. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 243 | Zh Nevrol Psikhiatr Im S S Korsakova 2010 -1 110: 48-52 |
| PMID | 21183914 |
| Title | [Molecular-genetic approach to the clinical and nosologic differentiation of schizoaffective disorder]. |
| Abstract | The aim of the study was to find molecular-genetic variants associated with nosologically independent schizoaffective disorder (SAD) which clinical presentations had been specified earlier. Authors studied a sample of 230 patients including 39 with "nuclear" (nosologically independent) and marginal (intermediate) variants of SAD, 53 with schizophrenia with schizoaffective states and 81 with schizophrenia with affective disorders in the structure of psychotic attacks. In these groups, authors studied the following polymorphisms: 5-HTTLPR, Val66Met BDNF, T102C 5-HTR2a and ?677? MTHFR. Frequencies of genotypes were compared to those in a sample of healthy controls (328 people). It has been shown that the "nuclear" variant has a genetic profile represented by a combination of genetic variants (SS*ValVal*TT*CC) that distinguishes this clinical entity from other groups and controls. The results may be used as an additional criteria for clinical and nosological differentiation of SAD from schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 244 | Nihon Shinkei Seishin Yakurigaku Zasshi 2010 Aug 30: 153-60 |
| PMID | 20857692 |
| Title | [Update on epigenetic regulation in pathophysiologies of stress-induced psychiatric disorders]. |
| Abstract | Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene transcription without altering the DNA code, could play a critical role in the pathophysiology of psychiatric disorders. The present review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in several psychiatric disorders such as depression, schizophrenia and Rett syndrome. The gene transcriptions of the key molecules such as brain-derived neurotrophic factor (BDNF) or Reelin that play a role in on psychiatric disorders are regulated with histone modification or DNA methylation. Furthermore, one potential mechanism whereby stress can disrupt prenatal and/or neonatal development is through epigenetics, because the key issue of epigenetics is its long-term influence. In addition, we also found in the recent research that the epigenetic mechanism of gene regulation, especially histonedeacetylase, in the brain may be involved in the development of emotional resistance to stress stimuli. A better understanding of epigenetic regulation might provide new therapeutic avenues for disorders such as depression, schizophrenia, Rett syndrome and neurodevelopmental diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 245 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Dec 34: 1412-8 |
| PMID | 20667458 |
| Title | Association study of BDNF and DRD3 genes in schizophrenia diagnosis using matched case-control and family based study designs. |
| Abstract | schizophrenia (SCZ) is a severe neuropsychiatric disorder with prominent genetic etiologic factors. The dopamine receptor DRD3 gene is a strong candidate in genetic studies of SCZ because of the dopamine hypothesis of SCZ and the selective expression of D(3) in areas of the limbic system implicated in the disease. We examined 15 single-nucleotide polymorphisms (SNPs) in DRD3 in our sample of European origin consisting of 95 small nuclear SCZ families and 167 case-control pairs. We also examined four BDNF SNPs in our samples because of evidence for BDNF regulation of DRD3 expression (Guillin et al., 2001). We found a nominally significant genotypic association with rs7633291 and allelic association with rs1025398 alleles. However, these observations did not survive correction for multiple testing. We did not find a statistically significant association with the other DRD3 and BDNF polymorphisms. Taken together, the results from the present study suggest that BDNF and DRD3 may not be involved in SCZ susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 246 | Psychopharmacology (Berl.) 2010 Oct 212: 301-7 |
| PMID | 20661552 |
| Title | Nicotine dependence and serum BDNF levels in male patients with schizophrenia. |
| Abstract | schizophrenia is associated with a significantly high prevalence of smoking. Upregulation of neurotrophins by nicotine is well established. Accumulating evidence shows that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The purposes of this study were to compare BDNF levels in smokers to nonsmokers with schizophrenia and examine the association between BDNF levels and psychopathological symptoms. Serum BDNF levels were measured in 139 male inpatients with DSM-IV schizophrenia: 102 smokers and 37 nonsmokers. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). The positive PANSS symptoms were lower in smokers than in nonsmokers, while the negative symptoms were lower in those who smoked more cigarettes. BDNF levels were significantly higher in smokers than in nonsmokers (p?BDNF levels correlated with fewer negative symptoms and with smoking more cigarettes. The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be associated with nicotine-induced upregulation of BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 247 | J. Biomed. Biotechnol. 2010 -1 2010: 783297 |
| PMID | 20625416 |
| Title | Postnatal BDNF expression profiles in prefrontal cortex and hippocampus of a rat schizophrenia model induced by MK-801 administration. |
| Abstract | Neonatal blockade of N-methyl-D-aspartic acid (NMDA) receptors represents one of experimental animal models for schizophrenia. This study is to investigate the long-term brain-derived neurotrophic factor (BDNF) expression profiles in different regions and correlation with "schizophrenia-like" behaviors in the adolescence and adult of this rat model. The NMDA receptor antagonist MK801 was administered to female Sprague-Dawley rats on postnatal days (PND) 5 through 14. Open-field test was performed on PND 42, and PND 77 to examine the validity of the current model. BDNF protein levels in hippocampus and prefrontal cortex (PFC) were analyzed on PND 15, PND 42, and PND 77. Results showed that neonatal challenge with MK-801 persistently elevated locomotor activity as well as BDNF expression; the alterations in BDNF expression varied at different developing stages and among brain regions. However, these findings provide neurochemical evidence that the blockade of NMDA receptors during brain development results in long-lasting alterations in BDNF expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia. Further study in the mechanisms and roles of the BDNF may lead to better understanding of the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 248 | Ann. Hum. Genet. 2010 Jul 74: 291-8 |
| PMID | 20456319 |
| Title | Association of polymorphisms in the BDNF, DRD1 and DRD3 genes with tobacco smoking in schizophrenia. |
| Abstract | Emerging evidence indicates that the DRD1-BDNF-DRD3 cluster plays an important role in nicotine addiction. We have performed an association analysis of 42 SNPs within these genes with cigarette consumption in a group of 341 schizophrenia patients. The ACCG haplotype consisting of four BDNF markers (Val66Met (rs6265), rs11030104, rs2049045 and rs7103411) showed an association with the risk of smoking (p = 0.0002). Both DRD1 markers tested (rs4532 and rs686) and the DRD3 marker (rs1025398) showed association with quantity of tobacco smoked (p = 0.01, 0.005 and 0.002, respectively). Our findings are preliminary; however, they support the involvement of the DRD1, BDNF and DRD3 genes in smoking behaviour. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 249 | Zh Nevrol Psikhiatr Im S S Korsakova 2010 -1 110: 66-9 |
| PMID | 20436453 |
| Title | [Molecular-genetic study of early-onset schizophrenia]. |
| Abstract | schizophrenia with early onset is a relatively rear form of the disease which characterized by severe chronic course and poor outcome. In the present paper, we studied several genes possibly involved in the pathogenesis of this form. These are genes for brain-derived neurotrophic factor (Val66Met polymorphism), serotonin transporter (5-HTTLPR), serotonin receptor type 2A (T102C) and dopamine receptor D2 (Taq1A). Sixty-five patients (age at onset before 15 years) and 111 healthy controls were included in the study. Out of all genes tested, the association was found only for the Val66Met BDNF polymorphism. Frequency of the ValVal genotype was higher in the group of patients (p=0.03; OR 2.1 CI 1.1-4.0) compared to the controls. These results were consistent with our previous study which was carried out on the sample of schizophrenic patients with later age of disease onset. In this study, the frequency of the ValVal genotype was higher only in the group of patients with chronic schizophrenia compared to the controls. It is concluded that the ValVal BDNF genotype may be considered as a marker of schizophrenia with more severe course. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 250 | Eur. Psychiatry 2010 Oct 25: 311-3 |
| PMID | 20430595 |
| Title | BDNF Val66Met polymorphism is associated with aggressive behavior in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) gene variants may potentially influence behaviour. In order to test this hypothesis, we investigated the relationship between BDNF Val66Met polymorphism and aggressive behaviour in a population of schizophrenic patients. Our results showed that increased number of BDNF Met alleles was associated with increased aggressive behaviour. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 251 | Neurol. Sci. 2010 Jun 31: 399-401 |
| PMID | 20112124 |
| Title | Serum levels of brain-derived neurotrophic factor in Sydenham's chorea. |
| Abstract | Sydenham's chorea (SC) is the neurologic manifestation of rheumatic fever. In addition to involuntary movements, SC patients show behavioral changes, such as hyperactivity, obsessions, and compulsions. Brain-derived neurotrophic factor (BDNF) is related to neuronal development and differentiation. Since BDNF serum levels are altered in a series of neuropsychiatric disorders, such as schizophrenia and Huntington's disease, we investigated the serum levels of BDNF in SC patients. Eighteen patients with acute SC, 4 with persistent SC and 27 control subjects were included in this study. BDNF was determined by ELISA. There was no significant difference between BDNF serum levels of control and acute SC groups (P = 0.12). Persistent SC patients presented decreased BDNF levels when compared to both control and acute SC groups (P < 0.001). Our results suggest that the persistence of symptoms in SC may be related to structural changes in the central nervous system as expressed by altered BDNF levels. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 252 | Psychiatry Res 2010 Mar 176: 82-4 |
| PMID | 20061032 |
| Title | NRG1 and BDNF genes in schizophrenia: an association study in an Italian case-control sample. |
| Abstract | We tested for associations between five single nucleotide polymorphisms (SNPs) located in the area containing the Neuregulin 1 gene (NRG1) and three SNPs within the brain-derived neutrophic factor gene (BDNF) in an Italian sample consisting of 171 schizophrenia subjects and 349 controls. No association was found for any of the polymorphisms tested, either in single locus or in haplotype analysis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 253 | Int. J. Neuropsychopharmacol. 2010 May 13: 535-9 |
| PMID | 19941699 |
| Title | Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. |
| Abstract | Brain-derived neurotrophic factor (BDNF), which plays an important role in neurodevelopmental plasticity and cognitive performance, has been implicated in neuropsychopathology of schizophrenia. We examined the levels of both cerebrospinal fluid (CSF) and plasma BDNF concomitantly in drug-naive first-episode psychotic (FEP) subjects with ELISA to determine if these levels were different from control values and if any correlation exists between CSF and plasma BDNF levels. A significant reduction in BDNF protein levels was observed in both plasma and CSF of FEP subjects compared to controls. BDNF levels showed significant negative correlation with the scores of baseline PANSS positive symptom subscales. In addition, there was a significant positive correlation between plasma and CSF BDNF levels in FEP subjects. The parallel changes in BDNF levels in plasma and CSF indicate that plasma BDNF levels reflect the brain changes in BDNF levels in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 254 | Neuroimage 2010 Jan 49: 767-71 |
| PMID | 19683059 |
| Title | Met carriers of BDNF Val66Met genotype show increased N-acetylaspartate concentration in the anterior cingulate cortex. |
| Abstract | Decreased levels of N-acetylaspartate (NAA) and brain-derived neurotrophic factor (BDNF) in the anterior cingulate cortex (ACC) have been linked to neuronal loss and psychiatric disorders like schizophrenia and bipolar disorder. We previously found that BDNF serum concentration was predicted by the concentration of NAA in the ACC, indicating that neuronal integrity and vitality of a cortical region like the ACC, as reflected by a high concentration of NAA, might be related to high concentrations of BDNF in serum. Moreover, our recent finding that Val66Met genotype appears to predict the BDNF serum level in healthy human volunteers suggests the Met allele to be connected to higher concentrations of BDNF in serum. We examined absolute NAA concentrations in the ACC and hippocampus of 40 male and 42 female healthy volunteers (age: 33.3+/-9 years). We found NAA in the ACC to be significantly increased in Met carriers (F=5.2, df=1, p=0.025). On the other hand, the concentration of creatine+phosphocreatine in the hippocampus was significantly decreased in Met carriers. We hypothesize that higher NAA levels in the ACC might contribute to the protection of Met allele carriers against major psychiatric disorders as schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 255 | Zh Nevrol Psikhiatr Im S S Korsakova 2010 -1 110: 66-9 |
| PMID | 20436453 |
| Title | [Molecular-genetic study of early-onset schizophrenia]. |
| Abstract | schizophrenia with early onset is a relatively rear form of the disease which characterized by severe chronic course and poor outcome. In the present paper, we studied several genes possibly involved in the pathogenesis of this form. These are genes for brain-derived neurotrophic factor (Val66Met polymorphism), serotonin transporter (5-HTTLPR), serotonin receptor type 2A (T102C) and dopamine receptor D2 (Taq1A). Sixty-five patients (age at onset before 15 years) and 111 healthy controls were included in the study. Out of all genes tested, the association was found only for the Val66Met BDNF polymorphism. Frequency of the ValVal genotype was higher in the group of patients (p=0.03; OR 2.1 CI 1.1-4.0) compared to the controls. These results were consistent with our previous study which was carried out on the sample of schizophrenic patients with later age of disease onset. In this study, the frequency of the ValVal genotype was higher only in the group of patients with chronic schizophrenia compared to the controls. It is concluded that the ValVal BDNF genotype may be considered as a marker of schizophrenia with more severe course. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 256 | Eur. Psychiatry 2010 Oct 25: 311-3 |
| PMID | 20430595 |
| Title | BDNF Val66Met polymorphism is associated with aggressive behavior in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) gene variants may potentially influence behaviour. In order to test this hypothesis, we investigated the relationship between BDNF Val66Met polymorphism and aggressive behaviour in a population of schizophrenic patients. Our results showed that increased number of BDNF Met alleles was associated with increased aggressive behaviour. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 257 | Neurosci. Lett. 2010 May 476: 104-9 |
| PMID | 20398734 |
| Title | Cortical neurons from intrauterine growth retardation rats exhibit lower response to neurotrophin BDNF. |
| Abstract | Intrauterine growth retardation (IUGR) is putatively involved in the pathophysiology of schizophrenia. The animal model of IUGR induced by synthetic thromboxane A2 (TXA2) is useful to clarify the effect of IUGR on pups' brains, however, analysis at the cellular level is still needed. Brain-derived neurotrophic factor (BDNF), which plays a role in neuronal survival and synaptic plasticity in the central nervous system (CNS), may also be associated with schizophrenia. However, the possible relationship between IUGR and BDNF function remains unclear. Here, we examined how IUGR by TXA2 impacts BDNF function by using dissociated cortical neurons. We found that, although BDNF levels in cultured neurons from the cerebral cortex of low birth weight pups with IUGR were unchanged, TrkB (BDNF receptor) was decreased compared with control-rats. BDNF-stimulated MAPK/ERK1/2 and PI3K/Akt pathways, which are downstream intracellular signaling pathways of TrkB, were repressed in IUGR-rat cultures. Expression of glutamate receptors such as GluA1 and GluN2A was also suppressed in IUGR-rat cultures. Furthermore, in IUGR-rat cultures, anti-apoptotic protein Bcl2 was decreased and BDNF failed to prevent neurons from cell death caused by serum-deprivation. Taken together, IUGR resulted in reductions in cell viability and in synaptic function following TrkB down-regulation, which may play a role in schizophrenia-like behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 258 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Dec 153B: 1474-82 |
| PMID | 20957650 |
| Title | Effects of the BDNF val66met polymorphism on prefrontal brain function in a population at high genetic risk of schizophrenia. |
| Abstract | A single nucleotide polymorphism (val66met) in the brain derived neurotrophic factor (BDNF) gene has been shown to be a risk factor for a number of psychiatric disorders, including schizophrenia. This polymorphism has also been shown to have effects on prefrontal brain morphology and function. This study aims to clarify the effects of the val66met polymorphism on prefrontal brain function in a population at high genetic risk for schizophrenia. The Edinburgh High Risk Study has followed young individuals who had one first- or second-degree relative with schizophrenia and a minimum of one further genetic relative with the illness. A sample of 62 individuals provided both genetic and functional imaging data using the Hayling sentence completion task. Individuals with the BDNF ValVal (presumed risk) genotype (n?=?41) showed relatively increased activation of the anterior cingulate cortex in relation to Met carrier individuals (n?=?21) during sentence completion conditions versus baseline, against a background of similar levels of task performance. It appeared from further investigation that this relatively increased activation was attributable to a failure to disengage or suppress activation in the high risk ValVal group during the task condition, suggesting that BDNF may contribute to the abnormal default network reported in schizophrenia. These results suggest that this gene affects prefrontal brain function in those at high genetic risk for the disorder, unconfounded by medication effects. BDNF may therefore be one of the heritable factors involved in the development of abnormal prefrontal function in schizophrenia. © 2010 Wiley-Liss, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 259 | Psychiatry Res 2010 Sep 183: 195-201 |
| PMID | 20708907 |
| Title | Functional magnetic resonance imaging of BDNF val66met polymorphism in unmedicated subjects at high genetic risk of schizophrenia performing a verbal memory task. |
| Abstract | Multiple strands of evidence suggest a role for Brain Derived Neurotrophic Factor (BDNF) in the pathophysiology of schizophrenia. It is not yet clear, however, how BDNF may contribute to altered brain function seen in the disorder, or in those at high genetic risk. The current study examines functional imaging correlates of the BDNF val66met polymorphism in a population at high genetic risk of schizophrenia. Subjects at high genetic risk for the disorder (n=58) provided both BDNF genotyping and fMRI data while performing a verbal memory task. During encoding, participants were presented with a word and asked to make a 'living'/'non-living' classification. During retrieval, individuals were requested to make an 'old'/'new' word classification. For encoding, we report decreased activation of the inferior occipital cortex and a trend in the cingulate cortex in Val homozygote individuals relative to Met carriers. For retrieval, we report decreases in activation in the prefrontal, cingulate cortex and bilateral posterior parietal regions in Val homozygote individuals versus Met carriers. These findings add to previous evidence suggesting that genetic variation in the BDNF gene modulates prefrontal and limbic functioning and suggests that it may contribute to differences in brain function seen in those at high risk of the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 260 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Oct 34: 1259-65 |
| PMID | 20638435 |
| Title | An exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes. |
| Abstract | Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls. Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects. Information on obstetric complications was collected from original birth records. Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects. Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume. The findings suggest a gene-environment (G x E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia. Due to the modest sample size, the results must be considered preliminary and require replication in independent samples. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 261 | Neuroscience 2010 Sep 169: 1071-84 |
| PMID | 20553817 |
| Title | Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia. |
| Abstract | The brain-derived neurotrophic factor (BDNF) gene contains multiple 5' promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein are reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the four most abundant and best characterized BDNF alternate transcripts, I-IX, II-IX, IV-IX, and VI-IX are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II-IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that BDNF protein expression [including prepro ( approximately 32 kDa), pro ( approximately 28 kDa) and mature ( approximately 14 kDa) BDNF] is reduced in the DLPFC of patients with schizophrenia. We next determined the regional specificity of the BDNF mRNA reduction by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes. The effect of antipsychotics on BDNF alternate transcript expression was also examined and we found no relationship between BDNF mRNA expression and antipsychotic use. As schizophrenic patients are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenic patients treated with antidepressants. Moreover, we found significant reductions in BDNF transcripts II-IX and IV-IX in the parietal cortex and VI-IX in the hippocampus of patients with schizophrenia who did not have a history of treatment with antidepressants. This suggests that down-regulation of at least one out of four major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 262 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Aug 34: 1001-6 |
| PMID | 20546816 |
| Title | Effects of olanzapine on brain-derived neurotrophic factor gene promoter activity in SH-SY5Y neuroblastoma cells. |
| Abstract | Atypical antipsychotics have neuroprotective effects, which may be one of the mechanisms for their success in the treatment of schizophrenia. Growing evidence suggest that brain-derived neurotrophic factor (BDNF) is abnormally regulated in patients with schizophrenia, and its expression can be up-regulated by atypical antipsychotics. Atypical antipsychotic drugs may positively regulate transcription of the BDNF gene, but the molecular mechanism of atypical antipsychotic drug action on BDNF gene activity has not been investigated. The aim of the present study was to explore the possible involvement of some intracellular signaling pathways in olanzapine action on BDNF promoter activity. We examined the effects of olanzapine on BDNF gene promoter activity in SH-SY5Y cells transfected with a rat BDNF promoter fragment (-108 to +340) linked to the luciferase reporter gene. The changes in glycogen synthase kinase-3beta (GSK-3beta) and cAMP response element (CRE) binding protein (CREB) phosphorylation were measured by Western blot analysis. Olanzapine treatment (10-100 microM) increased basal BDNF gene promoter activity in a dose-dependent manner and increased protein levels at high dose, and inhibitors of protein kinase A (PKA), H-89 (10 microM), phosphatidylinositol 3-kinase (PI3K), wortmannin (0.01 microM), PKC (protein kinase C), GF109203 (10 microM), calcium/calmodulin kinase II (CaMKII), and KN-93 (20 microM) partially attenuated the stimulatory effect of olanzapine on BDNF promoter activity. In line with these results, a Western blot study showed that olanzapine (100 microM) increased phosphorylated levels of GSK-3beta and CREB, which are notable downstream effectors of the PKA, PI3K, PKC, and CaMKII signaling pathways. These results demonstrate that the up-regulation of olanzapine on BDNF gene transcription is linked with enhancement of CREB-mediated transcription via PKA, PI3K, PKC, and CaMKII signaling pathways, and olanzapine may exert neuroprotective effects through these signaling pathways in neuronal cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 263 | Neuropsychobiology 2010 -1 62: 87-90 |
| PMID | 20523079 |
| Title | Association of serum brain-derived neurotrophic factor and duration of untreated psychosis in first-episode patients with schizophrenia. |
| Abstract | The brain-derived neurotrophic factor (BDNF) levels in serum and the central nervous system are altered in patients with schizophrenia, suggesting that changes in the expression of BDNF might contribute to the disease pathophysiology. Long duration of untreated psychosis (DUP) has been associated with poorer prognosis in patients with schizophrenia. Such a relationship of untreated psychosis to outcome may indicate a neurodegenerative process and may have important implications for understanding the pathophysiology of schizophrenia. In this study, we investigated the association between serum BDNF levels and DUP in a sample of drug-naïve patients in their first episode of schizophrenia (FEP). We investigated serum BDNF levels in a sample of 37 drug-naïve FEP patients and 21 matched healthy subjects. The serum BDNF level in the sample of FEP was significantly reduced compared to the healthy subjects (18.87 +/- 8.23 vs. 29.2 +/- 7.73 ng/ml, t = 4.76, d.f. = 57, p = 0.01). A negative correlation was found between serum BDNF levels and DUP in the group of patients (r = -0.346, p = 0.036). Our findings indicate that low serum BDNF levels at the onset of schizophrenia were associated with a long DUP and this could reflect an acute neurodegenerative reaction during the untreated phase of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 264 | Neurobiol. Dis. 2010 Sep 39: 327-33 |
| PMID | 20451611 |
| Title | An inverse relationship between cortisol and BDNF levels in schizophrenia: data from human postmortem and animal studies. |
| Abstract | Stress and stress-induced glucocorticoids have been implicated in many neuropsychiatric disorders including schizophrenia. In addition, the neurotrophin, brain derived neurotrophic factor (BDNF) has been shown to play an important role in stress-mediated changes in neuroplasticity, however, the exact relationship between glucocorticoid and BDNF levels in schizophrenia is unclear. Here, we measured the levels of cortisol (a major glucocorticoid hormone in humans) and BDNF in prefrontal cortex and CSF samples of postmortem schizophrenia subjects. We also assessed the levels of cortisol and BDNF in the frontal cortex and plasma from an animal model (the offspring of prenatally stressed rats), which demonstrates several behavioral and neuroendocrine abnormalities similar to schizophrenia. A significant increase in cortisol levels was found in prefrontal cortex and CSF samples from subjects with schizophrenia. The BDNF levels were significantly lower in prefrontal cortex and CSF samples of subjects with schizophrenia (compared to age-matched controls). Data from animal studies indicated that prenatally stressed offspring have significantly higher plasma and prefrontal cortex cortisol, whereas BDNF levels were significantly lower when compared to control, non-stressed offspring. Moreover, olanzapine treatment for 45 days starting at postnatal day 60 significantly attenuated prenatal stress-induced increase in cortisol levels in prefrontal cortex, but no change in BDNF levels was observed after olanzapine treatment. A significant negative correlation between BDNF and cortisol was observed in both human and animal studies. The above data from human and animal studies suggest that a negative association between stress hormone, cortisol and neuroprotective molecule, BDNF plays an important role in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 265 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Aug 34: 930-3 |
| PMID | 20420877 |
| Title | The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients. |
| Abstract | Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Recent studies have reported that the Val66Met polymorphism of the BDNF gene may be associated with susceptibility for schizophrenia and age of onset of this disease, with mix results. In the present study, the BDNF Val66Met gene polymorphism was examined in 387 inpatients (259 men and 128 women) meeting the DSM-IV criteria for schizophrenia and unrelated 365 healthy controls (255 men and 110 women). The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS). Age of onset was defined as the age at which the psychotic symptoms first appeared. Our results showed that genotype frequency distributions and allelic frequencies did not differ between patients and controls. No interaction was found between sex and genotypes. Analysis of covariance (ANCOVA) showed a significance of the BDNF Val66Met genotypes on the age of onset (F=3.76, p<0.02), after adjusting sex, age and duration of illness. Furthermore, ANCOVA showed that the significance of the BDNFVal66Met genotypes on age of onset was increased comparing the Val66Met heterozygotes with the combination of Val66Val and Met66Met homozygotes (F=5.85, p<0.01). Our results suggest that the BDNF Val66Met polymorphism may not contribute directly to the susceptibility to schizophrenia, but to the onset of the disease. Furthermore, our results show the heterozygous effect of the BDNF Val66Met gene on the clinical variability of schizophrenia phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 266 | World J. Biol. Psychiatry 2010 Mar 11: 251-5 |
| PMID | 20218789 |
| Title | Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse, who were treated with typical or atypical antipsychotics. |
| Abstract | Brain-derived neurotrophic factor signals and dopaminergic function in the brain are strongly associated, and research on BDNF in schizophrenia may enhance our insights on the pathophysiological mechanisms of this disease. In the present study we aimed to investigate the possible association between serum BDNF levels and schizophrenic relapses and the possible differential effects of treatment with typical and atypical antipsychotics on serum BDNF levels in the same group of patients. We measured serum BDNF levels in 47 patients with schizophrenia during a relapse and again 6 weeks after administration of antipsychotic treatment (14 on risperidone, 18 on haloperidol, 10 on olanzapine and five on amisulpride) and in 44 healthy volunteers. Patients with schizophrenia showed reduced serum BDNF levels in relation to healthy volunteers at study entry. No significant differences were revealed in BDNF serum levels after 6 weeks of antipsychotic treatment in the patients compared to their own levels at study entry. However, serum BDNF was significantly increased in the subgroup receiving olanzapine compared to the other antipsychotics. Our findings may indicate a differential effect of olanzapine on BDNF levels compared to haloperidol, risperidone, and amisulpride. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 267 | PLoS ONE 2010 -1 5: e9166 |
| PMID | 20161799 |
| Title | Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. |
| Abstract | Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 268 | Schizophr. Res. 2010 Jun 119: 47-51 |
| PMID | 20096541 |
| Title | Decreased BDNF in patients with antipsychotic naïve first episode schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls. Fasting serum BDNF levels were measured in 41 patients with treatment naive first episode psychosis (24 with schizophrenia, schizoaffective disorder or schizophreniform disorder, and 17 with non-schizophrenia psychotic disorders) and 41 age-matched healthy controls. A three group analyses of covariance (ANCOVA) showed a diagnosis effect (p=.038) in which patients with schizophrenia had lesser serum BDNF levels than patient with non-schizophrenia psychosis, who in turn had lesser BDNF levels than matched healthy controls. Planned two-group ANCOVAs suggested that patients with schizophrenia had lower serum BDNF level than matched controls (p=.016), whereas patients with non-schizophrenia psychosis did not differ from controls. There were no age effects on BDNF, but there was a trend (p=.08) for a gender by group interaction with greater reductions in female patients with schizophrenia. The BDNF levels did not correlate with magnitude of smoking, body mass index, severity of positive and negative symptoms or overall functioning. Serum BDNF may be reduced at the onset of psychosis but its role in the pathogenesis of schizophrenia remains unclear. Elucidating the role of BDNF in schizophrenia and related psychotic disorders may provide an important therapeutic target. Further studies are also needed to examine if patients with schizophrenia have more pronounced reductions in BDNF than those with affective psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 269 | Eur. J. Hum. Genet. 2010 Jun 18: 707-12 |
| PMID | 20087404 |
| Title | Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study. |
| Abstract | Risperidone is a widely used atypical antipsychotic agent that produces considerable interindividual differences in patient response. We investigated the pharmacogenetic relationship between the brain-derived neurotrophic factor (BDNF) gene and response to risperidone in 127 Han Chinese schizophrenic patients. Three functional polymorphisms, (GT)(n) dinucleotide repeat polymorphism, C-270T, and the rs6265G/A single-nucleotide polymorphism (SNP), were genotyped and analyzed for association, with reduction of Brief Psychiatric Rating Scale (BPRS) scores following an 8-week period of risperidone monotherapy. For individual polymorphic analysis, we found that the frequency of the 230-bp allele of the (GT)(n) polymorphism was much higher in responders (47.95%) than in nonresponders (32.41%) and the difference was statistically significant even after Bonferroni's adjustment (for the 230-bp allele: adjusted P=0.039). For haplotype-based analyses of the three polymorphisms, no positive finding was observed in the global test, but in specific haplotype tests, two haplotypes were also significantly related to response to risperidone (for haplotype 230-bp/C-270/rs6265G: P=0.0009; for haplotype 234-bp/C-270/rs6265A: P=0.043), indicating that patients with the 230-bp allele of the (GT)(n) polymorphism or the 230-bp/C-270/rs6265G haplotype responded better to risperidone than those with other alleles or haplotypes, and that the positive effect of the individual haplotype 230-bp/C-270/rs6265G was mainly driven by the 230-bp allele. These findings demonstrate that the individual and combinatorial genetic variants in the BDNF gene might have a role in the therapeutic response to risperidone in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 270 | Neuroimage 2010 Nov 53: 1007-15 |
| PMID | 19944766 |
| Title | A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia. |
| Abstract | Understanding genetic influences on both healthy and disordered brain function is a major focus in psychiatric neuroimaging. We utilized task-related imaging findings from an fMRI auditory oddball task known to be robustly associated with abnormal activation in schizophrenia, to investigate genomic factors derived from multiple single nucleotide polymorphisms (SNPs) from genes previously shown to be associated with schizophrenia. Our major aim was to investigate the relationship of these genomic factors to normal/abnormal brain functionality between controls and schizophrenia patients. We studied a Caucasian-only sample of 35 healthy controls and 31 schizophrenia patients. All subjects performed an auditory oddball task, which consists of detecting an infrequent sound within a series of frequent sounds. Each subject was characterized on 24 different SNP markers spanning multiple risk genes previously associated with schizophrenia. We used a recently developed technique named parallel independent component analysis (para-ICA) to analyze this multimodal data set (Liu et al., 2008). The method aims to identify simultaneously independent components of each modality (functional imaging, genetics) and the relationships between them. We detected three fMRI components significantly correlated with two distinct gene components. The fMRI components, along with their significant genetic profile (dominant SNP) correlations were as follows: (1) Inferior frontal-anterior/posterior cingulate-thalamus-caudate with SNPs from Brain derived neurotropic factor (BDNF) and dopamine transporter (DAT) [r=-0.51; p<0.0001], (2) superior/middle temporal gyrus-cingulate-premotor with SLC6A4_PR and SLC6A4_PR_AG (serotonin transporter promoter; 5HTTLPR) [r=0.27; p=0.03], and (3) default mode-fronto-temporal gyrus with Brain derived neurotropic factor and dopamine transporter (BDNF, DAT) [r=-0.25; p=0.04]. Functional components comprised task-relevant regions (including PFC, ACC, STG and MTG) frequently identified as abnormal in schizophrenia. Further, gene-fMRI combinations 1 (Z=1.75; p=0.03), 2 (Z=1.84; p=0.03) and 3 (Z=1.67; p=0.04) listed above showed significant differences between controls and patients, based on their correlated loading coefficients. We demonstrate a framework to identify interactions between "clusters" of brain function and of genetic information. Our results reveal the effect/influence of specific interactions, (perhaps epistastatic in nature), between schizophrenia risk genes on imaging endophenotypes representing attention/working memory and goal directed related brain function, thus establishing a useful methodology to probe multivariate genotype-phenotype relationships. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 271 | Neuropharmacology 2010 Feb 58: 330-6 |
| PMID | 19887077 |
| Title | Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways. |
| Abstract | Phencyclidine is an N-methyl d-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain-derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration-dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3beta activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3beta at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3beta inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3beta and activation of CREB. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 272 | Hippocampus 2010 Sep 20: 1010-7 |
| PMID | 19714565 |
| Title | Effects of brain-derived neurotrophic factor Val66Met polymorphism on hippocampal volume change in schizophrenia. |
| Abstract | A functional polymorphism of the brain-derived neurotrophic factor (BDNF) gene (Val66Met) has been associated with the risk for schizophrenia and volume differences in the hippocampus. However, little is known about the association between progressive brain volume change in schizophrenia and BDNF genotype. The aim of this study was to investigate the relationship between hippocampal volume change in patients with schizophrenia and healthy control subjects and BDNF genotype. Two structural magnetic resonance imaging brain scans were acquired of 68 patients with schizophrenia and 83 healthy subjects with an interval of approximately 5 yrs. Hippocampal volume change was measured and related to BDNF genotype in patients and healthy controls. BDNF genotype was not associated with hippocampal volume change over time in patients or healthy controls, nor could we replicate earlier findings on smaller hippocampal volume in Met-carriers. However, we did find a genotype-by-diagnosis interaction at baseline demonstrating smaller hippocampal volumes in patients homozygous for the Val-allele relative to healthy Val-homozygotes. In addition, irrespective of genotype, patients showed smaller hippocampal volumes compared with healthy controls at baseline. In summary, our results suggest that the BDNF Val66Met polymorphism is not associated with hippocampal volume change over time. Nevertheless, our findings may support the possibility that BDNF affects brain morphology differently in schizophrenia patients and healthy subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 273 | Eur Arch Psychiatry Clin Neurosci 2010 Mar 260: 151-62 |
| PMID | 19579000 |
| Title | Risperidone and haloperidol promote survival of stem cells in the rat hippocampus. |
| Abstract | Altered neuroplasticity contributes to the pathophysiology of schizophrenia. However, the idea that antipsychotics may act, at least in part, by normalizing neurogenesis has not been consistently supported. Our study seeks to determine whether hippocampal cell proliferation is altered in adult rats pretreated with ketamine, a validated model of schizophrenia, and whether chronic administration with neuroleptic drugs (haloperidol and risperidone) affect changes of cell genesis/survival. Ketamine per se has no effect on cell proliferation. Its withdrawal, however, significantly induced cell proliferation/survival in the hippocampus. Risperidone and haloperidol supported cell genesis/survival as well. During ketamine withdrawal, however, their application did not affect cell proliferation/survival additionally. TUNEL staining indicated a cell-protective potency of both neuroleptics with respect to a ketamine-induced cell death. As RT-PCR and Western blot revealed that the treatment effects of risperidone and haloperidol seemed to be mediated through activation of VEGF and MMP2. The mRNA expression of NGF, BDNF, and NT3 was unaffected. From the respective receptors, only TrkA was enhanced when ketamine withdrawal was combined with risperidone or haloperidol. Risperidone also induced BCL-2. Ketamine withdrawal has no effect on the expression of VEGF, MMP2, or BCL-2. It activated the expression of BDNF. This effect was normalized by risperidone or haloperidol. The findings indicate a promoting effect of risperidone and haloperidol on survival of young neurons in the hippocampus by enhancing the expression of the anti-apoptotic protein BCL-2 and by activation of VEGF/MMP2, whereby an interference with ketamine and thus a priority role of the NMDA system was not evident. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 274 | Neuroscience 2010 Sep 169: 1071-84 |
| PMID | 20553817 |
| Title | Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia. |
| Abstract | The brain-derived neurotrophic factor (BDNF) gene contains multiple 5' promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein are reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the four most abundant and best characterized BDNF alternate transcripts, I-IX, II-IX, IV-IX, and VI-IX are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II-IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that BDNF protein expression [including prepro ( approximately 32 kDa), pro ( approximately 28 kDa) and mature ( approximately 14 kDa) BDNF] is reduced in the DLPFC of patients with schizophrenia. We next determined the regional specificity of the BDNF mRNA reduction by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes. The effect of antipsychotics on BDNF alternate transcript expression was also examined and we found no relationship between BDNF mRNA expression and antipsychotic use. As schizophrenic patients are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenic patients treated with antidepressants. Moreover, we found significant reductions in BDNF transcripts II-IX and IV-IX in the parietal cortex and VI-IX in the hippocampus of patients with schizophrenia who did not have a history of treatment with antidepressants. This suggests that down-regulation of at least one out of four major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 275 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Aug 34: 930-3 |
| PMID | 20420877 |
| Title | The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients. |
| Abstract | Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Recent studies have reported that the Val66Met polymorphism of the BDNF gene may be associated with susceptibility for schizophrenia and age of onset of this disease, with mix results. In the present study, the BDNF Val66Met gene polymorphism was examined in 387 inpatients (259 men and 128 women) meeting the DSM-IV criteria for schizophrenia and unrelated 365 healthy controls (255 men and 110 women). The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS). Age of onset was defined as the age at which the psychotic symptoms first appeared. Our results showed that genotype frequency distributions and allelic frequencies did not differ between patients and controls. No interaction was found between sex and genotypes. Analysis of covariance (ANCOVA) showed a significance of the BDNF Val66Met genotypes on the age of onset (F=3.76, p<0.02), after adjusting sex, age and duration of illness. Furthermore, ANCOVA showed that the significance of the BDNFVal66Met genotypes on age of onset was increased comparing the Val66Met heterozygotes with the combination of Val66Val and Met66Met homozygotes (F=5.85, p<0.01). Our results suggest that the BDNF Val66Met polymorphism may not contribute directly to the susceptibility to schizophrenia, but to the onset of the disease. Furthermore, our results show the heterozygous effect of the BDNF Val66Met gene on the clinical variability of schizophrenia phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 276 | World J. Biol. Psychiatry 2010 Mar 11: 251-5 |
| PMID | 20218789 |
| Title | Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse, who were treated with typical or atypical antipsychotics. |
| Abstract | Brain-derived neurotrophic factor signals and dopaminergic function in the brain are strongly associated, and research on BDNF in schizophrenia may enhance our insights on the pathophysiological mechanisms of this disease. In the present study we aimed to investigate the possible association between serum BDNF levels and schizophrenic relapses and the possible differential effects of treatment with typical and atypical antipsychotics on serum BDNF levels in the same group of patients. We measured serum BDNF levels in 47 patients with schizophrenia during a relapse and again 6 weeks after administration of antipsychotic treatment (14 on risperidone, 18 on haloperidol, 10 on olanzapine and five on amisulpride) and in 44 healthy volunteers. Patients with schizophrenia showed reduced serum BDNF levels in relation to healthy volunteers at study entry. No significant differences were revealed in BDNF serum levels after 6 weeks of antipsychotic treatment in the patients compared to their own levels at study entry. However, serum BDNF was significantly increased in the subgroup receiving olanzapine compared to the other antipsychotics. Our findings may indicate a differential effect of olanzapine on BDNF levels compared to haloperidol, risperidone, and amisulpride. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 277 | PLoS ONE 2010 -1 5: e9166 |
| PMID | 20161799 |
| Title | Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. |
| Abstract | Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 278 | Eur. J. Hum. Genet. 2010 Jun 18: 707-12 |
| PMID | 20087404 |
| Title | Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study. |
| Abstract | Risperidone is a widely used atypical antipsychotic agent that produces considerable interindividual differences in patient response. We investigated the pharmacogenetic relationship between the brain-derived neurotrophic factor (BDNF) gene and response to risperidone in 127 Han Chinese schizophrenic patients. Three functional polymorphisms, (GT)(n) dinucleotide repeat polymorphism, C-270T, and the rs6265G/A single-nucleotide polymorphism (SNP), were genotyped and analyzed for association, with reduction of Brief Psychiatric Rating Scale (BPRS) scores following an 8-week period of risperidone monotherapy. For individual polymorphic analysis, we found that the frequency of the 230-bp allele of the (GT)(n) polymorphism was much higher in responders (47.95%) than in nonresponders (32.41%) and the difference was statistically significant even after Bonferroni's adjustment (for the 230-bp allele: adjusted P=0.039). For haplotype-based analyses of the three polymorphisms, no positive finding was observed in the global test, but in specific haplotype tests, two haplotypes were also significantly related to response to risperidone (for haplotype 230-bp/C-270/rs6265G: P=0.0009; for haplotype 234-bp/C-270/rs6265A: P=0.043), indicating that patients with the 230-bp allele of the (GT)(n) polymorphism or the 230-bp/C-270/rs6265G haplotype responded better to risperidone than those with other alleles or haplotypes, and that the positive effect of the individual haplotype 230-bp/C-270/rs6265G was mainly driven by the 230-bp allele. These findings demonstrate that the individual and combinatorial genetic variants in the BDNF gene might have a role in the therapeutic response to risperidone in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 279 | Psychopharmacology (Berl.) 2010 Sep 212: 105-15 |
| PMID | 20623106 |
| Title | The effects of clozapine on quinpirole-induced non-regulatory drinking and prepulse inhibition disruption in rats. |
| Abstract | The biological underpinnings of schizophrenic polydipsia are poorly understood. This study is aimed at fulfilling the requisites of an experimental model of this syndrome through the quinpirole (QNP) induction of non-regulatory drinking in rats. In a first experiment, clozapine (10 and 40 mg/kg p.o.) was substituted for haloperidol during the last 5 days of 10 days QNP (0.5 mg/kg i.p.) administration and water intake measured at 5 h. In a second experiment, animals treated with QNP alone or in combination with clozapine were assessed for water intake and prepulse inhibition (PPI). Expression of genes coding for the dopaminergic D2 receptor, as well as for the early genes BDNF (brain-derived neurotrophic factor) and c-Fos in prefrontal cortex, hippocampus, and striatum was also evaluated. Clozapine prevented QNP-induced drinking at 10 and 40 mg/kg, but only at 40 mg/kg when it was substituted for haloperidol. In the second experiment, QNP-treated rats showed both non-regulatory drinking and PPI disruption. Both these effects were prevented by clozapine 40 mg/kg. QNP-reduced BDNF expression in the hippocampus and increased c-Fos in the prefrontal cortex. This effect was prevented by clozapine. Given by itself, clozapine reduced the expression of both D2 receptors and BDNF in the prefrontal cortex and striatum. The present study lends further support to the hypothesis that non-regulatory drinking induced by QNP in rats is a robust and reliable pharmacological effect that might model psychotic polydipsia also in its sensitivity to clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 280 | World J. Biol. Psychiatry 2010 Mar 11: 256-61 |
| PMID | 20218790 |
| Title | Different patterns of longitudinal changes in plasma levels of catecholamine metabolites and brain-derived neurotrophic factor after administration of atypical antipsychotics in first episode untreated schizophrenic patients. |
| Abstract | In the present study, we longitudinally investigated the effects of risperidone, olanzapine, and aripiprazole on plasma levels of catecholamine metabolites and brain-derived neurotrophic factor (BDNF) in first-episode unmedicated schizophrenic patients. The subjects were 59 Japanese schizophrenic patients (35 males and 24 females; age range: 18-46 years; mean+/-SD: 25+/-16 years). The patients were treated with risperidone (n=32) in a dose range of 2-6 mg/day (mean+/-SD=3.4+/-1.9), olanzapine (n=18) in a dose range of 5-20 mg/day (mean+/-SD=12.1+/-5.8), or aripiprazole (n=9) in a dose range of 12-30 mg/day (mean+/-SD=22.8+/-10.1). All three drugs significantly decreased plasma homovanillic acid (HVA) levels within 8 weeks, although aripiprazole transiently raised this level before 8 weeks. All three drugs also significantly increased plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels within 8 weeks. On the other hand, none of them altered plasma BDNF levels. These results indicate that risperidone, olanzapine, and aripiprazole affect catecholaminergic systems in the brain, that the effects of aripiprazole on the dopaminergic systems seem to slightly different than those of risperidone and olanzapine, and that these atypical antipsychotic drugs might not alter BDNF levels, at least within 8 weeks of treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 281 | Neurosci. Lett. 2011 Nov 505: 282-5 |
| PMID | 22044873 |
| Title | Association of biomarkers and depressive symptoms in schizophrenia. |
| Abstract | Emergence of depressive symptoms in schizophrenia results in a deteriorating course and poor prognosis. schizophrenia and depressive disorder are both associated with low levels of brain-derived neurotrophic factor (BDNF) and with a longstanding low grade inflammatory state. The objective of this study is to analyze the relationship between these serum biomarkers and depressive and psychotic symptoms in schizophrenic patients. Thirty-nine individuals diagnosed with schizophrenia or schizoaffective disorder by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), assessed by Structured Clinical Interview for DSM-IV (SCID), were included. Interviews were conducted with The Positive and Negative Syndrome Scale (PANSS) and The Calgary Depression Scale for schizophrenia (CDSS). Blood samples were collected for determination of BDNF, IL-1beta, IL-6, IL-8, IL-10, IL-12 and TNF-alpha measurements. Positive correlations between BDNF and CDSS and between IL-1beta and severity in PANSS scores were found. BDNF levels were not correlated with any cytokine or with PANSS scores. The results of this study suggest that depressive and psychotic symptoms may be associated with different profiles of biomarkers in the association between schizophrenia and depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 282 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Dec 35: 1836-40 |
| PMID | 21930178 |
| Title | Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 283 | Neurosci. Lett. 2011 Sep 502: 37-40 |
| PMID | 21798311 |
| Title | Decreased serum brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia. |
| Abstract | The pathogenesis of tardive dyskinesia (TD) may involve neurodegeneration and associated dysfunction of brain-derived neurotrophic factor (BDNF) for the survival and maintenance of function in neurons. We therefore compared serum BDNF levels in schizophrenic patients with (n=129) and without TD (n=235), and normal controls (n=323). Assessments included the abnormal involuntary movement scale (AIMS) and the positive and negative syndrome scale (PANSS). Our results were that patients with TD had lower serum BDNF levels than those without TD and normals. Lower serum BDNF levels were correlated with greater PANSS negative subscores, but not correlated with the AIMS scores. Serum BDNF levels did not differ between patients on typical and atypical antipsychotics and were not correlated with antipsychotic doses or years of exposure. We concluded that decreased BDNF levels might be associated with TD pathophysiology and more negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 284 | Neuro Endocrinol. Lett. 2011 -1 32: 246-52 |
| PMID | 21712773 |
| Title | The effects of siRNA-mediated RGS4 gene silencing on the whole genome transcription profile: implications for schizophrenia. |
| Abstract | The regulator of G-protein signaling (RGS) molecules represent a class of proteins that modulate the signaling activity of G-protein coupled receptors. Regulator of G-protein signaling 4 (RGS4) is of particular interest in schizophrenia due to reported downregulation of RGS4 transcripts in schizophrenia as well as a connection between RGS4 and a number of receptors implicated in schizophrenia. The mechanism of RGS4 involvement in the pathophysiology of this illness is not clear. To elucidate thise role of RGS4 in pathophysiology of schizophrenia, we silenced RGS4 using siRNAs in human neuroblastoma cell lines and we studied the effects of differential RGS4 expression by microarray. The cell lines with downregulated expression of RGS4 showed 67 genes with changed expression (30 underexpressed and 37 overexpressed). We have detected three subgroups of genes which might be implicated in schizophrenia pathophysiology: histone genes, which suggest epigenetic mechanisms of the disease; genes for transcription factors associated with other genes relevant to schizophrenia pathology (BDNF and DISCI1) and a heterogeneous group containing genes for G-proteins (GPR50 and GPR64) and calcium binding proteins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 285 | Hum. Immunol. 2011 Sep 72: 746-8 |
| PMID | 21641949 |
| Title | Functional variants of the genes involved in neurodevelopment and susceptibility to schizophrenia in an Armenian population. |
| Abstract | Aberrant neurodevelopment contributes to the etiology of schizophrenia. This study aimed to investigate the potential association of netrin G1 (NTNG1) rs628117 and brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) genetic polymorphisms with susceptibility to schizophrenia. One hundred three Armenian patients with schizophrenia and 105 healthy control subjects were genotyped by polymerase chain reaction with sequence-specific primers. Whereas the NTNG1 rs628117 genotypes were equally distributed in the groups, the carriers of the less common BDNF 66Met allele were overrepresented among patients with schizophrenia when compared with healthy controls (55% vs 35%, odds ratio = 2.28, 95% confidence interval 1.14-1.98, p(corrected) = 0.006). Furthermore, the 66Met/Met genotype correlated with earlier disease onset (p = 0.024). In conclusion, our single-cohort study nominates the BDNF 66Met allele as a risk factor for schizophrenia in an Armenian population. This must be confirmed in other Armenian cohorts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 286 | J Clin Psychopharmacol 2011 Jun 31: 334-6 |
| PMID | 21508862 |
| Title | Reduced brain-derived neurotrophic factor serum concentrations in acute schizophrenic patients increase during antipsychotic treatment. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is not only involved in the development, differentiation, and survival of dopaminergic neurons; it also regulates fast neurotransmission and neuronal activity. In this study, 22 patients with acute schizophrenia and 22 age-matched healthy volunteers were recruited, and BDNF serum concentrations were measured in unmedicated patients and after 2 weeks and 4 weeks of medication. Brain-derived neurotrophic factor serum levels of unmedicated schizophrenic patients (n = 22; 4.38 ± 2.1 ng/mL) were significantly decreased compared to the age-matched healthy volunteers (n = 44, df = 42, P = 0.029). In a mixed-model repeated-measures analysis of variance, a significant BDNF increase has been found during treatment (?² = 2.91; df = 1; P < 0.0001). The percental change of BDNF (increase, 173% ± 110) correlated negatively with the percental change of PANSS score (decrease: 75% ± 22; n = 18; r = -0.554; P = 0.032). Our study replicates studies showing that unmedicated patients with schizophrenia have decreased serum BDNF levels compared with healthy controls. Brain-derived neurotrophic factor increase during treatment seems to parallel positive and negative symptom improvement. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 287 | Neurosci Biobehav Rev 2011 Jan 35: 848-70 |
| PMID | 20951727 |
| Title | Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. |
| Abstract | schizophrenia is a severe mental illness that afflicts nearly 1% of the world's population. One of the cardinal pathological features of schizophrenia is perturbation in synaptic connectivity. Although the etiology of schizophrenia is unknown, it appears to be a developmental disorder involving the interaction of a potentially large number of risk genes, with no one gene producing a strong effect except rare, highly penetrant copy number variants. The purpose of this review is to detail how putative schizophrenia risk genes (DISC-1, neuregulin/ErbB4, dysbindin, Akt1, BDNF, and the NMDA receptor) are involved in regulating neuroplasticity and how alterations in their expression may contribute to the disconnectivity observed in schizophrenia. Moreover, this review highlights how many of these risk genes converge to regulate common neurotransmitter systems and signaling pathways. Future studies aimed at elucidating the functions of these risk genes will provide new insights into the pathophysiology of schizophrenia and will likely lead to the nomination of novel therapeutic targets for restoring proper synaptic connectivity in the brain in schizophrenia and related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 288 | Zh Nevrol Psikhiatr Im S S Korsakova 2011 -1 111: 54-7 |
| PMID | 21423116 |
| Title | [Effect of haloperidol and risperidone on neuromarkers and indices of endothelial dysfunction in patients with acute schizophrenia]. |
| Abstract | Effect of haloperidol and risperidone on positive, negative, neurocognitive disorders, biological parameters and neurodestruction-neuroreparation processes have been studied in 23 patients with the first episode of paranoid schizophrenia. Risperidone, along with high therapeutic effect towards positive, negative, neurocognitive disorders, is able to reduce brain neurodestruction markers as well as to improve protective-compensatory processes directed to the neuroplasticity restoration. There were correlations between biological parameters studied: the higher were levels of GFAP and antibodies to NR2 subunit of NMDA receptors, the higher were BDNF and NO values. The association between parameters studied and psychopathological disorders measured with the PANSS has been found in patients treated with risperidone. The mentioned correlations were not observed in patients treated with haloperidol. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 289 | Neurobiol Learn Mem 2011 Jul 96: 68-78 |
| PMID | 21419233 |
| Title | Epigenetic gene regulation in the adult mammalian brain: multiple roles in memory formation. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is one of numerous gene products necessary for long-term memory formation and dysregulation of BDNF has been implicated in the pathogenesis of cognitive and mental disorders. Recent work indicates that epigenetic-regulatory mechanisms including the markings of histone proteins and associated DNA remain labile throughout the life-span and represent an attractive molecular process contributing to gene regulation in the brain. In this review, important information will be discussed on epigenetics as a set of newly identified dynamic transcriptional mechanisms serving to regulate gene expression changes in the adult brain with particular emphasis on BDNF transcriptional readout in learning and memory formation. This review will also highlight evidence for the role of epigenetics in aberrant BDNF gene regulation in the pathogenesis of cognitive dysfunction associated with seizure disorders, Rett syndrome, schizophrenia, and Alzheimer's disease. Such research offers novel concepts for understanding epigenetic transcriptional mechanisms subserving adult cognition and mental health, and furthermore promises novel avenues for therapeutic approach in the clinic. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 290 | Psychiatry Res 2011 Oct 189: 327-30 |
| PMID | 21320726 |
| Title | Effects of antipsychotics on the serum BDNF levels in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is active during a critical developmental period and likely influences the neuroplasticity of schizophrenia. This study longitudinally examined the effects of atypical antipsychotics on serum BDNF levels in schizophrenic patients. Specifically, this study measured serum BDNF levels in 53 patients with paranoid schizophrenia during a relapse and again 4 weeks following the administration of antipsychotic treatment (with risperidone in 32 cases, and clozapine in 21 cases). BDNF levels remained unchanged relative to study entry after 4 weeks of atypical antipsychotic treatment. However, serum BDNF was significantly increased in the subgroup receiving risperidone compared to that receiving clozapine, albeit only in the 15 male subjects and not in the 17 females. These results suggest that gender might significantly influence the antipsychotic treatment of schizophrenia from the perspective of BDNF. These findings may also indicate that the treatment with atypical antipsychotic agents differentially affects BDNF levels. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 291 | Neurosci. Lett. 2011 Mar 491: 207-10 |
| PMID | 21256922 |
| Title | Serum brain-derived neurotrophic factor and clozapine daily dose in patients with schizophrenia: a positive correlation. |
| Abstract | Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has been shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. To examine serum BDNF, two groups of chronically medicated DSM-IV SZ patients (n=44), on treatment with clozapine (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF levels concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 292 | Curr Opin Psychiatry 2011 Mar 24: 122-7 |
| PMID | 21248641 |
| Title | Brain-derived neurotrophic factor: findings in schizophrenia. |
| Abstract | To review the role of brain-derived neurotrophic factor (BDNF) in neuroplasticity related to schizophrenia and the recent findings that have been reported on the status of BDNF in patients with schizophrenia and its association with the clinical measures. Peripheral BDNF levels have been found altered in first-episode patients with psychosis and also in chronic schizophrenia patients. A few studies have reported changes in peripheral BDNF levels following antipsychotic treatment. The role of Val66Met polymorphism in BDNF has been shown to play an important role in structural and functional plasticity in schizophrenia. Although peripheral BDNF levels hold promise for providing new perspectives for the development of novel therapeutic strategies for the treatment of schizophrenia, additional studies including efforts to prove its potential as a biomarker are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 293 | J ECT 2011 Mar 27: e44-6 |
| PMID | 21206369 |
| Title | Brain-derived neurotrophic factor and electroconvulsive therapy in a schizophrenic patient with treatment-resistant paranoid-hallucinatory symptoms. |
| Abstract | It has been proposed that deficits in the production and the utilization of brain-derived neurotrophic factor (BDNF) may contribute to the pathogenesis of schizophrenia. At the same time, electroconvulsive shock, an experimental model of electroconvulsive therapy (ECT), has been shown to induce an increase of BDNF protein in brains of animal models. These findings suggest that one putative mechanism of action of ECT is the regulation of BDNF and/or related neurotrophins. In this case report, a 54-year-old man with severe treatment-resistant schizophrenic symptoms was treated with ECT. To evaluate the effect of ECT on BDNF serum levels, we collected a blood sample before each ECT session. During the course of ECT treatment, the paranoid and hallucinatory symptoms gradually improved, whereas BDNF levels increased over time. In addition, there was a general improvement of its positive and negative schizophrenic symptoms and depressive state. In conclusion, this case report further validates the therapeutic efficacy of ECT in schizophrenic patients with inadequate or poor response to traditional treatments. Moreover, ECT therapeutic effect is associated with an increase in BDNF serum levels. Further studies are needed to characterize the relationship between BDNF and ECT in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 294 | Neurosci. Lett. 2011 Feb 489: 34-7 |
| PMID | 21129438 |
| Title | The G-712A polymorphism of brain-derived neurotrophic factor is associated with major depression but not schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is needed to support neuronal survival and differentiation. It also promotes synaptic remodeling and modulates the function of many other neurotransmitters. BDNF is implicated in major depression (MD), and to a lesser extent, in schizophrenia. In the current study, we examined BDNF polymorphisms (G-712A, C270T and Val66Met) in 202 patients with MD and 323 patients with schizophrenia. Results were compared to 346 healthy individuals. The analysis revealed a strong association between the G-712A genotype distribution and MD (p=0.0005). The frequency of the -712A allele was significantly higher in MD patients than in the healthy controls (p=0.0007). The -712AG heterozygote was associated with higher Hamilton score in MD patients. No association was found between schizophrenia and the three BDNF variants. These findings support an important role of G-712A polymorphism of BDNF in MD, and may guide future studies to identify genetic risk factors for MD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 295 | Psychol Med 2011 Feb 41: 263-76 |
| PMID | 20102668 |
| Title | Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis? |
| Abstract | Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 296 | Neurosci. Lett. 2011 Nov 505: 282-5 |
| PMID | 22044873 |
| Title | Association of biomarkers and depressive symptoms in schizophrenia. |
| Abstract | Emergence of depressive symptoms in schizophrenia results in a deteriorating course and poor prognosis. schizophrenia and depressive disorder are both associated with low levels of brain-derived neurotrophic factor (BDNF) and with a longstanding low grade inflammatory state. The objective of this study is to analyze the relationship between these serum biomarkers and depressive and psychotic symptoms in schizophrenic patients. Thirty-nine individuals diagnosed with schizophrenia or schizoaffective disorder by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), assessed by Structured Clinical Interview for DSM-IV (SCID), were included. Interviews were conducted with The Positive and Negative Syndrome Scale (PANSS) and The Calgary Depression Scale for schizophrenia (CDSS). Blood samples were collected for determination of BDNF, IL-1beta, IL-6, IL-8, IL-10, IL-12 and TNF-alpha measurements. Positive correlations between BDNF and CDSS and between IL-1beta and severity in PANSS scores were found. BDNF levels were not correlated with any cytokine or with PANSS scores. The results of this study suggest that depressive and psychotic symptoms may be associated with different profiles of biomarkers in the association between schizophrenia and depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 297 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Dec 35: 1836-40 |
| PMID | 21930178 |
| Title | Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 298 | Neurosci. Lett. 2011 Sep 502: 37-40 |
| PMID | 21798311 |
| Title | Decreased serum brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia. |
| Abstract | The pathogenesis of tardive dyskinesia (TD) may involve neurodegeneration and associated dysfunction of brain-derived neurotrophic factor (BDNF) for the survival and maintenance of function in neurons. We therefore compared serum BDNF levels in schizophrenic patients with (n=129) and without TD (n=235), and normal controls (n=323). Assessments included the abnormal involuntary movement scale (AIMS) and the positive and negative syndrome scale (PANSS). Our results were that patients with TD had lower serum BDNF levels than those without TD and normals. Lower serum BDNF levels were correlated with greater PANSS negative subscores, but not correlated with the AIMS scores. Serum BDNF levels did not differ between patients on typical and atypical antipsychotics and were not correlated with antipsychotic doses or years of exposure. We concluded that decreased BDNF levels might be associated with TD pathophysiology and more negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 299 | J Clin Psychopharmacol 2011 Jun 31: 334-6 |
| PMID | 21508862 |
| Title | Reduced brain-derived neurotrophic factor serum concentrations in acute schizophrenic patients increase during antipsychotic treatment. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is not only involved in the development, differentiation, and survival of dopaminergic neurons; it also regulates fast neurotransmission and neuronal activity. In this study, 22 patients with acute schizophrenia and 22 age-matched healthy volunteers were recruited, and BDNF serum concentrations were measured in unmedicated patients and after 2 weeks and 4 weeks of medication. Brain-derived neurotrophic factor serum levels of unmedicated schizophrenic patients (n = 22; 4.38 ± 2.1 ng/mL) were significantly decreased compared to the age-matched healthy volunteers (n = 44, df = 42, P = 0.029). In a mixed-model repeated-measures analysis of variance, a significant BDNF increase has been found during treatment (?² = 2.91; df = 1; P < 0.0001). The percental change of BDNF (increase, 173% ± 110) correlated negatively with the percental change of PANSS score (decrease: 75% ± 22; n = 18; r = -0.554; P = 0.032). Our study replicates studies showing that unmedicated patients with schizophrenia have decreased serum BDNF levels compared with healthy controls. Brain-derived neurotrophic factor increase during treatment seems to parallel positive and negative symptom improvement. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 300 | Psychiatry Res 2011 Oct 189: 327-30 |
| PMID | 21320726 |
| Title | Effects of antipsychotics on the serum BDNF levels in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is active during a critical developmental period and likely influences the neuroplasticity of schizophrenia. This study longitudinally examined the effects of atypical antipsychotics on serum BDNF levels in schizophrenic patients. Specifically, this study measured serum BDNF levels in 53 patients with paranoid schizophrenia during a relapse and again 4 weeks following the administration of antipsychotic treatment (with risperidone in 32 cases, and clozapine in 21 cases). BDNF levels remained unchanged relative to study entry after 4 weeks of atypical antipsychotic treatment. However, serum BDNF was significantly increased in the subgroup receiving risperidone compared to that receiving clozapine, albeit only in the 15 male subjects and not in the 17 females. These results suggest that gender might significantly influence the antipsychotic treatment of schizophrenia from the perspective of BDNF. These findings may also indicate that the treatment with atypical antipsychotic agents differentially affects BDNF levels. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 301 | J ECT 2011 Mar 27: e44-6 |
| PMID | 21206369 |
| Title | Brain-derived neurotrophic factor and electroconvulsive therapy in a schizophrenic patient with treatment-resistant paranoid-hallucinatory symptoms. |
| Abstract | It has been proposed that deficits in the production and the utilization of brain-derived neurotrophic factor (BDNF) may contribute to the pathogenesis of schizophrenia. At the same time, electroconvulsive shock, an experimental model of electroconvulsive therapy (ECT), has been shown to induce an increase of BDNF protein in brains of animal models. These findings suggest that one putative mechanism of action of ECT is the regulation of BDNF and/or related neurotrophins. In this case report, a 54-year-old man with severe treatment-resistant schizophrenic symptoms was treated with ECT. To evaluate the effect of ECT on BDNF serum levels, we collected a blood sample before each ECT session. During the course of ECT treatment, the paranoid and hallucinatory symptoms gradually improved, whereas BDNF levels increased over time. In addition, there was a general improvement of its positive and negative schizophrenic symptoms and depressive state. In conclusion, this case report further validates the therapeutic efficacy of ECT in schizophrenic patients with inadequate or poor response to traditional treatments. Moreover, ECT therapeutic effect is associated with an increase in BDNF serum levels. Further studies are needed to characterize the relationship between BDNF and ECT in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 302 | Brain Behav 2011 Nov 1: 119-24 |
| PMID | 22399091 |
| Title | Genetic association of the Phosphoinositide-3 kinase in schizophrenia and bipolar disorder and interaction with a BDNF gene polymorphism. |
| Abstract | Phosphoinositide-3-kinase, class III (PIK3C3) is a member of the phosphoinosite-3-kinases family, involved in cell signaling, membrane trafficking, and neurodevelopment. Previous studies have indeed shown an association between PIK3C3 gene variants and both bipolar disorder (BD) and schizophrenia (SZ). Brain-derived neurotrophic factor (BDNF) is a neurodevelopmental factor, which can regulate the PI3K signaling pathway. Associations have been reported between BDNF gene polymorphisms and affective and psychotic disorders. The aim of the present study was to replicate an association between PIK3C3 and BDNF gene variants in SZ and BD and a putative epistasis between the two genes. Patients meeting the DSM-IV criteria of BD and SZ were included in this study (98 BD and 79 SZ) as well as 158 healthy controls. Blood DNA was extracted and genotyping was performed either by the polymerase chain reaction (PCR) technique followed by enzymatic digestion or by the high-resolution melt (HRM) method. Genotype and haplotype association was assessed with the UNPHASED statistical program.The results showed one nominal association with BD (P < 0.02) and two risk haplotypes in both SZ (P < 0.001) and BP (P < 0.0005), which survived multiple testing correction. A modest interaction between a BDNF variant and PI3KC3 polymorphism was observed (P < 0.04).These preliminary results confirm the genetic association of PI3K gene variants with both SZ and BD, and support the hypothesis that SZ and BD share a genetic background. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 303 | Int J Adolesc Med Health 2011 -1 23: 181-5 |
| PMID | 22191181 |
| Title | The role of brain-derived neurotrophic factor in the pathophysiology of adolescent suicidal behavior. |
| Abstract | Adolescent suicide research has mostly focused on demographic risk factors. Such studies focus on who is at risk, but do not explain why certain adolescents are at risk for suicide. Studies of the neurobiology of adolescent suicide could clarify why some youths are more suicidal than others and help to find biological markers of suicidal behavior in teenagers. Over the past decade the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior has attracted significant attention of scientists. BDNF is involved in the pathophysiology of many psychiatric disorders associated with suicidal behavior including depression, post-traumatic stress disorder, schizophrenia, and obsessive-compulsive disorder. BDNF dysregulation could be associated with increased suicidality independently of psychiatric diagnoses. BDNF plays an important role in the regulation and growth of neurons during childhood and adolescence. Prominent among the brain regions undergoing developmental change during adolescence are stressor-sensitive areas. The serotonin dysfunction found in adolescent and adult suicidal behavior could be related to the low level of BDNF, which impedes the normal development of serotonin neurons during brain development. BDNF dysfunction could play a more significant role in the pathophysiology of psychiatric disorders and suicidal behavior in adolescents than in adults. Treatment-induced enhancement in the BDNF function could reduce suicidal behavior secondary to the improvement in psychiatric pathology or independently of improvement in psychiatric disorders. It is interesting to hypothesize that BDNF could be a biological marker of suicidal behavior in adolescents or in certain adolescent populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 304 | Brain Res. 2011 Oct 1417: 146-50 |
| PMID | 21917241 |
| Title | Lack of effect of brain derived neurotrophic factor (BDNF) Val66Met polymorphism on early onset schizophrenia in Chinese Han population. |
| Abstract | schizophrenia is a chronic psychiatric disorder with high heritability. schizophrenic patients with early-age onset tend to have a greater genetic component and may be an attractive subpopulation for genetic studies. Brain-derived neurotrophic factor (BDNF) is considered a candidate gene for schizophrenia. A single nucleotide polymorphism (BDNF Val66Met) was reported to be associated with schizophrenia, although discrepancy remains. The aim of this study was to evaluate the association between BDNF Val66Met polymorphism and schizophrenia using an early onset sample in the Chinese Han population. Our sample consisted of 353 schizophrenic patients with onset before age 18 and 394 healthy controls. All subjects were of an ethnically homogenous Han Chinese origin. No significant differences of genotype or allele distribution were identified between the patients and controls. However, the Met allele was significantly associated with an earlier age of onset in male schizophrenic patients (Kaplan-Meier log-rank test P=0.005), but not in females (P=0.289). The BDNF Val66Met polymorphism has an important effect on the age of onset of schizophrenia in a gender-specific manner. This may represent a significant genetic clue for the etiology of schizophrenia and thus, further studies are required to uncover the exact role of BDNF in the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 305 | Neurosci. Res. 2011 Dec 71: 335-40 |
| PMID | 21893111 |
| Title | Effects of antipsychotic drugs on BDNF, GSK-3?, and ?-catenin expression in rats subjected to immobilization stress. |
| Abstract | Brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3? (GSK-3?), and ?-catenin have been reported to be altered in patients with schizophrenia and have been targeted by antipsychotic drugs. Atypical antipsychotics, but not typical antipsychotics, exert neuroprotective effects by regulating these proteins. In this study, we analyzed the effects of the atypical antipsychotic drugs olanzapine and aripiprazole and a typical antipsychotic drug, haloperidol, on the expression of BDNF, phosphorylated GSK-3?, and ?-catenin in the hippocampus of rats subjected to immobilization stress. Rats were subjected to immobilization stress 6h/day for 3 weeks. The effects of olanzapine (2 mg/kg), aripiprazole (1.5 mg/kg), and haloperidol (1.0 mg/kg) were determined on BDNF, serine?-phosphorylated GSK-3?, and ?-catenin expression by Western blotting. Immobilization stress significantly decreased the expression of BDNF, phosphorylated GSK-3?, and ?-catenin in the hippocampus. Chronic administration of olanzapine and aripiprazole significantly attenuated the decreased expression of these proteins in the hippocampus of rats caused by immobilization stress, and significantly increased the levels of these proteins even without the immobilization stress. However, chronic haloperidol had no such effect. These results suggest that olanzapine and aripiprazole may exert beneficial effects by upregulating BDNF, phosphorylated GSK-3?, and ?-catenin in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 306 | Neuromolecular Med. 2011 Dec 13: 328-33 |
| PMID | 21956459 |
| Title | Association study of brain-derived neurotrophic factor gene polymorphisms and body weight change in schizophrenic patients under long-term atypical antipsychotic treatment. |
| Abstract | schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain, which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the brain-derived neurotrophic factor (BDNF) gene may be associated with body weight change after AAP treatment. The study included 481 schizophrenic patients treated with clozapine (n = 266), olanzapine (n = 79), or risperidone (n = 136) for an average of 49.2 ± 28.2 months. Three common single-nucleotide polymorphisms (SNPs) of the BDNF gene were chosen as tagging SNPs. In single-marker-based analysis, the BDNF rs11030101-T homozygous genotype was found to be associated with significantly increased body weight gain (P = 0.037). The BDNF Val66Met (rs6265) polymorphism was not found to be associated with body weight gain. Haplotype analysis further showed that the rs11030101-T-allele-related haplotype is also associated with increased body weight gain (P = 0.047). Our findings suggest that there is a nominal association with rs11030101 but did not replicate the previously found relationship between the BDNF Val66Met polymorphism and body weight gain during long-term AAP treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 307 | J Neural Transm (Vienna) 2011 Nov 118: 1621-39 |
| PMID | 21688113 |
| Title | Neurocognitive-genetic and neuroimaging-genetic research paradigms in schizophrenia and bipolar disorder. |
| Abstract | Studies examining intermediate phenotypes such as neurocognitive and neuroanatomical measures along with susceptibility genes are important for improving our understanding of the neural basis of schizophrenia (SZ) and bipolar disorder (BD). In this paper, we review extant studies involving neurocognitive-genetic and neuroimaging-genetic perspectives and particularly related to catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin-1 (NRG1) genes in SZ and BD. In terms of neurocognitive-genetic investigations, COMT and BDNF are the two most studied candidate genes especially in patients with SZ. Whereas BDNF Met carriers perform worse on verbal working memory, problem solving and visuo-spatial abilities, COMT Met carriers perform better in working memory, attention, executive functioning with evidence of genotype by diagnosis interactions including high-risk individuals. In terms of genetic-structural MRI studies, patients with SZ are found to have reductions in the frontal, temporal, parietal cortices, and limbic regions, which are associated with BDNF, COMT, and NRGI genes. Genetic-functional MRI studies in psychotic disorders are sparse, especially with regard to BD. These neurocognitive and neuroimaging findings are associated with genes which are implicated in functional pathways related to neuronal signaling, inter-neuronal communication and neuroplasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 308 | J Affect Disord 2011 Oct 133: 646-54 |
| PMID | 21612826 |
| Title | Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder. |
| Abstract | The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders. We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n=15 each). While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12-34%) compared to the control (P=0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P=0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12-30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB-immunoreactive band, consistent with a truncated isoform, in all 60 cases. On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant. Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 309 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Aug 35: 1738-43 |
| PMID | 21601610 |
| Title | Expression of Ca²?-dependent activator protein for secretion 2 is increased in the brains of schizophrenic patients. |
| Abstract | Ca(2+)-dependent activator protein for secretion 2 (CADPS2), a secretory granule associate protein, mediates monoamine transmission and the release of neurotrophins including brain-derived neurotrophic factor (BDNF) which have been implicated in psychiatric disorders. Furthermore, the expression of CADPS2deltaExon3, a defective splice variant of CADPS2, has been reported to be associated with autism. Based on these observations, we examined whether expression levels of CADPS2 and CADPS2deltaExon3 are altered in psychiatric disorders. Quantitative polymerase chain reaction analysis was performed for postmortem frontal cortex tissues (BA6) from 15 individuals with schizophrenia, 15 with bipolar disorder, 15 with major depression, and 15 controls (Stanley neuropathology consortium). The mean CADPS2 expression levels normalized to human glyceraldehyde-3phosphate dehydrogenase (GAPDH) or TATA-box binding protein levels was found to be significantly increased in the brains of the schizophrenia group, compared to the control group. On the other hand, the ratio of CADPS2deltaExon3 to total CADPS2 was similar in the 4 diagnostic groups. We then analyzed CADPS2 expression in blood samples from 121 patients with schizophrenia and 318 healthy controls; however, there was no significant difference between the two groups. Chronic risperidone treatment did not alter the expression of CADPS2 in frontal cortex of mice. The observed increase in the expression of CADPS2 may be related to the impaired synaptic function in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 310 | Mol. Pharmacol. 2011 Jul 80: 174-82 |
| PMID | 21505039 |
| Title | Activation of group II metabotropic glutamate receptors promotes DNA demethylation in the mouse brain. |
| Abstract | Activation of group II metabotropic glutamate receptors (mGlu2 and -3 receptors) has shown a potential antipsychotic activity, yet the underlying mechanism is only partially known. Altered epigenetic mechanisms contribute to the pathogenesis of schizophrenia and currently used medications exert chromatin remodeling effects. Here, we show that systemic injection of the brain-permeant mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268; 0.3-1 mg/kg i.p.) increased the mRNA and protein levels of growth arrest and DNA damage 45-? (Gadd45-?), a molecular player of DNA demethylation, in the mouse frontal cortex and hippocampus. Induction of Gadd45-? by LY379268 was abrogated by the mGlu2/3 receptor antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495; 1 mg/kg i.p.). Treatment with LY379268 also increased the amount of Gadd45-? bound to specific promoter regions of reelin, brain-derived neurotrophic factor (BDNF), and glutamate decarboxylase-67 (GAD67). We directly assessed gene promoter methylation in control mice and in mice pretreated for 7 days with the methylating agent methionine (750 mg/kg i.p.). Both single and repeated injections with LY379268 reduce cytosine methylation in the promoters of the three genes, although the effect on the GAD67 was significant only in response to repeated injections. Single and repeated treatment with LY379268 could also reverse the defect in social interaction seen in mice pretreated with methionine. The action of LY379268 on Gadd45-? was mimicked by valproate and clozapine but not haloperidol. These findings show that pharmacological activation of mGlu2/3 receptors has a strong impact on the epigenetic regulation of genes that have been linked to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 311 | Schizophr. Res. 2011 Jul 129: 201-4 |
| PMID | 21470828 |
| Title | Association of serum BDNF levels with hippocampal volumes in first psychotic episode drug-naive schizophrenic patients. |
| Abstract | Evidence suggests that hippocampal volumetric abnormalities are present in first-episode schizophrenia. The hippocampus contains the highest brain levels of neurotrophic factors, which are major determinants of neuronal plasticity. Brain-derived neurotrophic factor (BDNF) influences neuronal survival, differentiation, synaptogenesis, and maintenance and is also correlated with neuronal activation in the hippocampus. BDNF is also involved in the development and modulation of dopaminergic-related systems. Alterations of serum BDNF levels have been shown in a number of studies with first episode patients with schizophrenia, probably reflecting an association between BDNF and the pathogenesis of the disorder. In the present study we investigated the correlation between serum BDNF levels and hippocampal volumes in a sample of first episode drug-naïve patients with schizophrenia (FEP) and healthy control subjects. We found that hippocampal volume (HV) was decreased in FEP patients. Corrected right HV of FEP patients were significantly smaller compared to corrected right HVs of healthy subjects. The serum BDNF levels in the sample of FEP patients was significantly reduced compared to the healthy subjects. A significant positive association was found between serum BDNF and the corrected right HV in the group of patients such that the smaller the HV, the more reduced the serum BDNF levels. (Pearson r=0.452, p=0.045). Our findings indicate that low serum BDNF levels are associated with reduction in HV at the onset of schizophrenia and may further support the theory of a neuroprogressive-neurotoxic reaction associated with the onset of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 312 | J. Biol. Chem. 2011 Jun 286: 21535-45 |
| PMID | 21464126 |
| Title | Structural and functional impairments of polysialic acid by a mutated polysialyltransferase found in schizophrenia. |
| Abstract | Polysialic acid (polySia), a unique acidic glycan modifying neural cell adhesion molecule (NCAM), is known to regulate embryonic neural development and adult brain functions. Polysialyltransferase STX is responsible for the synthesis of polySia, and two single nucleotide polymorphisms (SNPs) of the coding region of STX are reported from schizophrenic patients: SNP7 and SNP9, respectively, giving STX(G421A) with E141K and STX(C621G) with silent mutations. In this study, we focused on these mutations and a binding activity of polySia to neural materials, such as brain-derived neurotrophic factor (BDNF). Here we describe three new findings. First, STX(G421A) shows a dramatic decrease in polySia synthetic activity on NCAM, whereas STX(C621G) does not. The STX(G421A)-derived polySia-NCAM contains a lower amount of polySia with a shorter chain length. Second, polySia shows a dopamine (DA) binding activity, which is a new function of polySia as revealed by frontal affinity chromatography for measuring the polySia-neurotransmitter interactions. Interestingly, the STX(G421A)-derived polySia-NCAM completely loses the DA binding activity, whereas it greatly diminishes but does not lose the BDNF binding activity. Third, an impairment of the polySia structure with an endosialidase modulates the DA-mediated Akt signaling. Taken together, impairment of the amount and quality of polySia may be involved in psychiatric disorders through impaired binding to BDNF and DA, which are deeply involved in schizophrenia and other psychiatric disorders, such as depression and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 313 | Physiol. Behav. 2011 Aug 104: 334-9 |
| PMID | 21382392 |
| Title | Strain dependent effects of prenatal stress on gene expression in the rat hippocampus. |
| Abstract | Multiple animal models have been developed to recapitulate phenotypes of the human disease, schizophrenia. A model that simulates many of the cognitive and sensory deficits of the disorder is the use of random variable prenatal stress (PS) in the rat. These deficits suggest a molecular origin in the hippocampus, a brain region that plays a role in the regulation of stress. To study both hippocampal gene expression changes in offspring of prenatally stressed dams and to address genetic variability, we used a random array of prenatal stressors in three different rat strains with diverse responses to stress: Fischer, Sprague-Dawley, and Lewis rats. Candidate genes involved in stress, schizophrenia, cognition, neurotrophic effects, and immunity were selected for assessment by real-time quantitative PCR under resting conditions and following a brief exposure to restraint stress. PS resulted in significant differences in gene expression in the offspring that were strain dependent. mRNA expression for the N-methyl-D-aspartate receptor subtype 2B (Grin2b) was increased, and tumor necrosis factor-alpha (Tnf?) transcript was decreased in PS Sprague-Dawley and Lewis rats, but not in the Fischer rats. Expression of brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus was increased after an acute stress in all controls of each strain, yet a decrease was seen after acute stress in the PS Sprague-Dawley and Lewis rats. Expression of the glucocorticoid receptor (Nr3c1) was decreased in the Fischer strain when compared to Lewis or Sprague-Dawley rats, though the Fischer rats had markedly higher ?7 nicotinic receptor (Chrna7) expression. The expression differences seen in these animals may be important elements of the phenotypic differences seen due to PS and genetic background. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 314 | Eur. J. Neurosci. 2011 Apr 33: 1197-204 |
| PMID | 21366724 |
| Title | Ciproxifan, a histamine H?-receptor antagonist?/?inverse agonist, modulates methamphetamine-induced sensitization in mice. |
| Abstract | The role of histamine neurons in schizophrenia and psychostimulant abuse remains unclear. Behavioural sensitization to psychostimulants is a cardinal feature of these disorders. Here, we have explored the ability of imetit and ciproxifan (CPX), a reference H?-receptor agonist and inverse agonist, respectively, to modulate locomotor sensitization induced in mice by methamphetamine (MET). Mice received saline, CPX (3 mg/kg) or imetit (3 mg/kg) 2 h before MET (2 mg/kg), once daily for 12 days, and were killed after a 2-day wash out. Imetit had no effect, but CPX induced a decrease of MET-induced locomotor activity, which became significant at Day 5, and even more at Day 10. Quantitative polymerase chain reaction was used in the sensitized mice to quantify brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA)-receptor subunit 1 (NR1) mRNAs, two factors that are altered in both schizophrenia and drug abuse. Imetit and CPX used alone had no effect on any marker. Sensitization by MET decreased BDNF mRNAs by 40% in the hippocampus. This decrease was reversed by CPX. Sensitization by MET also induced strong decreases of NR1 mRNAs in the cerebral cortex, hippocampus and striatum, but not hypothalamus. These decreases were also reversed by CPX. The strong modulator effect of CPX in mice sensitized to MET may result from its modulator effect on NR1 mRNAs in the cerebral cortex and striatum. The reversal by CPX of BDNF and NR1 mRNAs in the hippocampus of sensitized animals further strengthens the interest of H?-receptor inverse agonists for the long-term treatment of cognitive deficits of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 315 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Apr 156B: 363-9 |
| PMID | 21305693 |
| Title | Age at onset of psychotic disorder: cannabis, BDNF Val66Met, and sex-specific models of gene-environment interaction. |
| Abstract | Discovering modifiable predictors for age at onset may help to identify predictors of transition to psychotic disorder in the "at-risk mental state." Inconsistent effects of sex, BDNF Val66Met (rs6265), and cannabis use on age of onset were previously reported. BDNF Val66Met and cannabis use before illness onset were retrospectively assessed in a sample of 585 patients with schizophrenia and their association with age at onset was evaluated. Cannabis use was significantly associated with earlier age at onset of psychotic disorder (AOP; average difference 2.7 years, P?BDNF Val66Met genotype and AOP (difference 1.2 years; P?=?0.050). No evidence was found for BDNF?×?cannabis interaction (interaction ?(2) (1)?=?0.65, P?=?0.420). However, a significant BDNF?×?cannabis?×?sex interaction was found (interaction ?(2) (1)?=?4.99, P?=?0.026). In female patients, cannabis use was associated with earlier AOP in BDNF Met-carriers (difference 7 years), but not in Val/Val-genotypes. In male patients, cannabis use was associated with earlier AOP irrespective of BDNF Val66Met genotype (difference 1.3 years). BDNF Val66Met genotype in the absence of cannabis use did not influence AOP, neither in female or male patients with psychotic disorder. Complex interactions between cannabis and BDNF may shape age at onset in female individuals at risk of psychotic disorder. No compelling evidence was found that BDNF genotype is associated with age at onset of psychotic disorder in the absence of cannabis use. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 316 | Brain Res. 2011 Apr 1384: 51-60 |
| PMID | 21281620 |
| Title | Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice. |
| Abstract | Altered expression of neurotrophins may contribute to the pathogenesis of schizophrenia. Several studies suggest sex steroid hormones may be involved in the regulation of brain-derived neurotrophic factor (BDNF) signaling, as well as the symptoms of schizophrenia. This study aimed to identify sex differences in BDNF-TrkB signaling in the forebrain of wild type (WT) and BDNF heterozygous (+/-) mice. Protein expression of neurotrophins and TrkB were measured by Western blot analysis in brain regions pertinent to schizophrenia, namely the frontal cortex, striatum, and dorsal (DHP) and ventral hippocampus (VHP). In both the frontal cortex and striatum, protein expression levels of phosphorylated TrkB (pTrkB) over total TrkB (pTrkB/TrkB) was significantly increased in male, but not female BDNF(+/-) mice, suggesting sex-specific changes in TrkB signaling. pTrkB/TrkB levels were also elevated in the DHP of both male and female BDNF(+/-), while levels remained unchanged in the VHP, indicating region-specific changes in TrkB signaling. Sex-specific phosphorylation of TrkB corresponded with downstream changes in ERK2 phosphorylation in the frontal cortex and striatum. No sex-specific effects of genotype were found in the expression of TrkB ligands, BDNF and NT-4. However, a marked, region-specific increase in NT-4 expression was found in the striatum of both male and female BDNF(+/-) mice. In conclusion, there are complex sex- and region-specific changes in BDNF-TrkB signaling in BDNF(+/-) mice. These results provide new insight into sex-dependent BDNF signaling in forebrain regions and assist in understanding the role of neurotrophins in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 317 | J Psychiatry Neurosci 2011 May 36: 195-203 |
| PMID | 21223646 |
| Title | Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. |
| Abstract | Brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor (trkB-TK+) and glutamic acid decarboxylase (GAD67) mRNA levels have previously been found to be reduced in the prefrontal cortex of patients with schizophrenia. To determine whether this reduction extends to other brain regions, we measured the expression levels of BDNF, trkB-TK+ and GAD67 mRNA in regions of the hippocampus, including the dentate gyrus (DG), cornu ammonis subfields (CA1-4), subiculum and entorhinal cortex (EC) of individuals with schizophrenia, bipolar disorder, major depression and unaffected controls. In situ hybridization was performed on postmortem brain tissue obtained from the Stanley Foundation Consortium and analyzed using film-based quantification. Analyses of covariance comparing the expression of mRNA among all groups revealed a significant decrease in BDNF mRNA in CA4 in the bipolar disorder group compared with controls (33%). We found trkB-TK+ mRNA levels to be significantly reduced in CA4 in the schizophrenia group (36%) and in layer II of the EC in the bipolar disorder and major depression groups (28%, 21%, respectively) compared with controls. In addition, GAD67 mRNA levels were reduced in patients with schizophrenia in both the DG (23%) and CA4 (60%) compared with controls. Individuals with major depression also expressed significantly less GAD67 mRNA (44%) compared with controls in CA4 of the hippocampus. It is necessary to account for factors that influence the molecular preservation in postmortem brain tissue, including pH, postmortem interval and tissue storage time. Moreover, there are limitations to the sensitivity of the film-based method of quantification. Our findings show abnormal BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders, indicating that fundamental properties of hippocampal signalling transmission, plasticity and circuitry may be affected in individuals with these major mental illnesses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 318 | Int. J. Neuropsychopharmacol. 2011 Jun 14: 573-84 |
| PMID | 21208484 |
| Title | SSRI augmentation of antipsychotic alters expression of GABA(A) receptor and related genes in PMC of schizophrenia patients. |
| Abstract | Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of each drug alone. To examine the clinical relevance of these findings, the current study examined the effects of SSRI augmentation treatment on GABA(A) receptor and related systems in schizophrenia patients. schizophrenia patients with high levels of negative symptoms unresponsive to antipsychotic treatment received add-on fluvoxamine (100 mg/d). Blood was taken before and 1, 3 and 6 wk after adding fluvoxamine and peripheral mononuclear cells (PMC) isolated. RNA encoding for GABA(A)?3, 5-HT2A, and 5-HT7 receptors, PKC?2, and brain-derived neurotrophic factor (BDNF) was assayed with real-time RT-PCR. Plasma BDNF protein was assayed using ELISA. Clinical symptoms were assessed with validated rating scales. We found significant increase in mRNA encoding for GABA(A)?3 and 5-HT2A, 5-HT7 receptors and BDNF and a reduction in PKC?2 mRNA. Plasma BDNF protein concentrations were increased. There were significant correlations among the genes. Clinical symptoms improved significantly. mRNA expression of PKC?2, 5-HT2A and 5-HT7 showed significant associations with clinical symptoms. Combined SSRI+antipsychotic treatment is associated with changes in GABA(A) receptor and in related signalling systems in patients. These changes may be part of the mechanism of clinically effective drug action and may prove to be biomarkers of pharmacological response. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 319 | Brain Res. Bull. 2011 Feb 84: 144-50 |
| PMID | 21134422 |
| Title | The influence of N-desmethylclozapine and clozapine on recognition memory and BDNF expression in hippocampus. |
| Abstract | Clozapine, which is the most effective treatment option for treatment-refractory schizophrenia, has been reported to have both positive and negative effects on specific cognitive symptoms in patients with schizophrenia and in animal models of cognition. Clozapine has a major metabolite, N-desmethylclozapine (NDMC), which has been suggested to be more effective than clozapine itself to improve cognition. Enhancement of brain derived neurotrophic factor (BDNF) expression in the hippocampus has been proposed to contribute to the cognitive-enhancing effects of antipsychotic drugs. The aims of this study were to investigate the change in short and long term memory as assessed by the novel object recognition (NOR) test and BDNF expression in hippocampus produced by an acute hypoglutamatergic model of memory impairment in schizophrenia induced by administration of the NMDA receptor non-competitive antagonist, MK-801 and the ability of clozapine and NDMC to prevent the deleterious effects of MK-801. Both short (1 h) and long-term (24 h) memory were impaired in MK-801 (0.1 mg/kg) - and clozapine (5 mg/kg)-, but not NDMC (5 mg/kg)-treated rats. Neither NDMC (5 mg/kg) nor clozapine (5 mg/kg) reversed the effect of MK-801. Western blotting studies showed that BDNF levels in hippocampus were not different in rats administered MK-801 alone, clozapine or NDMC alone. These results show that in this model clozapine affects memory negatively, while NDMC does not. The absence of impairment of NOR with NDMC is consistent with previous evidence that it has a more benign effect on cognition than does the parent compound, and may support the efforts to study its effects on other cognitive functions. These findings do not provide any support for the role of BDNF in the MK-801-induced impairment in NOR or for differences between clozapine and NDMC. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 320 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Mar 35: 356-62 |
| PMID | 21044653 |
| Title | Brain derived neurotrophic factor Val66Met polymorphism and psychotic symptoms in Alzheimer's disease. |
| Abstract | Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder with a high prevalence. Since behavioral disturbances, such as psychotic symptoms, represent a key feature of AD, genes related to dopamine, serotonin and brain derived neurotrophic factor (BDNF), are considered as candidate genes for AD. BDNF is a neurotrophin that regulates neurodevelopment, neuroplasticity, and neuronal functions. BDNF is involved in the etiopathogenesis of psychiatric and neurodegenerative disorders. A single base pair polymorphism (BDNF Val66Met) was reported to be associated with AD and/or schizophrenia, as well as other psychoses, although some studies failed to replicate these findings. The aim of the study was to evaluate the association between BDNF Val66Met variants and AD, as well as onset of AD or presence of psychotic symptoms in AD. BDNF Val66Met was analyzed in 211 patients with AD and in 402 aged healthy control subjects. All subjects were ethnically homogenous Caucasians from Croatia, and were subdivided according to the gender, onset of AD, and presence of psychotic symptoms. A ?(2) test, with Bonferroni correction and standardized residuals were used to evaluate the data. Distribution of the BDNF Val66Met genotypes differed significantly between male and female AD patients with or without psychotic symptoms. This difference was due to the significant contribution of the Met/Val genotype and the combined Met/Met and Met/Val genotypes between psychotic and non-psychotic symptoms in male, but not in female patients with AD. The frequency of the gene variants of the BDNF Val66Met did not differ significantly among male and female patients with AD and control subjects, or between male and female patients with early or late onset AD. There were significant sex related differences in age, duration of illness and scores of dementia between patients with AD. Our male patients were younger, had shorter duration of illness, and had less severe dementia and higher cognitive performance than female AD patients. The gene variants of the BDNF Val66Met polymorphism were significantly associated with the presence of psychotic symptoms in male, but not in female patients with AD. The results had adequate statistical power to suggest that BDNF Val66Met was not related to susceptibility to AD or the onset of AD, but that presence of one or two Met alleles of BDNF Val66Met polymorphism might present a risk factor for psychosis in AD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 321 | J. Mol. Neurosci. 2011 Mar 43: 337-45 |
| PMID | 20852970 |
| Title | Phencyclidine (PCP)-induced disruption in cognitive performance is gender-specific and associated with a reduction in brain-derived neurotrophic factor (BDNF) in specific regions of the female rat brain. |
| Abstract | Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n=8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p<0.05), motor cortex (p<0.01), orbital cortex (p<0.01), olfactory bulb (p<0.05), retrosplenial cortex (p<0.001), frontal cortex (p<0.01), parietal cortex (p<0.01), CA1 (p<0.05) and polymorphic layer of dentate gyrus (p<0.05) of the hippocampus and the central (p<0.01), lateral (p<0.05) and basolateral (p<0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p<0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 322 | Mol. Psychiatry 2011 Sep 16: 960-72 |
| PMID | 20733577 |
| Title | Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. |
| Abstract | Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Several studies report reduced peripheral (blood) levels of BDNF in schizophrenia, but findings are inconsistent. We undertook the first systematic review with meta-analysis of studies examining blood BDNF levels in schizophrenia compared with healthy controls, and examined potential effects of age, gender and medication. Included are individual studies of BDNF blood (serum or plasma) levels in schizophrenia (including schizoaffective disorder, or first episode psychosis), compared with age-matched healthy controls, obtained by electronic Medline and Embase searches, and hand searching. The decision to include or exclude studies, data extraction and quality assessment were completed by two independent reviewers. The initial search revealed 378 records, of which 342 were excluded on reading the Abstract, because they did not examine BDNF blood levels in schizophrenia compared with healthy controls. Of 36 papers screened in full, 17 were eligible for inclusion, but one was subsequently removed as an outlier. The remaining 16 studies provided moderate quality evidence of reduced blood BDNF levels in schizophrenia (Hedges g=-0.458, 95% confidence interval=-0.770 to -0.146, P<0.004, random effects model). Subgroup analyses reveal reduced BDNF in both drug-naïve and medicated patients, and in males and females with schizophrenia. Meta-regressions showed an association between reduced BDNF in schizophrenia and increasing age, but no effects of medication dosage. Overall, blood levels of BDNF are reduced in medicated and drug-naïve patients with schizophrenia; this evidence is of moderate quality, that is, precise but with considerable, unexplained heterogeneity across study results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 323 | World J. Biol. Psychiatry 2011 Feb 12: 42-7 |
| PMID | 20726824 |
| Title | Parent of origin effect and differential allelic expression of BDNF Val66Met in suicidal behaviour. |
| Abstract | Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since BDNF levels are decreased in brain and plasma of suicide victims. Because the differential allelic expression of Val66Met BDNF gene on suicidal behaviour has not been investigated, we analyzed the parent-of-origin effect (POE) in suicide attempters and the differential expression of BDNF Val66Met alleles in suicide victims. We performed a family-based association study and ETDT analyses of the Val66Met polymorphism in nuclear families with at least one subject affected by major psychosis with suicidal behaviour, and compared allele-specific mRNA levels in post-mortem brain samples from suicide and non-suicide victims. The subjects included in this study have diagnosis of schizophrenia, bipolar disorder type I and type II. Allele 3 in the GT repeat polymorphism was transmitted significantly more often to patients who attempted suicide (maternal transmissions: 46/22, P = 0.003; paternal transmissions: 55/30, P = 0.006). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of Val/Met-specific mRNA expression between suicide victims and controls. These data do not support a role for allelic imbalance or POE of BDNF for suicidal behaviour in major psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 324 | Int. J. Dev. Neurosci. 2011 May 29: 351-8 |
| PMID | 20691775 |
| Title | Changes in gene expression after phencyclidine administration in developing rats: a potential animal model for schizophrenia. |
| Abstract | Repeated administration of phencyclidine (PCP), an N-methyl-d-aspartate (NMDA) receptor antagonist, during development, may result in neuronal damage that leads to behavioral deficits in adulthood. The present study examined the potential neurotoxic effects of PCP exposure (10mg/kg) in rats on postnatal days (PNDs) 7, 9 and 11 and the possible underlying mechanism(s) for neurotoxicity. Brain tissue was harvested for RNA extraction and morphological assessments. RNA was collected from the frontal cortex for DNA microarray analysis and quantitative RT-PCR. Gene expression profiling was determined using Illumina Rat Ref-12 Expression BeadChips containing 22,226 probes. Based on criteria of a fold-change greater than 1.4 and a P-value less than 0.05, 19 genes including NMDAR1 (N-methyl-d-aspartate receptor) and four pro-apoptotic genes were up-regulated, and 25 genes including four anti-apoptotic genes were down-regulated, in the PCP-treated group. In addition, the schizophrenia-relevant genes, BDNF (Brain-derived neurotrophic factor) and Bhlhb2 (basic helix-loop-helix domain containing, class B, 2), were significantly different between the PCP and the control groups. Quantitative RT-PCR confirmed the microarray results. Elevated neuronal cell death was further confirmed using Fluoro-Jade C staining. These findings support the hypothesis that neurodegeneration caused by PCP occurs, at least in part, through the up-regulation of NMDA receptors, which makes neurons possessing these receptors more vulnerable to endogenous glutamate. The changes in schizophrenia-relevant genes after repeated PCP exposure during development may provide important information concerning the validation of an animal model for this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 325 | J Psychiatr Res 2011 Feb 45: 273-9 |
| PMID | 20630543 |
| Title | Low serum truncated-BDNF isoform correlates with higher cognitive impairment in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a key factor in learning and memory. Altered BDNF-signalling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. However, analysis of serum BDNF as a potential biomarker in schizophrenia has provided controversial data. We hypothesized that these confounding results might be due to a differential regulation of BDNF precursor pro-BDNF (32 KDa) and proteolytic products mature (mat-BDNF; 14 KDa), and truncated-BDNF (28 KDa). Accordingly, we investigated the serum abundance of these BDNF isoforms and its relationship with cognitive impairment in schizophrenia. schizophrenia was diagnosed with PANSS test. Abbreviated cognitive assessment included tests for attention, perceptual-motor skills, processing speed and memory. Using an ELISA assay, we found a slight reduction in serum BDNF levels in SZ patients (n = 40) with respect to healthy controls (HC, n = 40; p = 0.018). Western-blot analysis revealed increased serum pro-BDNF and mat-BDNF and reduced truncated-BDNF (p < 0.001) in SZ with respect to HC. Patients with an increase in pro-BDNF (n = 15/40) or mat-BDNF (n = 9/40) higher than the HC mean + 2 Standard Deviations (SD) also had >2SD reduction of truncated-BDNF (n = 27/40). Reduced truncated-BDNF correlated significantly with higher positive and lower negative PANNS scores and a worst performance in all cognitive assays but not with antipsychotic type. Measurement of serum truncated-BDNF abundance predicted for high cognitive deficits with sensitivity = 67.5%, specificity = 97.5%, Negative Predictive Value = 75% and Positive Predictive Value = 96.4%. These results suggest deficiency in pro-BDNF processing as a possible biological mechanism underlying schizophrenia with cognitive impairment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 326 | Eur. Psychiatry 2011 Jan 26: 57-63 |
| PMID | 20434315 |
| Title | Comparison of brain N-acetylaspartate levels and serum brain-derived neurotrophic factor (BDNF) levels between patients with first-episode schizophrenia psychosis and healthy controls. |
| Abstract | N-acetylaspartate (NAA) levels and serum brain-derived neurotrophic factor (BDNF) levels in patients with first-episode schizophrenia psychosis and age- and sex-matched healthy control subjects were investigated. In addition, plasma levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were compared between the two groups. Eighteen patients (nine males, nine females; age range: 13-52 years) were enrolled in the study, and 18 volunteers (nine males, nine females; age range: 15-49 years) with no current or past psychiatric history were also studied by magnetic resonance spectroscopy (MRS) as sex- and age-matched controls. Levels of NAA/Cr in the left basal ganglia (p=0.0065) and parieto-occipital lobe (p=0.00498), but not in the frontal lobe, were significantly lower in patients with first-episode schizophrenia psychosis than in control subjects. No difference was observed between the serum BDNF levels of patients with first-episode schizophrenia psychosis and control subjects. In regard to the plasma levels of catecholamine metabolites, plasma MHPG, but not HVA, was significantly lower in the patients with first-episode psychosis than in control subjects. In addition, a significantly positive correlation was observed between the levels of NAA/Cr of the left basal ganglia and plasma MHPG in all subjects. These results suggest that brain NAA levels in the left basal ganglia and plasma MHPG levels were significantly reduced at the first episode of schizophrenia psychosis, indicating that neurodegeneration via noradrenergic neurons might be associated with the initial progression of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 327 | Schizophr Bull 2011 Sep 37: 988-1000 |
| PMID | 20100784 |
| Title | Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia. |
| Abstract | Retrovirus has been suggested as one of agents involved in the development of schizophrenia. In the present study, we examined the role of the human endogenous retrovirus W family (HERV-W) env gene in the etiopathogenesis of recent-onset schizophrenia, using molecular and epidemiological approaches. Nested RT-PCR was used to detect the messenger RNA (mRNA) of the HERV-w env gene in plasmas. Quantitative real-time polymerase chain reaction (PCR) was employed to detect the viral reverse transcriptase activity in human sera. Human U251 glioma cells were used to study the potential role of the HERV-W env gene in the etiopathogenesis of recent-onset schizophrenia. We identified genes with mRNA sequences homologous to HERV-W env gene from plasmas of 42 out of 118 individuals with recent-onset schizophrenia but not from any of 106 normal persons (P < .01, t test). Quantitative real-time PCR showed a significantly increase in the reverse transcriptase activity in the sera of patients (by 35.59%) compared with controls (by 2.83%) (P < .05, t test). Overexpression of HERV-w env in human U251 glioma cells upregulated brain-derived neurotrophic factor (BDNF), an important schizophrenia-associated gene, neurotrophic tyrosine kinase receptor type 2 (NTRK2, also called TrkB), and dopamine receptor D3 and increased the phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein. BDNF promoter reporter gene assays showed that the HERV-W env triggers BDNF production in human U251 glioma cells. Using gene knockdown, we found that CREB is required for the expression of BDNF that is regulated by env. Our data revealed that the transcriptional activation of HERV is associated with the development of schizophrenia in some patients and indicated that HERV-W env regulates the expression of schizophrenia-associated genes. This report is the first to elucidate the signaling pathway responsible for the upregulation of HERV-W env-triggered BDNF. Our study provides new evidence for the involvement of HERV-W in the central nervous system, which will benefit the diagnosis and treatment of the devastating schizophrenia and related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 328 | Brain Res. 2011 Oct 1417: 146-50 |
| PMID | 21917241 |
| Title | Lack of effect of brain derived neurotrophic factor (BDNF) Val66Met polymorphism on early onset schizophrenia in Chinese Han population. |
| Abstract | schizophrenia is a chronic psychiatric disorder with high heritability. schizophrenic patients with early-age onset tend to have a greater genetic component and may be an attractive subpopulation for genetic studies. Brain-derived neurotrophic factor (BDNF) is considered a candidate gene for schizophrenia. A single nucleotide polymorphism (BDNF Val66Met) was reported to be associated with schizophrenia, although discrepancy remains. The aim of this study was to evaluate the association between BDNF Val66Met polymorphism and schizophrenia using an early onset sample in the Chinese Han population. Our sample consisted of 353 schizophrenic patients with onset before age 18 and 394 healthy controls. All subjects were of an ethnically homogenous Han Chinese origin. No significant differences of genotype or allele distribution were identified between the patients and controls. However, the Met allele was significantly associated with an earlier age of onset in male schizophrenic patients (Kaplan-Meier log-rank test P=0.005), but not in females (P=0.289). The BDNF Val66Met polymorphism has an important effect on the age of onset of schizophrenia in a gender-specific manner. This may represent a significant genetic clue for the etiology of schizophrenia and thus, further studies are required to uncover the exact role of BDNF in the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 329 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Aug 35: 1738-43 |
| PMID | 21601610 |
| Title | Expression of Ca²?-dependent activator protein for secretion 2 is increased in the brains of schizophrenic patients. |
| Abstract | Ca(2+)-dependent activator protein for secretion 2 (CADPS2), a secretory granule associate protein, mediates monoamine transmission and the release of neurotrophins including brain-derived neurotrophic factor (BDNF) which have been implicated in psychiatric disorders. Furthermore, the expression of CADPS2deltaExon3, a defective splice variant of CADPS2, has been reported to be associated with autism. Based on these observations, we examined whether expression levels of CADPS2 and CADPS2deltaExon3 are altered in psychiatric disorders. Quantitative polymerase chain reaction analysis was performed for postmortem frontal cortex tissues (BA6) from 15 individuals with schizophrenia, 15 with bipolar disorder, 15 with major depression, and 15 controls (Stanley neuropathology consortium). The mean CADPS2 expression levels normalized to human glyceraldehyde-3phosphate dehydrogenase (GAPDH) or TATA-box binding protein levels was found to be significantly increased in the brains of the schizophrenia group, compared to the control group. On the other hand, the ratio of CADPS2deltaExon3 to total CADPS2 was similar in the 4 diagnostic groups. We then analyzed CADPS2 expression in blood samples from 121 patients with schizophrenia and 318 healthy controls; however, there was no significant difference between the two groups. Chronic risperidone treatment did not alter the expression of CADPS2 in frontal cortex of mice. The observed increase in the expression of CADPS2 may be related to the impaired synaptic function in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 330 | Schizophr. Res. 2011 Jul 129: 201-4 |
| PMID | 21470828 |
| Title | Association of serum BDNF levels with hippocampal volumes in first psychotic episode drug-naive schizophrenic patients. |
| Abstract | Evidence suggests that hippocampal volumetric abnormalities are present in first-episode schizophrenia. The hippocampus contains the highest brain levels of neurotrophic factors, which are major determinants of neuronal plasticity. Brain-derived neurotrophic factor (BDNF) influences neuronal survival, differentiation, synaptogenesis, and maintenance and is also correlated with neuronal activation in the hippocampus. BDNF is also involved in the development and modulation of dopaminergic-related systems. Alterations of serum BDNF levels have been shown in a number of studies with first episode patients with schizophrenia, probably reflecting an association between BDNF and the pathogenesis of the disorder. In the present study we investigated the correlation between serum BDNF levels and hippocampal volumes in a sample of first episode drug-naïve patients with schizophrenia (FEP) and healthy control subjects. We found that hippocampal volume (HV) was decreased in FEP patients. Corrected right HV of FEP patients were significantly smaller compared to corrected right HVs of healthy subjects. The serum BDNF levels in the sample of FEP patients was significantly reduced compared to the healthy subjects. A significant positive association was found between serum BDNF and the corrected right HV in the group of patients such that the smaller the HV, the more reduced the serum BDNF levels. (Pearson r=0.452, p=0.045). Our findings indicate that low serum BDNF levels are associated with reduction in HV at the onset of schizophrenia and may further support the theory of a neuroprogressive-neurotoxic reaction associated with the onset of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 331 | J. Biol. Chem. 2011 Jun 286: 21535-45 |
| PMID | 21464126 |
| Title | Structural and functional impairments of polysialic acid by a mutated polysialyltransferase found in schizophrenia. |
| Abstract | Polysialic acid (polySia), a unique acidic glycan modifying neural cell adhesion molecule (NCAM), is known to regulate embryonic neural development and adult brain functions. Polysialyltransferase STX is responsible for the synthesis of polySia, and two single nucleotide polymorphisms (SNPs) of the coding region of STX are reported from schizophrenic patients: SNP7 and SNP9, respectively, giving STX(G421A) with E141K and STX(C621G) with silent mutations. In this study, we focused on these mutations and a binding activity of polySia to neural materials, such as brain-derived neurotrophic factor (BDNF). Here we describe three new findings. First, STX(G421A) shows a dramatic decrease in polySia synthetic activity on NCAM, whereas STX(C621G) does not. The STX(G421A)-derived polySia-NCAM contains a lower amount of polySia with a shorter chain length. Second, polySia shows a dopamine (DA) binding activity, which is a new function of polySia as revealed by frontal affinity chromatography for measuring the polySia-neurotransmitter interactions. Interestingly, the STX(G421A)-derived polySia-NCAM completely loses the DA binding activity, whereas it greatly diminishes but does not lose the BDNF binding activity. Third, an impairment of the polySia structure with an endosialidase modulates the DA-mediated Akt signaling. Taken together, impairment of the amount and quality of polySia may be involved in psychiatric disorders through impaired binding to BDNF and DA, which are deeply involved in schizophrenia and other psychiatric disorders, such as depression and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 332 | PLoS ONE 2011 -1 6: e28656 |
| PMID | 22194877 |
| Title | Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3'UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3'UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3'UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3'UTR functional variants altering miRNAs-BDNF binding. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 333 | Curr. Pharm. Des. 2012 -1 18: 5024-35 |
| PMID | 22716151 |
| Title | Gene-environment interactions underlying the effect of cannabis in first episode psychosis. |
| Abstract | Cannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 334 | Mol. Psychiatry 2012 Oct 17: 1007-16 |
| PMID | 21788944 |
| Title | Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications. |
| Abstract | AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use--lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 335 | Psychiatr Danub 2012 Sep 24 Suppl 1: S95-9 |
| PMID | 22945197 |
| Title | The differences between typical and atypical antipsychotics: the effects on neurogenesis. |
| Abstract | Recently, the pharmacological division between typical and atypical antipsychotics has been called into question. New evidence, however, continues to emerge showing differences between these two classes of drugs. Hence typical and atypical antipsychotics are clearly different classes of drugs, as evidenced by their actions, mechanisms, effects and side effects. The most recently investigated field in which both classes of drugs have opposing effects is neuron survival and neurogenesis. schizophrenia has been found to be a disease of progressive reductions in grey matter, and the more lost, the worse the outcome. Medication naive patients have lowered levels of neurotrophins e.g. NT-3, NGF BDNF. The antipsychotic drugs alter the levels of these neurotrophins. Haloperidol, of the typical antipsychotics, causes neuron apoptosis by a free radical induced mechanism, involving Bcl-XS, P53, cytochrome c translocation and caspase 3 activation. Haloperidol also lowers BDNF levels, reducing neuroprotection in the brain to enable haloperidol's toxic effects. Atypical drugs have opposing effects. They increase levels of BDNF, improve cell survival and enhance neurogenesis. Atypical drugs can also prevent or reverse the effects of haloperidol induced toxicity. The mechanism involves the inverse agonism of 5HT receptors, particularly those of the 2A subset, but the situation is considerably more complicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 336 | Isr J Psychiatry Relat Sci 2012 -1 49: 137-42 |
| PMID | 22801293 |
| Title | Evidence for an association between brain-derived neurotrophic factor Val66Met gene polymorphism and general intellectual ability in early-onset schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) plays a crucial role in the survival, development and maintenance of neuronal systems, and the Val66Met polymorphism has been implicated in memory functions. We examined the association of BDNF with general intellectual ability in 161 individuals including 53 early-onset patients with schizophrenia (EOS), 91 healthy biological relatives, and 17 relatives with major depressive disorder (MDD), using the Wechsler Intelligence Scales (WISC). Regardless of diagnosis, individuals with the Met66 allele had a significantly higher performance score than those homozygous for Val66 on vocabulary, block design and object assembly subtests of the WISC. EOS probands showed poor performance on all IQ subtests compared with relatives with and without MDD. Relatively smaller sample size of individual genotypes. BDNF genotype may play a role in specific cognitive functions and dimensions of intelligence. The Met allele appears to be associated with superior performance in IQ compared with relatives Val/Val genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 337 | Integr Biol (Camb) 2012 Sep 4: 1096-101 |
| PMID | 22777684 |
| Title | The severity of mental disorders is linked to interaction among candidate genes. |
| Abstract | There is a considerable overlap in the manifestation of symptoms in three mental disorders namely unipolar disorder, bipolar disorder and schizophrenia. A gene coexpression network was developed based on a mutual information approach including four candidate genes (NRG1, DISC1, BDNF and COMT) along with other coexpressing genes in unipolar disorder, bipolar disorder and schizophrenia. There is a significant difference in the degree distribution of nodes between normal and bipolar disorder network and bipolar disorder network and schizophrenia network. Moreover, there is a differential direct connectivity among candidate genes in various mental disorders and between normal and mental disorders. All candidate genes are directly connected to each other in schizophrenia except one pair (NRG1-BDNF) indicating a strong role of inter-gene interactions in the manifestation of severe symptoms in this disease. DISC1 and NRG1 are key hub genes in the unipolar disorder network and the bipolar disorder network but have lost the role of hub genes in schizophrenia network, despite their significant association with schizophrenia. This study indicates that the three psychiatric diseases may not have discrete classes but three phenotypic manifestations of the same continuous disease based on severity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 338 | Genet. Mol. Res. 2012 -1 11: 725-30 |
| PMID | 22576830 |
| Title | BDNF and DARPP-32 genes are not risk factors for schizophrenia in the Malay population. |
| Abstract | A number of studies have pointed to the association of BDNF (brain-derived neurotrophic factor) and DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) with schizophrenia. The purpose of this study was to determine whether these two genes are involved in the pathogenesis of schizophrenia in the Malay population. Two single nucleotide polymorphisms Val66Met of BDNF, -2036C>G and g.1238delG of DARPP-32 were genotyped in the Malay population in 200 patients with schizophrenia and 256 healthy controls. Analysis of allele and genotype frequencies in these two groups revealed no significant association of BDNF or DARPP-32 polymorphisms with schizophrenia in Malays. This is the first such association study in the Malay population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 339 | J Psychiatr Res 2012 Jun 46: 762-6 |
| PMID | 22521161 |
| Title | Brain-derived neurotrophic factor Val66Met polymorphism and obsessive-compulsive symptoms in Egyptian schizophrenia patients. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been advanced as a candidate gene for schizophrenia. BDNF promote the function and growth of 5-HT neurons in the brain and modulate the synaptic plasticity of DRD3-secreting neurons in the striatum, suggesting involvement of BDNF in the mediation of obsessive-compulsive disorder. To test the hypothesis that the BDNF Val66Met polymorphism influence obsessive-compulsive symptoms (OCS) in schizophrenia, we examined the association between the BDNF Val66Met genotypes and OCS in a group of patients with schizophrenia. 320 schizophrenia patients were assessed using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). BDNF Val66Met polymorphism was genotyped using PCR-RFLP method, and severity of OCS were compared between the genotype groups. Out of the 320 schizophrenia patients, 120 patients (37.5%) had significant OCS. There was a significant excess of valine allele in the schizophrenia with-OCS group compared to the without-OCS group. The mean YBOCS scores were significantly different among the three genotype groups. Val/Val homozygote patients had higher mean YBOCS scores compared to Val/Met genotype (p = 0.0001) as well as to the Met/Met homozygote group (p = 0.003). Our data suggested an association between BDNF Val66Met polymorphism and OCS in Egyptian schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 340 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012 Apr 29: 155-8 |
| PMID | 22487823 |
| Title | [Association study of brain-derived neurotrophic factor Val66Met polymorphism and clinical characteristics of first episode schizophrenia]. |
| Abstract | To assess the association between brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism and clinical characteristics of first episode schizophrenia in a Chinese Han population. Genotyping of BDNF Val66Met polymorphism was carried out for 135 schizophrenic patients and 483 healthy controls with TaqMan probe technology. The patients' psychotic symptoms were assessed using the positive and negative syndrome scale (PANSS). A significant difference was found in genotype distribution and allelic frequency of the Val66Met polymorphism between the two groups (P< 0.01). In patients, Met homozygotes had a significantly higher score in anxiety/depression factor, cognitive factor and total score of PANSS than Val carriers. BDNF gene Val66Met polymorphism is associated with the pathogenesis of schizophrenia. The Met/Met genotype of BDNF Val66Met variant may be a risk factor for symptoms in first episode schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 341 | Pharmacol. Rev. 2012 Apr 64: 238-58 |
| PMID | 22407616 |
| Title | Brain-derived neurotrophic factor and neuropsychiatric disorders. |
| Abstract | Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 342 | Psychopharmacology (Berl.) 2012 Jul 222: 277-84 |
| PMID | 22274000 |
| Title | Low BDNF is associated with cognitive impairment in chronic patients with schizophrenia. |
| Abstract | Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. schizophrenia has a range of cognitive deficits that may evolve from decreased BDNF, and this study examines this association of BDNF with cognitive deficits in schizophrenia. We recruited 251 chronic schizophrenic patients and 206 healthy control subjects and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF in both groups. schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale. BDNF levels were significantly lower in patients than controls (p??0.05) were significantly lower in schizophrenic patients than normal controls. For the patients, BDNF was positively associated with immediate memory in schizophrenia. Our findings suggest that BDNF may be involved in the pathophysiology of schizophrenia, and its associated cognitive impairment, especially immediate memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 343 | Scientifica (Cairo) 2012 -1 2012: 560514 |
| PMID | 24278715 |
| Title | The Association between COMT, BDNF, and NRG1 and Premorbid Social Functioning in Patients with Psychosis, Their Relatives, and Controls. |
| Abstract | We investigated the influences of putative candidate genes for psychosis on premorbid social adjustment and on premorbid schizoid-schizotypal traits. A family-based sample was used including 177 patients with schizophrenia or bipolar I disorder with a history of psychotic symptoms, 86 of their unaffected relatives, and 116 unrelated healthy controls. Association analyses on the combined sample were conducted using the Statistical Analysis for Genetic Epidemiology software (SAGE) and adjusting for age, sex, clinical group, and the family-based nature of the data. The COMT Val(158)Met and BDNF Val(66)Met polymorphisms showed no evidence of association with either phenotype. The SNP rs221533 of the NRG1 gene was significantly associated with premorbid adjustment in adolescence with TT homozygous subjects having a poorer performance than C allele carriers. In the context of neurodevelopmental disorders such as schizophrenia and other psychoses, this finding is plausible; however, it is preliminary and requires replication in an independent sample. In a broader sense, the use of intermediate quantitative phenotypes such as the ones presented in this study may be of help to understand the mechanism of action of genetic risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 344 | Neuropsychobiology 2012 -1 65: 1-11 |
| PMID | 22094229 |
| Title | Influence of BDNF variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia. |
| Abstract | The present study aimed to explore whether some single nucleotide polymorphisms (SNPs) within the BDNF gene could be associated with major depression (MD), bipolar disorder (BD) and schizophrenia, and whether they could predict clinical outcomes in Korean inpatients treated with antidepressants, mood stabilizers and antipsychotics, respectively. One hundred and forty-five patients with MD, 132 patients with BD, 221 patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for 5 BDNF SNPs (rs2030324, rs7103873, rs10835210, rs11030101 and rs6265). Baseline and final clinical measures--including the Montgomery-Asberg Depression Rating Scale, Young Mania Rating Scale and Positive and Negative Symptoms Scale for patients with MD, BD and schizophrenia, respectively--were recorded. rs10835210 CA and rs11030101 AT genotype frequencies were higher in BD and schizophrenia patients than in healthy and MD subjects. No significant association was found with clinical improvement. Our findings provide evidence of an association between BDNF and BD and schizophrenia. However, taking into account the several limitations of our study, including the moderately small sample size, further research is needed to draw more definitive conclusions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 345 | J Psychiatr Res 2012 Jan 46: 1-11 |
| PMID | 22030467 |
| Title | The role of BDNF in the pathophysiology and treatment of schizophrenia. |
| Abstract | Brain derived neurotrophic factor (BDNF) has been associated with the pathophysiology of schizophrenia (SCZ). However, it remains unclear whether alterations in BDNF observed in patients with SCZ are a core part of disease neurobiology or a consequence of treatment. In this manuscript we review existing knowledge relating the function of BDNF to synaptic transmission and neural plasticity and the relationship between BDNF and both pharmacological and non-pharmacological treatments for SCZ. With regards to synaptic transmission, exposure to BDNF or lack of this neurotrophin results in alteration to both excitatory and inhibitory synapses. Many authors have also evaluated the effects of both pharmacological and non-pharmacological treatments for SCZ in BDNF and despite some controversial results, it seems that medicated and non-medicated patients present with lower levels of BDNF when compared to controls. Further data suggests that typical antipsychotics may decrease BDNF expression whereas mixed results have been obtained with atypical antipsychotics. The authors found few studies reporting changes in BDNF after non-pharmacological treatments for SCZ, so the existing evidence in this area is limited. Although the study of BDNF provides some new insights into understanding of the pathophysiology and treatment of SCZ, additional work in this area is needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 346 | Clin Psychopharmacol Neurosci 2012 Aug 10: 61-70 |
| PMID | 23431036 |
| Title | A Review of Brain-derived Neurotrophic Factor as a Candidate Biomarker in Schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF), a neurotrophin known to be responsible for development, regeneration, survival and maintenance of neurons has been implicated in the pathophysiology of schizophrenia. This review seeks to complement previous reviews on biological roles of BDNF and summarizes evidence on the involvement of BDNF in the pathophysiology of schizophrenia with an emphasis on clinical relevance. The expressions of BDNF were altered in patients with schizophrenia and were found to be correlated with psychotic symptomatology. Antipsychotics appeared to have differential effects on expression of BDNF but did not restore BDNF expression of patients with schizophrenia to normal levels. In addition, evidence suggests that BDNF is involved in the major neurotransmitter systems and is associated with disruptions in brain structure, neurodevelopmental process, cognitive function, metabolic and immune systems commonly associated with schizophrenia. Besides that, BDNF has been demonstrated to be tightly regulated with estrogen which has also been previously implicated in schizophrenia. Evidence gathered in this review confirms the relevance of BDNF in the pathophysiology of schizophrenia and the potential utility of BDNF as a suitable biomarker for diagnostic and prognostic purposes for disease outcome and other co-morbidities. However, further investigations are warranted to examine the specificity of BDNF in schizophrenia compared to other neurodegenerative disorders and other neuropsychiatric illness. Longitudinal prospective studies will also be of added advantage for evaluation of prognostic utility of BDNF in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 347 | Mol. Psychiatry 2012 Sep 17: 887-905 |
| PMID | 22584867 |
| Title | Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. |
| Abstract | We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 348 | Transl Psychiatry 2012 -1 2: e173 |
| PMID | 23092977 |
| Title | Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation. |
| Abstract | The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 349 | Clin Transl Sci 2012 Dec 5: 486-90 |
| PMID | 23253673 |
| Title | The influence of the brain-derived neurotropic factor Val66Met genotype and HMG-CoA reductase inhibitors on insulin resistance in the schizophrenia and bipolar populations. |
| Abstract | The brain-derived neurotrophic factor (BDNF) Val66Met variant and HMG-COA reductase inhibitors (statins) have been implicated in insulin resistance with a possible increased risk of diabetes. We sought to determine the effect of the BDNF Met variant and statin medication use on insulin resistance in schizophrenia and bipolar disorder using the homeostasis model assessment of insulin resistance (HOMA-IR). A cross-sectional design was used and patients with diabetes or on any medications affecting glucose regulation were -excluded. Associations between insulin resistance and genotype were then analyzed by ANOVA and regression analysis. Subjects were grouped by BDNF genotype as well as presence of statin. Two hundred fifty-two subjects with a mean age of 44 years were included. The group was 53% male and 41% had a diagnosis of bipolar disorder; 78% and 19% were receiving atypical antipsychotics (AAPs) and statin medications, respectively. Analysis showed schizophrenia subjects with the BDNF met allele as well as schizophrenia subjects with both the BDNF met allele and were receiving a statin had significantly higher HOMA-IR values compared to the other groups (p= 0.046 and p= 0.016, respectively). Our results suggest that in the metabolically high-risk population of schizophrenia the BDNF met allele alone and in combination with statin medications is associated with higher insulin resistance values. This was not seen in the bipolar population. Further validation of these associations remains necessary. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 350 | Zh Nevrol Psikhiatr Im S S Korsakova 2012 -1 112: 39-44 |
| PMID | 23250597 |
| Title | [An association study of polymorphisms in HTR2A, BDNF and SLC6A4 genes with paranoid schizophrenia and suicidal behavior]. |
| Abstract | We have developed a biochip for the analysis of candidate genes for schizophrenia. Using this biochip, allele and genotype frequencies for the polymorphisms of HTR2A, BDNF and SLC6A4 genes in 198 patients with schizophrenia and 192 healthy individuals have been obtained. The allele T of the HTR2A polymorphism rs6314 was identified as protective against the development of paranoid schizophrenia (p=0,014). An analysis of gene-gene interactions using the Multifactor-Dimensionality Reduction (MDR) algorithm has shown a statistically significant association of combined genotypes rs6311 G/-, rs6313 C/-, rs6314 C/C, rs7997012 G/- with the disease (p=0.019). Also it has been shown that the G/G genotype of the polymorphism rs6311 (p=0.013) and the C/C genotype of the polymorphism rs6313 (p=0.008) in the HTR2A gene are associated with the suicide attempt in schizophrenic patients. Correspondingly, an A allele, ?/- genotypes of the polymorphism rs6311 G>A and a T allele, T/- genotypes of the polymorphism rs6313 C>T were found to be less frequent in schizophrenic patients with a history of suicide attempt than in schizophrenic patients without a history of suicide attempt, thus suggesting their protective role in the development of suicidal behavior. The results confirm the hypothesis that the HTR2A plays an important role in the etiology of schizophrenia and suicidal behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 351 | Curr Neuropharmacol 2012 Jun 10: 139-58 |
| PMID | 23204984 |
| Title | Somatic drugs for psychiatric diseases: aspirin or simvastatin for depression? |
| Abstract | The evolution in the understanding of the neurobiology of most prevalent mental disorders such as major depressive disorder (MDD), bipolar disorder or schizophrenia has not gone hand in hand with the synthesis and clinical use of new drugs that would represent a therapeutic revolution such as that brought about by selective serotonin reuptake inhibitors (SSRIs) or atypical antipsychotics. Although scientists are still a long way from understanding its true aetiology, the neurobiological concept of depression has evolved from receptor regulation disorder, to a neurodegenerative disorder with a hippocampal volume decrease with the controversial reduction in neurotrophins such as BDNF, to current hypotheses that consider depression to be an inflammatory and neuroprogressive process. As regards antidepressants, although researchers are still far from knowing their true mechanism of action, they have gone from monoaminergic hypotheses, in which serotonin was the main protagonist, to emphasising the anti-inflammatory action of some of these drugs, or the participation of p11 protein in their mechanism of action.In the same way, according to the inflammatory hypothesis of depression, it has been proposed that some NSAIDS such as aspirin or drugs like simvastatin that have an anti-inflammatory action could be useful in some depressive patients. Despite the fact that there may be some data to support their clinical use, common sense and the evidence advise us to use already tested protocols and wait for the future to undertake new therapeutic strategies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 352 | Shanghai Arch Psychiatry 2012 Dec 24: 328-34 |
| PMID | 25324637 |
| Title | Relationship between brain-derived neurotrophic factor gene C270T polymorphisms and the psychotic symptoms and cognitive functioning of patients with schizophrenia. |
| Abstract | Findings from previous studies linking brain-derived neurotrophic factor (BDNF) and schizophrenia are inconsistent and few studies have assessed the relationship between BDNF C270T gene polymorphisms and the clinical and cognitive symptoms of schizophrenia. Compare the prevalence of the BDNF C270T gene polymorphisms between patients with schizophrenia and controls and, in the patients, assess the relationship of genotypes to the severity of symptoms. BDNF C270T genotype and allele frequency were measured using Polymerase Chain Reaction methods in 224 drug-free patients with schizophrenia and 220 controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was assessed using the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT). In the patient group, differences in severity of symptoms across the three genotypes (i.e., C/C, C/T, and T/T) of C270T were assessed using one-way analysis of variance. The frequency of the T allele was much higher in patients than in controls (15.6% vs. 4.3%, ?(2)=31.47, p<0.001) and the C/T genotype was more common among patients than controls (27.7% vs. 7.7%, ?(2)=34.93, p<0.001). Compared to controls, patients performed poorly on all the cognitive tests, but there were no significant differences in the cognitive measures between patients with the three different genotypes. The total PANSS score, the PANSS negative symptoms subscale score, and the PANSS general psychopathology subscale score were not significantly different between the three groups of patients. However, the PANSS positive symptoms subscale score showed a small, statistically significant elevation in the severity of positive symptoms in the C/T genotype compared to the C/C genotype. We confirm previous findings about differences in the prevalence of the BDNF C270T gene polymorphisms in schizophrenia, but do not find strong evidence of a relationship between different genotypes and the severity of the clinical or cognitive symptoms of schizophrenia. Clinical and cognitive symptoms in schizophrenia fluctuate over the course of the illness and with treatment, so stable, individual-specific measures of these parameters (that is, traits) need to be identified before it will be possible to definitively assess their relationship to different genotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 353 | Mol. Biol. Rep. 2012 Dec 39: 10889-93 |
| PMID | 23065263 |
| Title | DNA methylation and expression profiles of the brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes in patients with schizophrenia. |
| Abstract | Methylation and expression profile of CpG islands were examined in the promoters of the brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes. These are well known to be involved in the pathophysiology of psychiatric disorders such as schizophrenia. Genomic DNA was extracted from peripheral blood of 80 patients with schizophrenia and 71 healthy controls. Methylation pattern was studied by Methylation-Specific PCR. RNA expression analysis was done on extracted RNA from blood samples from patients suffering from schizophrenia (n = 17) and healthy controls (n = 17). Frequency of the BDNF gene methylation was highlighted as a statistically significant relationship between cases and controls regarding decreased risk of disease in comparison to unmethylated patterns (OR = 0.24; 95 % CI = 1.11-0.50; P = 0.00007). For the DAT1 gene, this relationship was insignificant in 61 cases (76.25 %) and 52 controls (73.23 %) (OR = 1.17; 95 % CI = 0.53-2.61). Estimates of relative gene expression revealed a statistically significant association of the BDNF gene between schizophrenic patients and healthy controls (Mean ± SD: 13.3920 ± 15.19 and 0.437 ± 0.328, P = 0.0001) respectively; however, it was not significant for the DAT1 gene. This first hand evidence, regarding BDNF and DAT1 gene methylation and their expression profile with risk of schizophrenia, indicated a significant function for the BDNF gene in the development of schizophrenia. However, further populations with large sample sizes need to be studied to verify the exact role of BDNF in mental disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 354 | Shanghai Arch Psychiatry 2012 Oct 24: 250-61 |
| PMID | 25328348 |
| Title | Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia: A systematic review. |
| Abstract | There is increasing interest in the role of brain-derived neurotrophic factor (BDNF) in the onset and course of schizophrenia, but there are conflicting reports about serum levels of BDNF in patients with schizophrenia. Conduct a meta-analysis combining studies from China and other countries that have evaluated the relationship of serum BDNF levels to schizophrenia. We used Cochrane methodology and RevMan 5.1 software to identify and pool the results of studies. Electronic searches of western and Chinese registries and follow-up assessment of references located 268 potential articles. Twenty-five articles (20 in English and 5 in Chinese) published before December 2011 that used case-control methods, included patients with schizophrenia who had no concurrent disorders, and used ELISA technology to assess serum BDNF were included in the analysis. The main outcome was the pooled standardized mean difference (SMD) between cases and controls. The quality of the studies was independently assessed by two raters using the GRADE system. The heterogeneity, sensitivity and potential publication bias of the studies was evaluated using RevMan. The pooled sample included 1663 patients with schizophrenia and 1355 controls. Fifteen of the included studies were rated as 'poor quality' and 10 were rated as 'very poor quality'. The results of the studies were quite heterogenous (I(2)=95%) but subgroup analyses found that the heterogeneity was not related to country of origin, sample size, age, gender, prior use of antipsychotic medication, or study quality. The pooled SMD (computed using a random-effect model because of study heterogeneity) was -0.74 (95% CI, -0.99?-0.50; Z=5.99, p<0.001). Sensitivity analysis found that the result was stable and there was no evidence of publication bias. Despite the robust statistical findings of lower serum BDNF in patients with schizophrenia than in controls, given the low quality of the available studies and the substantial heterogeneity between studies, the evidence of lower serum BDNF in patients with schizophrenia must be considered 'weak'. The potential use of serum BDNF as a biomarker for schizophrenia must wait until higher-quality prospective studies that follow patients over time and that use uniform selection and monitoring procedures confirm these preliminary results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 355 | Schizophr. Res. 2012 Nov 141: 162-7 |
| PMID | 22954755 |
| Title | Effects of omega-3 dietary supplement in prevention of positive, negative and cognitive symptoms: a study in adolescent rats with ketamine-induced model of schizophrenia. |
| Abstract | Omega-3 has shown efficacy to prevent schizophrenia conversion in ultra-high risk population. We evaluated the efficacy of omega-3 in preventing ketamine-induced effects in an animal model of schizophrenia and its effect on brain-derived neurotrophic factor (BDNF). Omega-3 or vehicle was administered in Wistar male rats, both groups at the 30th day of life for 15days. Each group was split in two to receive along the following 7days ketamine or saline. Locomotor and exploratory activities, memory test and social interaction between pairs were evaluated at the 52nd day of life. Prefrontal-cortex, hippocampus and striatum tissues were extracted right after behavioral tasks for mRNA BDNF expression analysis. Bloods for serum BDNF were withdrawn 24h after the end of behavioral tasks. Locomotive was increased in ketamine-treated group compared to control, omega-3 and ketamine plus omega-3 groups. Ketamine group had fewer contacts and interaction compared to other groups. Working memory and short and long-term memories were significantly impaired in ketamine group compared to others. Serum BDNF levels were significantly higher in ketamine plus omega-3 group. There was no difference between groups in prefrontal-cortex, hippocampus and striatum for mRNA BDNF expression. Administration of omega-3 in adolescent rats prevents positive, negative and cognitive symptoms in a ketamine animal model of schizophrenia. Whether these findings are consequence of BDNF increase it is unclear. However, this study gives compelling evidence for larger clinical trials to confirm the use of omega-3 to prevent schizophrenia and for studies to reinforce the beneficial role of omega-3 in brain protection. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 356 | Schizophr. Res. 2012 Oct 141: 54-9 |
| PMID | 22910404 |
| Title | Genetic association study of the P300 endophenotype in schizophrenia. |
| Abstract | Although reduced amplitude of the P300 event-related potential is a well-documented intermediate phenotype of schizophrenia, little is known about its genetic underpinnings in patients with schizophrenia. This study aims to examine associations between P300 and a range of candidate genetic variants, selected from either candidate gene studies or genome-wide association studies, in a large sample of patients with schizophrenia. P300 amplitude at the midline parietal electrode and 193 single nucleotide polymorphisms (SNPs) in 67 genes were assessed in 336 patients with schizophrenia. The association between each SNP and P300 amplitude, controlled for illness duration and gender, was evaluated. Associations at p<.01 were considered of potential relevance, while Bonferroni correction was applied to determine formal statistical significance (Bonferroni-corrected threshold of significance p=.0003). Of the 193 selected SNPs, 4 SNPs showed potentially relevant association with P300 amplitude at a significance level of p<.01. One of these SNPs, rs1045642 in ABCB1, was most convincingly associated with P300 amplitude, reaching formal (Bonferroni-corrected) significance, while there was evidence for possible association with rs1572899 in DISC-1, rs6265 in BDNF and rs1625579 in MIR137. Genetic variation in ABCB1 may be associated with P300 amplitude in patients with schizophrenia. This result may encourage further efforts to elucidate the genetic underpinnings of P300 generation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 357 | Transl Psychiatry 2012 -1 2: e104 |
| PMID | 22832904 |
| Title | Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity. |
| Abstract | Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibility gene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific genetic variations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37 schizophrenia cases and 37 controls, we resequenced upstream of the type I-IV promoters, and the HapICE repeat regions in intron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared across diagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in cases compared with controls (?(2)=7.815; P=0.05). The average nucleotide diversity (? = 10.0 × 10(-4)) was approximately twofold higher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greater nucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (?((case)) = 13.2 × 10(-4); ?((control)) = 10.0 × 10(-4)). The specific HapICE risk haplotype was associated with increased type III mRNA (F = 3.76, P = 0.028), which in turn, was correlated with an earlier age of onset (r = -0.343, P = 0.038). We found a novel intronic five-SNP haplotype ~730?kb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that is suppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1, which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic association may increase risk of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 358 | J. Psychopharmacol. (Oxford) 2012 Sep 26: 1218-30 |
| PMID | 22767372 |
| Title | A gene expression and systems pathway analysis of the effects of clozapine compared to haloperidol in the mouse brain implicates susceptibility genes for schizophrenia. |
| Abstract | Clozapine has markedly superior clinical properties compared to other antipsychotic drugs but the side effects of agranulocytosis, weight gain and diabetes limit its use. The reason why clozapine is more effective is not well understood. We studied messenger RNA (mRNA) gene expression in the mouse brain to identify pathways changed by clozapine compared to those changed by haloperidol so that we could identify which changes were specific to clozapine. Data interpretation was performed using an over-representation analysis (ORA) of gene ontology (GO), pathways and gene-by-gene differences. Clozapine significantly changed gene expression in pathways related to neuronal growth and differentiation to a greater extent than haloperidol; including the microtubule-associated protein kinase (MAPK) signalling and GO terms related to axonogenesis and neuroblast proliferation. Several genes implicated genetically or functionally in schizophrenia such as frizzled homolog 3 (FZD3), U2AF homology motif kinase 1 (UHMK1), pericentriolar material 1 (PCM1) and brain-derived neurotrophic factor (BDNF) were changed by clozapine but not by haloperidol. Furthermore, when compared to untreated controls clozapine specifically regulated transcripts related to the glutamate system, microtubule function, presynaptic proteins and pathways associated with synaptic transmission such as clathrin cage assembly. Compared to untreated controls haloperidol modulated expression of neurotoxic and apoptotic responses such as NF-kappa B and caspase pathways, whilst clozapine did not. Pathways involving lipid and carbohydrate metabolism and appetite regulation were also more affected by clozapine than by haloperidol. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 359 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Oct 39: 170-4 |
| PMID | 22750309 |
| Title | Triiodothyronine may be possibly associated with better cognitive function and less extrapyramidal symptoms in chronic schizophrenia. |
| Abstract | Many chronic inpatients with schizophrenia demonstrate enduring psychiatric symptoms and various side effects of antipsychotic drugs. Several biological markers such as prolactin, thyroid hormones and brain-derived neurotrophic factor (BDNF) are reportedly associated with psychiatric symptoms and/or antipsychotic side effects in patients with schizophrenia but to date findings are inconsistent. The objective of the present study was to comprehensively investigate the association of psychiatric and extrapyramidal symptoms with hormones and BDNF in chronic schizophrenia. In this study, 93 chronic inpatients with schizophrenia were comprehensively investigated in order to examine the association of psychiatric and extrapyramidal symptoms with prolactin, thyroid hormones (free triiodothyronine (T?), free thyroxine (T?), thyroid stimulating hormone), cortisol and BDNF. Symptoms were assessed via the Positive and Negative Syndrome Scale (PANSS), Mini-Mental State Examination (MMSE), and drug-induced extrapyramidal symptoms scale (DIEPSS). Multiple regression analyses revealed that antipsychotic dose was the only variable that predicted significant variance in PANSS positive subscale scores, that BDNF and free T? predicted significant variance in MMSE scores, and that prolactin and free T? predicted significant variance in DIEPSS scores. These findings suggest that BDNF, free T?, and prolactin may be associated with cognitive function and/or extrapyramidal symptoms in patients with chronic schizophrenia. Notably, free T? may be possibly associated with better cognitive function and less extrapyramidal symptoms, although our cross-sectional study could not reveal a causal relationship. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 360 | J Neuroimmune Pharmacol 2012 Sep 7: 656-64 |
| PMID | 22730040 |
| Title | Inflammation in patients with schizophrenia: the therapeutic benefits of risperidone plus add-on dextromethorphan. |
| Abstract | Increasing evidence suggests that inflammation contributes to the etiology and progression of schizophrenia. Molecules that initiate inflammation, such as virus- and toxin-induced cytokines, are implicated in neuronal degeneration and schizophrenia-like behavior. Using therapeutic agents with anti-inflammatory or neurotrophic effects may be beneficial for treating schizophrenia. One hundred healthy controls and 95 Han Chinese patients with schizophrenia were tested in this double-blind study. Their PANSS scores, plasma interleukin (IL)-1?, tumor necrosis factor-? (TNF-?) and brain-derived neurotrophic factor (BDNF) levels were measured before and after pharmacological treatment. Pretreatment, plasma levels of IL-1? and TNF-? were significantly higher in patients with schizophrenia than in controls, but plasma BDNF levels were significantly lower. Patients were treated with the atypical antipsychotic risperidone (Risp) only or with Risp+ dextromethorphan (DM). PANSS scores and plasma IL-1? levels significantly decreased, but plasma TNF-? and BDNF levels significantly increased after 11 weeks of Risp treatment. Patients in the Risp+ DM group showed a greater and earlier reduction of symptoms than did those in the Risp-only group. Moreover, Risp+ DM treatment attenuated Risp-induced plasma increases in TNF-?. Patients with schizophrenia had a high level of peripheral inflammation and a low level of peripheral BDNF. Long-term Risp treatment attenuated inflammation and potentiated the neurotrophic function but also produced a certain degree of toxicity. Risp+ DM was more beneficial and less toxic than Risp-only treatment. Protocol Record: HR-93-50; NCT01189006; URL: http://www.clinicaltrials.gov. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 361 | Proc Nutr Soc 2012 Nov 71: 581-91 |
| PMID | 22716958 |
| Title | Recent advances in nutrition, genes and brain health. |
| Abstract | Molecular mechanisms underlying brain structure and function are affected by nutrition throughout the life cycle, with profound implications for health and disease. Responses to nutrition are in turn influenced by individual differences in multiple target genes. Recent advances in genomics and epigenomics are increasing understanding of mechanisms by which nutrition and genes interact. This review starts with a short account of current knowledge on nutrition-gene interactions, focusing on the significance of epigenetics to nutritional regulation of gene expression, and the roles of SNP and copy number variants (CNV) in determining individual responses to nutrition. A critical assessment is then provided of recent advances in nutrition-gene interactions, and especially energy status, in three related areas: (i) mental health and well-being, (ii) mental disorders and schizophrenia, (iii) neurological (neurodevelopmental and neurodegenerative) disorders and Alzheimer's disease. Optimal energy status, including physical activity, has a positive role in mental health. By contrast, sub-optimal energy status, including undernutrition and overnutrition, is implicated in many disorders of mental health and neurology. These actions are mediated by changes in energy metabolism and multiple signalling molecules, e.g. brain-derived neurotrophic factor (BDNF). They often involve epigenetic mechanisms, including DNA methylation and histone modifications. Recent advances show that many brain disorders result from a sophisticated network of interactions between numerous environmental and genetic factors. Personal, social and economic costs of sub-optimal brain health are immense. Future advances in understanding the complex interactions between nutrition, genes and the brain should help to reduce these costs and enhance quality of life. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 362 | Biol. Psychiatry 2012 Oct 72: 700-6 |
| PMID | 22695185 |
| Title | Brain-derived neurotrophic factor levels and its Val66Met gene polymorphism predict tardive dyskinesia treatment response to Ginkgo biloba. |
| Abstract | Tardive dyskinesia (TD) has no well-accepted treatments or known pathophysiology, but low brain-derived neurotrophic factor (BDNF) may play an important role in its pathophysiology. Ginkgo biloba (EGb-761) is a potent antioxidant that has neuroprotective effects mediated through enhancing BDNF levels. We hypothesized that treatment with EGb-761 would increase serum BDNF levels and reduce TD, particularly among schizophrenia patients who have the BDNF valine 66 to methionine (Val66Met) genotype (Val/Val). Serum BDNF levels and genotyping for the BDNF gene Val66Met polymorphism were assessed in Chinese schizophrenic patients with (n = 368) and without (n = 563) TD as well as healthy control subjects (n = 546). About half of the TD patients (n = 157) then participated in a double-blind, randomized, placebo-control 12-week treatment with 240 mg per day of EGb-761. Serum BDNF levels were measured again at posttreatment. Clinical efficacy was determined using the Abnormal Involuntary Movement Scale (AIMS). TD patients had lower BDNF levels than the non-TD patients and healthy controls. EGb-761 treatment improved symptoms of TD and increased BDNF levels compared with placebo treatment. Moreover, the improvement of AIMS total score correlated with the increase in BDNF levels. Furthermore, improvement in the AIMS score was greatest in those with the Val/Val allele and lowest with the Met/Met allele. The BDNF system may be implicated in the pathophysiology of TD and its improvement with antioxidant treatment. Furthermore, patients with the genetic potential for greater BDNF release (Val/Val at 66) may obtain a greater reduction in TD from EGb-761 treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 363 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012 Apr 29: 155-8 |
| PMID | 22487823 |
| Title | [Association study of brain-derived neurotrophic factor Val66Met polymorphism and clinical characteristics of first episode schizophrenia]. |
| Abstract | To assess the association between brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism and clinical characteristics of first episode schizophrenia in a Chinese Han population. Genotyping of BDNF Val66Met polymorphism was carried out for 135 schizophrenic patients and 483 healthy controls with TaqMan probe technology. The patients' psychotic symptoms were assessed using the positive and negative syndrome scale (PANSS). A significant difference was found in genotype distribution and allelic frequency of the Val66Met polymorphism between the two groups (P< 0.01). In patients, Met homozygotes had a significantly higher score in anxiety/depression factor, cognitive factor and total score of PANSS than Val carriers. BDNF gene Val66Met polymorphism is associated with the pathogenesis of schizophrenia. The Met/Met genotype of BDNF Val66Met variant may be a risk factor for symptoms in first episode schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 364 | Drug Des Devel Ther 2012 -1 6: 107-15 |
| PMID | 22675261 |
| Title | Update on the development of lurasidone as a treatment for patients with acute schizophrenia. |
| Abstract | Lurasidone is a novel benzisothiazole antipsychotic drug for the treatment of schizophrenia. Of the antipsychotic drugs, lurasidone has the highest affinity for the 5-hydroxytryptamine (5-HT)(7) receptor. Lurasidone also has high affinities for the dopamine D(2), 5HT(2A), 5-HT(1A) and ?(2C) adrenergic receptors. Moreover, lurasidone has low affinities for the ?(1) adrenergic, histamine H(1) and muscarinic M(1) receptors. The involvement of 5-HT(7) receptors in cognitive processes has been suggested by both pharmacological and molecular investigations. Chronic treatment with lurasidone increases neurotrophin BDNF mRNA levels in both the hippocampus (ventral and dorsal) and prefrontal cortex under basal conditions or in response to an acute swim stress. Lurasidone may potentiate N-methyl-D-aspartate receptor (NMDAR) function through antagonistic action on 5-HT(7) receptors without a direct affinity for NMDARs. These results suggest that lurasidone treatment may be a novel approach for the prevention of the development of cognitive impairment in individuals who are at risk for schizophrenia or related disorders involving cognitive impairment. In clinical trials, treatment with lurasidone was associated with significantly greater endpoint improvement versus placebo on the Positive and Negative Syndrome Scale total score after 6 weeks among subjects receiving 80 or 160 mg. The most frequent side effects of lurasidone were akathisia, nausea, parkinsonism, dizziness and somnolence. Once-daily treatment with lurasidone at 160 mg was superior to placebo based on the composite cognitive functioning measure. Lurasidone treatment produced improvements in Montgomery-Asberg Depression Rating Scale scores at 6 weeks that were significantly greater than placebo. A limitation of this review is that the majority of the data were obtained from abstracts and posters. These sources have not been subjected to the peer review processes of medical journals; thus, the results presented in these forums may require further quality review and subsequent revision prior to final publication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 365 | Psychopharmacology (Berl.) 2012 Jul 222: 277-84 |
| PMID | 22274000 |
| Title | Low BDNF is associated with cognitive impairment in chronic patients with schizophrenia. |
| Abstract | Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. schizophrenia has a range of cognitive deficits that may evolve from decreased BDNF, and this study examines this association of BDNF with cognitive deficits in schizophrenia. We recruited 251 chronic schizophrenic patients and 206 healthy control subjects and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF in both groups. schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale. BDNF levels were significantly lower in patients than controls (p??0.05) were significantly lower in schizophrenic patients than normal controls. For the patients, BDNF was positively associated with immediate memory in schizophrenia. Our findings suggest that BDNF may be involved in the pathophysiology of schizophrenia, and its associated cognitive impairment, especially immediate memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 366 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Oct 39: 96-101 |
| PMID | 22642961 |
| Title | The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has extensive effects on the nervous system including cell survival, differentiation, neuronal growth and maintenance, as well as cell death. Moreover, it promotes synaptic plasticity and interacts with dopaminergic and serotonergic neurons, suggesting an important role on the alteration of brain function with antipsychotic medications and induced weight gain in schizophrenia patients. The differential effects of BDNF gene variants could lead to changes in brain circuitry that would in turn cause variable response to antipsychotic medication. Therefore, we hypothesized that genetic variation in this candidate gene helps in explaining the inter-individual variation observed in antipsychotic drug treatment with respect to response and induced weight gain. We examined four single-nucleotide polymorphisms across the BDNF gene, including Val66Met (rs6265). Prospective BPRS change scores and weight change after six weeks were obtained from a total of 257 schizophrenia patients of European ancestry. The markers rs11030104 and Val66Met were associated with antipsychotic response (P=0.04; 0.007, respectively). On the other hand, marker rs1519480 was associated with weight gain (P=0.04). Moreover, a two-marker haplotype across rs6265 and rs1519480 was associated with weight change (P=0.001). Results with Val66Met in response, and results with rs6265-rs1519480 haplotypes remained significant at the modified Bonferroni corrected alpha of 0.017. BDNF genetic variants might play an important role in predicting antipsychotic response and antipsychotic-induced weight gain. However, replication in larger and independent samples is required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 367 | PLoS ONE 2012 -1 7: e36561 |
| PMID | 22615781 |
| Title | Candidate gene-based association study of antipsychotic-induced movement disorders in long-stay psychiatric patients: a prospective study. |
| Abstract | Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 10 candidate genes (PPP1R1B, BDNF, DRD3, DRD2, HTR2A, HTR2C, COMT, MnSOD, CYP1A2, and RGS2). Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 31 SNPs, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. VARIOUS SNPS REACHED NOMINAL SIGNIFICANCE: TD and orofacial dyskinesia with rs6265 and rs988748, limb truncal dyskinesia with rs6314, rest tremor with rs6275, rigidity with rs6265 and rs4680, bradykinesia with rs4795390, akathisia with rs4680, tardive dystonia with rs1799732, rs4880 and rs1152746. After controlling for multiple testing, no significant results remained. The findings suggest that selected SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 368 | Neuroscience 2012 Aug 216: 38-45 |
| PMID | 22561731 |
| Title | Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons. |
| Abstract | The cortical cholinergic innervation, which is important for memory and cognition, has been implicated in schizophrenia. To experimentally analyze such a possible role of the cholinergic system, we have used the dissociative drug phencyclidine (PCP), known to produce schizophrenia-like psychosis in humans, to model aspects of schizophrenia in rats. We previously showed that induced cortical cholinergic hypofunction leads to enhanced PCP-induced locomotor activity and attenuated social interaction. After PCP, rats lacking cortical cholinergic innervation also show impaired declarative memory. To directly study the role of the basalo-cortical cholinergic projections for PCP-induced neural activation in different cortical areas, we have now monitored the rapid (30 and 60 min) effects of low doses of PCP (2 and 3mg/kg) on neural activation as reflected by transcriptional activation of c-fos in cortical areas, using quantitative in situ hybridization. We find an almost pan-cortical neural induction of c-fos mRNA with doses of PCP low enough not to alter levels of either BDNF or Nogo receptor mRNA levels. Specific unilateral lesioning of the uncrossed cholinergic projections to the cortical mantle by 192-IgG-saporin immunotoxin delivery to nc basalis (NBM) caused a striking ipsilateral decrease of the PCP-induced cortical c-fos mRNA induction, restricted to areas which had become effectively denervated. Because PCP at low doses is unlikely to directly influence cortical neurons, we suggest that it acts by activation of the cholinergic input, which in turn leads to cortical c-fos mRNA increases. Our results are compatible with a role for the cholinergic system in symptoms of schizophrenia, by showing that the basalo-cortical cholinergic projections are needed in order for PCP to have full activating effects on cortical neurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 369 | J. Neurosci. 2012 Apr 32: 5964-72 |
| PMID | 22539856 |
| Title | Relationship of a variant in the NTRK1 gene to white matter microstructure in young adults. |
| Abstract | The NTRK1 gene (also known as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importance of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower fractional anisotropy in healthy adults. We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 ± 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy-a common diffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test reproducibility of results. The false discovery rate method corrected for voxelwise multiple comparisons. NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple-comparisons corrected: false discovery rate critical p = 0.038 for NTRK1-T and 0.013 for rs4661063-A). In each half-sample, the NTRK1-T effect was replicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 370 | J. Mol. Neurosci. 2012 Jul 47: 505-10 |
| PMID | 22477643 |
| Title | Association between BDNF Val66Met polymorphism and cognitive performance in antipsychotic-naïve patients with schizophrenia. |
| Abstract | Cognitive impairment is one of the core symptoms in schizophrenia, which reflects the neurodevelopmental deficits in the etiology of this disease. Brain-derived neurotrophic factor (BDNF) plays an important role in various neurodevelopmental processes. Growing evidence has shown that BDNF may be involved in the etiology of schizophrenia. The aim of this study was to examine the association of the BDNF Val66Met polymorphism with cognition in patients with schizophrenia. Various neuropsychological tests including the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale-Revised, and the Wisconsin Card Sorting Test (WCST) were employed in a sample of 112 antipsychotic-naïve patients with schizophrenia and 63 healthy controls. We examined the Val66Met polymorphism in the 112 patients and 394 controls. Among the patients, cognition was compared between Met allele carriers and non-Met allele carriers. A wide range of cognitive deficits were demonstrated in the schizophrenic patients, compared with the controls (Ps?schizophrenic patients. The BDNF Val66Met polymorphism may be involved in the impaired executive function. This effect may have gender-specific characteristics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 371 | PLoS ONE 2012 -1 7: e33352 |
| PMID | 22457755 |
| Title | Induction of the GABA cell phenotype: an in vitro model for studying neurodevelopmental disorders. |
| Abstract | Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD?? (GAD1) expression and may play a role in ?-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD?? regulation may result in GABAergic dysfunction, we have developed an in vitro model in which GABA cells are differentiated from the hippocampal precursor cell line, HiB5. Growth factors, such as PDGF, and BDNF, regulate the GABA phenotype by inducing the expression of GAD?? and stimulating the growth of cellular processes, many with growth cones that form appositions with the cell bodies and processes of other GAD??-positive cells. These changes are associated with increased expression of acetylated tubulin, microtubule-associated protein 2 (MAP2) and the post-synaptic density protein 95 (PSD95). The addition of BDNF, together with PDGF, increases the levels of mRNA and protein for GAD??, as well as the high affinity GABA uptake protein, GAT1. These changes are associated with increased concentrations of GABA in the cytoplasm of "differentiated" HiB5 neurons. In the presence of Ca²? and K?, newly synthesized GABA is released extracellularly. When the HiB5 cells appear to be fully differentiated, they also express GAD??, parvalbumin and calbindin, and GluR subtypes as well as HDAC1, DAXX, PAX5, Runx2, associated with GAD?? regulation. Overall, these results suggest that the HiB5 cells can differentiate into functionally mature GABA neurons in the presence of gene products that are associated with GAD?? regulation in the adult hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 372 | Brain Behav. Immun. 2012 May 26: 660-71 |
| PMID | 22426432 |
| Title | Phenotypic effects of repeated psychosocial stress during adolescence in mice mutant for the schizophrenia risk gene neuregulin-1: a putative model of gene × environment interaction. |
| Abstract | There is a paucity of animal models by which the contributions of environmental and genetic factors to the pathobiology of psychosis can be investigated. This study examined the individual and combined effects of chronic social stress during adolescence and deletion of the schizophrenia risk gene neuregulin-1 (NRG1) on adult mouse phenotype. Mice were exposed to repeated social defeat stress during adolescence and assessed for exploratory behaviour, working memory, sucrose preference, social behaviour and prepulse inhibition in adulthood. Thereafter, in vitro cytokine responses to mitogen stimulation and corticosterone inhibition were assayed in spleen cells, with measurement of cytokine and brain-derived neurotrophic factor (BDNF) mRNA in frontal cortex, hippocampus and striatum. NRG1 mutants exhibited hyperactivity, decreased anxiety, impaired sensorimotor gating and reduced preference for social novelty. The effects of stress on exploratory/anxiety-related parameters, spatial working memory, sucrose preference and basal cytokine levels were modified by NRG1 deletion. Stress also exerted varied effect on spleen cytokine response to concanavalin A and brain cytokine and BDNF mRNA expression in NRG1 mutants. The experience of psychosocial stress during adolescence may trigger further pathobiological features that contribute to the development of schizophrenia, particularly in those with underlying NRG1 gene abnormalities. This model elaborates the importance of gene × environment interactions in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 373 | Neurobiol. Dis. 2012 Jun 46: 722-31 |
| PMID | 22426399 |
| Title | Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice. |
| Abstract | Psychiatric illnesses, such as schizophrenia, are most likely caused by an interaction between genetic predisposition and environmental factors, including stress during development. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been implicated in this illness as BDNF levels are decreased in the brain of patients with schizophrenia. The aim of the present study was to assess the combined effect of reduced BDNF levels and postnatal stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone. From 6 weeks of age, female and male BDNF heterozygous mice and their wild-type controls were chronically treated with corticosterone in their drinking water for 3 weeks. At 11 weeks of age, male, but not female BDNF heterozygous mice treated with corticosterone exhibited a profound memory deficit in the Y-maze. There were no differences between the groups in baseline prepulse inhibition (PPI), a measure of sensorimotor gating, or its disruption by treatment with MK-801. However, an increase in startle caused by MK-801 treatment was absent in male, but not female BDNF heterozygous mice, irrespective of corticosterone treatment. Analysis of protein levels of the NMDA receptor subunits NR1, NR2A, NR2B and NR2C, showed a marked increase of NR2B levels in the dorsal hippocampus of male BDNF heterozygous mice treated with corticosterone. In the ventral hippocampus, significantly reduced levels of NR2A, NR2B and NR2C were observed in male BDNF heterozygous mice. The NMDA receptor effects in hippocampal sub-regions could be related to the spatial memory deficits and the loss of the effect of MK-801 on startle in these mice, respectively. No significant changes in NMDA receptor subunit levels were observed in any of the female groups. Similarly, no significant changes in levels of BDNF or its receptor, TrkB, were found other than the expected reduced levels of BDNF in heterozygous mice. In conclusion, the data show differential interactive effects of reduced levels of BDNF expression and corticosterone treatment on spatial memory and startle in male and female mice, accompanied by significant, but region-specific changes in NMDA receptor subunit levels in the dorsal and ventral hippocampus. These results could be important for our understanding of the interaction of neurodevelopmental stress and BDNF deficiency in cognitive and anxiety-related symptoms of psychiatric illnesses, such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 374 | Psychopharmacology (Berl.) 2012 Aug 222: 663-74 |
| PMID | 22414961 |
| Title | Effects of chronic clozapine administration on markers of arachidonic acid cascade and synaptic integrity in rat brain. |
| Abstract | The mode of action of clozapine, an atypical antipsychotic approved for treating schizophrenia (SZ) and used for bipolar disorder (BD) mania, remains unclear. We tested for overlap with the actions of the mood stabilizers, lithium, carbamazepine and valproate, which downregulate arachidonic acid (AA) cascade markers in rat brain and upregulate BDNF. AA cascade markers are upregulated in BD and SZ postmortem BD brain in association with neuroinflammation and synaptic loss, while BDNF is decreased. Rats were injected intraperitoneally with a therapeutically relevant dose of clozapine (10 mg/kg/day) or with saline for 30 days, and AA cascade and synaptic markers and BDNF were measured in the brain. Compared with saline-injected rats, chronic clozapine increased brain activity, mRNA and protein levels of docosahexaenoic acid (DHA)-selective calcium-independent phospholipase A? type VIA (iPLA?), mRNA and protein levels of BDNF and of the postsynaptic marker, drebrin, while decreasing cyclooxygenase (COX) activity and concentration of prostaglandin E? (PGE?), a proinflammatory AA metabolite. Activity and expression of AA-selective calcium-dependent cytosolic cPLA? type IVA and of secretory sPLA? Type II were unchanged. These results show overlap with effects of mood stabilizers with regard to downregulation of COX activity and PGE? and to increased BDNF and suggest a common action against the reported neuropathology of BD and SZ. The increased iPLA? expression following clozapine suggests increased production of anti-inflammatory DHA metabolites, and, with increased BDNF and drebrin, clear neuroprotective action. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 375 | Hum. Genet. 2012 Jul 131: 1187-95 |
| PMID | 22362486 |
| Title | Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. |
| Abstract | Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may mediate hippocampal-dependent cognitive functions. A few studies have reported its role in cognitive deficits in schizophrenia including its association with peripheral BDNF levels as a mediator of these cognitive deficits. We assessed 657 schizophrenic inpatients and 445 healthy controls on the repeatable battery for the assessment of neuropsychological status (RBANS), the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that visuospatial/constructional abilities significantly differed by genotype but not genotype × diagnosis, and the Val allele was associated with better visuospatial/constructional performance in both schizophrenic patients and healthy controls. Attention performance showed a significant genotype by diagnosis effect. Met allele-associated attention impairment was specific to schizophrenic patients and not shown in healthy controls. In the patient group, partial correlation analysis showed a significant positive correlation between serum BDNF and the RBANS total score. Furthermore, the RBANS total score showed a statistically significant BDNF level × genotype interaction. We demonstrated an association between the BDNF Met variant and poor visuospatial/constructional performance. Furthermore, the BDNF Met variant may be specific to attentional decrements in schizophrenic patients. The association between decreased BDNF serum levels and cognitive impairment in schizophrenia is dependent on the BDNF Val66Met polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 376 | J Psychiatr Res 2012 Mar 46: 285-9 |
| PMID | 22244515 |
| Title | Serum brain-derived neurotrophic factor level in relation to illness severity and episode duration in patients with major depression. |
| Abstract | Since there are few data on the possible association between BDNF levels and characteristics of major depression, the present study assesses brain-derived neurotrophic factor (BDNF) levels in three drug-free patient samples, and explores whether episode duration, and severity correlate with serum BDNF levels. Serum BDNF levels were measured in 42 drug-free patients with major depression. The duration of the index episode and the presence of psychotic features were assessed with the Schedule for Affective Disorders and schizophrenia, and the severity of depression was measured with the 17-item Hamilton Rating Scale for Depression. The sample was divided into three groups: severely depressed inpatients without psychotic features, severely depressed inpatients with psychotic features, and moderately depressed outpatients. Mean serum BDNF level in the total sample was 18.0 ± 2.8 ng/ml, with no significant difference between the three patient samples (F = 1.80, df = 2, p = 0.18). Mean serum BDNF level was significantly lower in patients with an index episode over one year, compared with patients who had a shorter index episode (F = 4.90, df = 1, p = 0.033). These data show that patients with a long index episode have significantly lower serum BDNF levels. We found no influence of the presence of psychotic features and severity of depression on serum BDNF levels. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 377 | Hum Psychopharmacol 2012 Jan 27: 33-8 |
| PMID | 22213405 |
| Title | Aripiprazole altered plasma levels of brain-derived neurotrophic factor and catecholamine metabolites in first-episode untreated Japanese schizophrenia patients. |
| Abstract | We investigated the effects of aripiprazole on plasma levels of brain-derived neurotrophic factor (BDNF) and catecholamine metabolites in first-episode untreated schizophrenia patients. The subjects were 50 Japanese first-episode untreated schizophrenia patients who met the Diagnostic and Statistical Manual of Mental Disorders Text Revision criteria and were treated with aripiprazole monotherapy. Twenty-nine were males, and 21 were females. The age ranged from 21 to 42?years (mean?±?SD; 30.8?±?5.3?years). Plasma BDNF and catecholamine metabolites were measured by ELISA and HPLC, respectively. Psychiatric symptoms were evaluated using by Positive and Negative Syndrome Scale. Treatment with aripiprazole for 8?weeks significantly increased plasma BDNF levels. It also changed plasma levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. A negative correlation was also observed between duration of psychosis and plasma BDNF levels. No correlation was observed however between plasma BDNF levels and the dose of aripiprazole. To the best of our knowledge, this is the first report showing that aripiprazole increases plasma BDNF levels in first-episode untreated schizophrenia patients. Furthermore, the BDNF Val66Met polymorphism was independent of the response to aripiprazole. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 378 | Neurobiol. Dis. 2012 Feb 45: 671-82 |
| PMID | 22024716 |
| Title | The NMDA receptor co-agonists, D-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex. |
| Abstract | There is substantial evidence, both pharmacological and genetic, that hypofunction of the N-methyl-d-aspartate receptor (NMDAR) is a core pathophysiological feature of schizophrenia. There are morphological brain changes associated with schizophrenia, including perturbations in the dendritic morphology of cortical pyramidal neurons and reduction in cortical volume. Our experiments investigated whether these changes in dendritic morphology could be recapitulated in a genetic model of NMDAR hypofunction, the serine racemase knockout (SR-/-) mouse. Pyramidal neurons in primary somatosensory cortex (S1) of SR-/- mice had reductions in the complexity, total length, and spine density of apical and basal dendrites. In accordance with reduced cortical neuropil, SR-/- mice also had reduced cortical volume as compared to wild type mice. Analysis of S1 mRNA by DNA microarray and gene expression analysis revealed gene changes in SR-/- that are associated with psychiatric and neurologic disorders, as well as neurodevelopment. The microarray analysis also identified reduced expression of brain derived neurotrophic factor (BDNF) in SR-/- mice. Follow-up analysis by ELISA confirmed a reduction of BDNF protein levels in the S1 of SR-/- mice. Finally, S1 pyramidal neurons in glycine transporter heterozygote (GlyT1+/-) mutants, which display enhanced NMDAR function, had increased dendritic spine density. These results suggest that proper NMDAR function is important for the arborization and spine density of pyramidal neurons in cortex. Moreover, they suggest that NMDAR hypofunction might, in part, be contributing to the dendritic and synaptic changes observed in schizophrenia and highlight this signaling pathway as a potential target for therapeutic intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 379 | Psychol Med 2012 Mar 42: 607-16 |
| PMID | 21854684 |
| Title | Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. |
| Abstract | Candidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS). We describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International schizophrenia Consortium (ISC). SZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p values in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1 and SLC6A4) had no notable ISC results. We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 380 | Int. J. Neuropsychopharmacol. 2012 Sep 15: 1073-86 |
| PMID | 21777509 |
| Title | Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice. |
| Abstract | Brain-derived neurotrophic factor (BDNF) signalling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signalling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioural and neurochemical abnormalities similar to schizophrenia. In this study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg.d, through drinking water) for 30 d significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioural studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signalling plays an important role in GAD67 regulation by cysteamine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 381 | J. Mol. Neurosci. 2012 Jan 46: 217-22 |
| PMID | 21710362 |
| Title | Association study between BDNF C-281A polymorphism and paranoid schizophrenia in Polish population. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. Polymorphism C-281A (rs28383487) in BDNF gene leads to the reduction of promoter activity in the hippocampal neurons in vitro. To our knowledge, this is the first study to examine the influence of alleles and genotypes of BDNF C-281A polymorphism on development, as well as the clinical course (age of onset, suicidal behaviour and psychopathology) of paranoid schizophrenia. The psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) as subscale scores and also single-item scores. We have also performed the haplotype analysis with val66met BDNF polymorphism, which is known to be involved in the pathogenesis of schizophrenia. We have not found significant differences in the distribution of genotypes and alleles between schizophrenic patients and controls in both the overall analysis, as well as sex stratified. Also, we have not shown statistically significant differences between genotype groups and PANSS scale. However, an association between C-281A polymorphism and time of the first episode of paranoid schizophrenia was revealed. Genotype C/A had been connected with later age of onset of paranoid schizophrenia in men but not in women (p?schizophrenia group compared to the controls. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 382 | Scientifica (Cairo) 2012 -1 2012: 560514 |
| PMID | 24278715 |
| Title | The Association between COMT, BDNF, and NRG1 and Premorbid Social Functioning in Patients with Psychosis, Their Relatives, and Controls. |
| Abstract | We investigated the influences of putative candidate genes for psychosis on premorbid social adjustment and on premorbid schizoid-schizotypal traits. A family-based sample was used including 177 patients with schizophrenia or bipolar I disorder with a history of psychotic symptoms, 86 of their unaffected relatives, and 116 unrelated healthy controls. Association analyses on the combined sample were conducted using the Statistical Analysis for Genetic Epidemiology software (SAGE) and adjusting for age, sex, clinical group, and the family-based nature of the data. The COMT Val(158)Met and BDNF Val(66)Met polymorphisms showed no evidence of association with either phenotype. The SNP rs221533 of the NRG1 gene was significantly associated with premorbid adjustment in adolescence with TT homozygous subjects having a poorer performance than C allele carriers. In the context of neurodevelopmental disorders such as schizophrenia and other psychoses, this finding is plausible; however, it is preliminary and requires replication in an independent sample. In a broader sense, the use of intermediate quantitative phenotypes such as the ones presented in this study may be of help to understand the mechanism of action of genetic risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 383 | Neuropharmacology 2012 Mar 62: 1204-20 |
| PMID | 21557953 |
| Title | Mouse models of genetic effects on cognition: relevance to schizophrenia. |
| Abstract | Cognitive dysfunction is a core feature of schizophrenia. Growing evidence indicates that a wide variety of genetic mutations and polymorphisms impact cognition and may thus be implicated in various aspects of this mental disorder. Despite differences between human and rodent brain structure and function, genetic mouse models have contributed critical information about brain mechanisms involved in cognitive processes. Here, we summarize discoveries of genetic modifications in mice that impact cognition. Based on functional hypotheses, gene modifications within five model systems are described: 1) dopamine (D1, D2, D3, D4, D5, DAT, COMT, MAO); 2) glutamate (GluR-A, NR1, NR2A, NR2B, GRM2, GRM3, GLAST); 3) GABA (?(5), ?(2), ?(4), ?GABA(A), GABA(B(1)), GAT1); 4) acetylcholine (nAChR?2, ?7, CHRM1); and 5) calcium (CaMKII-?, neurogranin, CaMKK?, CaMKIV). We also consider other risk-associated genes for schizophrenia such as dysbindin (DTNBP1), neuregulin (NRG1), disrupted-in-schizophrenia1 (DISC1), reelin and proline dehydrogenase (PRODH). Because of the presumed importance of environmental factors, we further consider genetic modifications within the stress-sensitive systems of corticotropin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF) and the endocannabinoid systems. We highlight the missing information and limitations of cognitive assays in genetically modified mice models relevant to schizophrenia pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 384 | Int. J. Neuropsychopharmacol. 2012 Mar 15: 235-46 |
| PMID | 21349227 |
| Title | Modulation of BDNF expression by repeated treatment with the novel antipsychotic lurasidone under basal condition and in response to acute stress. |
| Abstract | It is known that long-term treatment with antipsychotic drugs (APDs) produces neuroadaptive changes through the modulation of different proteins that, by enhancing neuronal plasticity and cellular resiliency, may improve core disease symptoms. The aim of this study was to investigate the ability of chronic treatment with the novel antipsychotic lurasidone to modulate BDNF expression in hippocampus and prefrontal cortex, under basal conditions or in response to an acute stress, a major precipitating element in psychiatric disorders. By means of real-time PCR, we found that (1) chronic lurasidone treatment increases total BDNF mRNA levels in rat prefrontal cortex and, to less extent, in hippocampus; (2) the modulation of BDNF mRNA levels in response to acute swim stress in lurasidone-treated rats was markedly potentiated in hippocampus, and to less extent in prefrontal cortex, through the selective regulation of different neurotrophin isoforms. The increase of BDNF mRNA levels in prefrontal cortex was paralleled by an enhancement of mature BDNF protein levels. In conclusion, repeated exposure to lurasidone regulates BDNF expression, through a finely tuned modulation of its transcripts. This effect may contribute to the amelioration of functions, such as cognition, closely associated with neuronal plasticity, which are deteriorated in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 385 | Transl Psychiatry 2012 -1 2: e173 |
| PMID | 23092977 |
| Title | Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation. |
| Abstract | The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 386 | Zh Nevrol Psikhiatr Im S S Korsakova 2012 -1 112: 39-44 |
| PMID | 23250597 |
| Title | [An association study of polymorphisms in HTR2A, BDNF and SLC6A4 genes with paranoid schizophrenia and suicidal behavior]. |
| Abstract | We have developed a biochip for the analysis of candidate genes for schizophrenia. Using this biochip, allele and genotype frequencies for the polymorphisms of HTR2A, BDNF and SLC6A4 genes in 198 patients with schizophrenia and 192 healthy individuals have been obtained. The allele T of the HTR2A polymorphism rs6314 was identified as protective against the development of paranoid schizophrenia (p=0,014). An analysis of gene-gene interactions using the Multifactor-Dimensionality Reduction (MDR) algorithm has shown a statistically significant association of combined genotypes rs6311 G/-, rs6313 C/-, rs6314 C/C, rs7997012 G/- with the disease (p=0.019). Also it has been shown that the G/G genotype of the polymorphism rs6311 (p=0.013) and the C/C genotype of the polymorphism rs6313 (p=0.008) in the HTR2A gene are associated with the suicide attempt in schizophrenic patients. Correspondingly, an A allele, ?/- genotypes of the polymorphism rs6311 G>A and a T allele, T/- genotypes of the polymorphism rs6313 C>T were found to be less frequent in schizophrenic patients with a history of suicide attempt than in schizophrenic patients without a history of suicide attempt, thus suggesting their protective role in the development of suicidal behavior. The results confirm the hypothesis that the HTR2A plays an important role in the etiology of schizophrenia and suicidal behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 387 | Mol. Biol. Rep. 2012 Dec 39: 10889-93 |
| PMID | 23065263 |
| Title | DNA methylation and expression profiles of the brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes in patients with schizophrenia. |
| Abstract | Methylation and expression profile of CpG islands were examined in the promoters of the brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes. These are well known to be involved in the pathophysiology of psychiatric disorders such as schizophrenia. Genomic DNA was extracted from peripheral blood of 80 patients with schizophrenia and 71 healthy controls. Methylation pattern was studied by Methylation-Specific PCR. RNA expression analysis was done on extracted RNA from blood samples from patients suffering from schizophrenia (n = 17) and healthy controls (n = 17). Frequency of the BDNF gene methylation was highlighted as a statistically significant relationship between cases and controls regarding decreased risk of disease in comparison to unmethylated patterns (OR = 0.24; 95 % CI = 1.11-0.50; P = 0.00007). For the DAT1 gene, this relationship was insignificant in 61 cases (76.25 %) and 52 controls (73.23 %) (OR = 1.17; 95 % CI = 0.53-2.61). Estimates of relative gene expression revealed a statistically significant association of the BDNF gene between schizophrenic patients and healthy controls (Mean ± SD: 13.3920 ± 15.19 and 0.437 ± 0.328, P = 0.0001) respectively; however, it was not significant for the DAT1 gene. This first hand evidence, regarding BDNF and DAT1 gene methylation and their expression profile with risk of schizophrenia, indicated a significant function for the BDNF gene in the development of schizophrenia. However, further populations with large sample sizes need to be studied to verify the exact role of BDNF in mental disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 388 | Biol. Psychiatry 2012 Oct 72: 700-6 |
| PMID | 22695185 |
| Title | Brain-derived neurotrophic factor levels and its Val66Met gene polymorphism predict tardive dyskinesia treatment response to Ginkgo biloba. |
| Abstract | Tardive dyskinesia (TD) has no well-accepted treatments or known pathophysiology, but low brain-derived neurotrophic factor (BDNF) may play an important role in its pathophysiology. Ginkgo biloba (EGb-761) is a potent antioxidant that has neuroprotective effects mediated through enhancing BDNF levels. We hypothesized that treatment with EGb-761 would increase serum BDNF levels and reduce TD, particularly among schizophrenia patients who have the BDNF valine 66 to methionine (Val66Met) genotype (Val/Val). Serum BDNF levels and genotyping for the BDNF gene Val66Met polymorphism were assessed in Chinese schizophrenic patients with (n = 368) and without (n = 563) TD as well as healthy control subjects (n = 546). About half of the TD patients (n = 157) then participated in a double-blind, randomized, placebo-control 12-week treatment with 240 mg per day of EGb-761. Serum BDNF levels were measured again at posttreatment. Clinical efficacy was determined using the Abnormal Involuntary Movement Scale (AIMS). TD patients had lower BDNF levels than the non-TD patients and healthy controls. EGb-761 treatment improved symptoms of TD and increased BDNF levels compared with placebo treatment. Moreover, the improvement of AIMS total score correlated with the increase in BDNF levels. Furthermore, improvement in the AIMS score was greatest in those with the Val/Val allele and lowest with the Met/Met allele. The BDNF system may be implicated in the pathophysiology of TD and its improvement with antioxidant treatment. Furthermore, patients with the genetic potential for greater BDNF release (Val/Val at 66) may obtain a greater reduction in TD from EGb-761 treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 389 | J. Mol. Neurosci. 2012 Jul 47: 505-10 |
| PMID | 22477643 |
| Title | Association between BDNF Val66Met polymorphism and cognitive performance in antipsychotic-naïve patients with schizophrenia. |
| Abstract | Cognitive impairment is one of the core symptoms in schizophrenia, which reflects the neurodevelopmental deficits in the etiology of this disease. Brain-derived neurotrophic factor (BDNF) plays an important role in various neurodevelopmental processes. Growing evidence has shown that BDNF may be involved in the etiology of schizophrenia. The aim of this study was to examine the association of the BDNF Val66Met polymorphism with cognition in patients with schizophrenia. Various neuropsychological tests including the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale-Revised, and the Wisconsin Card Sorting Test (WCST) were employed in a sample of 112 antipsychotic-naïve patients with schizophrenia and 63 healthy controls. We examined the Val66Met polymorphism in the 112 patients and 394 controls. Among the patients, cognition was compared between Met allele carriers and non-Met allele carriers. A wide range of cognitive deficits were demonstrated in the schizophrenic patients, compared with the controls (Ps?schizophrenic patients. The BDNF Val66Met polymorphism may be involved in the impaired executive function. This effect may have gender-specific characteristics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 390 | Hum. Genet. 2012 Jul 131: 1187-95 |
| PMID | 22362486 |
| Title | Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. |
| Abstract | Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may mediate hippocampal-dependent cognitive functions. A few studies have reported its role in cognitive deficits in schizophrenia including its association with peripheral BDNF levels as a mediator of these cognitive deficits. We assessed 657 schizophrenic inpatients and 445 healthy controls on the repeatable battery for the assessment of neuropsychological status (RBANS), the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that visuospatial/constructional abilities significantly differed by genotype but not genotype × diagnosis, and the Val allele was associated with better visuospatial/constructional performance in both schizophrenic patients and healthy controls. Attention performance showed a significant genotype by diagnosis effect. Met allele-associated attention impairment was specific to schizophrenic patients and not shown in healthy controls. In the patient group, partial correlation analysis showed a significant positive correlation between serum BDNF and the RBANS total score. Furthermore, the RBANS total score showed a statistically significant BDNF level × genotype interaction. We demonstrated an association between the BDNF Met variant and poor visuospatial/constructional performance. Furthermore, the BDNF Met variant may be specific to attentional decrements in schizophrenic patients. The association between decreased BDNF serum levels and cognitive impairment in schizophrenia is dependent on the BDNF Val66Met polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 391 | J. Mol. Neurosci. 2012 Jan 46: 217-22 |
| PMID | 21710362 |
| Title | Association study between BDNF C-281A polymorphism and paranoid schizophrenia in Polish population. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. Polymorphism C-281A (rs28383487) in BDNF gene leads to the reduction of promoter activity in the hippocampal neurons in vitro. To our knowledge, this is the first study to examine the influence of alleles and genotypes of BDNF C-281A polymorphism on development, as well as the clinical course (age of onset, suicidal behaviour and psychopathology) of paranoid schizophrenia. The psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) as subscale scores and also single-item scores. We have also performed the haplotype analysis with val66met BDNF polymorphism, which is known to be involved in the pathogenesis of schizophrenia. We have not found significant differences in the distribution of genotypes and alleles between schizophrenic patients and controls in both the overall analysis, as well as sex stratified. Also, we have not shown statistically significant differences between genotype groups and PANSS scale. However, an association between C-281A polymorphism and time of the first episode of paranoid schizophrenia was revealed. Genotype C/A had been connected with later age of onset of paranoid schizophrenia in men but not in women (p?schizophrenia group compared to the controls. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 392 | Proc. Natl. Acad. Sci. U.S.A. 2012 Jun 109: 9617-22 |
| PMID | 22645329 |
| Title | Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke. |
| Abstract | Erythropoietin (EPO) is a neuroprotective cytokine in models of ischemic and nervous system injury, where it reduces neuronal apoptosis and inflammatory cytokines and increases neurogenesis and angiogenesis. EPO also improves cognition in healthy volunteers and schizophrenic patients. We studied the effect of EPO administration on the gene-expression profile in the ischemic cortex of rats after cerebral ischemia at early time points (2 and 6 h). EPO treatment up-regulated genes already increased by ischemia. Hierarchical clustering and analysis of overrepresented functional categories identified genes implicated in synaptic plasticity-Arc, BDNF, Egr1, and Egr2, of which Egr2 was the most significantly regulated. Up-regulation of Arc, BDNF, Dusp5, Egr1, Egr2, Egr4, and Nr4a3 was confirmed by quantitative PCR. We investigated the up-regulation of Egr2/Krox20 further because of its role in neuronal plasticity. Its elevation by EPO was confirmed in an independent in vivo experiment of cerebral ischemia in rats. Using the rat neuroblastoma B104, we found that wild-type cells that do not express EPO receptor (EPOR) do not respond to EPO by inducing Egr2. However, EPOR-expressing B104 cells induce Egr2 early upon incubation with EPO, indicating that Egr2 induction is a direct effect of EPO and that EPOR mediates this effect. Because these changes occur in vivo before decreased inflammatory cytokines or neuronal apoptosis is evident, these findings provide a molecular mechanism for the neuroreparative effects of cytokines and suggest a mechanism of neuroprotection by which promotion of a plastic phenotype results in decreased inflammation and neuronal death. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 393 | Eur Arch Psychiatry Clin Neurosci 2012 Feb 262: 23-31 |
| PMID | 21509595 |
| Title | Association of the brain-derived neurotrophic factor val66met polymorphism with magnetic resonance spectroscopic markers in the human hippocampus: in vivo evidence for effects on the glutamate system. |
| Abstract | The brain-derived neurotrophic factor (BDNF) is a key regulator of synaptic plasticity and has been suggested to be involved in the pathophysiology and pathogenesis of psychotic disorders, with particular emphasis on dysfunctions of the hippocampus. The aim of the present study was to replicate and to extend prior findings of BDNF val66met genotype effects on hippocampal volume and N-acetyl aspartate (NAA) levels. Hundred and fifty-eight caucasians (66 schizophrenic, 45 bipolar, and 47 healthy subjects; 105 subjects underwent MRI and 103 MRS scanning) participated in the study and were genotyped with regard to the val66met polymorphism (rs6265) of the BDNF gene. Hippocampal volumes were determined using structural magnetic resonance imaging (MRI), and measures of biochemical markers were taken using proton magnetic resonance spectroscopy ((1)H-MRS) in the hippocampus and other brain regions. Verbal memory was assessed as a behavioral index of hippocampal function. BDNF genotype did not impact hippocampal volumes. Significant genotype effects were found on metabolic markers specifically in the left hippocampus. In particular, homozygous carriers of the met-allele exhibited significantly lower NAA/Cre and (Glu + Gln)/Cre metabolic ratios compared with val/val homozygotes, independently of psychiatric diagnoses. BDNF genotype had a numerical, but nonsignificant effect on verbal memory performance. These findings provide first in vivo evidence for an effect of the functional BDNF val66met polymorphism on the glutamate system in human hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 394 | Transl Psychiatry 2012 -1 2: e173 |
| PMID | 23092977 |
| Title | Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation. |
| Abstract | The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 395 | Nihon Shinkei Seishin Yakurigaku Zasshi 2012 Aug 32: 203-9 |
| PMID | 23012888 |
| Title | [The hypothalamic-pituitary-adrenal axis and depressive disorder: recent progress]. |
| Abstract | Depression is a stress-induced disorder and there is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in the disease. Chronic hyperactivity of the HPA axis and resultant excessive glucocorticoid (hypercortisolism) may be causal to depression. We demonstrated that the dexamethasone (DEX)/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities. Restoration from HPA axis abnormalities occurs with clinical responses to treatment. Brain-derived neurotrophic factor (BDNF) has also been implicated in depression. We found that glucocorticoid (DEX) suppresses BDNF-induced dendrite outgrowth and synaptic formation via blocking the MAPK pathway in early-developing cultured hippocampal neurons. Furthermore, we demonstrated that glucocorticoid receptor (GR) and TrkB (a specific receptor of BDNF) interact and that DEX acutely suppresses BDNF-induced glutamate release by affecting the PLC-gamma pathway in cultured cortical neurons, indicating a mechanism underlying the effect of excessive glucocorticoid on BDNF function and resultant damage in cortical neurons. In a macroscopic view using magnetic resonance imaging (MRI), we found that individuals with hypercortisolism detected by the DEX/CRH test demonstrated volume loss in gray matter and reduced neural network assessed with diffusion tensor imaging in several brain regions. Finally, we observed that individuals with hypocortisolism detected by the DEX/CRH test tend to present more distress symptoms, maladaptive coping styles, and schizotypal personality traits than their counterparts, which points to the important role of hypocortisolism as well as hypercortisolism in depression spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 396 | Neuropsychiatr Dis Treat 2013 -1 9: 1499-512 |
| PMID | 24109187 |
| Title | Role of nucleus accumbens glutamatergic plasticity in drug addiction. |
| Abstract | Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance's effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca(2+)-permeable AMPA receptors (CP-AMPARs) at the level of the NAc. Antagonism of the CP-AMPARs reduces cravings. It is necessary to pursue further exploration of the AMPA receptor subunit composition and variations at the level of the NAc for a better understanding of glutamatergic plastic changes. It is known that cocaine and morphine are able to induce changes in dendritic spine morphology by modifying actin cycling. These changes include an initial increase in spine head diameter and increases in AMPA receptor expression, followed by a second stage of spine head diameter retraction and reduction of the AMPA receptors' expression in spines. Besides glutamate and dopamine, other factors, like brain-derived neurotrophic factor (BDNF), can influence NAc activity and induce changes in dendritic spine density. BDNF also induces drug-related behaviors like self-administration and relapse. Neither apoptosis nor neurogenesis plays a relevant role in the neurobiological processes subjacent to cocaine addiction in adults (rodent or human). Different therapeutic drugs like N-acetylcysteine (NAC), modafinil, acamprosate, and topiramate have been tested in preclinical and/or clinical models for alleviating drug relapse. Moreover, these therapeutic drugs target the glutamatergic circuitry between the PFC and the NAc. NAC and acamprosate have shown inconsistent results in clinical trials. Modafinil and topiramate have shown some success, but more clinical trials are necessary. Based on the current review findings, it could be recommendable to explore therapeutic approaches that include synergism between different drugs and neurotransmitter systems. The discrepancy in the results of some therapeutic drugs between preclinical versus clinical trials for alleviating relapse or drug dependence could be linked to the scarce exploration of preclinical models that mimic polydrug abuse patterns, for example, cocaine plus alcohol. At the clinical level, the pattern of polydrug consumption is a phenomenon of considerable frequency. Finally, as a complement at the end, an updated summary is included about the role of glutamate in other neuropsychiatric disorders (for example, mood disorders, schizophrenia, and others). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 397 | PLoS Biol. 2013 Dec 11: e1001743 |
| PMID | 24391468 |
| Title | Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes. |
| Abstract | Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 398 | Front Biol (Beijing) 2013 Oct 8: -1 |
| PMID | 24285940 |
| Title | Novel functions of GABA signaling in adult neurogenesis. |
| Abstract | Neurotransmitter gamma-aminobutiric acid (GABA) through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells (NSCs/NPCs). The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na(+)/K(+)/2Cl(-) co-transporter NKCC1 driving Cl(-) influx and neuron-specific K(+)/Cl(-) co-transporter KCC2 driving Cl(-) efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-schizophrenia 1 (DISC1) and brain-derived neurotrophic factor (BDNF) signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and newborn neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 399 | Neuron 2013 Sep 79: 1169-82 |
| PMID | 24050404 |
| Title | CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. |
| Abstract | The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia. CYFIP1 plays a dual role in two apparently unrelated processes, inhibiting local protein synthesis and favoring actin remodeling. Here, we show that brain-derived neurotrophic factor (BDNF)-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex. Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes. CYFIP1 thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons. The CYFIP1 interactome reveals many interactors associated with brain disorders, opening new perspectives to define regulatory pathways shared by neurological disabilities characterized by spine dysmorphogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 400 | Clin Ter 2013 -1 164: e319-24 |
| PMID | 24045531 |
| Title | [Genetics and epigenetics of schizophrenia]. |
| Abstract | schizophrenia is a severe psychiatric disorder with an estimate prevalence of 0.3-0.7%. Studies on family aggregation showed a higher incidence of disease among family members of affected people. This observation lead to formulate the hypothesis that schizophrenia could be inheritable, but twin studies have shown a concordance of disease between monozygotic twins only of 50%, indicating the concomitant role of environmental factors in the pathogenesis of schizophrenia. Researches in molecular biology field have allowed the identification of genes that confer susceptibility to schizophrenia on chromosomes 1, 2, 3, 5, 6, 8, 10, 11, 13, 14, 20 and 22. Epigenetic modifications of gene expression, that not involve the primary DNA sequence, may also predispose to schizophrenia, in particular the methylation of genes involved in neurotransmission (RELN, GAD1, MARLIN-1, and NR3B GRIA2, VGLUT1 and 2, 5HT2a, COMT and BDNF), the histone modifications and the action of non-coding RNAs. This review deals with the results of a bibliographic retrieval on PubMed, carried out, using the key words: schizophrenia, genetics, epigenetics. From the epitomized results it can be derived that schizophrenia seems to be a multifactorial disease. Environmental factors, that can cause epigenetic modifications, are important in its pathogenesis, acting on a biological inheritable vulnerability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 401 | Neurosci. Res. 2013 Dec 77: 208-14 |
| PMID | 23973796 |
| Title | DNA methylation analysis of BDNF gene promoters in peripheral blood cells of schizophrenia patients. |
| Abstract | Accumulating evidence suggests that epigenetic alterations in brain-derived neurotrophic factor (BDNF) promoters are associated with the pathophysiology of psychiatric disorders. Epigenetic changes in BDNF were reported not only in brain tissues but also in other tissues, including peripheral blood cells (PBC) and saliva. We examined DNA methylation levels of BDNF promoters I and IV using genomic DNA derived from PBC of healthy controls (n=100), and patients with schizophrenia (n=100), all from the Japanese population, by pyrosequencing. The examined CpG sites were chosen based on previous epigenetic studies that reported altered DNA methylation. We found a significantly higher level of methylation at BDNF promoter I in patients with schizophrenia compared to controls, although the difference was small. Subsequent analysis revealed that in controls, the methylation level of BDNF promoters was associated with sex, and the methylation difference observed in promoter I was more prominent in male patients with schizophrenia. Epigenetic alteration of BDNF in the PBC might reflect the pathophysiology of schizophrenia, and could be a potential biomarker. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 402 | Schizophr. Res. 2013 Oct 150: 312-8 |
| PMID | 23938174 |
| Title | DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients. |
| Abstract | The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways-DNMT1 (DNA-methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation-demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL). The data show that increases in DNMT1 and TET1 and in glucocorticoid receptor (GCortR) and brain derived neurotrophic factor (BDNF) mRNAs in PBL of SZ patients are comparable to those reported in the brain of SZ patients. The finding that the expressions of DNMT1 and TET1 are increased and SZ candidate genes such as BDNF and GCortR are altered in the same direction in both the brain and PBL together with recent studies showing highly correlated patterns of DNA methylation across the brain and blood, support the hypothesis that a common epigenetic dysregulation may be operative in the brain and peripheral tissues of SZ patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 403 | Neurosci. Lett. 2013 Aug 550: 115-8 |
| PMID | 23831345 |
| Title | Effects of brain-derived and glial cell line-derived neurotrophic factors on startle response and disrupted prepulse inhibition in mice of DBA/2J inbred strain. |
| Abstract | Prepulse inhibition (PPI), the reduction in acoustic startle reflex when it is preceded by weak prepulse stimuli, is a measure of critical to normal brain functioning sensorimotor gating. PPI deficit was shown in a variety of psychiatric disorders including schizophrenia, and in DBA/2J mouse strain. In the current study, we examined the effects of brain-derived (BDNF) and glial cell line-derived (GDNF) neurotrophic factors on acoustic startle response and PPI in DBA/2J mice. It was found that BDNF (300 ng, i.c.v.) significantly increased amplitude of startle response and restored disrupted PPI in 7 days after acute administration. GDNF (800 ng, i.c.v.) did not produce significant alteration neither in amplitude of startle response nor in PPI in DBA/2J mice. The reversal effect of BDNF on PPI deficit was unusually long-lasting: significant increase in PPI was found 1.5 months after single acute BDNF administration. Long-term ameliorative effect BDNF on disrupted PPI suggested the implication of epigenetic mechanism in BDNF action on neurogenesis. BDNF rather than GDNF could be a perspective drug for the treatment of sensorimotor gating impairments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 404 | Front Psychiatry 2013 -1 4: 45 |
| PMID | 23785335 |
| Title | BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory. |
| Abstract | Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that has been related not only to neurodevelopment and neuroprotection, but also to synapse regulation, learning, and memory. Research focused on the neurobiology of schizophrenia has emphasized the relevance of neurodevelopmental and neurotoxicity-related elements in the pathogenesis of this disease. Research focused on the clinical features of schizophrenia in the past decades has emphasized the relevance of cognitive deficits of this illness, considered a core manifestation and an important predictor for functional outcome. Variations in neurotrophins such as BDNF may have a role as part of the molecular mechanisms underlying these processes, from the neurodevelopmental alterations to the molecular mechanisms of cognitive dysfunction in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 405 | J. Hum. Genet. 2013 Jul 58: 434-8 |
| PMID | 23739121 |
| Title | DNA methylation of the BDNF gene and its relevance to psychiatric disorders. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor, which is important for neuronal survival, development and synaptic plasticity. Accumulating evidence suggests that epigenetic modifications of BDNF are associated with the pathophysiology of psychiatric disorders, such as schizophrenia and mood disorders. Patients with psychiatric disorders generally show decreased neural BDNF levels, which are often associated with increased DNA methylation at the specific BDNF promoters. Importantly, observed DNA methylation changes are consistent across tissues including brain and peripheral blood, which suggests potential usefulness of these findings as a biomarker of psychiatric disorders. Here we review DNA methylation characteristics of BDNF promoters of cellular, animal and clinical samples and discuss future perspectives. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 406 | World Psychiatry 2013 Jun 12: 99-107 |
| PMID | 23737409 |
| Title | Future perspectives on the treatment of cognitive deficits and negative symptoms in schizophrenia. |
| Abstract | Drug discovery based on classic models for cognitive impairment and negative symptoms of schizophrenia have met with only modest success. Because cognitive impairment and negative symptoms may result from disruptions in neurodevelopment, more complex developmental models that integrate environmental and genetic risk factors are needed. In addition, it has become clear that biochemical pathways involved in schizophrenia form complex, interconnected networks. Points at which risk factors converge, such as brain-derived neurotrophic factor (BDNF) and protein kinase B (AKT), and from which processes involved in neuroplasticity diverge, are of particular interest for pharmacologic interventions. This paper reviews elements of neurodevelopmental models for cognitive deficits and negative symptoms of schizophrenia with the aim of identifying potential targets for interventions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 407 | Proc. Natl. Acad. Sci. U.S.A. 2013 Jun 110: E2400-9 |
| PMID | 23729812 |
| Title | Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. |
| Abstract | schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR(-/-)), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR(-/-) mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a trace-conditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR(-/-) mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 408 | J Neuropsychiatry Clin Neurosci 2013 -1 25: 88-94 |
| PMID | 23487199 |
| Title | BDNF val66met polymorphism is associated with age at onset and intensity of symptoms of paranoid schizophrenia in a Polish population. |
| Abstract | The brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. There is evidence that val66met polymorphism may be involved in the pathophysiology of schizophrenia. The authors genotyped val66met (rs6265) polymorphism of the BDNF gene in 208 inpatients with paranoid schizophrenia and 254 control subjects in a Polish population. There was no association between val66met polymorphism and development of paranoid schizophrenia in either men or women. However, an association was found between this polymorphism and age at onset and psychopathology of paranoid schizophrenia. Men with the val/met genotype had an earlier age at onset, and the val/val genotype predisposed to more severe symptoms, particularly on the General Psychopathology Scale of the Positive and Negative Symptoms Scale (PANSS-G). The analysis of PANSS single items has shown that patients with the val/met genotype had higher scores on a hallucinatory behavior item than those with other genotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 409 | Psychiatry Clin. Neurosci. 2013 Feb 67: 123-5 |
| PMID | 23438165 |
| Title | Association of the BDNF?C270T polymorphism with schizophrenia: updated meta-analysis. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been suggested to play a role in the pathophysiology of schizophrenia. The C270T polymorphism (rs56164415) in the BDNF 5'-non-coding region has been extensively investigated for an association with schizophrenia, but with conflicting results. An updated meta-analysis was therefore performed of 13 case-control association studies (3505 patients and 3992 controls). An association was found between the T allele and schizophrenia. The association was significant in the East Asian population, but not in the Caucasian population. It is suggested that the BDNF C270T polymorphism contributes to schizophrenia susceptibility, especially in East Asian subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 410 | Expert Opin Ther Pat 2013 May 23: 615-28 |
| PMID | 23405869 |
| Title | AMPA receptor positive allosteric modulators: a patent review. |
| Abstract | AMPA receptors represent an interesting target to develop innovative therapeutic drugs such as positive allosteric modulators, a subclass of modulators known to potentiate the effect of glutamate through this kind of glutamatergic ionotropic receptors. The enhancement of AMPA signals is expected to be beneficial in the management of several neurological disorders, such as depression, schizophrenia, Parkinson's disease and learning-memory deficits linked to Alzheimer's disease. AMPA receptor positive allosteric modulators continue to be the object of intensive research as evidenced by the diversification in the range of chemotypes explored. This article examines recent discoveries of new AMPA receptor modulators mainly described in the patent literature from 2008 to 2012. An important challenge is to discover an ideal drug candidate exhibiting appropriate in vivo activity after oral administration with an acceptable safety profile. The future remains promising because such compounds have proved to be able to stimulate the expression of the neurotrophic factor BDNF, a unique property opening interesting perspectives in new therapeutic applications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 411 | Neuroscience 2013 Jun 239: 271-9 |
| PMID | 23380505 |
| Title | Steroid hormones and BDNF. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a neurotrophin abundantly expressed in several areas of the central nervous system (CNS) and is known to induce a lasting potentiation of synaptic efficacy, to enhance specific learning and memory processes. BDNF is one of the key molecules modulating brain plasticity and it affects cognitive deficit associated with aging and neurodegenerative disease. Several studies have shown an altered BDNF production and secretion in a variety of neurodegenerative diseases like Alzheimer's and Parkinson's diseases but also in mood disorders like depression, eating disorders and schizophrenia. Plasma BDNF is also a biomarker of impaired memory and general cognitive function in aging women. Gonadal steroids are involved in the regulation of several CNS processes, specifically mood, affective and cognitive functions during fertile life and reproductive aging. These observations lead many scientists to investigate a putative co-regulation between BDNF and gonadal and/or adrenal steroids and their relationship with gender difference in the incidence of mental diseases. This overview aims to summarize the current knowledge on the correlation between BDNF expression/function and both gonadal (progesterone, estrogens, and testosterone) and adrenal hormones (mainly cortisol and dehydroepiandrosterone (DHEA)) with relevance in clinical application. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 412 | Asian J Psychiatr 2013 Feb 6: 22-8 |
| PMID | 23380313 |
| Title | BDNF-TrkB signaling and neuroprotection in schizophrenia. |
| Abstract | Neurotrophins such as brain-derived neurotropic factor (BDNF), play critical role in neuronal survival, synaptic plasticity and cognitive functions. BDNF is known to mediate its action through various intracellular signaling pathways triggered by activation of tyrosine kinase receptor B (TrkB). Evidence from clinical as well pre-clinical studies indicate alterations in BDNF signaling in schizophrenia. Moreover, several antipsychotic drugs have time-dependent effects on BDNF levels in both schizophrenia subjects and animal models of schizophrenia. Given the emerging interest in neuroplasticity in schizophrenia understanding the neuroprotective and cell survival roles of BDNF signaling will enhance our knowledge of its diverse effects, which may lead to more effective treatments for schizophrenia. This article will present an overview of recent findings on the role of BDNF signaling in the pathophysiology and treatment of schizophrenia, with a special focus on its neuroprotective effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 413 | J. Nerv. Ment. Dis. 2013 Jan 201: 23-9 |
| PMID | 23274291 |
| Title | Trauma profile in Egyptian adolescents with first-episode schizophrenia: relation to psychopathology and plasma brain-derived neurotrophic factor. |
| Abstract | We aimed to investigate the relation of trauma profile to schizophrenia psychopathology in a sample of Egyptian drug-naïve adolescent patients with first-episode schizophrenia. In addition, a hypothesized mediating effect of brain-derived neurotrophic factor (BDNF) in this relation was formally tested. We assessed 74 eligible outpatients using the Positive and Negative Syndrome Scale (PANSS) for measuring psychopathology. Trauma histories were recorded with the help of the Cumulative Trauma Measure. Serum BDNF levels were estimated by enzyme-linked immunosorbent assay. Total cumulative trauma, personal identity trauma, and survival trauma were found to be the significant predictors for schizophrenia psychopathology. BDNF fully mediated the associations between total cumulative trauma and overall schizophrenia psychopathology. BDNF also mediated the associations between some types of trauma and both PANSS-positive and PANSS-negative symptom factors. We concluded that total cumulative trauma and certain trauma types are linked with schizophrenia psychopathology. BDNF appears to mediate these links. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 414 | Neuroscientist 2013 Aug 19: 345-53 |
| PMID | 23242909 |
| Title | Is altered BDNF biosynthesis a general feature in patients with cognitive dysfunctions? |
| Abstract | Severe cognitive deficits are a frequent outcome of both neurodegenerative and neurodevelopmental disorders. In the attempt to define new clinical biomarkers, current research trends aim at the identification of common molecular features in these pathologies rather than searching for differences. Brain-derived neurotrophic factor (BDNF) has attracted great interest as possible biomarker because of its key role in synaptic remodeling during cognitive processes. BDNF undergoes proteolytic processing and studies in animal models have highlighted that different forms of learning and memory require either the proBDNF precursor or the mature BDNF form. Significantly, an altered expression of BDNF forms was found in postmortem brains and serum from patients with schizophrenia, Alzheimer's disease and mood disorders. Based on these studies, this review puts forward the hypothesis that abnormalities in proBDNF or mBDNF biosynthesis may correspond to different cognitive dysfunctions in these brain diseases, while the role of truncated BDNF remains unknown. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 415 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 214-23 |
| PMID | 23123357 |
| Title | Antioxidants as potential therapeutics for neuropsychiatric disorders. |
| Abstract | Oxidative stress has been implicated in the pathophysiology of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression etc. Both genetic and non-genetic factors have been found to cause increased cellular levels of reactive oxygen species beyond the capacity of antioxidant defense mechanism in patients of psychiatric disorders. These factors trigger oxidative cellular damage to lipids, proteins and DNA, leading to abnormal neural growth and differentiation. Therefore, novel therapeutic strategies such as supplementation with antioxidants can be effective for long-term treatment management of neuropsychiatric disorders. The use of antioxidants and PUFAs as supplements in the treatment of neuropsychiatric disorders has provided some promising results. At the same time, one should be cautious with the use of antioxidants since excessive antioxidants could dangerously interfere with some of the protective functions of reactive oxygen species. The present article will give an overview of the potential strategies and outcomes of using antioxidants as therapeutics in psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 416 | Int. J. Neuropsychopharmacol. 2013 Mar 16: 477-83 |
| PMID | 22827965 |
| Title | A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex. |
| Abstract | The dopamine D5 receptor (D5R) exhibits a wide distribution in prefrontal cortex (PFC) but its role in this region has not yet been elucidated. In the present study, we identified a novel physiological function for the D(5)R as a regulator of brain-derived neurotrophic factor (BDNF) and Akt signalling in PFC. Specifically, acute activation of the D(5)R by the dopamine agonist SKF 83959 enhanced BDNF expression and signalling through its receptor, tropomyosin receptor kinase B (TrkB), in rats and in mice gene-deleted for the D1 receptor but not the D(5)R. These changes were concomitant with increased expression of GAD67, a protein whose down-regulation has been implicated in the aetiology of schizophrenia. Furthermore, D(5)R activation increased phosphorylation of Akt at the Ser(473) site, consequently decreasing the activity of its substrate GSK-3?. These findings could have wide-reaching implications given evidence showing activation of these pathways in PFC has therapeutic effects in neuropsychiatric disorders such as drug addiction, schizophrenia and depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 417 | Acta Neuropsychiatr 2013 Dec 25: 356-60 |
| PMID | 25287876 |
| Title | Neurogenic locus notch homolog protein 4 and brain-derived neurotrophic factor variants combined effect on schizophrenia susceptibility. |
| Abstract | To investigate the relationships between single-nucleotide polymorphisms (SNPs) in NOTCH4 and brain-derived neurotrophic factor (BDNF) with schizophrenia among Han Chinese in Southern China. Two NOTCH4 SNPs (rs520688 and rs415929) and two BDNF SNPs (rs2030324 and rs12273539) were examined in 464 schizophrenics and 464 healthy controls from Hunan province in South China, using the Sequenom MassARRAY® iPLEX System. In the study population, rs520688 and rs2030324 were significantly associated with schizophrenia. A decreased risk of schizophrenia was associated with the rs520688 GA genotype (p = 0.035), whereas an increased risk of schizophrenia was associated with the rs2030324 CC/CT genotype (p = 0.044). The genotype distributions of rs415929 in NOTCH4 and rs12273539 in BDNF did not differ significantly between the case and control groups. Although no allele-allele interactions were detected between rs520688 and rs2030324, recombination analysis revealed a combined effect of the two on the susceptibility to schizophrenia, with GA-TT decreasing and CT/CC-GG/GA increasing the risk of schizophrenia. In conclusion, rs520688 in NOTCH4 and rs2030324 in BDNF are significantly associated with schizophrenia among Han Chinese in Southern China. The two had a combined effect on the susceptibility to schizophrenia among Han Chinese in Southern China, but this may not be caused by an allele-allele interaction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 418 | Neuropharmacology 2013 Dec 75: 233-45 |
| PMID | 23958448 |
| Title | Active DNA demethylation in post-mitotic neurons: a reason for optimism. |
| Abstract | Over the last several years proteins involved in base excision repair (BER) have been implicated in active DNA demethylation. We review the literature supporting BER as a means of active DNA demethylation, and explain how the various components function and cooperate to remove the potentially most enduring means of epigenetic gene regulation. Recent evidence indicates that the same pathways implicated during periods of widespread DNA demethylation, such as the erasure of methyl marks in the paternal pronucleus soon after fertilization, are operational in post-mitotic neurons. Neuronal functional identities, defined here as the result of a combination of neuronal subtype, location, and synaptic connections are largely maintained through DNA methylation. Chronic mental illnesses, such as schizophrenia, may be the result of both altered neurotransmitter levels and neurons that have assumed dysfunctional neuronal identities. A limitation of most current psychopharmacological agents is their focus on the former, while not addressing the more profound latter pathophysiological process. Previously, it was believed that active DNA demethylation in post-mitotic neurons was rare if not impossible. If this were the case, then reversing the factors that maintain neuronal identity, would be highly unlikely. The emergence of an active DNA demethylation pathway in the brain is a reason for great optimism in psychiatry as it provides a means by which previously pathological neurons may be reprogrammed to serve a more favorable role. Agents targeting epigenetic processes have shown much promise in this regard, and may lead to substantial gains over traditional pharmacological approaches. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 419 | Neuroscience 2013 Oct 250: 222-31 |
| PMID | 23872394 |
| Title | Effects of withdrawal from repeated amphetamine exposure in peri-puberty on neuroplasticity-related genes in mice. |
| Abstract | Although extensive evidence demonstrates that repeated administration of amphetamine (AMPH) induces behavioral and neurochemical sensitization, the influence of the developmental timing of AMPH administration is unknown. This is an important issue to address because it could help clarify the influence of early drug exposure on neuronal plasticity and the involvement of dopaminergic sensitization in the etiopathology of neuropsychiatric disorders. Thus, we decided to investigate the molecular alterations induced by the administration of AMPH during adolescence, when repeated exposure to the psychostimulant may interfere with developmental neuroplasticity. We investigated the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) and of two inducible-early genes (arc and cfos) that bridge neuronal activity with long-lasting functional alterations. We found that peri-pubertal treatment with AMPH induces long-lasting changes in the expression of BDNF and of activity-regulated genes in the hippocampus and in the prefrontal/frontal cortex, and leads to alterations of their short-term modulation in response to a subsequent acute AMPH challenge. These data suggest that AMPH exposure in peri-puberty may negatively affect the maturation of brain structures, such as the prefrontal cortex, which facilitate the development of dopamine sensitization and may contribute to dopamine-dependent behavioral dysfunctions and molecular alterations in adulthood. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 420 | Front Cell Neurosci 2013 -1 7: 92 |
| PMID | 23781174 |
| Title | BDNF deficiency and young-adult methamphetamine induce sex-specific effects on prepulse inhibition regulation. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH) users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous (HET) mutant mice has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and wildtype (WT) littermates were treated during young adulthood with METH and, following a 2-week break, prepulse inhibition (PPI) was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH) disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine (APO) or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioral endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behavior. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 421 | Neuropsychiatr Dis Treat 2013 -1 9: 1573-82 |
| PMID | 24143106 |
| Title | Evidence for single nucleotide polymorphisms and their association with bipolar disorder. |
| Abstract | Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 422 | J Psychiatr Res 2013 Oct 47: 1376-82 |
| PMID | 23806580 |
| Title | Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia. |
| Abstract | To investigate possible differences in peripheral levels of chemokines, BDNF and oxidative markers between patients with schizophrenia (SZ) and matched healthy controls, and investigate the correlation of these biomarkers with cognitive performance. Thirty individuals with SZ and 27 healthy controls were included and the following plasmatic biomarkers' levels were determined according to manufacturers' instructions: BDNF, TBARS, protein carbonyl content (PCC) and the chemokines CXCL-10/IP-10, CXCL-8/IL-8, CCL-11, CCL-24/Eotaxin-2, CCL-2/MCP-1, CCL-3/MIP-1. Selected neuropsychological tasks were administered to assess verbal learning (Hopkins Verbal Learning Test), verbal fluency (FAS test), working memory (Visual Working Memory Task, Keep Track Task, Letter Memory Task), set shifting (Plus-minus task, Number-letter task), inhibition (Computerized Stroop Task, Semantic Generation Task) and complex executive function tasks (Tower of London and the shortened version of the WCST-64). Compared with the healthy control group, individuals with SZ presented significantly higher levels of BDNF and the chemokine CCL-11, and lower levels of TBARS and the chemokine CXCL-10/IP-10. When we examined only the SZ group, BDNF levels were positively correlated with semantic generation tasks. Working memory ability was negatively correlated with PCC. Regarding chemokines, CCL-11 was negatively correlated to performance in working memory test, and positively correlated with cognitive flexibility task. CXCL-8/IL-8 was positively correlated with verbal fluency. CCL-24/Eotaxin-2 was positively correlated with semantic generation ability and letter memory task. Our results indicate that cognitive performance in SZ is associated with mediators of neuroplasticity that can be measured peripherally. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 423 | Pharmacol Rep 2013 -1 65: 1185-93 |
| PMID | 24399714 |
| Title | BDNF rs 6265 polymorphism and COMT rs 4680 polymorphism in deficit schizophrenia in Polish sample. |
| Abstract | Deficit schizophrenia (DS) is distinguished from the group of schizophrenic psychoses based on the presence of primary negative symptoms. It differs from nondeficit (NDS) forms of schizophrenia in dimensions such as risk factors, family history, course of illness and neurobiological differences. The aim of the study was assessment of a potential association of the investigated polymorphisms of the brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes with the deficit syndrome in schizophrenia. A cohort of 200 patients with schizophrenia (81 DS and 119 NDS subjects) and a group of 100 control subjects matched for ethnicity, sex and age were recruited. Somatic and psychometric assessment were conducted as well as structured interview about the influence of adverse biological, family and social factors. Genetic analysis of the BDNF (Val66Met) rs6265 and the COMT (Val158Met) rs4680 polymorphisms was performed. We found significant differences between DS and NDS in rs4680 COMT genotype distribution: more homozygous Val/Val were found (31 vs. 17%) in the NDS compared to the DS subgroup. No associations were found between the investigated polymorphisms of the BDNF gene and the presence of schizophrenia either in DS and NDS subgroups. The analysis of the COMT rs4680 polymorphism in the present DS and NDS study shows that some genetic factors may be relevant in analyzing the reasons for the differentiation of schizophrenic subtypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 424 | Zh Nevrol Psikhiatr Im S S Korsakova 2013 -1 113: 49-54 |
| PMID | 24300806 |
| Title | [Interaction effects of anxiety and the BDNF Val66Met polymorphism on attention in patients with schizophrenia spectrum disorders]. |
| Abstract | Authors investigated effects of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene and level of trait anxiety on attention in 90 patients with schizophrenia or schizoaffective psychosis. Attention was assessed using auditory event-related brain potentials (ERPs) and neuropsychological testing. There was a significant effect of the BDNF genotype, but not anxiety, on performance on the neuropsychological test and on the P300 amplitude in frontal and temporal leads. Carriers of a Met allele performed worse and showed lower P300 amplitude during the attention task than those with the ValVal genotype. The interaction effect of the genotype and anxiety was observed for non-target N100 amplitude in central and parietal leads. This effect depended on the level of anxiety: the interaction was significant only in the group with the lower level of anxiety. In this group, a Met allele was associated with the lower N100 amplitude. It was suggested that BDNF genotype does not contribute to brain electrical activity at the first stage of stimulus recognition (N100) because highly anxious people tend to be more attentive, regardless of genotype, due to the fear about their ability to cope with the task requirements. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 425 | Mol. Cells 2013 Dec 36: 534-41 |
| PMID | 24292945 |
| Title | Administration of mesenchymal stem cells and ziprasidone enhanced amelioration of ischemic brain damage in rats. |
| Abstract | Ziprasidone is a benzisothiazolyl piperazine derivative that was developed from the chemically related antipsychotic drug tiospirone, and it improves neurological functions of the ischemic brain and is effective in treatment of schizophrenia. Mesenchymal stem cells (MSCs) are considered as a leading candidate for neurological regenerative therapy because of their neural differentiation properties in damaged brain. We investigated whether the transplantation of neural progenitor cells (NPCs) derived from adipose mesenchymal stem cells combined with ziprasidone enhances neuroprotective effects in an animal model of focal cerebral ischemia. In combination therapy groups, significant reduction of infarct volume and improvement of neurological functions were observed at 3 days after middle cerebral artery occlusion (MCAO) compared with monotherapy. Co-administration of ziprasidone and NPCs enhanced the anti-apoptotic effect and reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells compared with the NPCs alone group at 7 days after MCAO. Ziprasidone or the combination of ziprasidone and NPCs induced the expression of endogenous neurotrophic factor gene brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF). The immunohistochemical investigation revealed that the ziprasidone and NPCs attenuated the increased intensity of microglial marker (Iba-1) in the infarcted cortical area. Moreover, the number of transplanted NPCs on day 7 with combination therapy was significantly higher than with NPCs alone. These effects might be responsible for improved functional behavior and increased survival of NPCs. Our finding indicates that combination therapy of ziprasidone and NPCs enhances neuroprotection against ischemic brain injury. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 426 | Front Behav Neurosci 2013 -1 7: 149 |
| PMID | 24155701 |
| Title | An investigation into "two hit" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice. |
| Abstract | Reduced brain-derived neurotrophic factor (BDNF) signaling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET) and wild-type controls were chronically treated during weeks 6, 7, and 8 of life with the cannabinoid receptor agonist, CP55,940 (CP). After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI) was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [(3)H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus. These results show that BDNF deficiency and chronic young-adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male "two hit" mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [(3)H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential "two hit" neurodevelopmental mechanisms in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 427 | Neurosci. Lett. 2013 Nov 556: 37-41 |
| PMID | 24141084 |
| Title | Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine. |
| Abstract | Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Peripheral BDNF levels in patients with schizophrenia have been widely reported in the literature. However, it is still controversial whether peripheral levels of BDNF are altered in patients with schizophrenia. The peripheral BDNF levels previously reported in patients with schizophrenia were total BDNF (proBDNF and mature BDNF) as it was unable to specifically measure mature BDNF due to limited BDNF antibody specificity. In this study, we examined whether peripheral levels of mature BDNF were altered in patients with treatment-resistant schizophrenia. Matrix metalloproteinase-9 (MMP-9) levels were also measured, as MMP-9 plays a role in the conversion of proBDNF to mature BDNF. Twenty-two patients with treatment-resistant schizophrenia treated with clozapine and 22 age- and sex-matched healthy controls were enrolled. The plasma levels of mature BDNF and MMP-9 were measured using ELISA kits. No significant difference was observed for mature BDNF however, MMP-9 was significantly increased in patients with schizophrenia. The significant correlation was observed between mature BDNF and MMP-9 plasma levels. Neither mature BDNF nor MMP-9 plasma levels were associated clinical variables. Our results do not support the view that peripheral BDNF levels are associated with schizophrenia. MMP-9 may play a role in the pathophysiology of schizophrenia and serve as a biomarker for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 428 | BMC Complement Altern Med 2013 -1 13: 272 |
| PMID | 24138845 |
| Title | Antidepressant-like effects of the aqueous macerate of the bulb of Gladiolus dalenii Van Geel (Iridaceae) in a rat model of epilepsy-associated depression. |
| Abstract | In Cameroonian traditional medicine various extracts of Gladiolus dalenii Van Geel (Iridaceae) have been used as a cure for various ailments that include headaches, digestive problems, muscle and joint aches, and some central nervous system disorders such as epilepsy, schizophrenia and mood disorders. Owning to this background, the aim of the study was to investigate whether an aqueous macerate of the bulb of Gladiolus dalenii has any antidepressant activity focusing specifically on depression-like behaviours associated with epilepsy. We used the combined administration of atropine and pilocarpine to rats as our animal model of epilepsy. The forced swim test and spontaneous locomotor activity in the open field test were the two tools used to assess the presence of depression-like behaviour in epileptic and control animals. The following depression-related parameters were determined: plasma ACTH, plasma corticosterone, adrenal gland weight and hippocampal levels of brain-derived neurotrophic factor (BDNF). The effects of Gladiolus dalenii were compared to that of fluoxetine. Our results showed that we had a valid animal model of epilepsy-induced depression as all 3 measures of construct, predictive and face validity were satisfied. The data indicated that Gladiolus dalenii significantly reduced the immobility times in the forced swim test and the locomotor activity as assessed in the open field. A similar pattern was observed when the HPA axis parameters were analysed. Gladiolus dalenii significantly reduced the levels of ACTH, corticosterone, but not the adrenal gland weight. Gladiolus dalenii significantly increased the level of BDNF in the hippocampus. In all parameters measured the effects of Gladiolus dalenii were significantly greater than those of fluoxetine. The results show that Gladiolus dalenii has antidepressant-like properties similar to those of fluoxetine in epilepsy-associated depressive states. The antidepressant activity of Gladiolus dalenii is likely to be mediated by restoring the activity of the HPA axis and increasing the levels of BDNF in the hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 429 | PLoS ONE 2013 -1 8: e74264 |
| PMID | 24069289 |
| Title | The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia. |
| Abstract | The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 430 | Neuropsychobiology 2013 -1 68: 146-55 |
| PMID | 24051573 |
| Title | Serum brain-derived neurotrophic factor levels and cocaine-induced transient psychotic symptoms. |
| Abstract | Cocaine-induced psychosis (CIP) is among the most serious adverse effects of cocaine. Reduced serum brain-derived neurotrophic factor (BDNF) levels have been reported in schizophrenia and psychosis; however, studies assessing the involvement of BDNF in CIP are lacking. A total of 22 cocaine-dependent patients (aged 33.65 ± 6.85) who had never experienced psychotic symptoms under the influence of cocaine (non-CIP) and 18 patients (aged 34.18 ± 8.54) with a history of CIP completed a 2-week detoxification program in an inpatient facility. Two serum samples were collected from each patient at baseline and at the end of the protocol. Demographic, consumption and clinical data were recorded for all patients. A paired group of healthy controls was also included. At the beginning of the detoxification treatment, serum BDNF levels were similar in both the non-CIP and the CIP groups. During early abstinence, the non-CIP group exhibited a significant increase in serum BDNF levels (p = 0.030), whereas the CIP group exhibited a decrease. Improvements in depression (Beck Depression Inventory, BDI, p = 0.003) and withdrawal symptoms (Cocaine Selective Severity Assessment, CSSA, p = 0.013) show a significant positive correlation with serum BDNF levels in the non-CIP group, whereas no correlation between the same variables was found in the CIP group. This study suggests that BDNF plays a role in the transient psychotic symptoms associated with cocaine consumption. In the non-CIP group, the increase in serum BDNF appears to be driven by the effects of chronic cocaine consumption and withdrawal. In contrast, patients with CIP share some of the neurotrophic deficiencies that characterize schizophrenia and psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 431 | Dev. Neurosci. 2013 -1 35: 384-95 |
| PMID | 24021607 |
| Title | Enhanced brain-derived neurotrophic factor signaling in the nucleus accumbens of juvenile rats. |
| Abstract | Brain-derived neurotrophic factor (BDNF) signaling through its receptor, tropomyosin receptor kinase B (TrkB), plays a critical role in neural plasticity and its dysregulation in striatum and prefrontal cortex (PFC) has been implicated in the etiology of mental health disorders such schizophrenia and drug addiction. In the present study, we characterized age-dependent differences in BDNF signaling and TrkB expression within the nucleus accumbens (NAc), caudate putamen (CP) and PFC in rats and determined the effects of administration of the dopamine agonist, SKF 83959, which activates the Gq-coupled dopamine receptors, the dopamine D5 receptor and the D1-D2 receptor heteromer. As proBDNF binds with high affinity to the p75 neurotrophin receptor (p75NTR), expression levels of these proteins were also assessed. The present findings showed that juvenile rats (aged 26-28 days) exhibited significantly elevated basal BDNF expression and activation of full-length TrkB (TrkBfull) in NAc compared to their adult counterparts, as evidenced by increased TrkBfull phosphorylation. These changes were concomitant with an increase in the relative expression of TrkBfull compared to the truncated isoform, TrkB.T1, in NAc and CP. Conversely, in PFC the basal expression of BDNF in juvenile rats was significantly lower than in adult rats with an elevated relative expression of TrkBfull. Acute administration of SKF 83959 to juvenile rats abolished the age-dependent differences in BDNF expression in NAc and PFC, and in the relative expression of TrkBfull in NAc and CP. Together these findings indicate that the expression and/or signaling of BDNF and TrkB in striatum and PFC of juvenile rats is fundamentally different from that of adult rats, a finding that may have implications in neuropsychiatric disorders that exhibit age-dependent susceptibility such as schizophrenia and drug addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 432 | PLoS ONE 2013 -1 8: e72652 |
| PMID | 23967328 |
| Title | Association study of Val66Met polymorphism in brain-derived neurotrophic factor gene with clozapine-induced metabolic syndrome: preliminary results. |
| Abstract | The prevalence of the metabolic syndrome (MetS) is higher among patients receiving atypical antipsychotics (AAPs) treatment, and even among AAPs, treatment with clozapine has been shown to be associated with a higher long-term incidence rate of MetS. Likewise, brain-derived neurotrophic factor (BDNF) deficiency has been reported to result in metabolic traits, such as increased food intake, hyperphagia and obesity, etc. In this study, we hypothesized that a functional polymorphism (Val66Met) in the BDNF gene may confer susceptibility to clozapine-induced MetS, potentially in a sex-specific manner, since an interaction between Val66Met polymorphism and sex was observed in our previous studies. A total of 199 schizophrenia patients being treated with clozapine were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We genotyped the Val66Met polymorphism, and measured the serum levels of fasting glucose (GLU), triglyceride (TG) and high density lipoprotein cholesterol (HDL). There was a trend indicating a significant association between the homozygous Met/Met genotype and MetS in male patients (OR?=?2.39; 95% CI: 1.05-5.41; p?=?0.039; corrected p?=?0.078). Among the six risk factors listed in the ATPIII criteria, we found a significant association between fasting GLU levels and Val66Met polymorphism in males (p?=?0.005; corrected p?=?0.03), but not in females (p?=?0.65). Post-hoc analysis in males revealed that the Met/Met carriers had significant higher levels of fasting GLU than those with Val/Val or Val/Met genotypes (p?=?0.007; corrected p?=?0.042 and p?=?0.002; corrected p?=?0.012, respectively). In conclusion, we observed a weak association between the Val66Met polymorphism and clozapine-induced MetS in a sex-specific manner. While preliminary, such findings prompt further, large-scale longitudinal studies to replicate these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 433 | Front Pharmacol 2013 -1 4: 99 |
| PMID | 23950745 |
| Title | Comorbid obsessive-compulsive symptoms in schizophrenia: contributions of pharmacological and genetic factors. |
| Abstract | A large subgroup of around 25% of schizophrenia patients suffers from obsessive-compulsive symptoms (OCS) and about 12% fulfill the diagnostic criteria of an obsessive-compulsive disorder (OCD). The additional occurrence of OCS is associated with high subjective burden of disease, additional neurocognitive impairment, poorer social and vocational functioning, greater service utilization and high levels of anxiety and depression. Comorbid patients can be assigned to heterogeneous subgroups. One hypothesis assumes that second generation antipsychotics (SGAs), most importantly clozapine, might aggravate or even induce second-onset OCS. Several arguments support this assumption, most importantly the observed chronological order of first psychotic manifestation, start of treatment with clozapine and onset of OCS. In addition, correlations between OCS-severity and dose and serum levels and duration of clozapine treatment hint toward a dose-dependent side effect. It has been hypothesized that genetic risk-factors dispose patients with schizophrenia to develop OCS. One study in a South Korean sample reported associations with polymorphisms in the gene SLC1A1 (solute carrier family 1A1) and SGA-induced OCS. However, this finding could not be replicated in European patients. Preliminary results also suggest an involvement of polymorphisms in the BDNF gene (brain-derived neurotrophic factor) and an interaction between markers of SLC1A1 and the gene DLGAP3 (disc large associated protein 3) as well as GRIN2B (N-methyl-D-aspartate receptor subunit 2B). Further research of well-defined samples, in particular studies investigating possible interactions of genetic risk-constellations and pharmacodynamic properties, are needed to clarify the assumed development of SGA-induced OCS. Results might improve pathogenic concepts and facilitate the definition of at risk populations, early detection and monitoring of OCS as well as multimodal therapeutic interventions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 434 | Int J Clin Exp Pathol 2013 -1 6: 1617-23 |
| PMID | 23923080 |
| Title | Association of the brain-derived neurotrophic factor gene G196A rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. |
| Abstract | This study aimed to explore the association between BDNF G196A gene rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. BDNF G196A rs6265 genotype and allele frequency were measured using Polymerase Chain Reaction (PCR) methods in 224 drug-free patients with schizophrenia and 220 controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was assessed using the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT). In the patient group, differences in severity of symptoms across the three genotypes (i.e., G/G, G/A and A/A) of G196A were assessed using one-way analysis of variance. G/A genotype had higher frequencies than GG or AA genotype in both patients and controls. There was no significant difference in G/G, G/A, A/A genotype frequency between patients and controls (P > 0.05). The allele G had higher frequencies than allele A in both patients and controls. There was no significant difference in G or A allele frequency between patients and controls (P > 0.05). There was significant difference in A/A genotype frequency between positive group patients and negative group patients. There was no significant difference in cognitive performance between patients with G/G, G/A and A/A genotype (all P > 0.05). BDNF G196A gene rs6265 polymorphism is not associated with the cognitive function but with the clinical symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 435 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 181-8 |
| PMID | 23876786 |
| Title | BDNF val66met modulates the association between childhood trauma, cognitive and brain abnormalities in psychoses. |
| Abstract | Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood abuse, cognitive function, and brain abnormalities in psychoses. 249 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited to the TOP research study (mean±age: 30.7±10.9; gender: 49% males). History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Cognitive function was assessed through a standardized neuropsychological test battery. BDNF val66met was genotyped using standardized procedures. A sub-sample of n=106 Caucasians with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder (mean±age: 32.67±10.85; 49% males) had data on sMRI. Carriers of the Methionine (met) allele exposed to high level of childhood abuse demonstrated significantly poorer cognitive functioning compared to homozygotic Valine (val/val) carriers. Taking in consideration multiple testing, using a more conservative p value, this was still shown for physical abuse and emotional abuse, as well as a trend level for sexual abuse. Further, met carriers exposed to high level of childhood sexual abuse showed reduced right hippocampal volume (r(2)=0.43; p=0.008), and larger right and left lateral ventricles (r(2)=0.37; p=0.002, and r(2)=0.27; p=0.009, respectively). Our findings were independent of age, gender, diagnosis and intracranial volume. Our data demonstrate that in patients with psychoses, met carriers of the BDNF val66met with high level of childhood abuse have more cognitive and brain abnormalities than all other groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 436 | Front Psychiatry 2013 -1 4: 64 |
| PMID | 23847552 |
| Title | Relationship between Brain-Derived Neurotrophic Factor and Schneiderian First Rank Symptoms in Antipsychotic-Naïve Schizophrenia. |
| Abstract | Neurodevelopmental aberrations influenced by neurotrophic factors are among the important paradigms to understand schizophrenia pathogenesis. Among various neurotrophic factors, Brain-Derived Neurotrophic Factor (BDNF) is strongly implicated by previous research studies. Evaluating co-morbidity free, antipsychotic-naïve schizophrenia patients for BDNF levels and examining the correlates of this factor with symptoms might facilitate elucidation of its pathogenetic role without confounds of potential influencing factors. In this study, 59 co-morbidity free, antipsychotic-naïve schizophrenia patients were compared with 60 healthy controls for serum BDNF levels. In addition, the relationship between Schneiderian First Rank Symptoms (FRS) and BDNF level in patients was examined. As a group, schizophrenia patients (28.8?±?11.7?ng/mL) had significantly lower serum BDNF than healthy controls (34.9?±?8.2?ng/mL) after controlling for the potential confounding effects of age and sex (F?=?7.8; p?=?0.006). Further analyses revealed FRS status to have significant effect on plasma BDNF after controlling for the potential confounding effects of age and sex (F?=?4.5; p?=?0.01). Follow-up post hoc analyses revealed FRS(+) patients to have significant deficit in plasma BDNF level in comparison with healthy controls (p?=?0.002); however, FRS(-) patients did not differ from healthy controls (p?=?0.38). Our study observations add further support to the role for BDNF in schizophrenia pathogenesis and suggest a potential novel link between deficient BDNF and FRS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 437 | Expert Opin Drug Discov 2013 Oct 8: 1297-307 |
| PMID | 23837554 |
| Title | The preclinical profile of lurasidone: clinical relevance for the treatment of schizophrenia. |
| Abstract | Lurasidone is a novel antipsychotic drug approved for the treatment of schizophrenia in adults. It is formulated into tablets, administered orally once/day (dose range 40-160 mg/day) does not require titration, but needs to be given with food to maximize its plasma exposure. This review focuses on the preclinical discovery of lurasidone. Furthermore, the article provides analysis on the pharmacological, behavioral and molecular mechanisms of lurasidone and their contribution to its therapeutic advantages. The article is based on the literature reported in published preclinical and clinical studies, product labels, poster presentations and press releases. Lurasidone demonstrated high affinity for serotonin 5-HT(1A), 5-HT(2A), 5-HT?, dopamine D? and adrenergic ?(2C) receptors followed by ?? and ?(2A) receptors. The drug was active in animal models predictive of antipsychotic and antidepressant activities. In addition, it demonstrated procognitive effects, as it was effective in several animal models that assessed memory, cognition and executive functions in rats and in primates. At a cellular level, lurasidone promotes neuronal plasticity, can modulate epigenetic mechanisms controlling gene transcription, and increases the expression of the neurotrophic factor BDNF in cortical and limbic brain regions. Lurasidone's mechanisms of action might contribute to its unique psychopharmacological properties in the improved treatment of schizophrenia, and perhaps other psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 438 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Sep 162B: 538-45 |
| PMID | 23832605 |
| Title | Association of BDNF gene polymorphisms with schizophrenia and clinical symptoms in a Chinese population. |
| Abstract | The neurodevelopmental hypothesis is well established in schizophrenia. Accumulating evidence has shown that BDNF may be involved in the pathogenesis of schizophrenia. This study aimed to investigate the potential association of BDNF gene polymorphisms with susceptibility to schizophrenia and with the psychopathological symptoms in patients with schizophrenia in a Han Chinese population. Three polymorphisms (rs6265, rs12273539, and rs10835210) of the BDNF gene were analyzed in a case-control study of 709 Han Chinese individuals (375 patients and 334 controls). The patients' psychopathology was assessed using the positive and negative syndrome scale (PANSS). We found no significant differences in the genotype and allele distributions of all three polymorphisms between the patient and control groups; however, we found a trend toward to significant overall difference in the estimated haplotype frequencies, with more frequent haplotype ATC of rs6265-rs12273539-rs10835210 in the schizophrenic patients than in controls (P?=?0.027). The quantitative trait analysis by the UNPHASED program showed significant associations between the rs6265 (A)-rs12273539 (C)-rs10835210 (A) haplotype and negative symptom scores from the PANSS (x(2) ?=?5.79, P?=?0.016). Our findings suggest that the BDNF gene polymorphisms may play a small effect on susceptibility to schizophrenia, but may contribute to the negative symptoms of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 439 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 1-12 |
| PMID | 23800465 |
| Title | Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis. |
| Abstract | Administration of NMDA receptor antagonists, such as ketamine and MK-801, may induce psychotic-like behaviors in preclinical models of schizophrenia. Ketamine has also been observed to exacerbate psychotic symptoms in schizophrenia patients. However, memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease and proposed for antipsychotic augmentation, may challenge this view. To date, the molecular mechanisms by which these NMDA receptor antagonists cause different neurochemical, behavioral, and clinical effects are still a matter of debate. Here, we investigated by molecular imaging whether these agents could differently modulate gene expression and topographical distribution of glutamatergic postsynaptic density (PSD) proteins. We focused on Homer1a/Homer1b/PSD-95 signaling network, which may be implicated in glutamate-dependent synaptic plasticity, as well as in psychosis pathophysiology and treatment. Ketamine (25 and 50mg/kg) and MK-801 (0.8mg/kg) significantly induced the transcripts of immediate-early genes (Arc, c-fos, and Homer1a) in cortical regions compared to vehicle, whereas they reduced Homer1b and PSD-95 expression in cortical and striatal regions. Differently, memantine (5mg/kg) did not increase Homer1a signal compared to vehicle, whereas it induced c-fos in the somatosensory and in the medial agranular cortices. Moreover, memantine did not affect Homer1b and PSD-95 expression. When compared to ketamine and MK-801, memantine significantly increased the expression of c-fos, Homer1b and PSD-95. Overall, ketamine and MK-801 prominently increased Homer1a/Homer1b expression ratio, whereas memantine elicited the opposite effect. These data may support the view that ketamine, MK-801 and memantine exert divergent effects on PSD transcripts, which may contribute to their partially different behavioral and clinical effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 440 | PLoS ONE 2013 -1 8: e65069 |
| PMID | 23750231 |
| Title | MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons. |
| Abstract | Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 441 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Aug 45: 201-6 |
| PMID | 23748016 |
| Title | BDNF Val66Met variants and brain volume changes in non-affective psychosis patients and healthy controls: a 3 year follow-up study. |
| Abstract | Functional gene polymorphisms modulating neuroplasticity might mediate brain longitudinal structural changes in schizophrenia. The present study aimed to explore possible effects of BDNF Val66Met polymorphism variations on progressive structural brain changes after 3 years from the first episode of psychosis. Patients were part of a large epidemiological and longitudinal intervention program of first-episode psychosis, carried out at the University Hospital Marqués de Valdecilla, Cantabria, Spain. Eighty first-episode patients and 54 healthy controls were included in the final analyses. Brain magnetic resonance imaging (baseline and 3-year follow-up) and BDNF genotype, and clinical and functional outcome were investigated. We did not detect significant association between brain changes and BDNF Val66Met polymorphism variations in patients and controls (all p>0.060). At baseline, there were no significant associations between brain anomalies and BDNF genotype. Functional deficits were similar in Met-carrier and Val homozygote patients after 3-year follow-up (X(2) = 0.66; p = 0.564); there was no relationship between significant volume change across time and functional outcome. Otherwise, Met-carrier controls had significant high rates of alcohol-consumption (p = 0.019) compared to Val homozygote controls. Our findings do not support the notion that BDNF genotype variations may mediate brain macroscopic morphological changes across time. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 442 | Neuroimage 2013 Nov 82: 146-53 |
| PMID | 23727532 |
| Title | Relation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in healthy young adults. |
| Abstract | The NTRK3 gene (also known as TRKC) encodes a high affinity receptor for the neurotrophin 3'-nucleotidase (NT3), which is implicated in oligodendrocyte and myelin development. We previously found that white matter integrity in young adults is related to common variants in genes encoding neurotrophins and their receptors. This underscores the importance of neurotrophins for white matter development. NTRK3 variants are putative risk factors for schizophrenia, bipolar disorder, and obsessive-compulsive disorder hoarding, suggesting that some NTRK3 variants may affect the brain. To test this, we scanned 392 healthy adult twins and their siblings (mean age, 23.6 ± 2.2 years; range: 20-29 years) with 105-gradient 4-Tesla diffusion tensor imaging (DTI). We identified 18 single nucleotide polymorphisms (SNPs) in the NTRK3 gene that have been associated with neuropsychiatric disorders. We used a multi-SNP model, adjusting for family relatedness, age, and sex, to relate these variants to voxelwise fractional anisotropy (FA) - a DTI measure of white matter integrity. FA was optimally predicted (based on the highest false discovery rate critical p), by five SNPs (rs1017412, rs2114252, rs16941261, rs3784406, and rs7176429; overall FDR critical p=0.028). Gene effects were widespread and included the corpus callosum genu and inferior longitudinal fasciculus - regions implicated in several neuropsychiatric disorders and previously associated with other neurotrophin-related genetic variants in an overlapping sample of subjects. NTRK3 genetic variants, and neurotrophins more generally, may influence white matter integrity in brain regions implicated in neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 443 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Aug 45: 92-9 |
| PMID | 23685202 |
| Title | Obesity and psychiatric disorders: commonalities in dysregulated biological pathways and their implications for treatment. |
| Abstract | Rates of obesity are higher than normal across a range of psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia and anxiety disorders. While the problem of obesity is generally acknowledged in mental health research and treatment, an understanding of their bi-directional relationship is still developing. In this review the association between obesity and psychiatric disorders is summarised, with a specific emphasis on similarities in their disturbed biological pathways; namely neurotransmitter imbalances, hypothalamus-pituitary-adrenal axis disturbances, dysregulated inflammatory pathways, increased oxidative and nitrosative stress, mitochondrial disturbances, and neuroprogression. The applicability and effectiveness of weight-loss interventions in psychiatric populations are reviewed along with their potential efficacy in ameliorating disturbed biological pathways, particularly those mediating inflammation and oxidative stress. It is proposed that weight loss may not only be an effective intervention to enhance physical health but may also improve mental health outcomes and slow the rate of neuroprogressive disturbances in psychiatric disorders. Areas of future research to help expand our understanding of the relationship between obesity and psychiatric disorders are also outlined. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 444 | Front Cell Neurosci 2013 -1 7: 61 |
| PMID | 23675315 |
| Title | Impact of structural aberrancy of polysialic acid and its synthetic enzyme ST8SIA2 in schizophrenia. |
| Abstract | Psychiatric disorders are a group of human diseases that impair higher cognitive functions. Whole-genomic analyses have recently identified susceptibility genes for several psychiatric disorders, including schizophrenia. Among the genes reported to be involved in psychiatric disorders, a gene encoding a polysialyltransferase involved in the biosynthesis of polysialic acid (polySia or PSA) on cell surfaces has attracted attention for its potential role in emotion, learning, memory, circadian rhythm, and behaviors. PolySia is a unique polymer that spatio-temporally modifies neural cell adhesion molecule (NCAM) and is predominantly found in embryonic brains, although it persists in areas of the adult brain where neural plasticity, remodeling of neural connections, or neural generation is ongoing, such as the hippocampus, subventricular zone (SVZ), thalamus, prefrontal cortex, and amygdala. PolySia is thought to be involved in the regulation of cell-cell interactions; however, recent evidence suggests that it is also involved in the functional regulation of ion channels and neurologically active molecules, such as Brain-derived neurotrophic factor (BDNF), FGF2, and dopamine (DA) that are deeply involved in psychiatric disorders. In this review, the possible involvement of polysialyltransferase (ST8SIA2/ST8SiaII/STX/Siat8B) and its enzymatic product, polySia, in schizophrenia is discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 445 | Pharmacol. Biochem. Behav. 2013 May 106: 124-7 |
| PMID | 23567202 |
| Title | Effects of TrkB agonist 7,8-dihydroxyflavone on sensory gating deficits in mice after administration of methamphetamine. |
| Abstract | Several lines of evidence suggest that the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway plays a role in behavioral abnormalities observed after administration of psychostimulants, such as methamphetamine (METH). This study was undertaken to examine whether the potent TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) could improve prepulse inhibition (PPI) deficits in mice seen after a single dose of METH. Treatment with 7,8-DHF (3.0, 10 or 30 mg/kg) improved PPI deficits in mice associated with exposure to METH (3.0 mg/kg), in a dose dependent manner. Furthermore, co-administration of ANA-12 (0.5 mg/kg), a TrkB antagonist, significantly blocked the effects of 7,8-DHF (30 mg/kg) on METH-induced PPI deficits. In contrast, administration of 5,7-dihydroxyflavone (5,7-DHF: 30 mg/kg), an inactive TrkB ligand, did not affect METH-induced PPI deficits in mice. An in vivo microdialysis study in conscious mice showed that 7,8-DHF (30 mg/kg) significantly attenuated increased dopamine release in the striatum, after METH administration (3 mg/kg). This study suggests that 7,8-DHF can improve PPI deficits in these mice, through the inhibition of METH-induced dopamine release. Therefore, it is likely that TrkB agonists, such as 7,8-DHF, may constitute a novel class of therapeutic drugs for neuropsychiatric diseases such as METH-use disorder and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 446 | Ann Agric Environ Med 2013 -1 20: 77-81 |
| PMID | 23540216 |
| Title | The efficacy of cognitive rehabilitation with RehaCom programme in schizophrenia patients. The role of selected genetic polymorphisms in successful cognitive rehabilitation. |
| Abstract | schizophrenic patients present cognitive dysfunctions which are regarded to be one of endophenotypical markers predisposing to schizophrenia. Currently, schizophrenia can be treated as a neurodegenerative and neurodeveloping disease with genetic background. Assessment of the possible positive effect of neuropsychological rehabilitation in schizophrenia, in patients presenting cognitive dysfunctions. An additional aim was to verify the hypothesis that some genetic polymorphisms can be a prognostic factor for success in neuropsychological rehabilitation. 41 participants and 40 control subjects were randomly selected. Both groups had the diagnosis of paranoid schizophrenia. Cognitive functions were checked with the Wisconsin Card Sorting Test, Trail Making Test, and Stroop Test at the beginning and end of the experiment. In the research group, each patient trained with the rehabilitation programme RehaCom, whereas the control group did not receive such training. Genes COMT rs4680 and BDNF rs6265 were analysed in the genetic part of study. RehaCom procedures appear to be useful in the neuropsychological rehabilitation of cognitive dysfunctions in patients diagnosed with schizophrenia. The research group showed a moderate improvement in the training programmes. Analysis of parameters obtained in the neuropsychological tests showed a slight improvement in both groups. At the present time, analysis of the polymorphisms of genes cannot be treated as a prognostic factor for the success of neuropsychological rehabilitation because statistical analyses showed few dependences with little statistical significance. Cognitive rehabilitation produces moderate improvement in cognitive functioning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 447 | Psychiatr. Genet. 2013 Jun 23: 124-9 |
| PMID | 23532065 |
| Title | BDNF Val66Met polymorphism and anxiety/depression symptoms in schizophrenia in a Chinese Han population. |
| Abstract | Although several lines of evidences suggest that the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be involved in the pathophysiology of schizophrenia, this association remains controversial. Here, we aim to investigate the genetic association between the BDNF Val66Met polymorphism and schizophrenia and to explore whether this polymorphism could influence the severity of clinical symptoms in schizophrenic patients in a Chinese Han population. Genotyping of the BDNF Val66Met polymorphism was carried out in 456 schizophrenic patients and 483 controls using the fluorescence resonance energy transfer method. The patients' psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. The general clinical data of schizophrenic patients were analyzed. There were significant differences in the genotype distribution and allelic frequencies of the BDNF Val66Met polymorphism between the schizophrenia group and the controls. Multiple linear regression analysis showed that the BDNF Val66Met polymorphism explained ~16% of the variance in anxiety/depression symptoms in schizophrenic patients. Our data provide evidence that the BDNF Val66Met polymorphism may be involved in the etiology of schizophrenia in a Chinese Han population. Furthermore, the BDNF Val66Met polymorphism is a significant factor influencing the severity of anxiety/depression symptoms in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 448 | Schizophr Bull 2013 Jul 39: 766-75 |
| PMID | 23512949 |
| Title | Clinical and molecular genetics of psychotic depression. |
| Abstract | This review provides a comprehensive overview of clinical and molecular genetic as well as pharmacogenetic studies regarding the clinical phenotype of "psychotic depression." Results are discussed with regard to the long-standing debate on categorical vs dimensional disease models of affective and psychotic disorders on a continuum from unipolar depression over bipolar disorder and schizoaffective disorder to schizophrenia. Clinical genetic studies suggest a familial aggregation and a considerable heritability (39%) of psychotic depression partly shared with schizoaffective disorder, schizophrenia, and affective disorders. Molecular genetic studies point to potential risk loci of psychotic depression shared with schizoaffective disorder (1q42, 22q11, 19p13), depression, bipolar disorder, and schizophrenia (6p, 8p22, 10p13-12, 10p14, 13q13-14, 13q32, 18p, 22q11-13) and several vulnerability genes possibly contributing to an increased risk of psychotic symptoms in depression (eg, BDNF, DBH, DTNBP1, DRD2, DRD4, GSK-3beta, MAO-A). Pharmacogenetic studies implicate 5-HTT, TPH1, and DTNBP1 gene variation in the mediation of antidepressant treatment response in psychotic depression. Genetic factors are suggested to contribute to the disease risk of psychotic depression in partial overlap with disorders along the affective-psychotic spectrum. Thus, genetic research focusing on psychotic depression might inspire a more dimensional, neurobiologically and symptom-oriented taxonomy of affective and psychotic disorders challenging the dichotomous Kraepelinian view. Additionally, pharmacogenetic studies might aid in the development of a more personalized treatment of psychotic depression with an individually tailored antidepressive/antipsychotic pharmacotherapy according to genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 449 | Anal. Biochem. 2013 Jun 437: 164-71 |
| PMID | 23481915 |
| Title | Design and interpretation of microRNA-reporter gene activity. |
| Abstract | MicroRNAs (miRNAs) are small noncoding RNA molecules that act as sequence specificity guides to direct post-transcriptional gene silencing. In doing so, miRNAs regulate many critical developmental processes, including cellular proliferation, differentiation, migration, and apoptosis, as well as more specialized biological functions such as dendritic spine development and synaptogenesis. Interactions between miRNAs and their miRNA recognition elements occur via partial complementarity, rendering tremendous redundancy in targeting such that miRNAs are predicted to regulate 60% of the genome, with each miRNA estimated to regulate more than 200 genes. Because these predictions are prone to false positives and false negatives, there is an ever present need to provide material support to these assertions to firmly establish the biological function of specific miRNAs in both normal and pathophysiological contexts. Using schizophrenia-associated miR-181b as an example, we present detailed guidelines and novel insights for the rapid establishment of a streamlined miRNA-reporter gene assay and explore various design concepts for miRNA-reporter gene applications, including bidirectional miRNA modulation. In exemplifying this approach, we report seven novel miR-181b target sites for five schizophrenia candidate genes (DISC1, BDNF, ENKUR, GRIA1, and GRIK1) and dissect a number of vital concepts regarding future developments for miRNA-reporter gene assays and the interpretation of their results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 450 | Schizophr. Res. 2013 May 146: 285-8 |
| PMID | 23433505 |
| Title | Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia. |
| Abstract | Antipsychotic drugs are the mainstay of treatment for schizophrenia. However, a substantial proportion of patients are poorly responsive or resistant to first-line treatments, and clozapine treatment is often indicated. Therefore, we and others have used clozapine treatment as a proxy phenotype for antipsychotic treatment resistance in pharmacogenetic studies. In the present study, we utilized this phenotype to test previously-identified candidate genes for antipsychotic treatment response. We assessed 89 Caucasian schizophrenia patients clinically assigned to clozapine treatment versus 190 Caucasian patients that were not selected for clozapine treatment. We conducted gene-based association tests on a set of 74 relevant candidate genes nominated in the CATIE pharmacogenetic study (Need et al., 2009), using the GATES procedure (Li et al., 2011). After correcting for multiple testing in the gene-based association test, the gene for brain derived neurotrophic factor (BDNF) was significantly associated with treatment resistance. The top single nucleotide polymorphisms (SNPs) in BDNF included rs11030104 (OR = 2.57), rs10501087 (OR = 2.19) and rs6265 (Val66Met) (OR = 2.08). These SNPs appear to be in high linkage disequilibrium with each other. BDNF appears to have a strong association with antipsychotic treatment resistance. Future studies are needed to replicate this finding and further elucidate the biological pathways underlying the association between BDNF and antipsychotic drug response. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 451 | J. Neurochem. 2013 Aug 126: 389-99 |
| PMID | 23414458 |
| Title | Sex-dependent alterations in BDNF-TrkB signaling in the hippocampus of reelin heterozygous mice: a role for sex steroid hormones. |
| Abstract | Neurodevelopmental psychiatric disorders such as schizophrenia may be caused by a combination of gene × environment, gene × gene, and/or gene × sex interactions. Reduced expression of both Reelin and Brain-Derived Neurotrophic factor (BDNF) has been associated with schizophrenia in human post-mortem studies. However, it remains unclear how Reelin and BDNF interact (gene × gene) and whether this is sex-specific (gene × sex). This study investigated BDNF-TrkB signaling in the hippocampus of male and female Reelin heterozygous (Rln(+/-) ) mice. We found significantly increased levels of BDNF in the ventral hippocampus (VHP) of female, but not male Rln(+/-) compared to wild-type (WT) controls. While levels of TrkB were not significantly altered, phosphorylated TrkB (pTrkB) levels were significantly lower, again only in female Rln(+/-) compared to WT. This translated to downstream effects with a significant decrease in phosphorylated ERK1 (pERK1). No changes in BDNF, TrkB, pTrkB or pERK1/2 were observed in the dorsal hippocampus of Rln(+/-) mice. Ovariectomy (OVX) had no effect in WT controls, but caused a significant decrease in BDNF expression in the VHP of Rln(+/-) mice to the levels of intact WT controls. The high expression of BDNF was restored in OVX Rln(+/-) mice by 17?-estradiol treatment, suggesting that Rln(+/-) mice respond differently to an altered estradiol state than WT controls. In addition, while OVX had no significant effect on TrkB or ERK expression/phosphorylation, OVX + estradiol treatment markedly increased TrkB and ERK1 phosphorylation in Rln(+/-) and, to a lesser extent in WT controls, compared to intact genotype-matched controls. These data may provide a better understanding of the interaction of Reelin and BDNF in the hippocampus, which may be involved in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 452 | Neurotox Res 2013 Aug 24: 205-15 |
| PMID | 23385624 |
| Title | Nicotine restores Wt-like levels of reelin and GAD67 gene expression in brain of heterozygous reeler mice. |
| Abstract | Important reduction of reelin, a neural development- and plasticity-associated protein, and glutamic acid decarboxylase (GAD67) are reported in brains of schizophrenic patients. These individuals are consistently engaged in tobacco smoking and nicotine is thought to alleviate negative behavioral symptoms or cognitive alterations. In mouse brain, nicotine has been shown to reduce GAD67 promoter methylation and increase its transcription. We assessed the effects of administration of nicotine (1 mg/kg s.c.) for 6 days, in male mice heterozygous for reelin (HRM), a putative model for symptoms related to schizophrenia. Expression of reelin, GAD67 and brain-derived neurotrophic factor (BDNF) was measured in different brain areas. RNA expression analysis evidenced genotype-related changes, with a marked reduction in reelin and GAD67 gene expression in prefrontal cortex, hippocampus, cerebellum, and striatum from HRM. Nicotine treatment selectively reversed the HRM-related phenotype in most brain areas and increased BDNF gene expression in cortex and hippocampus of both genotypes. Locomotor performance in their home cage revealed that HRM subjects were characterized by general hyperactivity; with nicotine administration restoring WT-like levels of locomotion. These findings are interpreted within the hypothesis of pre-existing vulnerability (based on haploinsufficiency of reelin) to brain and behavioral disorders and regulative effects associated with nicotine exposure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 453 | Mol. Psychiatry 2013 Jun 18: 713-20 |
| PMID | 23319002 |
| Title | Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia. |
| Abstract | A Val(66)Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val(66)Met SNP and [(15)O]H(2)O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val(66)Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 454 | Neuroscience 2013 Sep 249: 172-91 |
| PMID | 23298853 |
| Title | Stress and neurodevelopmental processes in the emergence of psychosis. |
| Abstract | The notion that stress plays a role in the etiology of psychotic disorders, especially schizophrenia, is longstanding. However, it is only in recent years that the potential neural mechanisms mediating this effect have come into sharper focus. The introduction of more sophisticated models of the interplay between psychosocial factors and brain function has expanded our opportunities for conceptualizing more detailed psychobiological models of stress in psychosis. Further, scientific advances in our understanding of adolescent brain development have shed light on a pivotal question that has challenged researchers; namely, why the first episode of psychosis typically occurs in late adolescence/young adulthood. In this paper, we begin by reviewing the evidence supporting associations between psychosocial stress and psychosis in diagnosed patients as well as individuals at clinical high risk for psychosis. We then discuss biological stress systems and examine changes that precede and follow psychosis onset. Next, research findings on structural and functional brain characteristics associated with psychosis are presented; these findings suggest that normal adolescent neuromaturational processes may go awry, thereby setting the stage for the emergence of psychotic syndromes. Finally, a model of neural mechanisms underlying the pathogenesis of psychosis is presented and directions for future research strategies are explored. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 455 | Behav. Brain Res. 2013 Apr 243: 118-28 |
| PMID | 23295397 |
| Title | The effects of enriched environment on BDNF expression in the mouse cerebellum depending on the length of exposure. |
| Abstract | Environmental enrichment (EE) has been proposed as a factor that improves neuronal connectivity and brain plasticity. The induction of molecular mechanisms that takes place in the cortex, nucleus accumbens and hippocampus resulting from exposure to EE has been attributed partly to the role of neurotrophins as brain-derived neurotrophic factor (BDNF). Recent data directly implicate this neurotrophin in the modulation of plasticity changes in the cerebellum produced by living under environmental enrichment. In the present study, we aimed to assess the effects of different lengths of exposure to EE on cerebellar BDNF expression and western blotting analysis. On the whole, the present data has shown that BDNF increased under EE. However, changes in expression as a result of extending the duration of EE were only seen in Purkinje neurons. In Purkinje neurons, long-term exposure was required in order to fully express this neurotrophin. These data support BDNF as one of the long-term plasticity mechanisms induced by environment, suggesting that cerebellar plasticity can be stimulated as a response to challenges generated by environment. Our findings could have functional implications for various neurodegenerative disorders such as spinocerebellar ataxias, autism, schizophrenia and certain prion encephalopathies, most of them pathologies which have demonstrated to be characterized by alterations in Purkinje neurons and to show a partial recovery by exposure to EE. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 456 | Behav. Brain Res. 2013 Apr 242: 102-9 |
| PMID | 23291224 |
| Title | Adolescent nicotine sensitization and effects of nicotine on accumbal dopamine release in a rodent model of increased dopamine D2 receptor sensitivity. |
| Abstract | Our laboratory has reported neonatal quinpirole (D(2)/D(3) agonist) treatment to rats increases dopamine D(2) receptor sensitivity that persists throughout the animal's lifetime. This model appears to have clinical relevance to schizophrenia, and smoking is common in this population. Male and female Sprague-dawley rats were neonatally treated with quinpirole from postnatal (P) days 1-21. After habituation from P30 to 32, animals were administered saline or nicotine (0.3, 0.5, or 0.7mg/kg free base) every other day from P33 to 49 and locomotor activity was assessed. Generally, animals neonatally treated with quinpirole and administered nicotine during adolescence demonstrated increased behavioral activity and/or sensitization compared to animals neonatally given saline and sensitized to nicotine as well as controls. However, animals neonatally treated with quinpirole and given the 0.7mg/kg dose of nicotine demonstrated elevated activity throughout testing but did not show sensitization, and only mild sex differences were reported. Therefore, microdialysis was performed on male rats sensitized to the 0.5mg/kg dose of nicotine, and results revealed that neonatal quinpirole sensitized dopamine overflow in response to nicotine to 500% above animals neonatally given saline and sensitized to nicotine at peak levels. In addition, neonatal quinpirole increased the accumbal BDNF in response to nicotine compared to all other groups, and nicotine alone also produced significant increases in striatal and accumbal BDNF. This study reveals that neonatal quinpirole enhanced adolescent nicotine sensitization, accumbal dopamine overflow, and BDNF protein in response to nicotine, which may be related to changes in the brain's reward system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 457 | Psychiatry Res 2013 Sep 209: 150-4 |
| PMID | 23219101 |
| Title | Lifestyle modification and behavior therapy effectively reduce body weight and increase serum level of brain-derived neurotrophic factor in obese non-diabetic patients with schizophrenia. |
| Abstract | The goal of the study was to elucidate the relationship between serum circulating brain-derived neurotrophic factor (BDNF) and body weight reduction via lifestyle modification and behavior therapy in obese non-diabetic patients with chronic schizophrenia. Thirty-three obese non-diabetic subjects with schizophrenia treated with stable antipsychotic medication in a day-care unit for at least 3 months were recruited. Thirty age-, body weight-matched subjects without psychiatric disorders were enrolled as controls. All participants underwent a 10-week weight reduction program, including lifestyle modification, psychosocial treatment, behavior therapy and exercise in the day-care unit. Blood biochemistry, serum BDNF, adipokine (adiponectin), inflammatory markers (C-reactive protein, tumor necrosis factor-alpha and interleukin-6) and oral glucose tolerance test were evaluated before and after the program. Serum BDNF concentrations were significantly lower among patients with schizophrenia compared to control subjects. Serum BDNF levels were significantly increased following the weight reduction program. Elevations in serum BDNF levels were positively correlated with body weight and body mass index reduction. Altogether, our results demonstrate that a non-pharmacological weight reduction program effectively reduces body weight with significant elevation of serum BDNF levels in obese non-diabetic patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 458 | Curr. Med. Chem. 2013 -1 20: 345-50 |
| PMID | 23157625 |
| Title | Effects of antipsychotics on the BDNF in schizophrenia. |
| Abstract | Brain-derived neurotropic factor (BDNF) is involved in the development of the brain, and likely influences the neuroplasticity in schizophrenia. BDNF is also believed to interact with other neurotransmitter systems implicated in schizophrenia, such as dopamine, glutamate, serotonin and GABA. Therefore, BDNF is a candidate gene for schizophrenia. In past decades, the blood (serum or plasma) BDNF protein levels and BDNF gene alleles and genotypes to the clinical features of schizophrenia, such as age of onset, clinical subtypes, symptom severity, and drug response, have been evaluated among different populations. However, the results are still inconsistent. Further, different drugs have been reported to have different effects on BDNF protein levels. A cross-sectional survey revealed that serum BDNF levels in chronic schizophrenic patients treated with clozapine exceeded those of patients treated with risperidone or with typical antipsychotics. In recent times, BDNF epigenetic studies have also been conducted in clinical studies of schizophrenia to address the question of why patients with the same gene genotype and alleles have different clinical presentations. In addition, the effects of different antipsychotic drugs on gene methylation and protein acetylation have also been reported. In conclusion, more data are needed regarding BDNF in the brain and in peripheral blood, including protein levels, single nucleotide polymorphisms, epigenetic regulation, and clinical data in order to understand the role of BDNF in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 459 | Psychopharmacology (Berl.) 2013 Mar 226: 101-12 |
| PMID | 23093383 |
| Title | Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid. |
| Abstract | Combinatory therapy is widely used in psychiatry owing to the possibility that drugs with different mechanisms of action may synergize to improve functions deteriorated in schizophrenia, bipolar disorders, and major depression. While combinatory strategies rely on receptor and synaptic mechanisms, it should also be considered that two drugs may also "interact" on the long-term to determine more robust changes in neuronal plasticity, which represents a downstream target important for functional recovery. The aim of the study is to investigate neuroadaptive changes set in motion by chronic concomitant administration of the novel antipsychotic lurasidone and the mood stabilizer valproate. Animals were chronically treated with lurasidone, valproate, or the combination of the two drugs and killed 24 h after the last injection to evaluate alterations of different measures of neuronal plasticity such as the neurotrophin brain-derived neurotrophic factor (BDNF), the immediate early gene Activity-regulated cytoskeletal associated protein, and the epigenetic regulators HDAC 1, 2, and 5 in dorsal and ventral hippocampus. The results suggest that coadministration of lurasidone and valproate produces, when compared to the single drugs, a larger increase in the expression of BDNF in the ventral hippocampus, through the regulation of specific neurotrophin transcripts. We also found that the histone deacetylases were regulated by the drug combination, suggesting that some of the transcriptional changes may be sustained by epigenetic mechanisms. Our results suggest that the beneficial effects associated with combinatory treatment between a second-generation antipsychotic and a mood stabilizer could result from the ability to modulate neuroplastic molecules, whose expression and function is deteriorated in different psychiatric conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 460 | Neuroscience 2013 Jun 239: 67-83 |
| PMID | 23085218 |
| Title | Sex differences and the role of estrogen in animal models of schizophrenia: interaction with BDNF. |
| Abstract | schizophrenia is a severe psychiatric disorder with a complex and variable set of symptoms. Both genetic and environmental mechanisms are involved in the development of the illness and lead to structural and neurochemical abnormalities in the brain. An intriguing facet of schizophrenia is sex differences, which have been described for nearly all features of the illness, including the peak age of onset, symptoms and treatment response. The ovarian hormone, estrogen, may be protective against schizophrenia and evidence is accumulating that estrogen may exert this effect via an interaction with brain-derived neurotrophic factor (BDNF). Both estrogen and BDNF have trophic effects on the developing brain and promote synaptic plasticity and maintain neurons well into adulthood. Major neurotransmitter systems including dopaminergic, serotonergic and glutamatergic pathways are modulated and supported by estrogen and BDNF. Despite their commonalities, estrogen and BDNF have mostly been examined independently but increasing evidence suggests an interaction between the two in brain regions pertinent to schizophrenia. This review will focus on the role of estrogen and BDNF in clinical and animal studies of schizophrenia. We include animal models of neurotransmitter dysfunction and genetic manipulation to show how estrogen may provide a protective effect in schizophrenia, including through mediating BDNF expression and activity. This posited estrogen-BDNF interaction could play a key role in modulating sex-dependent results reported in animal work as well as sex differences in clinical aspects of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 461 | Psychoneuroendocrinology 2013 Apr 38: 509-21 |
| PMID | 22910687 |
| Title | Prenatal stress delays inhibitory neuron progenitor migration in the developing neocortex. |
| Abstract | Prenatal stress has been widely demonstrated to have links with behavioral problems in clinical populations and animal models, however, few investigations have examined the immediate developmental events that are affected by prenatal stress. Here, we utilize GAD67GFP transgenic mice in which GABAergic progenitors express green fluorescent protein (GFP) to examine the impact of prenatal stress on the development of these precursors to inhibitory neurons. Pregnant female mice were exposed to restraint stress three times daily from embryonic day 12 (E12) onwards. Their offspring demonstrated changes in the distribution of GFP-positive (GFP+) GABAergic progenitors in the telencephalon as early as E13 and persisting until postnatal day 0. Changes in distribution reflected alterations in tangential migration and radial integration of GFP+ cells into the developing cortical plate. Fate mapping of GAD67GFP+ progenitors with bromodeoxyuridine injected at E13 demonstrated a significant increase of these cells at P0 in anterior white matter. An overall decrease in GAD67GFP+ progenitors at P0 in medial frontal cortex could not be attributed to a reduction in cell proliferation. Significant changes in dlx2, nkx2.1 and their downstream target erbb4, transcription factors which regulate interneuron migration, were found within the prenatally stressed developing forebrain, while no differences were seen in mash1, a determinant of interneuron fate, BDNF, a maturation factor for GABAergic cells or fgf2, an early growth/differentiation factor. These results demonstrate that early disruption in GABAergic progenitor migration caused by prenatal stress may be responsible for neuronal defects in disorders with GABAergic abnormalities like schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 462 | Schizophr Bull 2013 Jul 39: 848-56 |
| PMID | 22532702 |
| Title | Intermediate phenotype analysis of patients, unaffected siblings, and healthy controls identifies VMAT2 as a candidate gene for psychotic disorder and neurocognition. |
| Abstract | Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members, suggesting that genetic vulnerability to psychotic disorder impacts neurocognition. The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms (SNPs) are associated with (1) neurocognitive functioning across populations at different genetic risk for psychosis (2) and psychotic disorder. The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder. Follow-up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects. In the patients, 13 associations between SNPs and cognitive functioning were significant at P < .05, situated in DRD1, DRD3, SLC6A3, BDNF, FGF2, SLC18A2, FKBP5, and DNMT3B. Follow-up of these SNPs revealed a significant and directionally similar association for SLC18A2 (alternatively VMAT2) rs363227 in siblings (B = -0.13, P = .04) and a trend association in control subjects (B = -0.10, P = .12). This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele (linear OR = 1.51, 95% CI 1.10-2.07, P = .01), which was reduced when covarying for cognitive performance (OR = 1.29, 95% CI 0.92-1.81, P = .14), suggesting mediation. Genetic variation in VMAT2 may be linked to alterations in cognitive functioning underlying psychotic disorder, possibly through altered transport of monoamines into synaptic vesicles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 463 | Cereb. Cortex 2013 Apr 23: 847-58 |
| PMID | 22467667 |
| Title | Phencyclidine-induced decrease of synaptic connectivity via inhibition of BDNF secretion in cultured cortical neurons. |
| Abstract | Repeated administration of phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor blocker, produces schizophrenia-like behaviors in humans and rodents. Although impairment of synaptic function has been implicated in the effect of PCP, the molecular mechanisms have not yet been elucidated. Considering that brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity, we examined whether exposure to PCP leads to impaired BDNF function in cultured cortical neurons. We found that PCP caused a transient increase in the level of intracellular BDNF within 3 h. Despite the increased intracellular amount of BDNF, activation of Trk receptors and downstream signaling cascades, including MAPK/ERK1/2 and PI3K/Akt pathways, were decreased. The number of synaptic sites and expression of synaptic proteins were decreased 48 h after PCP application without any impact on cell viability. Both electrophysiological and biochemical analyses revealed that PCP diminished glutamatergic neurotransmission. Furthermore, we found that the secretion of BDNF from cortical neurons was suppressed by PCP. We also confirmed that PCP-caused downregulation of Trk signalings and synaptic proteins were restored by exogenous BDNF application. It is possible that impaired secretion of BDNF and subsequent decreases in Trk signaling are responsible for the loss of synaptic connections caused by PCP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 464 | Schizophr Bull 2013 Jan 39: 130-40 |
| PMID | 21795612 |
| Title | Increases in two truncated TrkB isoforms in the prefrontal cortex of people with schizophrenia. |
| Abstract | The truncated brain-derived neurotrophic factor (BDNF) receptors (truncated TrkB [TrkB-TK-] and sarc homology containing TrkB [TrkB-Shc]) are alternative transcripts of the full-length TrkB receptor (TrkB-TK+) that produce isoforms capable of binding to BDNF but not being able to mediate the classic neurotrophic response via tyrosine kinase signaling. We hypothesized that in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia, truncated TrkB receptors (TK- and Shc) would be altered and may contribute to deficits in BDNF function. Using a large cohort of controls and schizophrenics (n = 72/72), we measured mRNA expression of the full-length TrkB receptor, TrkB-TK+ and the truncated TrkB receptors, TrkB-TK- and TrkB-Shc, by quantitative real-time polymerase chain reaction and protein expression by western blotting. We found highly significant increases in mRNA expression of both truncated TrkB receptor isoforms in people with schizophrenia. When we examined the full-length TrkB-TK+:truncated TrkB ratios, we observed significant decreases in schizophrenia both on the mRNA and protein level. We found a slight reduction in TrkB-TK+ mRNA and a significant reduction in TrkB-TK+ protein expression in schizophrenia, which was evident in females. No gender-specific changes were found for the truncated TrkB receptors. Diagnostic changes in TrkB-TK+ mRNA and protein may be subtle and/or gender-specific, whereas changes in TrkB-TK- and TrkB-Shc expression are robust and may generalize to both males and females with schizophrenia. Increased truncated TrkB receptors may contribute to reduced overall BDNF/tyrosine receptor kinase B (TrkB) signaling and lead to reduced neuronal plasticity in the DLPFC in schizophrenia suggesting that therapies aimed at ameliorating neurotrophin deficits may need to consider blocking excessive truncated TrkB function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 465 | Pharmacol Rep 2013 -1 65: 1185-93 |
| PMID | 24399714 |
| Title | BDNF rs 6265 polymorphism and COMT rs 4680 polymorphism in deficit schizophrenia in Polish sample. |
| Abstract | Deficit schizophrenia (DS) is distinguished from the group of schizophrenic psychoses based on the presence of primary negative symptoms. It differs from nondeficit (NDS) forms of schizophrenia in dimensions such as risk factors, family history, course of illness and neurobiological differences. The aim of the study was assessment of a potential association of the investigated polymorphisms of the brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes with the deficit syndrome in schizophrenia. A cohort of 200 patients with schizophrenia (81 DS and 119 NDS subjects) and a group of 100 control subjects matched for ethnicity, sex and age were recruited. Somatic and psychometric assessment were conducted as well as structured interview about the influence of adverse biological, family and social factors. Genetic analysis of the BDNF (Val66Met) rs6265 and the COMT (Val158Met) rs4680 polymorphisms was performed. We found significant differences between DS and NDS in rs4680 COMT genotype distribution: more homozygous Val/Val were found (31 vs. 17%) in the NDS compared to the DS subgroup. No associations were found between the investigated polymorphisms of the BDNF gene and the presence of schizophrenia either in DS and NDS subgroups. The analysis of the COMT rs4680 polymorphism in the present DS and NDS study shows that some genetic factors may be relevant in analyzing the reasons for the differentiation of schizophrenic subtypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 466 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Sep 162B: 538-45 |
| PMID | 23832605 |
| Title | Association of BDNF gene polymorphisms with schizophrenia and clinical symptoms in a Chinese population. |
| Abstract | The neurodevelopmental hypothesis is well established in schizophrenia. Accumulating evidence has shown that BDNF may be involved in the pathogenesis of schizophrenia. This study aimed to investigate the potential association of BDNF gene polymorphisms with susceptibility to schizophrenia and with the psychopathological symptoms in patients with schizophrenia in a Han Chinese population. Three polymorphisms (rs6265, rs12273539, and rs10835210) of the BDNF gene were analyzed in a case-control study of 709 Han Chinese individuals (375 patients and 334 controls). The patients' psychopathology was assessed using the positive and negative syndrome scale (PANSS). We found no significant differences in the genotype and allele distributions of all three polymorphisms between the patient and control groups; however, we found a trend toward to significant overall difference in the estimated haplotype frequencies, with more frequent haplotype ATC of rs6265-rs12273539-rs10835210 in the schizophrenic patients than in controls (P?=?0.027). The quantitative trait analysis by the UNPHASED program showed significant associations between the rs6265 (A)-rs12273539 (C)-rs10835210 (A) haplotype and negative symptom scores from the PANSS (x(2) ?=?5.79, P?=?0.016). Our findings suggest that the BDNF gene polymorphisms may play a small effect on susceptibility to schizophrenia, but may contribute to the negative symptoms of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 467 | Ann Agric Environ Med 2013 -1 20: 77-81 |
| PMID | 23540216 |
| Title | The efficacy of cognitive rehabilitation with RehaCom programme in schizophrenia patients. The role of selected genetic polymorphisms in successful cognitive rehabilitation. |
| Abstract | schizophrenic patients present cognitive dysfunctions which are regarded to be one of endophenotypical markers predisposing to schizophrenia. Currently, schizophrenia can be treated as a neurodegenerative and neurodeveloping disease with genetic background. Assessment of the possible positive effect of neuropsychological rehabilitation in schizophrenia, in patients presenting cognitive dysfunctions. An additional aim was to verify the hypothesis that some genetic polymorphisms can be a prognostic factor for success in neuropsychological rehabilitation. 41 participants and 40 control subjects were randomly selected. Both groups had the diagnosis of paranoid schizophrenia. Cognitive functions were checked with the Wisconsin Card Sorting Test, Trail Making Test, and Stroop Test at the beginning and end of the experiment. In the research group, each patient trained with the rehabilitation programme RehaCom, whereas the control group did not receive such training. Genes COMT rs4680 and BDNF rs6265 were analysed in the genetic part of study. RehaCom procedures appear to be useful in the neuropsychological rehabilitation of cognitive dysfunctions in patients diagnosed with schizophrenia. The research group showed a moderate improvement in the training programmes. Analysis of parameters obtained in the neuropsychological tests showed a slight improvement in both groups. At the present time, analysis of the polymorphisms of genes cannot be treated as a prognostic factor for the success of neuropsychological rehabilitation because statistical analyses showed few dependences with little statistical significance. Cognitive rehabilitation produces moderate improvement in cognitive functioning. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 468 | Psychiatr. Genet. 2013 Jun 23: 124-9 |
| PMID | 23532065 |
| Title | BDNF Val66Met polymorphism and anxiety/depression symptoms in schizophrenia in a Chinese Han population. |
| Abstract | Although several lines of evidences suggest that the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be involved in the pathophysiology of schizophrenia, this association remains controversial. Here, we aim to investigate the genetic association between the BDNF Val66Met polymorphism and schizophrenia and to explore whether this polymorphism could influence the severity of clinical symptoms in schizophrenic patients in a Chinese Han population. Genotyping of the BDNF Val66Met polymorphism was carried out in 456 schizophrenic patients and 483 controls using the fluorescence resonance energy transfer method. The patients' psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. The general clinical data of schizophrenic patients were analyzed. There were significant differences in the genotype distribution and allelic frequencies of the BDNF Val66Met polymorphism between the schizophrenia group and the controls. Multiple linear regression analysis showed that the BDNF Val66Met polymorphism explained ~16% of the variance in anxiety/depression symptoms in schizophrenic patients. Our data provide evidence that the BDNF Val66Met polymorphism may be involved in the etiology of schizophrenia in a Chinese Han population. Furthermore, the BDNF Val66Met polymorphism is a significant factor influencing the severity of anxiety/depression symptoms in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 469 | Neurotox Res 2013 Aug 24: 205-15 |
| PMID | 23385624 |
| Title | Nicotine restores Wt-like levels of reelin and GAD67 gene expression in brain of heterozygous reeler mice. |
| Abstract | Important reduction of reelin, a neural development- and plasticity-associated protein, and glutamic acid decarboxylase (GAD67) are reported in brains of schizophrenic patients. These individuals are consistently engaged in tobacco smoking and nicotine is thought to alleviate negative behavioral symptoms or cognitive alterations. In mouse brain, nicotine has been shown to reduce GAD67 promoter methylation and increase its transcription. We assessed the effects of administration of nicotine (1 mg/kg s.c.) for 6 days, in male mice heterozygous for reelin (HRM), a putative model for symptoms related to schizophrenia. Expression of reelin, GAD67 and brain-derived neurotrophic factor (BDNF) was measured in different brain areas. RNA expression analysis evidenced genotype-related changes, with a marked reduction in reelin and GAD67 gene expression in prefrontal cortex, hippocampus, cerebellum, and striatum from HRM. Nicotine treatment selectively reversed the HRM-related phenotype in most brain areas and increased BDNF gene expression in cortex and hippocampus of both genotypes. Locomotor performance in their home cage revealed that HRM subjects were characterized by general hyperactivity; with nicotine administration restoring WT-like levels of locomotion. These findings are interpreted within the hypothesis of pre-existing vulnerability (based on haploinsufficiency of reelin) to brain and behavioral disorders and regulative effects associated with nicotine exposure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 470 | Mol. Psychiatry 2013 Jun 18: 713-20 |
| PMID | 23319002 |
| Title | Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia. |
| Abstract | A Val(66)Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val(66)Met SNP and [(15)O]H(2)O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val(66)Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 471 | Curr. Med. Chem. 2013 -1 20: 345-50 |
| PMID | 23157625 |
| Title | Effects of antipsychotics on the BDNF in schizophrenia. |
| Abstract | Brain-derived neurotropic factor (BDNF) is involved in the development of the brain, and likely influences the neuroplasticity in schizophrenia. BDNF is also believed to interact with other neurotransmitter systems implicated in schizophrenia, such as dopamine, glutamate, serotonin and GABA. Therefore, BDNF is a candidate gene for schizophrenia. In past decades, the blood (serum or plasma) BDNF protein levels and BDNF gene alleles and genotypes to the clinical features of schizophrenia, such as age of onset, clinical subtypes, symptom severity, and drug response, have been evaluated among different populations. However, the results are still inconsistent. Further, different drugs have been reported to have different effects on BDNF protein levels. A cross-sectional survey revealed that serum BDNF levels in chronic schizophrenic patients treated with clozapine exceeded those of patients treated with risperidone or with typical antipsychotics. In recent times, BDNF epigenetic studies have also been conducted in clinical studies of schizophrenia to address the question of why patients with the same gene genotype and alleles have different clinical presentations. In addition, the effects of different antipsychotic drugs on gene methylation and protein acetylation have also been reported. In conclusion, more data are needed regarding BDNF in the brain and in peripheral blood, including protein levels, single nucleotide polymorphisms, epigenetic regulation, and clinical data in order to understand the role of BDNF in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 472 | Life Sci. 2013 Mar 92: 305-10 |
| PMID | 23333821 |
| Title | BDNF serum concentrations in first psychotic episode drug-naïve schizophrenic patients: associations with personality and BDNF Val66Met polymorphism. |
| Abstract | To investigate the relationship among brain derived neurotrophic factor (BDNF) serum concentrations, BDNF Val66Met polymorphism and personality profile in drug-naïve schizophrenic patients with first-episode psychosis (FEP) and healthy participants. This cross-sectional study included fifty FEP patients and fifty healthy participants who served as controls. To study their personality profile the standardized Greek version of the Alternative Five-Factor Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) was administered. Serum BDNF levels were measured and genotyping of BDNF Val66Met polymorphism was performed in patients and healthy subjects. FEP patients presented lower BDNF serum concentrations (P=0.002) and higher scores in ZKPQ Neuroticism (P=0.001) and Aggression-Hostility (P=0.002) scales while lower scores in the ZKPQ Sociability scale (P<0.001) than healthy participants. Multivariate analysis revealed that the odds of being assessed with FEP were 0.4 times lower in those with higher BDNF values (P<0.001) and 1.8 times greater in those with higher Neuroticism scores (P<0.001). There were no significant differences with respect to the Val66Met polymorphism between patients and healthy participants. Reduced BDNF serum concentrations along with higher Neuroticism scores might be associated with FEP. A complex interplay between BDNF serum concentrations, personality traits, BDNF Val66Met polymorphism, and psychotic symptomatology has been arisen but further investigation is needed to better clarify the observed associations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 473 | Neuropharmacology 2013 May 68: 223-31 |
| PMID | 22939999 |
| Title | Maternal deprivation effects on brain plasticity and recognition memory in adolescent male and female rats. |
| Abstract | Data from both human and animal studies suggest that exposure to stressful life events at neonatal stages may increase the risk of psychopathology at adulthood. In particular, early maternal deprivation, 24 h at postnatal day (pnd) 9, has been associated with persistent neurobehavioural changes similar to those present in developmental psychopathologies such as depression and schizophrenic-related disorders. Most neuropsychiatric disorders first appear during adolescence, however, the effects of MD on adolescent animals' brain and behaviour have been scarcely explored. In the present study, we aimed to investigate the emotional and cognitive consequences of MD in adolescent male and female rats, as well as possible underlying neurobiological mechanisms within frontal cortex and hippocampus. Animals were exposed to a battery of behavioural tasks, from pnd 35 to 42, to evaluate cognitive [spontaneous alternation task (SAT) and novel object test (NOT)] and anxiety-related responses [elevated plus maze (EPM)] during adolescence. Changes in neuronal and glial cells, alterations in synaptic plasticity as well as modifications in cannabinoid receptor expression were investigated in a parallel group of control and adolescent (pnd 40) male and female animals. Notably, MD induced a significant impairment in recognition memory exclusively among females. A generalized decrease in NeuN expression was found in MD animals, together with an increase in hippocampal glial fibrillar acidic protein (GFAP) expression exclusively among MD adolescent males. In addition, MD induced in the frontal cortex and hippocampus of male and female adolescent rats a significant reduction in brain derived neurotrophic factor (BDNF) and postsynaptic density (PSD95) levels, together with a decrease in synaptophysin in frontal cortex and neural cell adhesion molecule (NCAM) in hippocampus. MD induced, in animals of both sexes, a significant reduction in CB1R expression, but an increase in CB2R that was statistically significant only for the frontal cortex. Taken together, these results indicate that adolescent females are more vulnerable than males to the cognitive deficits derived from MD despite the changes in neural cells, cannabinoid receptors, as well as the reduction in neural plasticity seem to be similar in both sexes. Further investigation is needed to understand the neurobiological mechanisms underlying the sexual dimorphisms associated to the MD effects, and thus, for a better understanding of the specific sex-dependent vulnerabilities to early life stress. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 474 | Acta Neuropsychiatr 2013 Dec 25: 356-60 |
| PMID | 25287876 |
| Title | Neurogenic locus notch homolog protein 4 and brain-derived neurotrophic factor variants combined effect on schizophrenia susceptibility. |
| Abstract | To investigate the relationships between single-nucleotide polymorphisms (SNPs) in NOTCH4 and brain-derived neurotrophic factor (BDNF) with schizophrenia among Han Chinese in Southern China. Two NOTCH4 SNPs (rs520688 and rs415929) and two BDNF SNPs (rs2030324 and rs12273539) were examined in 464 schizophrenics and 464 healthy controls from Hunan province in South China, using the Sequenom MassARRAY® iPLEX System. In the study population, rs520688 and rs2030324 were significantly associated with schizophrenia. A decreased risk of schizophrenia was associated with the rs520688 GA genotype (p = 0.035), whereas an increased risk of schizophrenia was associated with the rs2030324 CC/CT genotype (p = 0.044). The genotype distributions of rs415929 in NOTCH4 and rs12273539 in BDNF did not differ significantly between the case and control groups. Although no allele-allele interactions were detected between rs520688 and rs2030324, recombination analysis revealed a combined effect of the two on the susceptibility to schizophrenia, with GA-TT decreasing and CT/CC-GG/GA increasing the risk of schizophrenia. In conclusion, rs520688 in NOTCH4 and rs2030324 in BDNF are significantly associated with schizophrenia among Han Chinese in Southern China. The two had a combined effect on the susceptibility to schizophrenia among Han Chinese in Southern China, but this may not be caused by an allele-allele interaction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 475 | Schizophr Bull 2013 Jan 39: 130-40 |
| PMID | 21795612 |
| Title | Increases in two truncated TrkB isoforms in the prefrontal cortex of people with schizophrenia. |
| Abstract | The truncated brain-derived neurotrophic factor (BDNF) receptors (truncated TrkB [TrkB-TK-] and sarc homology containing TrkB [TrkB-Shc]) are alternative transcripts of the full-length TrkB receptor (TrkB-TK+) that produce isoforms capable of binding to BDNF but not being able to mediate the classic neurotrophic response via tyrosine kinase signaling. We hypothesized that in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia, truncated TrkB receptors (TK- and Shc) would be altered and may contribute to deficits in BDNF function. Using a large cohort of controls and schizophrenics (n = 72/72), we measured mRNA expression of the full-length TrkB receptor, TrkB-TK+ and the truncated TrkB receptors, TrkB-TK- and TrkB-Shc, by quantitative real-time polymerase chain reaction and protein expression by western blotting. We found highly significant increases in mRNA expression of both truncated TrkB receptor isoforms in people with schizophrenia. When we examined the full-length TrkB-TK+:truncated TrkB ratios, we observed significant decreases in schizophrenia both on the mRNA and protein level. We found a slight reduction in TrkB-TK+ mRNA and a significant reduction in TrkB-TK+ protein expression in schizophrenia, which was evident in females. No gender-specific changes were found for the truncated TrkB receptors. Diagnostic changes in TrkB-TK+ mRNA and protein may be subtle and/or gender-specific, whereas changes in TrkB-TK- and TrkB-Shc expression are robust and may generalize to both males and females with schizophrenia. Increased truncated TrkB receptors may contribute to reduced overall BDNF/tyrosine receptor kinase B (TrkB) signaling and lead to reduced neuronal plasticity in the DLPFC in schizophrenia suggesting that therapies aimed at ameliorating neurotrophin deficits may need to consider blocking excessive truncated TrkB function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 476 | Schizophr. Res. 2014 Sep 158: 268-9 |
| PMID | 25052781 |
| Title | Cysteamine, a pro-BDNF drug, as an adjunctive treatment for schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 477 | Seishin Shinkeigaku Zasshi 2014 -1 116: 832-41 |
| PMID | 25672210 |
| Title | [Immune system and psychiatric disorders: involvement of BDNF and intracellular Ca2+ signaling]. |
| Abstract | Nonresolving low-grade inflammation is supposed to underly the basis of chronic disorders including cancer, type 2 diabetes, cardiovascular diseases, obesity and psychiatric disorders such as depression. There is increasing evidence suggesting that pathophysiology of psychiatric disorders is related to the inflammatory responses mediated by microglial cells. Elevation of intracellular Ca2+ is important in activation of microglial cell functions, including proliferation, release of NO, cytokines and BDNF. It has been shown that alteration of intracellular Ca2+ signaling underlies the pathophysiology of psychiatric disorders, including schizophrenia, depression and bipolar disorders. Microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 478 | Schizophr Res Treatment 2014 -1 2014: 463757 |
| PMID | 25548672 |
| Title | Gender identity disorder and schizophrenia: neurodevelopmental disorders with common causal mechanisms? |
| Abstract | Gender identity disorder (GID), recently renamed gender dysphoria (GD), is a rare condition characterized by an incongruity between gender identity and biological sex. Clinical evidence suggests that schizophrenia occurs in patients with GID at rates higher than in the general population and that patients with GID may have schizophrenia-like personality traits. Conversely, patients with schizophrenia may experience alterations in gender identity and gender role perception. Neurobiological research, including brain imaging and studies of finger length ratio and handedness, suggests that both these disorders are associated with altered cerebral sexual dimorphism and changes in cerebral lateralization. Various mechanisms, such as Toxoplasma infection, reduced levels of brain-derived neurotrophic factor (BDNF), early childhood adversity, and links with autism spectrum disorders, may account for some of this overlap. The implications of this association for further research are discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 479 | World J Biol Chem 2014 Nov 5: 409-28 |
| PMID | 25426265 |
| Title | New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases. |
| Abstract | Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer's disease, Huntington's disease, depression and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 480 | Front Cell Neurosci 2014 -1 8: 370 |
| PMID | 25414641 |
| Title | Microglial intracellular Ca(2+) signaling as a target of antipsychotic actions for the treatment of schizophrenia. |
| Abstract | Microglia are resident innate immune cells which release many factors including proinflammatory cytokines, nitric oxide (NO) and neurotrophic factors when they are activated in response to immunological stimuli. Recent reports show that pathophysiology of schizophrenia is related to the inflammatory responses mediated by microglia. Intracellular Ca(2+) signaling, which is mainly controlled by the endoplasmic reticulum (ER), is important for microglial functions such as release of NO and cytokines, migration, ramification and deramification. In addition, alteration of intracellular Ca(2+) signaling underlies the pathophysiology of schizophrenia, while it remains unclear how typical or atypical antipsychotics affect intracellular Ca(2+) mobilization in microglial cells. This mini-review article summarizes recent findings on cellular mechanisms underlying the characteristic differences in the actions of antipsychotics on microglial intracellular Ca(2+) signaling and reinforces the importance of the ER of microglial cells as a target of antipsychotics for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 481 | Dialogues Clin Neurosci 2014 Sep 16: 419-29 |
| PMID | 25364290 |
| Title | DNA methylation and demethylation as targets for antipsychotic therapy. |
| Abstract | schizophrenia (SZ) and bipolar disorder (BPD) patients show a downregulation of GAD67, reelin (RELN), brain-derived neurotrophic factor (BDNF), and other genes expressed in telencephalic GABAergic and glutamatergic neurons. This downregulation is associated with the enrichment of 5-methylcytosine and 5-hydroxymethylcytosine proximally at gene regulatory domains at the respective genes. A pharmacological strategy to reduce promoter hypermethylation and to induce a more permissive chromatin conformation is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that facilitate chromatin remodeling. Studies in mouse models of SZ indicate that clozapine induces DNA demethylation at relevant promoters, and that this action is potentiated by VPA. By activating DNA demethylation, clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be a promising treatment strategy to correct the gene expression deficits detected in postmortem brain of SZ and BPD patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 482 | Brain Res. 2014 Oct 1586: 162-72 |
| PMID | 25223903 |
| Title | Brain Derived Neurotrophic Factor: epigenetic regulation in psychiatric disorders. |
| Abstract | Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies are currently being investigated in animal models and clinical studies. However, very little is currently known about the mechanisms that deregulate BDNF gene expression in these disorders. The BDNF gene structure and tissue expression pattern is complex, controlled in humans by 9 different gene promoters. Recently, epigenetic changes at the BDNF gene locus have been proposed to provide a link between gene and environment. In this review, we will summarize the current knowledge of BDNF epigenetic regulation with respect to psychiatric disorders and describe how this information can be applied in therapy and future research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 483 | Psychiatry Res 2014 Dec 220: 1147-50 |
| PMID | 25219617 |
| Title | DNA methylation state of BDNF gene is not altered in prefrontal cortex and striatum of schizophrenia subjects. |
| Abstract | In this study we assessed the BDNF promoter IV methylation state of a large genomic region surrounding promoter IV and evaluated BDNF transcript IV expression from prefrontal cortex and striatum of 15 schizophrenic and 15 control subjects. In prefrontal cortex, a single CpG site at -93, appeared to be undermethylated in patients?group. BDNF mRNA levels in frontal cortex and striatum were variable among individuals but did not associate with disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 484 | Psychiatry Res 2014 Dec 220: 197-200 |
| PMID | 25219612 |
| Title | Comparison of serum BDNF levels in deficit and nondeficit chronic schizophrenia and healthy controls. |
| Abstract | The aim of this study was to compare serum BDNF levels of chronic schizophrenic patients, with or without deficit syndrome, and healthy controls. A comparative study of serum BDNF levels, determined by ELISA, was performed in 47 chronic patients with schizophrenia matched with 47 healthy controls. A part of the chronic schizophrenic sample was further divided into patients with a deficit (n=14) and a nondeficit syndrome (n=20), according to the Proxy for the Deficit Syndrome Scale. A significant difference was observed in decreased serum BDNF levels between chronic schizophrenia and healthy controls. No statistical significant differences in BDNF levels between deficit and nondeficit chronic schizophrenic patients were found. Our study confirms differences of serum BDNF levels of chronic schizophrenia and healthy controls, which correspond to the clinical progression of the disease. Our results do not support a relation between deficit profile in chronic schizophrenia and lower serum BDNF levels. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 485 | Psychiatry Res 2014 Dec 220: 193-6 |
| PMID | 25174850 |
| Title | Serum brain-derived neurotrophic factor (BDNF) and its association with remission status in Chinese patients with schizophrenia. |
| Abstract | The neurotrophin, brain-derived neurotrophic factor (BDNF), characterises a probable neurobiochemical explanation of maldevelopments in schizophrenia and is a candidate biomarker of the illness. A paucity of studies examining neurobiochemical predictors of remission in schizophrenia exists. In this study, we seek to examine if serum BDNF level is associated with remission status in a sample of Chinese patients with schizophrenia. This study did not find a significant relationship between serum BDNF and remission in patients with schizophrenia. Identification of a suitable biomarker for diagnosis, management, and prognostic outcome is crucial and warrants further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 486 | J Exerc Rehabil 2014 Feb 10: 15-21 |
| PMID | 24678500 |
| Title | Treadmill exercise enhances NMDA receptor expression in schizophrenia mice. |
| Abstract | schizophrenia is a serious psychiatric disorder with several symptoms including cognitive dysfunction. Although the causes of schizophrenia are still unclear, there is a strong suspicion that the abnormality in N-methyl-D-aspartate (NMDA) receptor may contribute to schizophrenia symptoms. In the present study, the effect of treadmill exercise on the NMDA receptor expression was evaluated using MK-801-induced schizophrenia mice. Immunohistochemistry for expressions of NMDA receptor tyrosine hydroxylase (TH) was conducted. Western blot for brain-derived neurotrophic factor (BDNF) was also performed. In the present results, the mice in the MK-801-treated group displayed reduced NMDA receptor expression. Enhanced TH expression and suppressed BDNF expression were also observed in the MK-801-treated mice. Treadmill exercise improved NMDA receptor expression in the MK-801-induced schizophrenia mice. Treadmill exercise also suppressed TH expression and enhanced BDNF expression in the MK-801-induced schizophrenia mice. The present study showed that down-regulation of NMDA receptor demonstrated schizophrenia-like parameters, meanwhile treadmill running improved schizophrenia-related parameters through enhancing NMDA receptor expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 487 | Mol. Cell. Neurosci. 2014 Jan 58: 53-61 |
| PMID | 24321455 |
| Title | G?z regulates BDNF-induction of axon growth in cortical neurons. |
| Abstract | The disruption of neurotransmitter and neurotrophic factor signaling in the central nervous system (CNS) is implicated as the root cause of neuropsychiatric disorders, including schizophrenia, epilepsy, chronic pain, and depression. Therefore, identifying the underlying molecular mechanisms by which neurotransmitter and neurotrophic factor signaling regulates neuronal survival or growth may facilitate identification of more effective therapies for these disorders. Previously, our lab found that the heterotrimeric G protein, Gz, mediates crosstalk between G protein-coupled receptors and neurotrophin signaling in the neural cell line PC12. These data, combined with G?z expression profiles--predominantly in neuronal cells with higher expression levels corresponding to developmental times of target tissue innervation--suggested that G?z may play an important role in neurotrophin signaling and neuronal development. Here, we provide evidence in cortical neurons, both manipulated ex vivo and those cultured from Gz knockout mice, that G?z is localized to axonal growth cones and plays a significant role in the development of axons of cortical neurons in the CNS. Our findings indicate that G?z inhibits BDNF-stimulated axon growth in cortical neurons, establishing an endogenous role for G?z in regulating neurotrophin signaling in the CNS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 488 | Psychiatry Res 2014 Jan 215: 244-5 |
| PMID | 24289908 |
| Title | Lack of association between brain-derived neurotrophic factor Val66Met polymorphism and aggressive behavior in schizophrenia. |
| Abstract | We investigated the association of the Val66Met gene polymorphism in the Brain-Derived Neurotrophic Factor (BDNF) gene with aggressive behavior among Southern Han Chinese schizophrenia patients. We used polymerase chain reaction-restriction fragment length polymorphism to determine the genotypes and the Modified Overt Aggression Scale (MOAS) to measure aggressive behavior. No significant differences in genotype or allele distribution of Val66Met were identified between aggressive and non-aggressive schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 489 | World J. Biol. Psychiatry 2014 Jan 15: 76-82 |
| PMID | 24219803 |
| Title | Dominant negative DISC1 mutant mice display specific social behaviour deficits and aberration in BDNF and cannabinoid receptor expression. |
| Abstract | OBJECTIVES. Disrupted in schizophrenia 1 (DISC1) is considered the most prominent candidate gene for schizophrenia. In this study, we aimed to characterize behavioural and brain biochemical traits in a mouse expressing a dominant negative DISC1mutant (DN-DISC1). DN-DISC1 mice underwent behavioural tests to evaluate object recognition, social preference and social novelty seeking. ELISA was conducted on brain tissue to evaluate BDNF levels. Western blot was employed to measure BDNF receptor (TrkB) and cannabinoid receptor CB1. The mutant DISC1 mice displayed deficits in preference to social novelty while both social preference and object recognition were intact. Biochemical analysis of prefrontal cortex and hippocampus revealed a modest reduction in cortical TrkB protein levels of male mice while no differences in BDNF levels were observed. We found sex dependent differences in the expression of cannabinoid-1 receptors. We describe novel behavioural and biochemical abnormalities in the DN-DISC1 mouse model of schizophrenia. The data shows for the first time a possible link between DISC1 mutation and the cannabinoid system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 490 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 186-92 |
| PMID | 24140928 |
| Title | Psychosis effect on hippocampal reduction in schizophrenia. |
| Abstract | In schizophrenia, disruption of the neurodevelopmental processes may lead to brain changes and subsequent clinical manifestations of the illness. Reports of the progressive nature of these morphological brain changes raise questions about their causes. The possible toxic effects of repeated stressful psychotic episodes may contribute to the disease progression. To analyze the influence of illness duration and previous psychotic episodes on hippocampal gray matter volume (GMV) in schizophrenia. We performed an analysis of hippocampal GMV correlations with illness duration, number of previous psychotic episodes, and age in 24 schizophrenia patients and 24 matched healthy controls. We found a cluster of GMV voxels in the left hippocampal tail that negatively correlated with the number of previous psychotic episodes, independent from the effect of age. On the other hand we found no effect of illness duration independent of age on the hippocampal GMV. Finally, we found a cluster of significant group-by-age interaction in the left hippocampal head. We found an additive adverse effect of psychotic episodes on hippocampal morphology in schizophrenia. Our findings support toxicity of psychosis concept, together with etiological heterogeneity of brain changes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 491 | Front Psychiatry 2014 -1 5: 48 |
| PMID | 24860514 |
| Title | Gene-environment interactions in severe mental illness. |
| Abstract | Severe mental illness (SMI) is a broad category that includes schizophrenia, bipolar disorder, and severe depression. Both genetic disposition and environmental exposures play important roles in the development of SMI. Multiple lines of evidence suggest that the roles of genetic and environmental factors depend on each other. Gene-environment interactions may underlie the paradox of strong environmental factors for highly heritable disorders, the low estimates of shared environmental influences in twin studies of SMI, and the heritability gap between twin and molecular heritability estimates. Sons and daughters of parents with SMI are more vulnerable to the effects of prenatal and postnatal environmental exposures, suggesting that the expression of genetic liability depends on environment. In the last decade, gene-environment interactions involving specific molecular variants in candidate genes have been identified. Replicated findings include an interaction between a polymorphism in the AKT1 gene and cannabis use in the development of psychosis and an interaction between the length polymorphism of the serotonin transporter gene and childhood maltreatment in the development of persistent depressive disorder. Bipolar disorder has been underinvestigated, with only a single study showing an interaction between a functional polymorphism in the BDNF gene and stressful life events triggering bipolar depressive episodes. The first systematic search for gene-environment interactions has found that a polymorphism in CTNNA3 may sensitize the developing brain to the pathogenic effect of cytomegalovirus in utero, leading to schizophrenia in adulthood. Strategies for genome-wide investigations will likely include coordination between epidemiological and genetic research efforts, systematic assessment of multiple environmental factors in large samples, and prioritization of genetic variants. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 492 | Neuropharmacology 2014 Aug 83: 1-8 |
| PMID | 24704148 |
| Title | Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. |
| Abstract | Chronic administration of lysergic acid diethylamide (LSD) every other day to rats results in a variety of abnormal behaviors. These build over the 90 day course of treatment and can persist at full strength for at least several months after cessation of treatment. The behaviors are consistent with those observed in animal models of schizophrenia and include hyperactivity, reduced sucrose-preference, and decreased social interaction. In order to elucidate molecular changes that underlie these aberrant behaviors, we chronically treated rats with LSD and performed RNA-sequencing on the medial prefrontal cortex (mPFC), an area highly associated with both the actions of LSD and the pathophysiology of schizophrenia and other psychiatric illnesses. We observed widespread changes in the neurogenetic state of treated animals four weeks after cessation of LSD treatment. QPCR was used to validate a subset of gene expression changes observed with RNA-Seq, and confirmed a significant correlation between the two methods. Functional clustering analysis indicates differentially expressed genes are enriched in pathways involving neurotransmission (Drd2, Gabrb1), synaptic plasticity (Nr2a, Krox20), energy metabolism (Atp5d, Ndufa1) and neuropeptide signaling (Npy, BDNF), among others. Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia, and genes affected by LSD are enriched with putative schizophrenia genes. Our results provide a relatively comprehensive analysis of mPFC transcriptional regulation in response to chronic LSD, and indicate that the long-term effects of LSD may bear relevance to psychiatric illnesses, including schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 493 | Front Behav Neurosci 2014 -1 8: 417 |
| PMID | 25538582 |
| Title | Relationships between brain-derived neurotrophic factor, clinical symptoms, and decision-making in chronic schizophrenia: data from the Iowa Gambling Task. |
| Abstract | The levels of brain-derived neurotrophic factor (BDNF) are significantly decreased in patients with schizophrenia and correlate with impairments in cognitive function. However, no study has investigated the relationship between the serum BDNF levels and decision-making. We compared patients with schizophrenia to healthy controls with respect to their decision-making ability and serum BDNF levels. Eighty-six chronic schizophrenia patients and 51 healthy controls participated in this study. We controlled for gender, age, and estimated intelligence quotient (IQ), and we investigated the differences in decision-making performance on the Iowa Gambling Task (IGT) between the schizophrenia patient and control groups. We also compared the IGT scores, the serum BDNF levels, and the clinical symptoms between the groups. The IGT scores of the schizophrenia patients were lower than those of the controls. A negative correlation was detected between the mean net scores on the trials in the final two blocks and the serum BDNF levels (p < 0.05). Multiple regression analysis revealed that depressive symptoms and the serum BDNF levels were significantly associated with the mean net scores on the trials in the final two blocks. Based on these results, impaired sensitivity to both reward and punishment is associated with depressive symptoms and reduced serum BDNF levels in chronic schizophrenia patients and may be related to their poor performance on the IGT. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 494 | PLoS ONE 2014 -1 9: e115135 |
| PMID | 25517604 |
| Title | A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events. |
| Abstract | Genome-wide association studies (GWASs) have identified a number of susceptibility genes for schizophrenia (SCZ) and bipolar disorder (BD). However, the identification of risk genes for major depressive disorder (MDD) has been unsuccessful because the etiology of MDD is more influenced by environmental factors; thus, gene-environment (G × E) interactions are important, such as interplay with stressful life events (SLEs). We assessed the G×E interactions and main effects of genes targeting depressive symptoms. Using a case-control design, 922 hospital staff members were evaluated for depressive symptoms according to Beck Depressive Inventory (BDI; "depression" and "control" groups were classified by scores of 10 in the BDI test), SLEs, and personality. A total of sixty-three genetic variants were selected on the basis of previous GWASs of MDD, SCZ, and BD as well as candidate-gene (SLC6A4, BDNF, DBH, and FKBP5) studies. Logistic regression analysis revealed a marginally significant interaction (genetic variant × SLE) at rs4523957 (P uncorrected = 0.0034) with depression and a significant association of single nucleotide polymorphism identified from evidence of BD GWAS (rs7296288, downstream of DHH at 12q13.1) with depression as the main effect (P uncorrected = 9.4 × 10(-4), P corrected = 0.0424). We also found that SLEs had a larger impact on depression (odds ratio ? 3), as reported previously. These results suggest that DHH plays a possible role in depression etiology; however, variants from MDD or SCZ GWAS evidence or candidate genes showed no significant associations or minimal effects of interactions with SLEs on depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 495 | Psychiatry Res 2014 Dec 220: 792-6 |
| PMID | 25446461 |
| Title | Increase of circulating BDNF levels and its relation to improvement of physical fitness following 12 weeks of combined exercise in chronic patients with schizophrenia: a pilot study. |
| Abstract | Brain-derived neurotrophic factor (BDNF), the most abundant of neurotrophins in the brain, is known to be responsible for maintenance of neurons has been implicated in the pathology of schizophrenia. In the present pilot study, we investigated the effect of a combined exercise program on circulating BDNF expression and the relationship between BDNF and improvements in physical fitness. Twenty-four patients with schizophrenia participated in the exercise intervention, three nonconsecutive days per week for 12 weeks. The resistance exercise program used the elastic band for eight different exercises for 25 min, and the aerobic exercise consisted of moderate walking for 25 min. After the training program, there were positive improvements in body composition and blood pressure. Also, there was significant improvement in leg strength, cardiovascular fitness, balance, and jump. Serum BDNF values had significantly increased following the combined exercise program. The elevation in serum BDNF concentrations correlated significantly with improvements in cardiovascular fitness and leg strength. These results suggest that exercise induced modulation of BDNF may play an important role in developing non-pharmacological treatment for chronic schizophrenic patients. In addition, these preliminary results serve to generate further hypothesis and facilitate the planning the exercise training program and management of participants. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 496 | Prog Mol Biol Transl Sci 2014 -1 128: 89-101 |
| PMID | 25410542 |
| Title | Modeling the molecular epigenetic profile of psychosis in prenatally stressed mice. |
| Abstract | Based on postmortem brain studies, our overarching epigenetic hypothesis is that chronic schizophrenia (SZ) is a psychopathological condition involving dysregulation of the dynamic equilibrium among DNA methylation/demethylation network components and the expression of SZ target genes, including GABAergic and glutamatergic genes. SZ has a natural course, starting with a prodromal phase, a first episode that occurs in adolescents or in young adults, and later deterioration over the adult years. Hence, the epigenetic status at each neurodevelopmental stage of the disease cannot be studied just in postmortem brain of chronic SZ patients, but requires the use of neurodevelopmental animal models. We have directed the focus of our research toward studying the epigenetic signature of the SZ brain in the offspring of dams stressed during pregnancy (PRS mice). Adult PRS mice have behavioral deficits reminiscent of behaviors observed in psychotic patients. The adult PRS brain, like that of postmortem chronic SZ patients, is characterized by a significant increase in DNA methyltransferase 1, Tet methylcytosine dioxygenase 1 (TET1), 5-methylcytosine, and 5-hydroxymethylcytosine at SZ candidate gene promoters and a reduction in the expression of glutamatergic and GABAergic genes. In PRS mice, measurements of epigenetic biomarkers for SZ can be assessed at different stages of development with the goal of further elucidating the pathophysiology of this disease and predicting treatment responses at specific stages of the illness, with particular attention to early detection and possibly early intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 497 | J Altern Complement Med 2014 Nov 20: 823-30 |
| PMID | 25364946 |
| Title | Effects of weekly one-hour Hatha yoga therapy on resilience and stress levels in patients with schizophrenia-spectrum disorders: an eight-week randomized controlled trial. |
| Abstract | To examine the effects of Hatha yoga therapy on resilience, brain-derived neurotrophic factor (BDNF) levels, and salivary alpha amylase (SAA) activity in patients with schizophrenia-spectrum disorders. Single-blinded, randomized controlled study in which outpatients with schizophrenia or related psychotic disorders (according to International Classification of Diseases, 10th Revision) were randomly assigned to a yoga or a control group. November 2012-April 2013 at Yamanashi Prefectural Kita Hospital, Japan. In the yoga group, patients received weekly 1-hour Hatha yoga sessions, in addition to regular treatment, for 8 weeks. Those in the control group underwent regular treatment, which included a daycare rehabilitation program. Assessments included the 25-item Resilience Scale (RS), Positive and Negative Syndrome Scale (PANSS), plasma and salivary BDNF level, and SAA activity. Fifty patients participated (25 in each group; mean age±standard deviation, 50.9±11.3 years; mean duration of illness, 25.0±10.3 years; mean total PANSS score, 78.2±17.3). No significant differences in changes in any variable from baseline to week 8 were found between the two groups (changes in the yoga group versus the control group: RS score, -1.6±19.9 versus 0.3±17.2; PANSS score, 0.5±12.0 versus 5.0±15.6; plasma BDNF, 41.6±377.0?pg/dl versus 73.4±346.0?pg/dl; SAA, -26.2±72.6?kU/l versus -13.8±68.0?kU/l, respectively). Adjunct yoga therapy showed no positive changes in resilience level or stress markers. Duration and intensity of yoga sessions and the focus on patients with chronic illness may explain the negative observations in light of past positive evidence regarding yoga therapy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 498 | Mol Med Rep 2014 Dec 10: 2924-30 |
| PMID | 25323073 |
| Title | Voluntary wheel running ameliorates symptoms of MK-801-induced schizophrenia in mice. |
| Abstract | schizophrenia is a chronic and severe mental disorder characterized by the disintegration of cognitive thought processes and emotional responses. Despite the precise cause of schizophrenia remains unclear, it is hypothesized that a dysregulation of the N?methyl?D?aspartate (NMDA) receptor in the brain is a major contributing factor to its development. Brain?derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is implicated in learning and memory processes. In the present study, we investigated in vivo the effects of voluntary wheel running on behavioral symptoms associated with NMDA receptor expression, using MK?801?induced schizophrenic mice. Abilify (aripiprazole), a drug used to treat human schizophrenia patients, was used as the positive control. For the assessment of behavioral symptoms affecting locomotion, social interaction and spatial working memory, the open?field, social interaction and Morris water maze tests were conducted. For investigating the biochemical parameters, NMDA receptor expression in the hippocampal CA2?3 regions and prefrontal cortex was detected by NMDA immunofluorescence and BDNF expression in the hippocampus was measured using western blot analysis. MK?801 injection for 14 days induced schizophrenia?like behavioral abnormalities with decreased expression of the NMDA receptor and BDNF in the brains of mice. The results indicated that free access to voluntary wheel running for 2 weeks alleviated schizophrenia?like behavioral abnormalities and increased the expression of NMDA receptor and BDNF, comparable to the effects of aripiprazole treatment. In the present study, the results suggest that NMDA receptor hypofunctioning induced schizophrenia?like behaviors, and that voluntary wheel running was effective in reducing these symptoms by increasing NMDA receptor and BDNF expression, resulting in an improvement of disease related behavioral deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 499 | J Psychiatr Res 2014 Dec 59: 14-21 |
| PMID | 25246365 |
| Title | Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders. |
| Abstract | Here we investigated a two hit gene environment model in relation to functional genomic factors (BDNF mRNA), and volume of hippocampal subfields in schizophrenia spectrum and bipolar disorders, focusing on both an environmental (childhood trauma) and genetic risk factor (BDNF val66met). A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF DNA and RNA were analyzed using standardized procedures. A subsample of n = 108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. All MRI data were corrected for age and gender, with post-hoc analysis correcting for ICV. A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus. The current findings demonstrate that the reduced BDNF mRNA levels found in psychosis may be associated with both a history of childhood trauma and BDNF val66met variants. Further, our study supports a two hit model including a history of childhood trauma as well as genetic vulnerability (met carriers of the BDNF val66met) behind reduced volume of hippocampal subfields in psychosis. This was specifically found for areas important for neurogenesis, the CA2/3 and the CA4 DG. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 500 | Acta Neuropsychiatr 2014 Oct 26: 291-7 |
| PMID | 25241757 |
| Title | Can BDNF and IL-2 be indicators for the diagnosis in schizophrenic patients with depressive symptoms? |
| Abstract | The aim of the current study is to determine whether serum levels of brain-derived neurotrophic factor (BDNF) and interleukin-2 (IL-2) can be biological indicators for the diagnosis of schizophrenia in patients with depressive symptoms. Forty-seven patients (11 patients diagnosed with schizophrenia, 16 patients diagnosed with schizophrenia and comorbid depression and 20 patients diagnosed with major depressive disorder) and 20 healthy subjects were enrolled. The Positive and Negative Symptoms Scale, the Calgary Depression Scale for schizophrenia and the Hamilton Depression Rating Scale were used for assessment. The serum BDNF and IL-2 levels of all the subjects were studied. Decreased levels of serum BDNF and increased levels of serum IL-2 were found in the patients diagnosed with either schizophrenia, schizophrenia with depression, or major depressive disorder (p = 0.049, p = 0.010; p = 0.001 and p = 0.044; p = 0.027, p = 0.003; respectively) compared with control group. There were no significant differences between the patient groups in their serum BDNF and IL-2 levels. The present study suggests that neurotrophic factors and immune system changes are involved in the pathogenesis of schizophrenia with or without depressive symptomatology. However, the data do not clarify whether depressive symptoms in schizophrenia occur as a dimension of schizophrenia or as symptoms of major depression that is comorbid with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 501 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014 Dec 165B: 635-46 |
| PMID | 25209194 |
| Title | Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness. |
| Abstract | Literature indicates key role of glutamatergic pathway genes in antipsychotic response among schizophrenia patients. However, molecular basis of their underlying role in antipsychotic response remained unexplained. Thus, to unravel their molecular underpinnings, we sought to investigate interactions amongst GRM3, SLC1A1, SLC1A2, SLC1A3, SLC1A4 gene polymorphisms with drug response in south Indian schizophrenia patients. We genotyped 48 SNPs from these genes in 423 schizophrenia patients stratified into low and high severity of illness groups. The SNPs and haplotypic combinations of associated SNPs were examined for their association with antipsychotic response. Multifactor-dimensionality-reduction was further used to explore gene-gene interaction among these SNPs and 53 SNPs from previously studied genes (BDNF, RGS4, SLC6A3, PI4KA, and PIP4K2A). Single SNP and haplotype analyses revealed no significant association with drug response irrespective of severity of illness. Gene-gene interaction analyses yielded promising leads, including an observed synergistic effect between PI4KA_rs165854 and GRM3_rs1468412 polymorphisms and incomplete antipsychotic response in schizophrenia patients with low severity of illness (OR = 12.4; 95%CI = 3.69-41.69). Further, this interaction was also observed in atypical monotherapy (n = 355) and risperidone (n = 260) treatment subgroups (OR = 11.21; 95%CI = 3.30-38.12 and OR = 13.5; 95%CI = 3.03-121.61 respectively). PI4KA is known to be involved in the biosynthesis of phosphatidylinositol-4, 5-bisphosphate which regulates exocytotic fusion of synaptic vesicles (glutamate, dopamine) with the plasma membrane and regulates duration of signal transduction of GPCRs. Whereas GRM3 regulates glutamate and dopamine transmission. Present findings indicate that PI4KA and GRM3 polymorphisms have potential to jointly modulate antipsychotic response. These results warrant additional replication studies to shed further light on these interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 502 | J Clin Psychiatry 2014 Aug 75: e794-801 |
| PMID | 25191916 |
| Title | Combining serum protein concentrations to diagnose schizophrenia: a preliminary exploration. |
| Abstract | It is difficult for clinicians to diagnose schizophrenia solely based on interviews. We explored the diagnostic efficiency and predictive capability of serum biomarkers for schizophrenia. Levels of ? nerve growth factor (?-NGF), brain-derived neurotrophic factor (BDNF), interleukin 6 (IL-6), tumor necrosis factor ? (TNF-?), interferon ? (IFN-?), calcium binding protein S100?, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) were measured in the sera of 278 schizophrenia patients, 240 depression and bipolar disorder patients, and 260 healthy controls. DSM-IV-TR criteria were used as the diagnostic criteria for schizophrenia and depressive and bipolar disorders. The diagnostic efficiency was high in patients with schizophrenia compared with the healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain the diagnostic efficiency of the 8 proteins. Data were collected between July 2010 and December 2012. One-way analysis of variance significantly demonstrated lower serum BDNF, MBP, and GFAP levels (F = 16.504, P < .001; F = 207.209, P < .001; F = 33.668, P < .001, respectively) but higher serum IL-6 and S100? concentrations (F = 15.250, P < .001; F = 12.751, P < .001, respectively) among patients with schizophrenia. ROC analysis of the discriminant scores of the serum ?-NGF, BDNF, IL-6, S100?, MBP, and GFAP levels resulted in significant discrimination between the schizophrenia and control groups (AUC = 0.922) and the depressive/bipolar disorder and control groups (AUC = 0.762). Serum levels of 6 proteins (but not TNF-? and IFN-?) contribute most to the diagnosis of schizophrenia. These proteins may prove to be useful adjuncts for the clinical assessment of this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 503 | Schizophr. Res. 2014 Oct 159: 56-61 |
| PMID | 25171858 |
| Title | Brain derived Neurotropic Factor (BDNF) is associated with childhood abuse but not cognitive domains in first episode psychosis. |
| Abstract | The Brain-derived Neurotrophic Factor (BDNF) modulates cognitive processes and is associated with increased risk of schizophrenia. Childhood trauma (CT) is frequent in patients with psychosis and severely affects course and outcome. We investigated the hypothesis that BDNF is associated with both CT and cognitive deficits in a sample of first-episode psychosis (FEP) cases and unaffected controls. Participants with FEP and healthy controls were recruited between August 2008 and July 2011 from South London, UK. Childhood traumatic events were detected using the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Neuropsychological data were also collected. BDNF plasma levels were measured from fasting blood samples. Data were available on 87 FEP patients and 152 controls. Our results showed a significant effect of separation (F=5.5; df=1,115; p=.02), physical (F=4.7; df=1, 118; p=.03) and sexual abuse (F=5.4; df=1,117; p=.02) on BDNF levels with lower levels among those who experienced the traumatic event compared to those who did not. Physical abuse predicted lower plasma levels of BDNF (?=-.30; p=.03) whereas sexual and/or physical abuse showed a trend (?=-.26; p=.06) in FEP patients but not in unaffected controls. No association between BDNF plasma levels and cognitive functions was found among patients with FEP and controls. Our findings suggest the possible involvement of BDNF in the onset of first-episode psychosis in individuals exposed to early trauma and propose BDNF as a potential clinical biomarker to detect the detrimental effects of CT on human brain plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 504 | Biochim. Biophys. Acta 2014 Nov 1842: 2126-35 |
| PMID | 25159716 |
| Title | Long-term effects of combined neonatal and adolescent stress on brain-derived neurotrophic factor and dopamine receptor expression in the rat forebrain. |
| Abstract | Altered brain-derived neurotrophic factor (BDNF) signalling and dopaminergic neurotransmission have been shown in the forebrain in schizophrenia. The 'two hit' hypothesis proposes that two major disruptions during development are involved in the pathophysiology of this illness. We therefore used a 'two hit' rat model of combined neonatal and young-adult stress to assess effects on BDNF signalling and dopamine receptor expression. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. At adulthood the medial prefrontal cortex (mPFC), caudate putamen (CPu) and nucleus accumbens (NAc) were analysed by qPCR and Western blot. The 'two hit' combination of MS and CORT treatment caused significant increases in BDNF mRNA and protein levels in the mPFC of male, but not female rats. BDNF mRNA expression was unchanged in the CPu but was significantly reduced by CORT in the NAc. DR3 and DR2 mRNA were significantly up-regulated in the mPFC of two-hit rats and a positive correlation was found between BDNF and DR3 expression in male, but not female rats. DR2 and DR3 expression were significantly increased following CORT treatment in the NAc and a significant negative correlation between BDNF and DR3 and DR2 mRNA levels was found. Our data demonstrate male-specific two-hit effects of developmental stress on BDNF and DR3 expression in the mPFC. Furthermore, following chronic adolescent CORT treatment, the relationship between BDNF and dopamine receptor expression was significantly altered in the NAc. These results elucidate the long-term effects of 'two hit' developmental stress on behaviour. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 505 | Schizophr. Res. 2014 Oct 159: 51-5 |
| PMID | 25128453 |
| Title | Serum levels of BDNF, folate and homocysteine: in relation to hippocampal volume and psychopathology in drug naïve, first episode schizophrenia. |
| Abstract | The present study was to examine serum levels of brain-derived neurotrophic factor (BDNF), folate, homocysteine (Hcy), and their relationships with hippocampal volume and psychopathology in drug naïve, first episode schizophrenia. Drug naïve, first episode schizophrenia patients and healthy controls were enrolled in the study. Serum levels of BDNF, folate and Hcy were measured using enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassay (ECLIA), and enzymatic cycling method respectively. Hippocampus was parcellated and bilateral hippocampal volumes were measured using FreeSurfer. Forty-six patients with drug naïve, first episode schizophrenia (SZ group) and 30 healthy controls (control group) were enrolled. The SZ group had significantly lower serum levels of BDNF and folate, and significantly higher serum levels of Hcy compared with the control group (p=0.013, p<0.001, p=0.003 respectively). There were no significant differences in hippocampal volumes between the two groups (ps>0.2). Within the SZ group, there were significant positive relationships between serum levels of BDNF and both left and right hippocampal volumes (r=0.327, p=0.026; r=0.338, p=0.022 respectively). In contrast, such relationships did not exist in the control group. Within the SZ group, there were significant negative relationships between serum levels of folate and PANSS-total scores and PANSS-negative symptom scores (r=0.319, p=0.031; r=0.321, p=0.030 respectively); and there was a positive relationship between serum levels of Hcy and PANSS-total scores (r=0.312, p=0.035). Controlling for potential confounding variables resulted in similar findings. Drug naïve, first episode schizophrenia presents decreased serum levels of BDNF, folate and increased serum levels of Hcy, which may play an important role in the neurodevelopmental process and clinical manifestation of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 506 | Behav. Brain Res. 2014 Nov 274: 137-42 |
| PMID | 25125238 |
| Title | BDNF val66met genotype and schizotypal personality traits interact to influence probabilistic association learning. |
| Abstract | The brain derived neurotrophic factor (BDNF) val66met polymorphism rs6265 influences learning and may represent a risk factor for schizophrenia. Healthy people with high schizotypal personality traits display cognitive deficits that are similar to but not as severe as those observed in schizophrenia and they can be studied without confounds of antipsychotics or chronic illness. How genetic variation in BDNF may impact learning in individuals falling along the schizophrenia spectrum is unknown. We predicted that schizotypal personality traits would influence learning and that schizotypal personality-based differences in learning would vary depending on the BDNF val66met genotype. Eighty-nine healthy adults completed the schizotypal Personality Questionnaire (SPQ) and a probabilistic association learning test. Blood samples were genotyped for the BDNF val66met polymorphism. An ANOVA was performed with BDNF genotype (val homozygotes and met-carriers) and SPQ score (high/low) as grouping variables and probabilistic association learning as the dependent variable. Participants with low SPQ scores (fewer schizotypal personality traits) showed significantly better learning than those with high SPQ scores. BDNF met-carriers displaying few schizotypal personality traits performed best, whereas BDNF met-carriers displaying high schizotypal personality traits performed worst. Thus, the BDNF val66met polymorphism appears to influence probabilistic association learning differently depending on the extent of schizotypal personality traits displayed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 507 | Med. Hypotheses 2014 Oct 83: 429-35 |
| PMID | 25113167 |
| Title | Activity-dependent alterations in the sensitivity to BDNF-TrkB signaling may promote excessive dendritic arborization and spinogenesis in fragile X syndrome in order to compensate for compromised postsynaptic activity. |
| Abstract | Fragile X syndrome (FXS), the most common cause of inherited human mental retardation, results from the loss of function of fragile X mental retardation protein (FMRP). To date, most researchers have thought that FXS neural pathologies are primarily caused by extreme dendritic branching and spine formation. With this rationale, several researchers attempted to prune dendritic branches and reduce the number of spines in FXS animal models. We propose that increased dendritic arborization and spinogenesis in FXS are developed rather as secondary compensatory responses to counteract the compromised postsynaptic activity during uncontrollable metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD). When postsynaptic and electrical activities become dampened in FXS, dendritic trees can increase their sensitivity to brain-derived neurotrophic factor (BDNF) by using the molecular sensor called eukaryotic elongation factor 2 (eEF2) and taking advantage of the tight coupling of mGluR and BDNF-TrkB signaling pathways. Then, this activity-dependent elevation of the BDNF signaling can strategically alter dendritic morphologies to foster branching and develop spine structures in order to improve the postsynaptic response in FXS. Our model suggests a new therapeutic rationale for FXS: correcting the postsynaptic and electrical activity first, and then repairing structural abnormalities of dendrites. Then, it may be possible to successfully fix the dendritic morphologies without affecting the survival of neurons. Our theory may also be generalized to explain aberrant dendritic structures observed in other neurobehavioral diseases, such as tuberous sclerosis, Rett syndrome, schizophrenia, and channelopathies, which accompany high postsynaptic and electrical activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 508 | Cell Commun. Signal 2014 -1 12: 47 |
| PMID | 25052836 |
| Title | TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis. |
| Abstract | Neuregulin 1 (NRG1) and NMDARs play important roles in various neuronal functions including neural development. NMDARs also promote many cellular events such as proliferation and survival of neuroblasts before synapse formation. Although many recent studies have indicated that NRG1 regulates NMDAR function in cortical neurons, the effect of NRG1 on NMDAR activation before synapse formation is not well studied. NRG1 induces activation of NMDAR subunit NR2B, and tropomyosin-related kinase receptor B (TrkB), the receptor for BDNF via activation of phospholipase C-gamma (PLC-?) in immature primary cortical neurons. Our data using TrkB inhibitor (K252a), TrkB siRNA and TrkB-/- neurons demonstrated that TrkB inhibition suppresses NRG1-induced NR2B activation in neurons. We found that NRG1 stimulation leads to GABAA receptor-mediated TrkB activation. Co-immunoprecipitation and proximity ligase assay showed that TrkB interacts with ErbB4 (NRG1 receptor) and the TrkB-ErbB4 interaction was increased following NRG1 treatment. A significant reduction in TrkB-ErbB4 interaction was observed in the prefrontal cortex of schizophrenia subjects. We found significant increase in released BDNF levels following NRG1 treatment, which was inhibited by ErbB4 inhibitor, AG1478. In addition, pretreatment with BDNF neutralizing antibody, but not control IgG abolished NRG1-induced increases in phospho-TrkB and phospho-NR2B levels. Moreover, studies using TrkB mutants showed that intercellular domain of TrkB is necessary for TrkB-ErbB4 interaction and NR2B activation. BDNF/TrkB signaling plays an important role in the NRG1-stimulated NR2B regulation. These findings could be of relevance to many neurodevelopmental disorders, as NRG1 and BDNF signaling pathways have been implicated in autism and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 509 | PLoS ONE 2014 -1 9: e102556 |
| PMID | 25025909 |
| Title | Genetic variations of PIP4K2A confer vulnerability to poor antipsychotic response in severely ill schizophrenia patients. |
| Abstract | Literature suggests that disease severity and neurotransmitter signaling pathway genes can accurately identify antipsychotic response in schizophrenia patients. However, putative role of signaling molecules has not been tested in schizophrenia patients based on severity of illness, despite its biological plausibility. In the present study we investigated the possible association of polymorphisms from five candidate genes RGS4, SLC6A3, PIP4K2A, BDNF, PI4KA with response to antipsychotic in variably ill schizophrenia patients. Thus in present study, a total 53 SNPs on the basis of previous reports and functional grounds were examined for their association with antipsychotic response in 423 schizophrenia patients segregated into low and high severity groups. Additionally, haplotype, diplotype, multivariate logistic regression and multifactor-dimensionality reduction (MDR) analyses were performed. Furthermore, observed associations were investigated in atypical monotherapy (n?=?355) and risperidone (n?=?260) treated subgroups. All associations were estimated as odds ratio (OR) and 95% confidence interval (CI) and test for multiple corrections was applied. Single locus analysis showed significant association of nine variants from SLC6A3, PIP4K2A and BDNF genes with incomplete antipsychotic response in schizophrenia patients with high severity. We identified significant association of six marker diplotype ATTGCT/ATTGCT (rs746203-rs10828317-rs7094131-rs2296624-rs11013052-rs1409396) of PIP4K2A gene in incomplete responders (corrected p-value?=?0.001; adjusted-OR?=?3.19, 95%-CI?=?1.46-6.98) with high severity. These associations were further observed in atypical monotherapy and risperidone sub-groups. MDR approach identified gene-gene interaction among BDNF_rs7103411-BDNF_rs1491851-SLC6A3_rs40184 in severely ill incomplete responders (OR?=?7.91, 95%-CI?=?4.08-15.36). While RGS4_rs2842026-SLC6A3_rs2975226 interacted synergistically in incomplete responders with low severity (OR?=?4.09, 95%-CI?=?2.09-8.02). Our findings provide strong evidence that diplotype ATTGCT/ATTGCT of PIP4K2A gene conferred approximately three-times higher incomplete responsiveness towards antipsychotics in severely ill patients. These results are consistent with the known role of phosphatidyl-inositol-signaling elements in antipsychotic action and outcome. Findings have implication for future molecular genetic studies as well as personalized medicine. However more work is warranted to elucidate underlying causal biological pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 510 | Psychoneuroendocrinology 2014 Oct 48: 136-46 |
| PMID | 24999831 |
| Title | Gender difference in association of cognition with BDNF in chronic schizophrenia. |
| Abstract | While numerous studies have reported that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia, very few studies have explored its association with cognitive impairment or gender differences in schizophrenia which we explored. We compared gender differences in 248 chronic schizophrenic patients (male/female=185/63) to 188 healthy controls (male/female=98/90) on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF. schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Our results showed that schizophrenic patients performed worse than normals on most of the cognitive tasks, and male patients had significantly lower immediate memory and delayed memory scores than female patients. BDNF levels were significantly lower in patients than controls, and male patients had significantly lower BDNF levels than female patients. For the patients, BDNF was positively associated with immediate memory and the RBANS total score. Furthermore, these associations were only observed in female not male patients. Among healthy controls, no gender difference was observed in cognitive domains and BDNF levels, or in the association between BDNF and cognition. Our results suggest gender differences in cognitive impairments, BDNF levels and their association in chronic patients with schizophrenia. However, the findings should be regarded as preliminary due to the cross-sectional design and our chronic patients, which need replication in a first-episode and drug naïve patients using a longitudinal study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 511 | Schizophr. Res. 2014 Aug 157: 244-8 |
| PMID | 24934904 |
| Title | The relationship between serum brain-derived neurotrophic factor (BDNF) and cardiometabolic indices in schizophrenia. |
| Abstract | Brain derived neurotrophic factor (BDNF), which has been implicated in the pathogenesis of schizophrenia, has been recently shown to be involved in the regulation of metabolism and energy homeostasis. This study seeks to examine the relationship between BDNF, metabolic indices and cardiovascular (CVD) risk in patients with schizophrenia. Medical histories, demographic information and anthropometric measurements were collected and analyzed from 61 participants with schizophrenia. Fasting glucose and lipids were measured in a central laboratory, and serum BDNF was analyzed using commercially available enzyme-linked immunosorbent assay (ELISA). The 10-year CVD risk for each participant was computed using the Framingham risk score (FRS). Linear regressions were performed to examine the relationships between serum BDNF with body mass index (BMI), blood pressure (BP), triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C) and glucose. To examine the relationship between serum BDNF and FRS, serum BDNF was categorized into quartiles, and a multiple regression was performed. After adjusting for age, gender and current smoking status, diastolic BP (dBP) (p=0.045) and TG (p=0.015) were found to be significantly associated with serum BDNF. Participants in the highest quartile of serum BDNF had a 3.3 times increase in FRS over those in the lowest quartile. Our findings support the possible regulatory role of BDNF in metabolism and cardiovascular homeostasis among patients with schizophrenia similar to that observed among the non-mentally ill. Serum BDNF not only present itself as a candidate biomarker of schizophrenia but also might be a viable marker of metabolic co-morbidities associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 512 | Pharmacol Rep 2014 Jun 66: 404-11 |
| PMID | 24905516 |
| Title | The influence of aripiprazole, olanzapine and enriched environment on depressant-like behavior, spatial memory dysfunction and hippocampal level of BDNF in prenatally stressed rats. |
| Abstract | Cognitive function deficits caused by impaired neurogenesis of the brain structures are considered an important pathogenic factor in many neurological and mental diseases such as schizophrenia and depression. The aim of the study was to determine the effect of the enriched environment on cognitive functions and antidepressant-like effect of prenatally stressed rats. It was important to determine the effect of aripiprazole ARI and olanzapine OLA and clarify whether the enriched environment induces increases in brain derived neurothropic factor BDNF in the hippocampus in the prenatally stressed group (PSG) and non-stressed control group (NSCG). The effect of chronic stress applied to pregnant rats and the use of ARI (1.5mg/kg ip) and OLA (0.5mg/kg ip) were studied in the Morris water maze (MWM), Porsolt Forced swimming test (FST) and by determining BDNF levels. The results indicated that enriched environment improved spatial memory and also had an antidepressant-like effect on prenatally stressed rats. ARI improved spatial memory both in the NSCG and PSG, while OLA caused memory improvement only in the PSG. Moreover, both ARI and OLA reduced immobility time in the NSCG and PSG. In PSG rats, BDNF decrease was observed while chronic treatment with ARI and OLA increased BDNF levels in the hippocampi of NSCG and PSG rats. It has been confirmed that enriched environment improves spatial memory of animals, removes symptoms of stress, has an antidepressant-like effect, and that new neuroleptics, such as ARI or OLA, modulate these functions (increased BDNF). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 513 | J Affect Disord 2014 Aug 165: 24-30 |
| PMID | 24882173 |
| Title | The effect of exercise on hippocampal volume and neurotrophines in patients with major depression--a randomized clinical trial. |
| Abstract | The hippocampal volume is reduced in patients with major depression. Exercise leads to an increased hippocampal volume in schizophrenia and in healthy old adults. The effect of exercise on hippocampal volume is potentially mediated by brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin like growth factor 1 (IGF-1). The aim of this trial was to assess the effect of an aerobic exercise intervention on hippocampal volume and serum BDNF, VEGF, and IGF-1 in patients with major depression. Patients were randomized to an aerobic exercise intervention (n=41) or a control condition (n=38). Both interventions consisted of three supervised sessions per week during a three months period. Post-intervention the increase in maximal oxygen uptake was 3.90 ml/kg/min (SD 5.1) in the aerobic exercise group and 0.95 ml/kg/min (SD 6.2) in the control group (p=0.03). The hippocampal volume, BDNF, VEGF, or IGF-1 did not differ between the two groups. Post-hoc we found a positive association between change in hippocampal volume and verbal memory (Rho=0.27; p=0.05) and change in hippocampal volume and depressive symptoms (Rho=0.30; p=0.03). Participation was low in both groups corresponding to an average participation of one session per week. Despite a significant increase in maximal oxygen uptake, a pragmatic exercise intervention did not increase hippocampal volume or resting levels of neurotrophines in out-patients with mild to moderate major depression. Trial identifier: ClinicalTrials.gov (NCT00695552). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 514 | Nature 2014 Jul 511: 236-40 |
| PMID | 24870235 |
| Title | Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. |
| Abstract | Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (?-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 515 | Hippocampus 2014 Oct 24: 1197-211 |
| PMID | 24802968 |
| Title | Sex-specific disruptions in spatial memory and anhedonia in a "two hit" rat model correspond with alterations in hippocampal brain-derived neurotrophic factor expression and signaling. |
| Abstract | Post-mortem studies have demonstrated reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of schizophrenia and major depression patients. The "two hit" hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these "two hit" effects is unclear. Our aim was to behaviorally characterize a "two hit" rat model of developmental stress accompanied by an in-depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon-specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male "two hit" rats showed marked disruptions in short-term spatial memory (Y-maze) which were absent in females. However, female "two hit" rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two "hits". In the DHP, MS caused a male-specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region-specific and sex-specific long-term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex-specific effects of developmental stress on anhedonic behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 516 | Transl Psychiatry 2014 -1 4: e389 |
| PMID | 24802307 |
| Title | Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. |
| Abstract | Abnormalities in brain-derived neurotrophic factor (BDNF)/trkB signaling have been implicated in the etiology of schizophrenia and mood disorders. Patients with schizophrenia, bipolar disorder (BPD) and major depression (MDD) have reduced levels of neurotrophins in their brains when compared with normal unaffected individuals; however, only a few brain areas have been examined to date. Owing to the broad range of symptoms manifested in these disorders, we hypothesized that multiple associative areas of the neocortex may be implicated and that the degree of change in BDNF and trkB-TK+ mRNA expression and the cortical region or layers involved may vary according to Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis. We compared BDNF and trkB-TK+ mRNA levels across all layers of the prefrontal cortex (dorsolateral prefrontal cortex, DLPFC), orbital frontal cortex (OFC), anterior cingulate cortex (ACC), inferior temporal gyrus (ITG) and superior temporal gyrus (STG) in four groups: schizophrenia, BPD, MDD and unaffected controls (n=60). BDNF mRNA levels were significantly decreased in layers IV and V of DLPFC in schizophrenia patients, in layer VI of ACC in schizophrenia and MDD and in layer VI of ITG in schizophrenia, BPD and MDD. BDNF mRNA levels were also significantly decreased in layer V and/or VI of STG in schizophrenia, BPD and MDD. TrkB-TK+ mRNA levels were only significantly decreased in the cortical layer VI of OFC in BPD. The shared and distinct patterns of neurotrophin transcript reductions, with some specific to each group, may compromise the function and plasticity of distinct cortical areas to various degrees in the different groups and contribute to the range and overlap of symptoms manifested across the diagnoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 517 | J Affect Disord 2014 Jun 162: 67-72 |
| PMID | 24767008 |
| Title | Serum level of brain derived neurotrophic factor (BDNF) among patients with bipolar disorder. |
| Abstract | There is a growing body of evidence that serum brain derived neurotrophic factor (BDNF) is altered during the episodes of bipolar disorder. The aim of this study was to investigate serum BDNF levels in bipolar disorder patients during manic and depressive episodes and its clinical utility in bipolar disorder compared to other psychiatric disorders. The study was conducted on 80 Egyptian patients, who were classified into 4 groups: group Ia (25 patients with depressive episodes), group Ib (25 patients with manic episodes), group II (15 patients having schizophrenia) as pathological controls and group III (15 healthy subjects) as controls. All subjects were diagnosed according to DSM-IV, assessed using the Hamilton Rating Scale for depression (HAM-D), and the Young Mania Rating Scale (YMRS). sBDNF concentrations were measured using the quantitative sandwich enzyme immunoassay technique. sBDNF showed significantly lower levels in patients with depressive episodes or manic episodes. The best cut-off for sBDNF in discriminating depressed patient from healthy control was ?33,000pg/ml (AUC=0.891, sensitivity of 84%, and specificity of 80%). Moreover, the best cut-off for sBDNF in discriminating mania patients? group from healthy control was ?29,500pg/ml, (AUC=0.984, asensitivity of 96%, and specificity of 86.7%). Only a small sample size was considered which included only drug free patients. BDNF was measured in serum not in CSF or brain tissue. Low sBDNF levels are strongly associated with active phases of bipolar disorder, in depressive and manic episodes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 518 | Clin. Biochem. 2014 Aug 47: 1052-5 |
| PMID | 24713399 |
| Title | Brain-derived neurotrophic factor blood levels are decreased in schizophrenia patients and associate with rs6265 genotypes. |
| Abstract | A growing number of studies implicate brain-derived neurotrophic factor (BDNF), an important promoter of synaptic transmission and neural plasticity, in the pathogenesis of schizophrenia. However, the existing data are controversial, that may reflect population differences between studied groups. In the present study we performed a comparative analysis of BDNF plasma levels and its relation with rs6265 (G196A; Val66Met) polymorphism of BDNF gene (BDNF) in schizophrenia-affected and healthy subjects (controls) of the Armenian population. To check the influence of antipsychotics on BDNF plasma levels both medicated and non-medicated patients were involved in this study. Patients with paranoid form of schizophrenia chronically treated with typical antipsychotics (n=103), age- and sex-matched controls (n=105), and 25 antipsychotic-naive first-episode schizophrenia patients were involved. The levels of BDNF in the blood plasma were measured with a solid-phase enzyme-linked immunosorbent assay. Decreased plasma levels of BDNF in both medicated and non-medicated schizophrenia patients compared to controls were observed. No significant difference in BDNF levels between medicated and non-medicated patients was detected. It was also detected that, compared to individuals homozygous for the standard allele (G/G) of rs6265, carriers of the rs6265 minor allele (A/G+A/A), which is significantly more frequent in schizophrenia patients than in controls, had decreased BDNF levels. The data obtained suggested that the pathogenesis of schizophrenia is characterized by genetically predetermined decreased blood levels of BDNF. These results indicated that genetically determined alterations of neuroimmune modulators may be among the risk factors of schizophrenia and contribute to disease-specific pathologic changes in functional activity of both the neuronal synaptic plasticity and the immune system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 519 | Pharmacol. Biochem. Behav. 2014 Jul 122: 30-6 |
| PMID | 24662915 |
| Title | Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia. |
| Abstract | Cognitive deficits are the core symptoms of schizophrenia and major contributors to disability in schizophrenic patients, but effective treatments are still lacking. Previous studies have demonstrated that impaired BDNF/TrkB signaling is associated with the cognitive impairments of schizophrenia. 7,8-Dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The present study aimed to assess the effect of 7,8-DHF on the cognitive and synaptic impairments of schizophrenia. A brief disruption of NMDA receptors with MK-801 during early development serves as an animal model for cognitive deficits of schizophrenia. We found that MK-801-treated rats showed significant deficits in working learning ability and hippocampal synaptic plasticity, as well as reduction of BDNF, TrkB, and phosphorylated TrkB in the hippocampus. After intraperitoneal administration with 7,8-DHF (5 mg/kg) once daily for a consecutive 14days, we found that chronic 7,8-DHF treatment significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased the phosphorylation levels of TrkB downstream signal cascades including ERK1/2, CaMKII, CREB and GluR1, and promoted hippocampal synaptic plasticity, which in turn rescued performance in spatial working learning. Our results thus demonstrate that activation of TrkB signaling can reverse the cognitive deficits of schizophrenia and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in treating schizophrenia-related cognitive impairments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 520 | PLoS ONE 2014 -1 9: e90425 |
| PMID | 24632812 |
| Title | Transcriptomic analysis of the effects of a fish oil enriched diet on murine brains. |
| Abstract | The health benefits of fish oil enriched with high omega-3 polyunsaturated fatty acids (n-3 PUFA) are widely documented. Fish oil as dietary supplements, however, show moderate clinical efficacy, highlighting an immediate scope of systematic in vitro feedback. Our transcriptomic study was designed to investigate the genomic shift of murine brains fed on fish oil enriched diets. A customized fish oil enriched diet (FD) and standard lab diet (SD) were separately administered to two randomly chosen populations of C57BL/6J mice from their weaning age until late adolescence. Statistical analysis mined 1,142 genes of interest (GOI) differentially altered in the hemibrains collected from the FD- and SD-fed mice at the age of five months. The majority of identified GOI (? 40%) encodes proteins located in the plasma membrane, suggesting that fish oil primarily facilitated the membrane-oriented biofunctions. FD potentially augmented the nervous system's development and functions by selectively stimulating the Src-mediated calcium-induced growth cascade and the downstream PI3K-AKT-PKC pathways. FD reduced the amyloidal burden, attenuated oxidative stress, and assisted in somatostatin activation-the signatures of attenuation of Alzheimer's disease, Parkinson's disease, and affective disorder. FD induced elevation of FKBP5 and suppression of BDNF, which are often linked with the improvement of anxiety disorder, depression, and post-traumatic stress disorder. Hence we anticipate efficacy of FD in treating illnesses such as depression that are typically triggered by the hypoactivities of dopaminergic, adrenergic, cholinergic, and GABAergic networks. Contrastingly, FD's efficacy could be compromised in treating illnesses such as bipolar disorder and schizophrenia, which are triggered by hyperactivities of the same set of neuromodulators. A more comprehensive investigation is recommended to elucidate the implications of fish oil on disease pathomechanisms, and the result-driven repositioning of fish oil utilization may revitalize its therapeutic efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 521 | Synapse 2014 Jun 68: 257-65 |
| PMID | 24615983 |
| Title | Phencyclidine rapidly decreases neuronal mRNA of brain-derived neurotrophic factor. |
| Abstract | Downregulation of brain-derived neurotrophic factor (BDNF), a member of neurotrophin family, has been implicated in psychiatric diseases including schizophrenia. However, detailed mechanisms of its reduction in patients with schizophrenia remain unclear. Here, using cultured cortical neurons, we monitored BDNF mRNA levels following acute application of phencyclidine [PCP; an N-methyl-d-aspartate (NMDA) receptor blocker], which is known to produce schizophrenia-like symptoms. We found that PCP rapidly caused a reduction in total amount of BDNF transcripts without effect on cell viability, while mRNA levels of nerve growth factor was intact. Actinomycin-D (ActD), an RNA synthesis inhibitor, decreased total BDNF mRNA levels similar to PCP, and coapplication of ActD with PCP did not show further reduction in BDNF mRNA compared with solo application of each drug. Among BDNF exons I, IV, and VI, the exon IV, which is positively regulated by neuronal activity, was highly sensitive to PCP. Furthermore, PCP inactivated cAMP response element-binding protein (CREB; a regulator of transcriptional activity of exon IV). The inactivation of CREB was also achieved by an inhibitor for Ca(2+) /calmodulin kinase II (CaMKII), although coapplication with PCP induced no further inhibition on the CREB activity. It is possible that PCP decreases BDNF transcription via blocking the NMDA receptor/CaMKII/CREB signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 522 | Neurochem. Res. 2014 Apr 39: 785-92 |
| PMID | 24599793 |
| Title | Impairments in brain-derived neurotrophic factor-induced glutamate release in cultured cortical neurons derived from rats with intrauterine growth retardation: possible involvement of suppression of TrkB/phospholipase C-? activation. |
| Abstract | Low birth weight due to intrauterine growth retardation (IUGR) is suggested to be a risk factor for various psychiatric disorders such as schizophrenia. It has been reported that developmental cortical dysfunction and neurocognitive deficits are observed in individuals with IUGR, however, the underlying molecular mechanisms have yet to be elucidated. Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are associated with schizophrenia and play a role in cortical development. We previously demonstrated that BDNF induced glutamate release through activation of the TrkB/phospholipase C-? (PLC-?) pathway in developing cultured cortical neurons, and that, using a rat model for IUGR caused by maternal administration of thromboxane A2, cortical levels of TrkB were significantly reduced in IUGR rats at birth. These studies prompted us to hypothesize that TrkB reduction in IUGR cortex led to impairment of BDNF-dependent glutamatergic neurotransmission. In the present study, we found that BDNF-induced glutamate release was strongly impaired in cultured IUGR cortical neurons where TrkB reduction was maintained. Impairment of BDNF-induced glutamate release in IUGR neurons was ameliorated by transfection of human TrkB (hTrkB). Although BDNF-stimulated phosphorylation of TrkB and of PLC-? was decreased in IUGR neurons, the hTrkB transfection recovered the deficits in their phosphorylation. These results suggest that TrkB reduction causes impairment of BDNF-stimulated glutamatergic function via suppression of TrkB/PLC-? activation in IUGR cortical neurons. Our findings provide molecular insights into how IUGR links to downregulation of BDNF function in the cortex, which might be involved in the development of IUGR-related diseases such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 523 | Psychopharmacology (Berl.) 2014 Sep 231: 3757-64 |
| PMID | 24595507 |
| Title | Association between the brain-derived neurotrophic factor Val66Met polymorphism and therapeutic response to olanzapine in schizophrenia patients. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a major role in neurogenesis and neuroplasticity, and in the modulation of several neurotransmitter systems including the dopaminergic system. There are mixed reports about the association between the BDNF Val66Met polymorphism, schizophrenia, and treatment response to antipsychotic drugs. The present study evaluated the association of the BDNF Val66Met polymorphism with treatment response to atypical antipsychotic olanzapine in schizophrenia and the possible predictive value of the BDNF Val66Met genotype status in treatment response to antipsychotic medication. The study included 590 ethnically homogenous Caucasian patients with schizophrenia (diagnosed using the SCID), 40.2?±?12.0 years old, treated with olanzapine monotherapy (10-20 mg/day), or with other antipsychotics such as risperidone (3-6 mg/day), clozapine (100-500 mg/day), haloperidol (3-115 mg/day), fluphenazine (4-25 mg/day), and quetiapine (50-800 mg/day). Patients were subdivided into responders and non-responders according to a 50 % reduction in the Positive and Negative Syndrome Scale (PANSS) total and subscale scores after 8 weeks of treatment. The results, corrected for possible effects of gender and age, showed a significant association between the BDNF Val66Met polymorphism and treatment response to olanzapine in patients. The Val/Val genotype was observed more frequently in treatment responders to olanzapine, and this genotype was associated with an improvement in clinical symptoms. Our results suggest that BDNF Val66Met variants might influence the response to 8 weeks of monotherapy with olanzapine, in a relatively large sample of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 524 | Schizophr. Res. 2014 Mar 153: 225-30 |
| PMID | 24556472 |
| Title | Transcriptional consequences of schizophrenia candidate miR-137 manipulation in human neural progenitor cells. |
| Abstract | MIR137, transcribed as the microRNA miR-137, is one of the leading candidate schizophrenia susceptibility genes to arise from large genome-wide association studies (GWAS) of the disorder. Recent data suggest that miR-137 modulates the expression of other schizophrenia susceptibility genes. Although bioinformatic resources are available with which to predict genes regulated by individual microRNA, there has been a lack of empirical data on genome-wide gene expression changes following miR-137 manipulation. We have therefore performed a genome-wide assessment of transcriptional changes in a human neural progenitor cell line after miR-137 over-expression and inhibition in order to elucidate molecular pathways by which genetic perturbation of miR-137 could promote susceptibility to schizophrenia. Bioinformatically-predicted miR-137 targets showed a small but highly significant down-regulation following miR-137 over-expression. Genes that were significantly down-regulated in association with miR-137 over-expression were enriched for involvement in neuronal differentiation. Differentially expressed genes that were confirmed by qPCR included others at genome-wide significant risk loci for schizophrenia (MAD1L1 and DPYD) and BDNF. These data point to molecular pathways through which genetic variation at the MIR137 locus could confer risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 525 | PLoS ONE 2014 -1 9: e87997 |
| PMID | 24551075 |
| Title | A longitudinal study of alterations of hippocampal volumes and serum BDNF levels in association to atypical antipsychotics in a sample of first-episode patients with schizophrenia. |
| Abstract | schizophrenia is associated with structural and functional abnormalities of the hippocampus, which have been suggested to play an important role in the formation and emergence of schizophrenia syndrome. Patients with schizophrenia exhibit significant bilateral hippocampal volume reduction and progressive hippocampal volume decrease in first-episode patients with schizophrenia has been shown in many neuroimaging studies. Dysfunction of the neurotrophic system has been implicated in the pathophysiology of schizophrenia. The initiation of antipsychotic medication alters the levels of serum Brain Derived Neurotrophic Factor (BDNF) levels. However it is unclear whether treatment with antipsychotics is associated with alterations of hippocampal volume and BDNF levels. In the present longitudinal study we investigated the association between serum BDNF levels and hippocampal volumes in a sample of fourteen first-episode drug-naïve patients with schizophrenia (FEP). MRI scans, BDNF and clinical measurements were performed twice: at baseline before the initiation of antipsychotic treatment and 8 months later, while the patients were receiving monotherapy with second generation antipsychotics (SGAs). We found that left hippocampal volume was decreased (corrected left HV [t = 2.977, df = 13, p =?.011] at follow-up; We also found that the higher the BDNF levels change the higher were the differences of corrected left hippocampus after 8 months of treatment with atypical antipsychotics (Pearson r = 0.597, p = 0.024). The association of BDNF with hippocampal volume alterations in schizophrenia merits further investigation and replication in larger longitudinal studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 526 | Scand. J. Immunol. 2014 Jul 80: 36-42 |
| PMID | 24498860 |
| Title | Changes in serum levels of brain derived neurotrophic factor and nerve growth factor-beta in schizophrenic patients before and after treatment. |
| Abstract | schizophrenia is one of the most debilitating diseases among psychiatric disorders. Recent studies suggest the existence of effective immunological changes in the pathophysiology of this disease. The purpose of the current study was to determine the changes in serum levels of Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor-beta (NGF) in schizophrenic patients before treatment and 40 days after treatment. In this case-control study, serum levels of BDNF and NGF were measured by ELISA in 26 patients with schizophrenia and 26 healthy controls. All patients were treated with clozapine or risperidone for 40 days. A positive and negative syndrome scale (PANSS) questionnaire has been used to recognize the severity of the disease and to assess the response to treatment. Neurotrophin concentrations were compared before and after the treatment and with control groups using paired t-test and ANOVA test. BDNF and NGF levels in the case group were more than levels after treatment, but these differences were significant only for NGF. Concentrations in both neurotrophins were higher than the control group. The statistically significant difference was observed between changes in the NGF levels in the case and the control group, while no significant difference was seen in changes of BDNF. The main conclusion to be drawn from this study was that the increase in BDNF and particularly NGF may have an important role in causing schizophrenia. And possibly drugs clozapine and risperidone help to treat the disease by reducing the concentration of Neurotrophins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 527 | Neuroscience 2014 Mar 263: 257-68 |
| PMID | 24444829 |
| Title | Soft-diet feeding after weaning affects behavior in mice: Potential increase in vulnerability to mental disorders. |
| Abstract | Mastication is one of the most important oral functions, and the period during which mastication is acquired overlaps with the term of rapid development and maturation of the neural systems. In particular, the acquisition period after weaning is related to the potential onset of mental disorders. However, the roles of mastication during this period for brain development remain largely unknown. Therefore, we used a series of standard behavioral analyses, assessment of hippocampal cell proliferation, and the expression of brain-derived neurotrophic factor (BDNF), TrkB, and Akt1 in the hippocampus and frontal cortex of mice to investigate the effects of post-weaning mastication on brain function. We fed 21-day-old C57BL6/J male mice either a hard or a soft diet for 4weeks and conducted a series of standard behavioral tests from 7weeks of age. Further, histological analysis with bromodeoxyuridine was performed to compare hippocampal cell proliferation at 7 and 14weeks of age. Real-time polymerase chain reaction was performed to compare BDNF, TrkB, and Akt1 expression in the hippocampus and frontal cortex of 14-week-old mice. Compared to mice fed a hard diet (HDM), soft-diet mice (SDM) showed behavioral impairments, including decreased home cage activity, increased open field test activity, and deficits in prepulse inhibition. These results were similar to those observed in mouse models of schizophrenia. However, no effects were observed on anxiety-like behaviors or memory/learning tests. Compared to HDM, SDM showed significantly decreased hippocampal cell proliferation and hippocampal BDNF and Akt1 gene expression at 14weeks of age. A soft diet after weaning may have resulted in histological and molecular changes in the hippocampus and influenced outcomes of behavioral tests related to mental disorders. Our findings suggest that soft-diet feeding after weaning may affect both physical and mental development of mice, and may increase vulnerability to mental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 528 | PLoS ONE 2014 -1 9: e85768 |
| PMID | 24465693 |
| Title | Human variants in the neuronal basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) transcription factor complex NPAS4/ARNT2 disrupt function. |
| Abstract | Neuronal Per-Arnt-Sim homology (PAS) Factor 4 (NPAS4) is a neuronal activity-dependent transcription factor which heterodimerises with ARNT2 to regulate genes involved in inhibitory synapse formation. NPAS4 functions to maintain excitatory/inhibitory balance in neurons, while mouse models have shown it to play roles in memory formation, social interaction and neurodegeneration. NPAS4 has therefore been implicated in a number of neuropsychiatric or neurodegenerative diseases which are underpinned by defects in excitatory/inhibitory balance. Here we have explored a broad set of non-synonymous human variants in NPAS4 and ARNT2 for disruption of NPAS4 function. We found two variants in NPAS4 (F147S and E257K) and two variants in ARNT2 (R46W and R107H) which significantly reduced transcriptional activity of the heterodimer on a luciferase reporter gene. Furthermore, we found that NPAS4.F147S was unable to activate expression of the NPAS4 target gene BDNF due to reduced dimerisation with ARNT2. Homology modelling predicts F147 in NPAS4 to lie at the dimer interface, where it appears to directly contribute to protein/protein interaction. We also found that reduced transcriptional activation by ARNT2 R46W was due to disruption of nuclear localisation. These results provide insight into the mechanisms of NPAS4/ARNT dimerisation and transcriptional activation and have potential implications for cognitive phenotypic variation and diseases such as autism, schizophrenia and dementia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 529 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jun 51: 99-104 |
| PMID | 24468644 |
| Title | The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese patients with bipolar disorder and schizophrenia. |
| Abstract | Brain-derived neurotropic factor (BDNF) is widely distributed in the peripheral and central nervous systems. BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of several mental illnesses. To elucidate the role of BDNF, we compared the plasma BDNF levels and the BDNF Val66Met gene variants effect in several mental disorders. We enrolled 644 participants: 177 patients with bipolar I disorder (BP-I), 190 with bipolar II disorder (BP-II), 151 with schizophrenia, and 126 healthy controls. Their plasma BDNF levels and BDNF Val66Met single nucleotide polymorphisms (SNP) were checked before pharmacological treatment. Plasma levels of BDNF were significantly lower in patients with schizophrenia than in healthy controls and patients with bipolar disorder (F = 37.667, p<0.001); the distribution of the BDNF Val66Met SNP was not different between groups (?(2) = 5.289, p = 0.507). Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not influence plasma BDNF levels in our participants. Plasma BDNF levels were, however, significantly negatively correlated with depression scores in patients with bipolar disorder and with negative symptoms in patients with schizophrenia. We conclude that plasma BDNF profiles in different mental disorders are not affected by BDNF Val66Met gene variants, but by the process and progression of the illness itself. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 530 | Eur Neuropsychopharmacol 2014 Jun 24: 986-95 |
| PMID | 24440552 |
| Title | Delayed BDNF alterations in the prefrontal cortex of rats exposed to prenatal stress: preventive effect of lurasidone treatment during adolescence. |
| Abstract | Psychiatric diseases may often represent the consequence of exposure to adverse events early in life. Accordingly, exposure to stress during gestation in rats has a strong impact on development and can cause long-term abnormalities in adult behavior. Considering that neuronal plasticity has emerged as a major vulnerability element in psychiatric disorders, we investigated the postnatal developmental profile of Brain-Derived Neurotrophic Factor expression (BDNF), an important mediator for long-term functional deterioration associated to mental illness, in male and female rats following exposure to prenatal stress (PNS). Since we found that the majority of alterations became fully manifest at early adulthood, we tried to prevent these abnormalities with an early pharmacological intervention. To address this point, we treated rats during adolescence with the multi-receptor antipsychotic lurasidone, which was proven to be effective in animal models of schizophrenia. Interestingly, we show that lurasidone treatment was able to prevent the reduction of BDNF expression in adult rats that were exposed to PNS. Collectively, our results provide further support to the notion that exposure to early life stress has a negative impact on neuronal plasticity and that pharmacological intervention during critical time windows may prove effective in preventing neuroplastic dysfunction, leading to long-term beneficial effects on brain function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 531 | Schizophr. Res. 2014 Feb 152: 365-72 |
| PMID | 24411528 |
| Title | BDNF Val66Met polymorphism and antipsychotic-induced tardive dyskinesia occurrence and severity: a meta-analysis. |
| Abstract | Tardive dyskinesia (TD) is a serious long-term consequence of antipsychotic treatment. Since brain-derived neurotrophic factor (BDNF) has potent neurotrophic activity, genetic alterations in the BDNF gene may affect antipsychotic-induced TD. Searching PubMed and Web of Science until 05/31/13, we conducted a systematic review and a meta-analysis of the effects of BDNF Val66Met polymorphism on antipsychotic-induced TD. Pooled odds ratio was calculated to assess the effects of BDNF Val66Met polymorphism on TD occurrence. Additionally, pooled standardized mean differences (Hedges' g) were calculated to assess the effects on Abnormal Involuntary Movement Scale (AIMS) total score. Out of 699 potentially eligible hits, 6 studies (N=1740, mean age=46.0±10.4years; males=73.1%; Asians=80.5%, Caucasians=19.5%; schizophrenia=96.2%) were included in this meta-analysis. Pooling data from all studies, no significant associations were found between BDNF Val66Met polymorphism and TD (p=0.82) or AIMS total scores (p=0.11). However, in studies including only Caucasians (n=339), Met allele carriers had significantly higher AIMS total scores (Hedges' g=0.253, 95% confidence interval=0.030 to 0.476, p=0.026) and non-significantly higher TD occurrence (p=0.127). Conversely, there was no association between BDNF and AIMS scores (p=0.57) or TD (p=0.65) in Asians. Although there was no significant association between BDNF Val66Met polymorphism and TD or AIMS scores across all patients, our results suggest that BDNF Val66Met polymorphism affects severity and, possibly, TD development in Caucasians. Since the number of studies and patients was still small, additional data are needed to confirm genotype-racial interactions. Furthermore, BDNF enhancing treatments for TD may require further study, especially in Caucasians. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 532 | Eur Neuropsychopharmacol 2014 Mar 24: 425-36 |
| PMID | 24389121 |
| Title | A novel analog of olanzapine linked to sarcosinyl moiety (PGW5) demonstrates high efficacy and good safety profile in mouse models of schizophrenia. |
| Abstract | schizophrenia is a chronic mental disorder related to hypo-functioning of glutamatergic neurotransmission. N-methyl-D-aspartate-receptor (NMDA-R) positive modulators were reported to reduce schizophrenia symptoms. However, their efficacy is low and inconsistent. We developed a novel antipsychotic possessing an olanzapine moiety linked to the positive modulator of glutamate NMDA-R sarcosine (PGW5) and characterized the pharmacodynamic properties of the novel molecule in-vivo using MK-801 and in-vitro using receptor binding analysis. We investigated the pharmacological activity of PGW5 (olanzapine linked to sarcosinyl moiety) in male mice (BALB/c or C57BL). In an open field test, up to 50mg/kg PGW5 did not affect motility while higher doses were sedative. PGW5 (25-50mg/kg po) antagonized MK-801 (0.15 mg/kg ip) and amphetamine-induced (5mg/kg ip) hyperactivity. PGW5 (25mg/kg po/d) treatment for 15 or 22 days exhibited antidepressant and anxiolytic activity in mice. Moreover, PGW5, but not olanzapine, attenuated phencyclidine (PCP)-induced deficits of social preference in mice and promoted the expression of brain derived neurotrophic factor (BDNF) in the hippocampus and the frontal cortex and glutamic acid decarboxylase (GAD67) in the hippocampus. Mice treated with PGW5 (25 and 50mg/kg/d) for 28 days did not show toxic effects in terms of weight gain and blood-chemistry analysis. PGW5 is a novel and safe antipsychotic, efficacious against schizophrenia-like positive and negative symptoms at nonsedative doses. The drug shows anxiolytic and antidepressant activity, and improves impaired social performance in phencyclidine (PCP) treated mice. The mechanism underlying its activity seems to involve potentiation of NMDA receptor as well as stimulation of brain BDNF and GAD67 expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 533 | Psychiatry Res 2014 Feb 215: 268-73 |
| PMID | 24377440 |
| Title | A positive correlation between serum levels of mature brain-derived neurotrophic factor and negative symptoms in schizophrenia. |
| Abstract | A meta-analysis study reported serum brain-derived neurotrophic factor (BDNF) levels as a potential biomarker for schizophrenia. However, at the time, commercially available human ELISA kits were unable to distinguish between pro-BDNF (precursor BDNF) and mature BDNF, because of limited antibody specificity. Here, we used new ELISA kits, to examine serum levels of mature BDNF and matrix metalloproteinase-9 (MMP-9), which converts pro-BDNF to mature BDNF in schizophrenia. Sixty-three patients with chronic schizophrenia and 52 age- and sex-matched healthy controls were enrolled. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Neither serum mature BDNF nor MMP-9 levels differed between patients and controls. In male subgroups, serum MMP-9 levels of smoking patients were higher than those of non-smoking patients, but this was not observed in male controls or the female subgroup. In patients, serum mature BDNF levels were associated with SANS total scores and the Information subtest scores of the Wechsler Adult Intelligence Scale Revised (WAIS-R), while serum MMP-9 levels were associated with smoking and category fluency scores. These findings suggest that neither mature BDNF nor MMP-9 is a suitable biomarker for schizophrenia, although further studies using large samples are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 534 | Adv Med 2014 -1 2014: 317980 |
| PMID | 26556409 |
| Title | Comorbid Obsessive-Compulsive Symptoms in Schizophrenia: Insight into Pathomechanisms Facilitates Treatment. |
| Abstract | Insight into the biological pathomechanism of a clinical syndrome facilitates the development of effective interventions. This paper applies this perspective to the important clinical problem of obsessive-compulsive symptoms (OCS) occurring during the lifetime diagnosis of schizophrenia. Up to 25% of schizophrenia patients suffer from OCS and about 12% fulfil the diagnostic criteria of obsessive-compulsive disorder (OCD). This is accompanied by marked subjective burden of disease, high levels of anxiety, depression and suicidality, increased neurocognitive impairment, less favourable levels of social and vocational functioning, and greater service utilization. Comorbid patients can be assigned to heterogeneous subgroups. It is assumed that second generation antipsychotics (SGAs), most importantly clozapine, might aggravate or even induce second-onset OCS. Several epidemiological and pharmacological arguments support this assumption. Specific genetic risk factors seem to dispose patients with schizophrenia to develop OCS and risk-conferring polymorphisms has been defined in SLC1A1, BDNF, DLGAP3, and GRIN2B and in interactions between these individual genes. Further research is needed with detailed characterization of large samples. In particular interactions between genetic risk constellations, pharmacological and psychosocial factors should be analysed. Results will further define homogeneous subgroups, which are in need for differential causative interventions. In clinical practise, schizophrenia patients should be carefully monitored for OCS, starting with at-risk mental states of psychosis and longitudinal follow-ups, hopefully leading to the development of multimodal therapeutic interventions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 535 | Neuroscience 2014 Feb 260: 265-75 |
| PMID | 24345476 |
| Title | Lack of BDNF expression through promoter IV disturbs expression of monoamine genes in the frontal cortex and hippocampus. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of psychiatric conditions including major depression and schizophrenia. Mice lacking activity-driven BDNF expression through promoter IV (knock-in promoter IV: KIV) exhibit depression-like behavior, inflexible learning, and impaired response inhibition. Monoamine systems (serotonin, dopamine, and noradrenaline) are suggested to be involved in depression and schizophrenia since many of the current antidepressants and antipsychotics increase the brain levels of monoamines and/or act on monoamine receptors. To elucidate the impact of activity-driven BDNF on the monoamine systems, we examined mRNA levels for 30 monoamine-related genes, including receptors, transporters, and synthesizing enzymes, in KIV and control wild-type mice by using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). mRNA levels were measured in the frontal cortex and hippocampus, which are regions related to depression and schizophrenia and where promoter IV is active. The frontal cortex of KIV mice showed reduced levels of mRNA expression for serotonin receptors 1b, 2a, and 5b (5HTR1b, 5HTR2a, 5HTR5b), dopamine D2 receptors (DRD2), and adrenergic receptors alpha 1a and 1d (AdR?1a and AdR?1b), but increased levels for serotonin synthesizing enzyme, tryptophan hydroxylase (TPH), and dopamine D4 receptor (DRD4) when compared to control wild-type mice. The hippocampus of KIV mice showed decreased levels of 5HTR5b. Our results provide causal evidence that lack of promoter IV-driven BDNF disturbs expression of monoaminergic genes in the frontal cortex and hippocampus. These disturbed expression changes in the monoamine systems may mediate the depression- and schizophrenia-like behavior of KIV mice. Our results also suggest that antidepressant and antipsychotic treatments may actually interfere with and normalize the disturbed monoamine systems caused by reduced activity-dependent BDNF, while the treatment responses to these drugs may differ in the subject with reduced BDNF levels caused by stress and lack of neuronal activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 536 | Prog. Lipid Res. 2014 Jan 53: 1-17 |
| PMID | 24334113 |
| Title | Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration. |
| Abstract | Many clinical and animal studies demonstrate the importance of long-chain polyunsaturated fatty acids (LCPUFA) in neural development and neurodegeneration. This review will focus on involvement of LCPUFA from genesis to senescence. The LCPUFA docosahexaenoic acid and arachidonic acid are important components of neuronal membranes, while eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid also affect cardiovascular health and inflammation. In neural development, LCPUFA deficiency can lead to severe disorders like schizophrenia and attention deficit hyperactivity disorder. Perinatal LCPUFA supplementation demonstrated beneficial effects in neural development in humans and rodents resulting in improved cognition and sensorimotor integration. In normal aging, the effect of LCPUFA on prevention of cognitive impairment will be discussed. LCPUFA are important for neuronal membrane integrity and function, and also contribute in prevention of brain hypoperfusion. Cerebral perfusion can be compromised as result of obesity, cerebrovascular disease, hypertension, or diabetes mellitus type 2. Last, we will focus on the role of LCPUFA in most common neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. These disorders are characterized by impaired cognition and connectivity and both clinical and animal supplementation studies have shown the potential of LCPUFA to decrease neurodegeneration and inflammation. This review shows that LCPUFA are essential throughout life. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 537 | Neuroscience 2014 Feb 259: 223-31 |
| PMID | 24316471 |
| Title | Omega-3 prevents behavior response and brain oxidative damage in the ketamine model of schizophrenia. |
| Abstract | Supplementation with omega-3 has been identified as an adjunctive alternative for the treatment of psychiatric disorders, in order to minimize symptoms. Considering the lack of understanding concerning the pathophysiology of schizophrenia, the present study hypothesized that omega 3 prevents the onset of symptoms similar to schizophrenia in young Wistar rats submitted to ketamine treatment. Moreover, the role of oxidative stress in this model was assessed. Omega-3 (0.8g/kg) or vehicle was given by orogastric gavage once daily. Both treatments were performed during 21days, starting at the 30th day of life in young rats. After 14days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25mg/kg ip daily) was started and maintained until the last day of the experiment. We evaluated the pre-pulse inhibition of the startle reflex, activity of antioxidant systems and damage to proteins and lipids. Our results demonstrate that supplementation of omega-3 prevented: decreased inhibition of startle reflex, damage to lipids in the hippocampus and striatum and damage to proteins in the prefrontal cortex. Furthermore, these changes are associated with decreased GPx in brain tissues evaluated. Together, our results suggest the prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 538 | Pharmacol. Res. 2014 Feb 80: 1-8 |
| PMID | 24309096 |
| Title | Repeated aripiprazole treatment regulates Bdnf, Arc and Npas4 expression under basal condition as well as after an acute swim stress in the rat brain. |
| Abstract | Despite the rapid control of schizophrenic symptoms is due to the ability of antipsychotic drugs (APDs) to block D2 receptors in the mesolimbic pathway, it is now well-established that the therapeutic effects rely on adaptive mechanisms set in motion by their long-term administration. Such neuroplastic mechanisms depend on the pharmacological profile of the drug employed, with marked differences existing between first and second generation APDs. On these bases, the major accomplishment of this work was to investigate neuroadaptive changes set in motion by repeated treatment with aripiprazole, a novel APD that is unique for being a partial agonist at dopamine D2 receptors. Moreover, given that stress plays a critical role in the exacerbation of disease symptoms, we also investigated whether aripiprazole could influence the dynamic response of the brain to an acute challenge. We found that repeated aripiprazole treatment in rats regulates the expression of different markers of neuroplasticity such as BDNF, Arc and Npas4 in a brain-region specific fashion; more importantly, the expression of these molecules was significantly up-regulated by an acute swim stress only in aripiprazole-treated animals, which is suggestive of increased ability to cope with the adverse event. We indeed found an overall facilitation of BDNF expression, an effect that is mainly evident in the prefrontal cortex on the pool of transcripts undergoing dendritic localization. Overall, our results provide novel information regarding the mechanisms through which aripiprazole may regulate brain function and could contribute to improve neuroplastic defects that are associated with schizophrenia symptomatology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 539 | J. Neurochem. 2014 May 129: 377-87 |
| PMID | 24266366 |
| Title | Is the mTOR-signalling cascade disrupted in Schizophrenia? |
| Abstract | The mammalian target of rapamycin (mTOR) signalling cascade is involved in the intracellular regulation of protein synthesis, specifically for proteins involved in controlling neuronal morphology and facilitating synaptic plasticity. Research has revealed that the activity of the mTOR cascade is influenced by several extracellular and environmental factors that have been implicated in schizophrenia. Therefore, there is reason to believe that one of the downstream consequences of dysfunction or hypofunction of these factors in schizophrenia is disrupted mTOR signalling and hence impaired protein synthesis. This results in abnormal neurodevelopment and deficient synaptic plasticity, outcomes which could underlie some of the positive, negative and cognitive symptoms of schizophrenia. This review will discuss the functional roles of the mTOR cascade and present evidence in support of a novel mTOR-based hypothesis of the neuropathology of schizophrenia. During neurodevelopment, genetic and epigenetic factors can disrupt mTOR signalling which affects synthesis of proteins essential for correct neuronal growth and network connectivity. This renders the CNS particularly vulnerable to the effects of secondary factors during adolescence which increases the risk of developing schizophrenia in adulthood. This review discusses the functional roles of the mTOR cascade and presents evidence in support of a novel mTOR-based hypothesis of the neuropathology of schizophrenia. Testing this hypothesis will advance our understanding of the aetiology of this illness and reveal novel therapeutic targets. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 540 | Cereb. Cortex 2014 May 24: 1230-46 |
| PMID | 23283688 |
| Title | Common variants in psychiatric risk genes predict brain structure at birth. |
| Abstract | Studies in adolescents and adults have demonstrated that polymorphisms in putative psychiatric risk genes are associated with differences in brain structure, but cannot address when in development these relationships arise. To determine if common genetic variants in disrupted-in-schizophrenia-1 (DISC1; rs821616 and rs6675281), catechol-O-methyltransferase (COMT; rs4680), neuregulin 1 (NRG1; rs35753505 and rs6994992), apolipoprotein E (APOE; ?3?4 vs. ?3?3), estrogen receptor alpha (ESR1; rs9340799 and rs2234693), brain-derived neurotrophic factor (BDNF; rs6265), and glutamate decarboxylase 1 (GAD1; rs2270335) are associated with individual differences in brain tissue volumes in neonates, we applied both automated region-of-interest volumetry and tensor-based morphometry to a sample of 272 neonates who had received high-resolution magnetic resonance imaging scans. ESR1 (rs9340799) predicted intracranial volume. Local variation in gray matter (GM) volume was significantly associated with polymorphisms in DISC1 (rs821616), COMT, NRG1, APOE, ESR1 (rs9340799), and BDNF. No associations were identified for DISC1 (rs6675281), ESR1 (rs2234693), or GAD1. Of note, neonates homozygous for the DISC1 (rs821616) serine allele exhibited numerous large clusters of reduced GM in the frontal lobes, and neonates homozygous for the COMT valine allele exhibited reduced GM in the temporal cortex and hippocampus, mirroring findings in adults. The results highlight the importance of prenatal brain development in mediating psychiatric risk. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 541 | Psychiatry Res 2014 Dec 220: 1147-50 |
| PMID | 25219617 |
| Title | DNA methylation state of BDNF gene is not altered in prefrontal cortex and striatum of schizophrenia subjects. |
| Abstract | In this study we assessed the BDNF promoter IV methylation state of a large genomic region surrounding promoter IV and evaluated BDNF transcript IV expression from prefrontal cortex and striatum of 15 schizophrenic and 15 control subjects. In prefrontal cortex, a single CpG site at -93, appeared to be undermethylated in patients?group. BDNF mRNA levels in frontal cortex and striatum were variable among individuals but did not associate with disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 542 | Psychiatry Res 2014 Dec 220: 197-200 |
| PMID | 25219612 |
| Title | Comparison of serum BDNF levels in deficit and nondeficit chronic schizophrenia and healthy controls. |
| Abstract | The aim of this study was to compare serum BDNF levels of chronic schizophrenic patients, with or without deficit syndrome, and healthy controls. A comparative study of serum BDNF levels, determined by ELISA, was performed in 47 chronic patients with schizophrenia matched with 47 healthy controls. A part of the chronic schizophrenic sample was further divided into patients with a deficit (n=14) and a nondeficit syndrome (n=20), according to the Proxy for the Deficit Syndrome Scale. A significant difference was observed in decreased serum BDNF levels between chronic schizophrenia and healthy controls. No statistical significant differences in BDNF levels between deficit and nondeficit chronic schizophrenic patients were found. Our study confirms differences of serum BDNF levels of chronic schizophrenia and healthy controls, which correspond to the clinical progression of the disease. Our results do not support a relation between deficit profile in chronic schizophrenia and lower serum BDNF levels. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 543 | Psychiatry Res 2014 Dec 220: 792-6 |
| PMID | 25446461 |
| Title | Increase of circulating BDNF levels and its relation to improvement of physical fitness following 12 weeks of combined exercise in chronic patients with schizophrenia: a pilot study. |
| Abstract | Brain-derived neurotrophic factor (BDNF), the most abundant of neurotrophins in the brain, is known to be responsible for maintenance of neurons has been implicated in the pathology of schizophrenia. In the present pilot study, we investigated the effect of a combined exercise program on circulating BDNF expression and the relationship between BDNF and improvements in physical fitness. Twenty-four patients with schizophrenia participated in the exercise intervention, three nonconsecutive days per week for 12 weeks. The resistance exercise program used the elastic band for eight different exercises for 25 min, and the aerobic exercise consisted of moderate walking for 25 min. After the training program, there were positive improvements in body composition and blood pressure. Also, there was significant improvement in leg strength, cardiovascular fitness, balance, and jump. Serum BDNF values had significantly increased following the combined exercise program. The elevation in serum BDNF concentrations correlated significantly with improvements in cardiovascular fitness and leg strength. These results suggest that exercise induced modulation of BDNF may play an important role in developing non-pharmacological treatment for chronic schizophrenic patients. In addition, these preliminary results serve to generate further hypothesis and facilitate the planning the exercise training program and management of participants. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 544 | Mol Med Rep 2014 Dec 10: 2924-30 |
| PMID | 25323073 |
| Title | Voluntary wheel running ameliorates symptoms of MK-801-induced schizophrenia in mice. |
| Abstract | schizophrenia is a chronic and severe mental disorder characterized by the disintegration of cognitive thought processes and emotional responses. Despite the precise cause of schizophrenia remains unclear, it is hypothesized that a dysregulation of the N?methyl?D?aspartate (NMDA) receptor in the brain is a major contributing factor to its development. Brain?derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is implicated in learning and memory processes. In the present study, we investigated in vivo the effects of voluntary wheel running on behavioral symptoms associated with NMDA receptor expression, using MK?801?induced schizophrenic mice. Abilify (aripiprazole), a drug used to treat human schizophrenia patients, was used as the positive control. For the assessment of behavioral symptoms affecting locomotion, social interaction and spatial working memory, the open?field, social interaction and Morris water maze tests were conducted. For investigating the biochemical parameters, NMDA receptor expression in the hippocampal CA2?3 regions and prefrontal cortex was detected by NMDA immunofluorescence and BDNF expression in the hippocampus was measured using western blot analysis. MK?801 injection for 14 days induced schizophrenia?like behavioral abnormalities with decreased expression of the NMDA receptor and BDNF in the brains of mice. The results indicated that free access to voluntary wheel running for 2 weeks alleviated schizophrenia?like behavioral abnormalities and increased the expression of NMDA receptor and BDNF, comparable to the effects of aripiprazole treatment. In the present study, the results suggest that NMDA receptor hypofunctioning induced schizophrenia?like behaviors, and that voluntary wheel running was effective in reducing these symptoms by increasing NMDA receptor and BDNF expression, resulting in an improvement of disease related behavioral deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 545 | Acta Neuropsychiatr 2014 Oct 26: 291-7 |
| PMID | 25241757 |
| Title | Can BDNF and IL-2 be indicators for the diagnosis in schizophrenic patients with depressive symptoms? |
| Abstract | The aim of the current study is to determine whether serum levels of brain-derived neurotrophic factor (BDNF) and interleukin-2 (IL-2) can be biological indicators for the diagnosis of schizophrenia in patients with depressive symptoms. Forty-seven patients (11 patients diagnosed with schizophrenia, 16 patients diagnosed with schizophrenia and comorbid depression and 20 patients diagnosed with major depressive disorder) and 20 healthy subjects were enrolled. The Positive and Negative Symptoms Scale, the Calgary Depression Scale for schizophrenia and the Hamilton Depression Rating Scale were used for assessment. The serum BDNF and IL-2 levels of all the subjects were studied. Decreased levels of serum BDNF and increased levels of serum IL-2 were found in the patients diagnosed with either schizophrenia, schizophrenia with depression, or major depressive disorder (p = 0.049, p = 0.010; p = 0.001 and p = 0.044; p = 0.027, p = 0.003; respectively) compared with control group. There were no significant differences between the patient groups in their serum BDNF and IL-2 levels. The present study suggests that neurotrophic factors and immune system changes are involved in the pathogenesis of schizophrenia with or without depressive symptomatology. However, the data do not clarify whether depressive symptoms in schizophrenia occur as a dimension of schizophrenia or as symptoms of major depression that is comorbid with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 546 | Psychoneuroendocrinology 2014 Oct 48: 136-46 |
| PMID | 24999831 |
| Title | Gender difference in association of cognition with BDNF in chronic schizophrenia. |
| Abstract | While numerous studies have reported that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia, very few studies have explored its association with cognitive impairment or gender differences in schizophrenia which we explored. We compared gender differences in 248 chronic schizophrenic patients (male/female=185/63) to 188 healthy controls (male/female=98/90) on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum BDNF. schizophrenic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Our results showed that schizophrenic patients performed worse than normals on most of the cognitive tasks, and male patients had significantly lower immediate memory and delayed memory scores than female patients. BDNF levels were significantly lower in patients than controls, and male patients had significantly lower BDNF levels than female patients. For the patients, BDNF was positively associated with immediate memory and the RBANS total score. Furthermore, these associations were only observed in female not male patients. Among healthy controls, no gender difference was observed in cognitive domains and BDNF levels, or in the association between BDNF and cognition. Our results suggest gender differences in cognitive impairments, BDNF levels and their association in chronic patients with schizophrenia. However, the findings should be regarded as preliminary due to the cross-sectional design and our chronic patients, which need replication in a first-episode and drug naïve patients using a longitudinal study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 547 | Pharmacol. Biochem. Behav. 2014 Jul 122: 30-6 |
| PMID | 24662915 |
| Title | Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia. |
| Abstract | Cognitive deficits are the core symptoms of schizophrenia and major contributors to disability in schizophrenic patients, but effective treatments are still lacking. Previous studies have demonstrated that impaired BDNF/TrkB signaling is associated with the cognitive impairments of schizophrenia. 7,8-Dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The present study aimed to assess the effect of 7,8-DHF on the cognitive and synaptic impairments of schizophrenia. A brief disruption of NMDA receptors with MK-801 during early development serves as an animal model for cognitive deficits of schizophrenia. We found that MK-801-treated rats showed significant deficits in working learning ability and hippocampal synaptic plasticity, as well as reduction of BDNF, TrkB, and phosphorylated TrkB in the hippocampus. After intraperitoneal administration with 7,8-DHF (5 mg/kg) once daily for a consecutive 14days, we found that chronic 7,8-DHF treatment significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased the phosphorylation levels of TrkB downstream signal cascades including ERK1/2, CaMKII, CREB and GluR1, and promoted hippocampal synaptic plasticity, which in turn rescued performance in spatial working learning. Our results thus demonstrate that activation of TrkB signaling can reverse the cognitive deficits of schizophrenia and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in treating schizophrenia-related cognitive impairments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 548 | Scand. J. Immunol. 2014 Jul 80: 36-42 |
| PMID | 24498860 |
| Title | Changes in serum levels of brain derived neurotrophic factor and nerve growth factor-beta in schizophrenic patients before and after treatment. |
| Abstract | schizophrenia is one of the most debilitating diseases among psychiatric disorders. Recent studies suggest the existence of effective immunological changes in the pathophysiology of this disease. The purpose of the current study was to determine the changes in serum levels of Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor-beta (NGF) in schizophrenic patients before treatment and 40 days after treatment. In this case-control study, serum levels of BDNF and NGF were measured by ELISA in 26 patients with schizophrenia and 26 healthy controls. All patients were treated with clozapine or risperidone for 40 days. A positive and negative syndrome scale (PANSS) questionnaire has been used to recognize the severity of the disease and to assess the response to treatment. Neurotrophin concentrations were compared before and after the treatment and with control groups using paired t-test and ANOVA test. BDNF and NGF levels in the case group were more than levels after treatment, but these differences were significant only for NGF. Concentrations in both neurotrophins were higher than the control group. The statistically significant difference was observed between changes in the NGF levels in the case and the control group, while no significant difference was seen in changes of BDNF. The main conclusion to be drawn from this study was that the increase in BDNF and particularly NGF may have an important role in causing schizophrenia. And possibly drugs clozapine and risperidone help to treat the disease by reducing the concentration of Neurotrophins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 549 | Pharmacol. Res. 2014 Feb 80: 1-8 |
| PMID | 24309096 |
| Title | Repeated aripiprazole treatment regulates Bdnf, Arc and Npas4 expression under basal condition as well as after an acute swim stress in the rat brain. |
| Abstract | Despite the rapid control of schizophrenic symptoms is due to the ability of antipsychotic drugs (APDs) to block D2 receptors in the mesolimbic pathway, it is now well-established that the therapeutic effects rely on adaptive mechanisms set in motion by their long-term administration. Such neuroplastic mechanisms depend on the pharmacological profile of the drug employed, with marked differences existing between first and second generation APDs. On these bases, the major accomplishment of this work was to investigate neuroadaptive changes set in motion by repeated treatment with aripiprazole, a novel APD that is unique for being a partial agonist at dopamine D2 receptors. Moreover, given that stress plays a critical role in the exacerbation of disease symptoms, we also investigated whether aripiprazole could influence the dynamic response of the brain to an acute challenge. We found that repeated aripiprazole treatment in rats regulates the expression of different markers of neuroplasticity such as BDNF, Arc and Npas4 in a brain-region specific fashion; more importantly, the expression of these molecules was significantly up-regulated by an acute swim stress only in aripiprazole-treated animals, which is suggestive of increased ability to cope with the adverse event. We indeed found an overall facilitation of BDNF expression, an effect that is mainly evident in the prefrontal cortex on the pool of transcripts undergoing dendritic localization. Overall, our results provide novel information regarding the mechanisms through which aripiprazole may regulate brain function and could contribute to improve neuroplastic defects that are associated with schizophrenia symptomatology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 550 | Behav. Brain Res. 2014 Nov 274: 137-42 |
| PMID | 25125238 |
| Title | BDNF val66met genotype and schizotypal personality traits interact to influence probabilistic association learning. |
| Abstract | The brain derived neurotrophic factor (BDNF) val66met polymorphism rs6265 influences learning and may represent a risk factor for schizophrenia. Healthy people with high schizotypal personality traits display cognitive deficits that are similar to but not as severe as those observed in schizophrenia and they can be studied without confounds of antipsychotics or chronic illness. How genetic variation in BDNF may impact learning in individuals falling along the schizophrenia spectrum is unknown. We predicted that schizotypal personality traits would influence learning and that schizotypal personality-based differences in learning would vary depending on the BDNF val66met genotype. Eighty-nine healthy adults completed the schizotypal Personality Questionnaire (SPQ) and a probabilistic association learning test. Blood samples were genotyped for the BDNF val66met polymorphism. An ANOVA was performed with BDNF genotype (val homozygotes and met-carriers) and SPQ score (high/low) as grouping variables and probabilistic association learning as the dependent variable. Participants with low SPQ scores (fewer schizotypal personality traits) showed significantly better learning than those with high SPQ scores. BDNF met-carriers displaying few schizotypal personality traits performed best, whereas BDNF met-carriers displaying high schizotypal personality traits performed worst. Thus, the BDNF val66met polymorphism appears to influence probabilistic association learning differently depending on the extent of schizotypal personality traits displayed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 551 | Life Sci. 2015 May 128: 79-93 |
| PMID | 25744402 |
| Title | Angiogenesis in the pathophysiology of schizophrenia - a comprehensive review and a conceptual hypothesis. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 552 | Brain Behav. Immun. 2015 May 46: 60-9 |
| PMID | 25728234 |
| Title | Gadd45b is an epigenetic regulator of juvenile social behavior and alters local pro-inflammatory cytokine production in the rodent amygdala. |
| Abstract | Precise regulation of the epigenome during perinatal development is critical to the formation of species-typical behavior later in life. Recent data suggests that Gadd45b facilitates active DNA demethylation by recruiting proteins involved in base excision repair (BER), which will catalyze substitution of 5-methyl-cytosine (5mC) for an unmodified cytosine. While a role for Gadd45b has been implicated in both hippocampal and amygdalar learning tasks, to the best of our knowledge, no study has been done investigating the involvement of Gadd45b in neurodevelopmental programming of social behavior. To address this, we used a targeted siRNA delivery approach to transiently knock down Gadd45b expression in the neonatal rat amygdala. We chose to examine social behavior in the juvenile period, as social deficits associated with neurodevelopmental disorders tend to emerge in humans at an equivalent age. We find that neonatal Gadd45b knock-down results in altered juvenile social behavior and reduced expression of several genes implicated in psychiatric disorders, including methyl-CpG-binding protein 2 (MeCP2), Reelin, and brain derived neurotrophic factor (BDNF). We furthermore report a novel role for Gadd45b in the programmed expression of ?2-adrenoceptor (Adra2a). Consistent with Gadd45b's role in the periphery, we also observed changes in the expression of pro-inflammatory cytokines interleukin-6 (Il-6) and interleukin-1beta (Il-1beta) in the amygdala, which could potentially mediate or exacerbate effects of Gadd45b knockdown on the organization of social behavior. These data suggest a prominent role for Gadd45b in the epigenetic programming of complex juvenile social interactions, and may provide insight into the etiology of juvenile behavioral disorders such as ADHD, autism, and/or schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 553 | Adv Gerontol 2015 -1 28: 228-47 |
| PMID | 26856084 |
| Title | GENETICS OF HUMAN AGE RELATED DISORDERS. |
| Abstract | Aging is an inevitable biological phenomenon. The incidence of age related disorders (ARDs) such as cardiovascular diseases, cancer, arthritis, dementia, osteoporosis, diabetes, neurodegenerative diseases increase rapidly with aging. ARDs are becoming a key social and economic trouble for the world's elderly population (above 60 years), which is expected to reach 2 billion by 2050. Advancement in understanding of genetic associations, particularly through genome wide association studies (GWAS), has revealed a substantial contribution of genes to human aging and ARDs. In this review, we have focused on the recent understanding of the extent to which genetic predisposition may influence the aging process. Further analysis of the genetic association studies through pathway analysis several genes associated with multiple ARDs have been highlighted such as apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), cadherin 13 (CDH13), CDK5 regulatory subunit associated protein 1 (CDKAL-1), methylenetetrahydrofolate reductase (MTHFR), disrupted in schizophrenia 1 (DISC1), nitric oxide synthase 3 (NOS3), paraoxonase 1 (PON1), indicating that these genes could play a pivotal role in ARD causation. These genes were found to be significantly enriched in Jak-STAT signalling pathway, asthma and allograft rejection. Further, interleukin-6 (IL-6), insulin (INS), vascular endothelial growth factor A (VEGFA), estrogen receptor1 (ESR1), transforming growth factor, beta 1(TGFB1) and calmodulin 1 (CALM1) were found to be highly interconnected in network analysis. We believe that extensive research on the presence of common genetic variants among various ARDs may facilitate scientists to understand the biology behind ARDs causation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 554 | PLoS ONE 2015 -1 10: e0145651 |
| PMID | 26700309 |
| Title | Reactive Transformation and Increased BDNF Signaling by Hippocampal Astrocytes in Response to MK-801. |
| Abstract | MK-801, also known as dizocilpine, is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. While astrocytes have been implicated in the pathophysiology of psychiatric disorders, including schizophrenia, astrocytic responses to MK-801 and their significance to schizotypic symptoms are unclear. Changes in the expression levels of glial fibrillary acid protein (GFAP), a marker of astrocyte activation in response to a variety of pathogenic stimuli, were examined in the hippocampus of rats treated with the repeated MK-801 injection (0.5 mg/10 ml/kg body weight for 6 days) and in primary cultured hippocampal astrocytes incubated with MK-801 (5 or 20 ?M for 24 h). Moreover, the expression levels of BDNF and its receptors TrkB and p75 were examined in MK-801-treated astrocyte cultures. MK-801 treatment enhanced GFAP expression in the rat hippocampus and also increased the levels of GFAP protein and mRNA in hippocampal astrocytes in vitro. Treatment of cultured hippocampal astrocytes with MK-801 enhanced protein and mRNA levels of BDNF, TrkB, and p75. Collectively, our results suggest that hippocampal astrocytes may contribute to the pathophysiology of schizophrenia symptoms associated with NMDA receptor hypofunction by reactive transformation and altered BDNF signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 555 | Psychiatr Q 2015 Nov -1: -1 |
| PMID | 26603624 |
| Title | Cognitive Impairment in Schizophrenia: Interplay of BDNF and Childhood Trauma? A Review of Literature. |
| Abstract | Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 556 | Genetika 2015 Jul 51: 799-811 |
| PMID | 26410934 |
| Title | [The Role of Neurotrophins and Neurexins Genes in the Risk of Paranoid Schizophrenia in Russians and Tatars]. |
| Abstract | schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 557 | An. Acad. Bras. Cienc. 2015 Aug 87: 1475-86 |
| PMID | 26397829 |
| Title | Effects of omega-3 supplementation on interleukin and neurotrophin levels in an animal model of schizophrenia. |
| Abstract | New studies suggest that polyunsaturated fatty acids, such as omega-3, may reduce the symptoms of schizophrenia. The present study evaluated the preventive effect of omega-3 on interleukines (IL) and neurotrophin brain-derived neurotrophic factor (BDNF) levels in the brains of young rats subjected to a model of schizophrenia. Treatment was performed over 21 days, starting on the 30th day of rat's life. After 14 days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25 mg/kg) was started and maintained until the last day of the experiment. BDNF levels in the rat's prefrontal cortex were decreased at 1 h and 24 h after the last administration of ketamine, whereas the group administered with ketamine and omega-3 showed a decrease in BDNF levels only after 24 h. In contrast, both interventions induced similar responses in levels of IL-1? and IL6. These findings suggest that the similarity of IL-1? and IL6 levels in our experimental groups is due to the mechanism of action of ketamine on the immune system. More studies have to be carried out to explain this pathology. In conclusion, according to previous studies and considering the current study, we could suggest a prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 558 | Compr Psychiatry 2015 Oct 62: 80-5 |
| PMID | 26343470 |
| Title | Serum brain-derived neurotrophic factor levels and psychotic symptoms in heroin dependence. |
| Abstract | Psychotic symptoms are commonly observed among heroin users. Low serum brain-derived neurotrophic factor (BDNF) levels have been reported in schizophrenia and psychosis; however, studies assessing the relationship between serum BDNF levels and psychotic symptoms in heroin dependence are lacking. A total of 31 heroin-dependent patients who had never experienced psychotic symptoms during heroin consumption and 21 patients with a history of psychotic symptoms were consecutively recruited. We measured by enzyme-linked immunosorbent assay (ELISA) serum BDNF levels during early abstinence. A gender- and age-matched sample of healthy controls was also recruited and underwent measurement of BDNF. BDNF levels were significantly lower in patients with psychotic symptoms than in those without psychotic symptoms (P<0.001). BDNF levels were not found to be correlated with sex, age, age of onset, duration of heroin use, average daily dose of heroin use, frequency of heroin use, SDS scores, BAI scores and BDI scores in the psychotic subsamples (all P>0.05). Our findings suggest that heroin-dependent patients with psychotic symptoms share some of the neurotrophic insult that characterizes schizophrenia and psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 559 | Psychiatry Res 2015 Oct 234: 84-9 |
| PMID | 26341949 |
| Title | Serum brain-derived neurotrophic factor and cortical thickness are differently related in patients with schizophrenia and controls. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been implicated in neuronal plasticity, a key process related to the pathophysiology of schizophrenia. However, the relationship of peripheral levels of BDNF to cortical thickness and subcortical structures has not been extensively investigated. This study aims to investigate the relationship of peripheral serum BDNF levels to cortical thickness and volumes of the hippocampus and amygdala. Twenty-nine patients with schizophrenia and 32 healthy controls were included in this study. Structural magnetic resonance imaging (MRI) scans obtained in a 1.5 T scanner were performed in all subjects. Images were processed using Freesurfer software. Blood samples were collected on the same day of the MRI scan for BDNF peripheral levels. Vertex-wise analysis revealed significantly thinner cortex in patients compared with controls. BDNF levels and cortical thickness showed different patterns of correlation for patients and healthy controls in one cluster in the right hemisphere distributed across the supramarginal, postcentral, and inferior frontal cortices. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 560 | Glycobiology 2015 Oct 25: 1112-24 |
| PMID | 26163659 |
| Title | Protective effects of polysialic acid on proteolytic cleavage of FGF2 and proBDNF/BDNF. |
| Abstract | Polysialic acid (polySia) is a linear polymer of sialic acid that modifies neural cell adhesion molecule (NCAM) in the vertebrate brain. PolySia is a large and exclusive molecule that functions as a negative regulator of cell-cell interactions. Recently, we demonstrated that polySia can specifically bind fibroblast growth factor 2 (FGF2) and BDNF; however, the protective effects of polySia on the proteolytic cleavage of these proteins remain unknown, although heparin/heparan sulfate has been shown to impair the cleavage of FGF2 by trypsin. Here, we analyzed the protective effects of polySia on the proteolytic cleavage of FGF2 and proBDNF/BDNF. We found that polySia protected intact FGF2 from tryptic activity via the specific binding of extended polySia chains on NCAM to FGF2. Oligo/polySia also functioned to impair the processing of proBDNF by plasmin via binding of oligo/polySia chains on NCAM. In addition, the polySia structure synthesized by mutated polysialyltransferase, ST8SIA2/STX(SNP7), which was previously identified from a schizophrenia patient, was impaired for these functions compared with polySia produced by normal ST8SIA2. Taken together, these data suggest that the protective effects of polySia toward FGF2 and proBDNF may be involved in the regulation of the concentrations of these neurologically active molecules. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 561 | Epigenomics 2015 -1 7: 567-79 |
| PMID | 26111030 |
| Title | Gadd45b and N-methyl-D-aspartate induced DNA demethylation in postmitotic neurons. |
| Abstract | In nondividing neurons examine the role of Gadd45b in active 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) removal at a gene promoter highly implicated in mental illnesses and cognition, BDNF. Mouse primary cortical neuronal cultures with and without Gadd45b siRNA transfection were treated with N-methyl-d-aspartate (NMDA). Expression changes of genes reportedly involved in DNA demethylation, BDNF mRNA and protein and 5MC and 5HMC at BDNF promoters were measured. Gadd45b siRNA transfection in neurons abolishes the NMDA-induced increase in BDNF IXa mRNA and reductions in 5MC and 5HMC at the BDNF IXa promoter. These results contribute to our understanding of DNA demethylation mechanisms in neurons, and its role in regulating NMDA responsive genes implicated in mental illnesses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 562 | Neurobiol. Dis. 2015 May 77: 228-37 |
| PMID | 25771167 |
| Title | The BDNF Val66Met variant affects gene expression through miR-146b. |
| Abstract | Variation in gene expression is an important mechanism underlying susceptibility to complex disease and traits. Single nucleotide polymorphisms (SNPs) account for a substantial portion of the total detected genetic variation in gene expression but how exactly variants acting in trans modulate gene expression and disease susceptibility remains largely unknown. The BDNF Val66Met SNP has been associated with a number of psychiatric disorders such as depression, anxiety disorders, schizophrenia and related traits. Using global microRNA expression profiling in hippocampus of humanized BDNF Val66Met knock-in mice we showed that this variant results in dysregulation of at least one microRNA, which in turn affects downstream target genes. Specifically, we show that reduced levels of miR-146b (mir146b), lead to increased Per1 and Npas4 mRNA levels and increased Irak1 protein levels in vitro and are associated with similar changes in the hippocampus of hBDNF(Met/Met) mice. Our findings highlight trans effects of common variants on microRNA-mediated gene expression as an integral part of the genetic architecture of complex disorders and traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 563 | Pharmacogenet. Genomics 2015 May 25: 274-7 |
| PMID | 25751398 |
| Title | Hypothalamic-pituitary-adrenal system, neurotrophic factors and clozapine response: association with FKBP5 and NTRK2 genes. |
| Abstract | Clozapine is an atypical antipsychotic drug known as being more effective compared with traditional antipsychotics for patients with poor response or resistance to treatment. It has been demonstrated that clozapine modulates hypothalamic-pituitary-adrenal activity and affects central brain-derived neurotrophic factor levels, which could explain part of its therapeutic efficacy. In this study, we investigated the role of genes related to the hypothalamic-pituitary-adrenal axis (FKBP5 and NR3C1) and neurotrophic factors (BDNF and NTRK2) in clinical response to clozapine in 591 schizophrenia patients. We found significant allelic and genotype associations between FKBP5-rs1360780, NTRK2-rs1778929 and NTRK2-rs10465180 polymorphisms and clozapine response. The haplotypes composed of rs1360780-rs3777747-rs17542466-rs2766533 (FKBP5) and rs1619120-rs1778929-rs10465180 (NTRK2) were also nominally significant. Our results suggest that genetic variability in FKBP5 and NTRK2 genes may partially explain clinical response to clozapine. Further studies are needed to clarify the involvement of these genes in clinical response to atypical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 564 | Neurosci Biobehav Rev 2015 Apr 51: 15-30 |
| PMID | 25562189 |
| Title | A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. |
| Abstract | schizophrenia is believed to arise from complex gene-environment interactions. Brain-derived neurotrophic factor (BDNF) is involved in neuronal development, differentiation and plasticity. A functional single nucleotide polymorphism that results in a valine (Val) to methionine (Met) substitution at codon 66 (Val66Met) results in the aberrant sorting and release of mature BDNF through the activity-dependent secretion pathway. The Val66Met polymorphism has been linked to impaired neurocognitive function in healthy adults, and identified as a locus of risk for a range of neuropsychiatric disorders including schizophrenia. Here we provide a comprehensive review of the relationship between the BDNF Val66Met polymorphism and schizophrenia, integrating evidence from the fields of genetic epidemiology, clinical psychiatry, behavioral neuroscience and neuroimaging. We argue that while the Val66Met polymorphism may not be a major risk-conferring agent for the development of schizophrenia per se, there is mounting evidence that the polymorphism modulates a range of clinical features of the illness, including age of onset, symptoms, therapeutic responsiveness, neurocognitive function and brain morphology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 565 | J. Mol. Neurosci. 2015 May 56: 205-11 |
| PMID | 25529856 |
| Title | Genetic variability testing of neurodevelopmental genes in schizophrenic patients. |
| Abstract | This study investigated the associations between single nucleotide polymorphisms in the neurodevelopmental Disrupted In schizophrenia 1 (DISC1 ), neuregulin 1 (NRG1), brain-derived neurotrophic factor (BDNF) and NOTCH4 genes and the clinical symptoms and the occurrence of treatment-resistant schizophrenia in the Slovenian population. We included 138 schizophrenia patients, divided into treatment-responsive and treatment-resistant group and 94 healthy blood donors. All subjects were genotyped for eight polymorphisms (DISC1 rs6675281, DISC1 rs821616, NRG1 rs3735781, NRG1 rs3735782, NRG1 rs10503929, NRG1 rs3924999, BDNF rs6265, NOTCH rs367398) and investigated for associations with clinical variables. NOTCH4 rs367398 AA/AG was significantly associated with worse Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) score. NOTCH4 rs367398 was not statistically significantly associated with the occurrence of treatment-resistant schizophrenia after the correction for multiple testing. Our data indicate that NOTCH4 polymorphism can influence clinical symptoms in Slovenian patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 566 | Mol. Psychiatry 2015 Dec -1: -1 |
| PMID | 26666204 |
| Title | Polygenic associations of neurodevelopmental genes in suicide attempt. |
| Abstract | The risk for suicidal behavior (SB) is elevated in schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD), but also occurs in subjects without psychiatric diagnoses. Genome-wide association studies (GWAS) on SB may help to understand this risk, but have been hampered by low power due to limited sample sizes, weakly ascertained SB or a reliance on single-nucleotide protein (SNP)-by-SNP analyses. Here, we tried to mitigate such issues with polygenic risk score (PRS) association tests combined with hypothesis-driven strategies using a family-based sample of 660 trios with a well-ascertained suicide attempt (SA) outcome in the offspring (Genetic Investigation of Suicide and SA, GISS). Two complementary sources of PRS information were used. First, a PRS that was discovered and validated in the GISS SA revealed the polygenic association of SNPs in 750 neurodevelopmental genes, which was driven by the SA phenotype, rather than the major psychiatric diagnoses. Second, a PRS based on three different genome-wide association studies (on SCZ, BPD or MDD) from the Psychiatric Genomics Consortium (PGC) showed an association of the PGC-SCZ PRS in the SA subjects with and without major psychiatric diagnoses. We characterized the PGC-SCZ overlap in the SA subjects without diagnoses. The extended major histocompatibility complex region did not contribute to the overlap, but we delineated the genic overlap to neurodevelopmental genes that partially overlapped with those identified by the GISS PRS. Among the 590 SA polygenes implicated here, there were several developmentally important functions (cell adhesion/migration, small GTPase and receptor tyrosine kinase signaling), and 16 of the SA polygenes have previously been studied in SB (BDNF, CDH10, CDH12, CDH13, CDH9, CREB1, DLK1, DLK2, EFEMP1, FOXN3, IL2, LSAMP, NCAM1, nerve growth factor (NGF), NTRK2 and TBC1D1). These novel genome-wide insights, supported by two lines of evidence, suggested the importance of a polygenic neurodevelopmental etiology in SB, even in the absence of major psychiatric diagnoses.Molecular Psychiatry advance online publication, 15 December 2015; doi:10.1038/mp.2015.187. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 567 | Clin Epigenetics 2015 -1 7: 122 |
| PMID | 26583053 |
| Title | Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders. |
| Abstract | Stressor exposure during early life has the potential to increase an individual's susceptibility to a number of neuropsychiatric conditions such as mood and anxiety disorders and schizophrenia in adulthood. This occurs in part due to the dysfunctional stress axis that persists following early adversity impairing stress responsivity across life. The mechanisms underlying the prolonged nature of this vulnerability remain to be established. Alterations in the epigenetic signature of genes involved in stress responsivity may represent one of the neurobiological mechanisms. The overall aim of this review is to provide current evidence demonstrating changes in the epigenetic signature of candidate gene(s) in response to early environmental adversity. More specifically, this review analyses the epigenetic signatures of postnatal adversity such as childhood abuse or maltreatment and later-life psychopathology in human and animal models of early life stress. The results of this review shows that focus to date has been on genes involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and its correlation to subsequent neurobiology, for example, the role of glucocorticoid receptor gene. However, epigenetic changes in other candidate genes such as brain-derived neurotrophic factor (BDNF) and serotonin transporter are also implicated in early life stress (ELS) and susceptibility to adult psychiatric disorders. DNA methylation is the predominantly studied epigenetic mark followed by histone modifications specifically acetylation and methylation. Further, these epigenetic changes are cell/tissue-specific in regulating expression of genes, providing potential biomarkers for understanding the trajectory of early stress-induced susceptibility to adult psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 568 | Acta Neurobiol Exp (Wars) 2015 -1 75: 314-25 |
| PMID | 26581387 |
| Title | Biochemical and cognitive impairments observed in animal models of schizophrenia induced by prenatal stress paradigm or methylazoxymethanol acetate administration. |
| Abstract | The aim of the study was to find whether spatial memory impairment and disruption in locomotor activity were found in prenatally stressed rats (PSG) or prenatally methylazoxymethanol acetate-treated rats (MAMG). In addition to this, we examined basal plasma corticosterone level as well as brain-derived neurothropic factor (BDNF) in the PSG and MAMG rats. The effect of prenatal stress (stress paradigm between 14 and 21 day of gestation) and methylazoxymethanol acetate (MAM) administration (17 day of gestation) to the female Wistar rats were studied on the male offspring in the Morris Water Maze (spatial memory) and locomotor activity test. Through Morris Water Maze rats were injected with saline 4 times (on 1, 7, 14 and 21 day of testing) while in locomotor activity test saline was injected only once. Corticosterone level was measured using ELISA Kit while BDNF levels were assessed using ELISA Chemikine TM BDNF kit. Results indicate that both PSG and MAMG rats deteriorate spatial memory as well as increase locomotor activity compared to the control group. Biochemical studies indicate that basal plasma corticosterone level increased in both PSG and MAMG rats compared to the control group. Analyses of the BDNF level, on the other hand, have shown decrease of the neurothropin level in both hippocampus and prefrontal cortex (PFC) in both PSG and MAMG groups of rats. As shown by the obtained results, both the prenatal stress model and prenatal MAM administration model generate a number of behavioural (e.g. spatial memory disorders, increased locomotor activity) and biochemical (e.g. increased corticosterone and decreased BDNF levels) changes in the examined offspring, Thus, these models can be successfully used in the efficacy analysis of the pharmacotherapy applied. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 569 | Acta Neuropsychiatr 2015 Dec 27: 327-35 |
| PMID | 26503495 |
| Title | Meta-analysis of the association of brain-derived neurotrophic factor Val66Met polymorphism with obsessive-compulsive disorder. |
| Abstract | Brain-derived neurotrophic factor (BDNF) plays an important role in neural survival and was proposed to be related to psychiatric disorders. Val66Met (also known as rs6265 or G196A), the only known functional polymorphism of the BDNF gene, has been widely studied and considered to be associated with risk of some psychiatric disorders such as bipolar disorder and schizophrenia. However, studies evaluating its association with obsessive-compulsive disorder (OCD) obtained inconsistent results. The purpose of this study was to derive a more precise estimation of the association between BDNF Val66Met polymorphism and OCD susceptibility by a meta-analysis. We carried a structured literature search in PubMed, Embase, PsycINFO and Chinese Biomedical Database up to December 2014; and retrieved all eligible case-control studies according to the including criteria. Meta-analysis was performed for four genetic models: allelic model: Met versus Val; additive model: Met/Met versus Val/Val; recessive model: Met/Met versus Val/Val+Val/Met; and dominant model: Val/Met+Met/Met versus Val/Val. Stratified analyses were performed by ethnicity and gender where appropriate. A total of eight articles with nine studies including 1632 OCD cases and 2417 controls were identified. No significant association was detected in any comparison when the whole data were pooled together or stratified by ethnicity or gender in all four genetic models (p>0.05 for each comparison). Despite some limitations, our meta-analysis suggests that no significant association exists between the BDNF Val66Met polymorphism and OCD susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 570 | CNS Drugs 2015 Oct 29: 819-32 |
| PMID | 26482261 |
| Title | Anxiety in Patients with Schizophrenia: Epidemiology and Management. |
| Abstract | Anxiety symptoms can occur in up to 65 % of patients with schizophrenia, and may reach the threshold for diagnosis of various comorbid anxiety disorders, including obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). We review the clinical presentation, diagnosis, neurobiology, and management of anxiety in patients with schizophrenia, with a particular focus on pharmacotherapy. The prevalence of any anxiety disorder (at syndrome level) in schizophrenia is estimated to be up to 38 %, with social anxiety disorder (SAD) being the most prevalent. Severity of positive symptoms may correlate with severity of anxiety symptoms, but anxiety can occur independently of psychotic symptoms. While anxiety may be associated with greater levels of insight, it is also associated with increased depression, suicidality, medical service utilization, and cognitive impairment. Patients with anxiety symptoms are more likely to have other internalizing symptoms as opposed to externalizing symptoms. Diagnosis of anxiety in schizophrenia may be challenging, with positive symptoms obscuring anxiety, lower levels of emotional expressivity and communication impeding diagnosis, and conflation with akathisia. Higher diagnostic yield may be achieved by assessment following the resolution of the acute phase of psychosis as well as by the use of screening questions and disorder-specific self-report instruments. In schizophrenia patients with anxiety, there is evidence of underactive fear circuitry during anxiety-provoking stimuli but increased autonomic responsivity and increased responsiveness to neutral stimuli. Recent findings implicate the serotonin transporter (SERT) genes, brain-derived neurotropic factor (BDNF) genes, and the serotonin 1a (5HT1a) receptor, but are preliminary and in need of replication. There are few randomized controlled trials (RCTs) of psychotherapy for anxiety symptoms or disorders in schizophrenia. For pharmacotherapy, data from a few randomized and open trials have shown that aripiprazole and risperidone may be efficacious for obsessive-compulsive and social anxiety symptoms, and quetiapine and olanzapine for generalized anxiety. Older agents such as trifluoperazine may also reduce comorbid anxiety symptoms. Alternative options include selective serotonin re-uptake inhibitor (SSRI) augmentation of antipsychotics, although evidence is based on a few randomized trials, small open trials, and case series, and caution is needed with regards to cytochrome P450 interactions and QTc interval prolongation. Buspirone and pregabalin augmentation may also be considered. Diagnosis and treatment of anxiety symptoms and disorders in schizophrenia is an important and often neglected aspect of the management of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 571 | Biol. Psychiatry 2015 Aug -1: -1 |
| PMID | 26386481 |
| Title | Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1. |
| Abstract | Genetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown. We investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis transsynaptically affected the number of inhibitory synapses formed on excitatory neurons via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy. A decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis transsynaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures. Taken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 572 | J Clin Psychopharmacol 2015 Oct 35: 596-9 |
| PMID | 26267416 |
| Title | Lower Brain-Derived Neurotropic Factor Levels in Untreated Adolescents With First-Episode Psychosis. |
| Abstract | Brain-derived neurotropic factor (BDNF) is known to play a role in the pathogenesis of schizophrenia. However, the relationship between early onset schizophrenia and BDNF has not been extensively studied. The aim of the study was to compare the levels of BDNF between adolescent patients with first-episode psychosis (FEP) and the healthy control subjects. The study was conducted in the Department of Child Psychiatry at Dicle University. A total of 26 adolescent patients aged between 11 and 17 years who had not received previous therapy and whose conditions were diagnosed with psychosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and 26 age- and sex-matched healthy adolescent control subjects were included. Kiddie Schedule for Affective Disorders and schizophrenia, Present and Lifetime version, and the Positive and Negative Symptom Scale were conducted with all participants. The clinical global impression was used to evaluate disease severity. The BDNF levels were measured in the serum by enzyme-linked immunosorbent assay method. The mean (SD) age was 14.6 (1.6) years in both FEP group (male/female, 11/15) and the control group (P > 0.05). The FEP group had significantly lower serum BDNF levels (2.0 ± 1.9 ng/mL) compared with the control group (3.4 ± 3.0 ng/mL, P = 0.03). There was no significant relationship between BDNF concentration and the Positive and Negative Symptom Scale (positive and negative scores) scores (r = -0.14, P = 0.74 and r = 0.49, P = 0.22, respectively). There was no significant relationship between the duration of untreated psychosis and serum BDNF levels (r = -0.22, P = 0.32). High incidence of schizophrenia in patients with FEP suggests a relationship between BDNF levels and the pathogenesis of schizophrenia. We suggest that BDNF may be a useful neurobiological marker of early onset schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 573 | Schizophr. Res. 2015 Oct 168: 411-20 |
| PMID | 26206493 |
| Title | Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation. |
| Abstract | Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or vehicle. Utilizing in situ hybridization, expression of NRG-1, ErbB4, BDNF, and trkB was examined in male rat offspring at postnatal day (P) 14, P30 and P60. ErbB4 mRNA expression was significantly increased at P30 in the anterior cingulate (AC Ctx), frontal, and parietal cortices, with increases in AC Ctx expression continuing through P60. ErbB4 expression was also elevated in the prefrontal cortex (PFC) at P14. In contrast, NRG-1 mRNA was decreased in the PFC at P60. Expression of BDNF mRNA was significantly upregulated in the PFC at P60 and decreased in the AC Ctx at P14. Expression of trkB was increased in two regions, the piriform cortex at P14 and the striatum at P60. These findings demonstrate developmentally and regionally selective alterations in the expression of schizophrenia-related genes as a consequence of MIA. Further study is needed to determine contributions of these effects to the development of alterations of relevance to neuropsychiatric diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 574 | Front Aging Neurosci 2015 -1 7: 117 |
| PMID | 26157387 |
| Title | Role of physical and mental training in brain network configuration. |
| Abstract | It is hypothesized that the topology of brain networks is constructed by connecting nodes which may be continuously remodeled by appropriate training. Efficiency of physical and/or mental training on the brain relies on the flexibility of networks' architecture molded by local remodeling of proteins and synapses of excitatory neurons producing transformations in network topology. Continuous remodeling of proteins of excitatory neurons is fine-tuning the scaling and strength of excitatory synapses up or down via regulation of intra-cellular metabolic and regulatory networks of the genome-transcriptome-proteome interface. Alzheimer's disease is a model of "energy cost-driven small-world network disorder" with dysfunction of high-energy cost wiring as the network global efficiency is impaired by the deposition of an informed agent, the amyloid-?, selectively targeting high-degree nodes. In schizophrenia, the interconnectivity and density of rich-club networks are significantly reduced. Training-induced homeostatic synaptogenesis-enhancement, presumably via reconfiguration of brain networks into greater small-worldness, appears essential in learning, memory, and executive functions. A macroscopic cartography of creation-removal of synaptic connections in a macro-network, and at the intra-cellular scale, micro-networks regulate the physiological mechanisms for the preferential attachment of synapses. The strongest molecular relationship of exercise and functional connectivity was identified for brain-derived neurotrophic factor (BDNF). The allele variant, rs7294919, also shows a powerful relationship with the hippocampal volume. How the brain achieves this unique quest of reconfiguration remains a puzzle. What are the underlying mechanisms of synaptogenesis promoting communications brain ? muscle and brain ? brain in such trainings? What is the respective role of independent mental, physical, or combined-mental-physical trainings? Physical practice seems to be playing an instrumental role in the cognitive enhancement (brain ? muscle com.). However, mental training, meditation or virtual reality (films, games) require only minimal motor activity and cardio-respiratory stimulation. Therefore, other potential paths (brain ? brain com.) molding brain networks are nonetheless essential. Patients with motor neuron disease/injury (e.g., amyotrophic lateral sclerosis, traumatism) also achieve successful cognitive enhancement albeit they may only elicit mental practice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 575 | Int J Methods Psychiatr Res 2015 Sep 24: 235-44 |
| PMID | 26118823 |
| Title | Development of a cost-efficient novel method for rapid, concurrent genotyping of five common single nucleotide polymorphisms of the brain derived neurotrophic factor (BDNF) gene by tetra-primer amplification refractory mutation system. |
| Abstract | Brain derived neurotrophic factor (BDNF) is a molecular trophic factor that plays a key role in neuronal survival and plasticity. Single nucleotide polymorphisms (SNPs) of the BDNF gene have been associated with specific phenotypic traits in a large number of neuropsychiatric disorders and the response to psychotherapeutic medications in patient populations. Nevertheless, due to study differences and occasionally contrasting findings, substantial further research is required to understand in better detail the association between specific BDNF SNPs and these psychiatric disorders. While considerable progress has been made recently in developing advanced genotyping platforms of SNPs, many high-throughput probe- or array-based detection methods currently available are limited by high costs, slow processing times or access to advanced instrumentation. The polymerase chain reaction (PCR)-based, tetra-primer amplification refractory mutation system (T-ARMS) method is a potential alternative technique for detecting SNP genotypes efficiently, quickly, easily, and cheaply. As a tool in psychopathology research, T-ARMS was shown to be capable of detecting five common SNPs in the BDNF gene (rs6265, rs988748, rs11030104, 11757G/C and rs7103411), which are all SNPs with previously demonstrated clinical relevance to schizophrenia and depression. The present technique therefore represents a suitable protocol for many research laboratories to study the genetic correlates of BDNF in psychiatric disorders. Copyright Copyright © 2015 John Wiley & Sons, Ltd. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 576 | Schizophr. Res. 2015 Nov 168: 661-70 |
| PMID | 26088421 |
| Title | Adolescent testosterone influences BDNF and TrkB mRNA and neurotrophin-interneuron marker relationships in mammalian frontal cortex. |
| Abstract | Late adolescence in males is a period of increased susceptibility for the onset of schizophrenia, coinciding with increased circulating testosterone. The cognitive deficits prevalent in schizophrenia may be related to unhealthy cortical interneurons, which are trophically dependent on brain derived neurotrophic factor. We investigated, under conditions of depleted (monkey and rat) and replaced (rat) testosterone over adolescence, changes in gene expression of cortical BDNF and TrkB transcripts and interneuron markers and the relationships between these mRNAs and circulating testosterone. Testosterone removal by gonadectomy reduced gene expression of some BDNF transcripts in monkey and rat frontal cortices and the BDNF mRNA reduction was prevented by testosterone replacement. In rat, testosterone replacement increased the potential for classical TrkB signalling by increasing the full length to truncated TrkB mRNA ratio, whereas in the monkey cortex, circulating testosterone was negatively correlated with the TrkB full length/truncated mRNA ratio. We did not identify changes in interneuron gene expression in monkey frontal cortex in response to gonadectomy, and in rat, we showed that only somatostatin mRNA was decreased by gonadectomy but not restored by testosterone replacement. We identified complex and possibly species-specific, relationships between BDNF/TrkB gene expression and interneuron marker gene expression that appear to be dependent on the presence of testosterone at adolescence in rat and monkey frontal cortices. Taken together, our findings suggest there are dynamic relationships between BDNF/TrkB and interneuron markers that are dependent on the presence of testosterone but that this may not be a straightforward increase in testosterone leading to changes in BDNF/TrkB that contributes to interneuron health. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 577 | Prilozi 2015 -1 36: 53-67 |
| PMID | 26076775 |
| Title | Pharmacogenetics and antipsychotic treatment response. |
| Abstract | (Full text is available at http://www.manu.edu.mk/prilozi). Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients. Key words: Pharmacogenetics, antipsychotics, schizophrenia, biomarkers, CYP450, P-glycoprotein, seroto-nergic receptors, dopaminergic receptors, COMT, BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 578 | Biomark Insights 2015 -1 10: 47-54 |
| PMID | 26052224 |
| Title | Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. |
| Abstract | Although peripheral immune system abnormalities have been linked to schizophrenia pathophysiology, standard antipsychotic drugs show limited immunological effects. Thus, more effective treatment approaches are required. Probiotics are microorganisms that modulate the immune response of the host and, therefore, may be beneficial to schizophrenia patients. The aim of this study was to examine the possible immunomodulatory effects of probiotic supplementation in chronic schizophrenia patients. The concentrations of 47 immune-related serum proteins were measured using multiplexed immunoassays in samples collected from patients before and after 14 weeks of adjuvant treatment with probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12; n = 31) or placebo (n = 27). Probiotic add-on treatment significantly reduced levels of von Willebrand factor (vWF) and increased levels of monocyte chemotactic protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), RANTES, and macrophage inflammatory protein-1 beta (MIP-1) beta with borderline significance (P ? 0.08). In silico pathway analysis revealed that probiotic-induced alterations are related to regulation of immune and intestinal epithelial cells through the IL-17 family of cytokines. We hypothesize that supplementation of probiotics to schizophrenia patients may improve control of gastrointestinal leakage. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 579 | Neurosci Biobehav Rev 2015 Aug 55: 107-18 |
| PMID | 25956254 |
| Title | BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: A systematic review and meta-analysis. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis and synaptic plasticity in the central nervous system, especially in the hippocampus, and has been implicated in the pathophysiology of several neuropsychiatric disorders. Its Val66Met polymorphism (refSNP Cluster Report: rs6265) is a functionally relevant single nucleotide polymorphism affecting the secretion of BDNF and is implicated in differences in hippocampal volumes. This is a systematic meta-analytical review of findings from imaging genetic studies on the impact of the rs6265 SNP on hippocampal volumes in neuropsychiatric patients with major depressive disorder, anxiety, bipolar disorder or schizophrenia. The overall sample size of 18 independent clinical cohorts comprised 1695 patients. Our results indicated no significant association of left (Hedge's g=0.08, p=0.12), right (g=0.07, p=0.22) or bilateral (g=0.07, p=0.16) hippocampal volumes with BDNF rs6265 in neuropsychiatric patients. There was no evidence for a publication bias or any demographic, clinical, or methodological moderating effects. Both Val/Val homozygotes (g=0.32, p=0.004) and Met-carriers (g=0.20, p=0.004) from the patient sample had significantly smaller hippocampal volumes than the healthy control sample with the same allele. The magnitude of these effects did not differ between the two genotypes. This meta-analysis suggests that there is no association between this BDNF polymorphism and hippocampal volumes. For each BDNF genotype, the hippocampal volumes were significantly lower in neuropsychiatric patients than in healthy controls. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 580 | Schizophr. Res. 2015 Jul 165: 163-70 |
| PMID | 25937462 |
| Title | Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms. |
| Abstract | Oxidative stress has important implications in schizophrenia. Alpha-lipoic acid (ALA) is a natural antioxidant synthesized in human tissues with clinical uses. We studied the effect of ALA or clozapine (CLZ) alone or in combination in the reversal of schizophrenia-like alterations induced by ketamine (KET). Adult male mice received saline or KET for 14 days. From 8th to 14th days mice were additionally administered saline, ALA (100 mg/kg), CLZ 2.5 or 5 mg/kg or the combinations ALA+CLZ2.5 or ALA+CLZ5. schizophrenia-like symptoms were evaluated by prepulse inhibition of the startle (PPI) and locomotor activity (positive-like), social preference (negative-like) and Y maze (cognitive-like). Oxidative alterations (reduced glutathione - GSH and lipid peroxidation - LP) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) and BDNF in the PFC were also determined. KET caused deficits in PPI, working memory, social interaction and hyperlocomotion. Decreased levels of GSH, nitrite (HC) and BDNF and increased LP were also observed in KET-treated mice. ALA and CLZ alone reversed KET-induced behavioral alterations. These drugs also reversed the decreases in GSH (HC) and BDNF and increase in LP (PFC, HC and ST). The combination ALA+CLZ2.5 reversed behavioral and some neurochemical parameters. However, ALA+CLZ5 caused motor impairment. Therefore, ALA presented an antipsychotic-like profile reversing KET-induced positive- and negative-like symptoms. The mechanism partially involves antioxidant, neurotrophic and nitrergic pathways. The combination of ALA+CLZ2.5 improved most of the parameters evaluated in this study without causing motor impairment demonstrating, thus, that possibly when combined with ALA a lower dose of CLZ is required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 581 | Metab Brain Dis 2015 Aug 30: 1043-53 |
| PMID | 25920483 |
| Title | Maternal deprivation disrupts mitochondrial energy homeostasis in the brain of rats subjected to ketamine-induced schizophrenia. |
| Abstract | Maternal deprivation (MD) appears to be one of the environmental factors involved in the pathophysiology of schizophrenia. A widely used animal model of the schizophrenia involves the administration of ketamine, a dissociative anesthetic, NMDA receptors noncompetitive antagonist, that induce symptoms such as schizophrenia. To clarify the molecular mechanism of schizophrenia induced by MD, we investigated alterations in energetic metabolism, oxidative stress and neurotrophic factor levels in the brain of rats following MD and/or a single administration of ketamine during adulthood. Male Wistar rats were subjected to MD for 10 days. Additionally, these animals received acute ketamine (5, 15 or 25 mg/kg by intraperitoneal route, i.p.) during adulthood, and 30 min later, they were killed and the prefrontal cortex (PFC), the hippocampus and the striatum were removed for molecular analyses. Ketamine 25 mg/kg and/or MD and Ketamine 15 and 5 mg/kg with MD decreased the creatine kinase (CK) activity in the hippocampus. The enzyme activity of succinate dehydrogenase (SDH) in the Krebs cycle had increased in the striatum following the administration of ketamine 25 mg/kg, MD per se or MD plus ketamine 5 and 15 mg/kg. MD per se or MD combined with ketamine in different doses increased the activity of mitochondrial complexes. The PFC of animals subjected to MD and administered with ketamine 5 mg/kg exhibited increased protein carbonyl content. In the hippocampus, ketamine 15 mg/kg, ketamine 25 mg/kg and MD each increased the carbonyl content. In the striatum, the TBARS levels were increased by the administration of ketamine 25 mg/kg. Finally, in the hippocampus, MD alone or in combination with ketamine reduced the Nerve Growth Factor (NGF) levels; however, the Brain-derived Neurotrophic Factor (BDNF) levels were unaltered. In the present study, we suggest that MD increased the risk of psychotic symptoms in adulthood, altering different parameters of energy and oxidative stress. Our results suggest that adverse experiences occurring early in life may sensitize specific neurocircuits to subsequent stressors, inducing vulnerability, and may help us understand the pathophysiological mechanisms involved in this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 582 | Zh Nevrol Psikhiatr Im S S Korsakova 2015 -1 115: 75-9 |
| PMID | 25909793 |
| Title | [No effect of the BDNF Val66Met polymorphism on cognitive deficit in patients with schizophrenia and on the risk of the disease in their relatives]. |
| Abstract | The brain-derived neurotrophic factor (BDNF) gene is thought to be a candidate gene for schizophrenia. At the same time, many studies failed to find the association between BDNF and the disease though the contribution of the BDNF Val66Met polymorphism to the variance of characteristics of schizophrenia has been confirmed. Authors suggested that this contribution was the consequence of the involvement of this gene in the formation of "cognitive reserve" that had a protective effect on the different aspects of the disease. This protective effect should emerge in relatively intact cognitive function in patients with the protective Val66Met genotype as well as in the accumulation of the protective genotypes in unaffected relatives. We examined 169 patients with schizophrenia spectrum disorders, 320 their first-degree relatives and control groups using molecular-genetic and experimental psychological methods. No effect of the Val66Met polymorphism on verbal memory, executive functions and total index of cognitive functioning was found. Besides, we did not find any differences in Val66Met genotype frequencies in first-degree relatives of patients with schizophrenia and healthy people without family history of schizophrenia. The results do not support our hypothesis that BDNF is a gene of "cognitive reserve". |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 583 | Bipolar Disord 2015 Aug 17: 528-35 |
| PMID | 25874530 |
| Title | The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia. |
| Abstract | We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested. This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76). BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01). The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 584 | Neuropsychiatr Dis Treat 2015 -1 11: 865-72 |
| PMID | 25848285 |
| Title | Decreased serum levels of brain-derived neurotrophic factor in schizophrenic patients with deficit syndrome. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a well-established neurotrophin that plays a role in the pathophysiology of numerous psychiatric disorders. Many studies have investigated the serum BDNF levels in patients with schizophrenia. However, there are restricted data in the literature that compare the serum BDNF levels in patients with deficit and nondeficit syndromes. In this study, we aimed to compare the serum BDNF levels between schizophrenic patients with deficit or nondeficit syndrome and healthy controls. After fulfilling the inclusion and exclusion criteria, 58 patients with schizophrenia and 36 healthy controls were included in the study. The patients were grouped as deficit syndrome (N=23) and nondeficit syndrome (N=35) according to the Schedule for the Deficit Syndrome. Three groups were compared in terms of the sociodemographic and clinical variants and serum BDNF levels. The groups were similar in terms of age, sex, body mass index, and smoking status. The serum BDNF levels in patients with deficit syndrome were significantly lower than those in healthy controls. In contrast, the serum BDNF levels in patients with nondeficit syndrome were similar to those in healthy controls. This study suggests that decreased BDNF levels may play a role in the pathophysiology of schizophrenic patients with deficit syndrome. Nonetheless, additional studies using a larger patient sample size are needed to investigate the serum BDNF levels in schizophrenic patients with deficit syndrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 585 | Schizophr Bull 2015 Jul 41: 859-68 |
| PMID | 25805886 |
| Title | The Impact of Aerobic Exercise on Brain-Derived Neurotrophic Factor and Neurocognition in Individuals With Schizophrenia: A Single-Blind, Randomized Clinical Trial. |
| Abstract | Individuals with schizophrenia display substantial neurocognitive deficits for which available treatments offer only limited benefits. Yet, findings from studies of animals, clinical and nonclinical populations have linked neurocognitive improvements to increases in aerobic fitness (AF) via aerobic exercise training (AE). Such improvements have been attributed to up-regulation of brain-derived neurotrophic factor (BDNF). However, the impact of AE on neurocognition, and the putative role of BDNF, have not been investigated in schizophrenia. Employing a proof-of-concept, single-blind, randomized clinical trial design, 33 individuals with schizophrenia were randomized to receive standard psychiatric treatment (n = 17; "treatment as usual"; TAU) or attend a 12-week AE program (n = 16) utilizing active-play video games (Xbox 360 Kinect) and traditional AE equipment. Participants completed assessments of AF (indexed by VO2 peak ml/kg/min), neurocognition (MATRICS Consensus Cognitive Battery), and serum-BDNF before and after and 12-week period. Twenty-six participants (79%) completed the study. At follow-up, the AE participants improved their AF by 18.0% vs a -0.5% decline in the TAU group (P = .002) and improved their neurocognition by 15.1% vs -2.0% decline in the TAU group (P = .031). Hierarchical multiple regression analyses indicated that enhancement in AF and increases in BDNF predicted 25.4% and 14.6% of the neurocognitive improvement variance, respectively. The results indicate AE is effective in enhancing neurocognitive functioning in people with schizophrenia and provide preliminary support for the impact of AE-related BDNF up-regulation on neurocognition in this population. Poor AF represents a modifiable risk factor for neurocognitive dysfunction in schizophrenia for which AE training offer a safe, nonstigmatizing, and side-effect-free intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 586 | Neurobiol. Dis. 2015 May 77: 220-7 |
| PMID | 25796564 |
| Title | Evaluation of TrkB and BDNF transcripts in prefrontal cortex, hippocampus, and striatum from subjects with schizophrenia, bipolar disorder, and major depressive disorder. |
| Abstract | Brain-derived neurotrophic factor (BDNF) signaling is integral to a range of neural functions, including synaptic plasticity and exhibits activity-dependent regulation of expression. As altered BDNF signaling has been implicated in multiple psychiatric diseases, here we report a quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis of mRNAs encoding TrkB, total BDNF, and the four most abundant BDNF transcripts (I, IIc, IV, and VI) in postmortem tissue from matched tetrads of subjects with schizophrenia, bipolar disorder, or major depressive disorder (MDD) and healthy comparison subjects. In all three regions examined, dorsolateral prefrontal cortex (DLPFC), associative striatum and hippocampus, total BDNF mRNA levels did not differ in any disease state. In DLPFC, BDNF IIc was significantly lower in schizophrenia relative to healthy comparison subjects. In hippocampus, BDNF I, IIc, and VI were lower in subjects with both schizophrenia and bipolar disorder relative to comparison subjects. In striatum, TrkB mRNA was lower in bipolar disorder and MDD, while BDNF IIc was elevated in MDD, relative to comparison subjects. These data highlight potential alterations in BDNF signaling in the corticohippocampal circuit in schizophrenia, and within the striatum in mood disorders. Novel therapies aimed at improving BDNF-TrkB signaling may therefore have potential to impact on a range of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 587 | Int Clin Psychopharmacol 2015 May 30: 158-66 |
| PMID | 25756551 |
| Title | Improvement in verbal memory following SSRI augmentation of antipsychotic treatment is associated with changes in the expression of mRNA encoding for the GABA-A receptor and BDNF in PMC of schizophrenic patients. |
| Abstract | Verbal memory impairment in schizophrenia is associated with abnormalities in gamma-aminobutyric acid (GABA)-ergic and brain-derived neurotrophic factor (BDNF) systems. Recent evidence from animal and clinical studies that adding fluvoxamine to antipsychotics alters the expression of transcripts encoding for the GABA-A receptor and BDNF led us to postulate that fluvoxamine augmentation may improve memory in schizophrenia. To test this, we examined the effect of add-on fluvoxamine on verbal memory and other cognitive functions and related it to the expression of mRNA coding for the GABA-A receptor and BDNF in peripheral mononuclear cells (PMC) of schizophrenic patients. Twenty-nine patients completed a 6-week study in which fluvoxamine (100 mg/day) was added to ongoing antipsychotic treatment. Verbal memory, abstraction working memory, object and face recognition, and psychomotor speed and clinical symptoms were assessed at baseline and after 3 and 6 weeks of treatment. Blood samples were taken at baseline and weeks 1, 3, and 6 and PMC was assayed for the GABA-A beta3 receptor and BDNF mRNA by quantitative real-time reverse transcription-PCR. Associative and logical verbal memory improved significantly and showed a significant correlation with changes in PMC BDNF and GABA-A beta3 receptor mRNA, which increased during treatment. Abstraction and object recognition improved, but this did not correlate with PMC measures. Negative and positive symptoms improved significantly; the latter showed significant correlations with changes in PMC measures. Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 588 | Psychiatry Res 2015 Mar 226: 1-13 |
| PMID | 25681004 |
| Title | Brain-derived neurotrophic factor (BDNF) and neurocognitive deficits in people with schizophrenia: a meta-analysis. |
| Abstract | Studies suggest that the BDNF Val66Met (rs6265) polymorphism is associated with the incidence of schizophrenia and neurocognitive functioning. These associations appear to be however somewhat mixed. We conducted two separate meta-analyses to investigate (1) the association between the Val66Met polymorphism and neurocognition in people with schizophrenia and (2) the association between peripheral expression of BDNF and neurocognitive phenotypes. For the first aim, we identified 12 studies and 67 comparisons of Met allele carriers and Val homozygotes. These comparisons included 1890 people with schizophrenia (men=1465, women=553), of whom 972 were Met allele carriers and 918 were Val homozygotes. For the second aim, we identified five studies and 25 correlations of peripheral BDNF and neurocognitive scores. The meta-analysis for the second aim included 414 people with schizophrenia (men=292, women=170). First, we found non-significant difference between the genotype groups on most neurocognitive domains. Second, correlations between peripheral BDNF and neurocognitive phenotypes were minimal but we obtained significant effects for the reasoning and problem-solving domains; thus, higher levels of BDNF expression corresponded to better performance on reasoning/problem-solving tasks. The meta-analyses did not robustly establish an association between BDNF Val66Met polymorphism and neurocognition in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 589 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 Jan 56: 149-54 |
| PMID | 25194460 |
| Title | Perinatal asphyxia alters neuregulin-1 and COMT gene expression in the medial prefrontal cortex in rats. |
| Abstract | Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12 weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12 weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12 weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 590 | J Psychiatr Res 2015 Jan 60: 1-13 |
| PMID | 25287955 |
| Title | Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. |
| Abstract | Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 591 | Neuropsychopharmacology 2015 Jul 40: 1947-56 |
| PMID | 25666312 |
| Title | Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5. |
| Abstract | schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophrenia-related behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 592 | Int. J. Neuropsychopharmacol. 2015 Feb 18: -1 |
| PMID | 25612896 |
| Title | BDNF-Val66Met-polymorphism impact on cortical plasticity in schizophrenia patients: a proof-of-concept study. |
| Abstract | Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients. Cortical plasticity was investigated in 22 schizophrenia patients and 35 healthy controls using anodal and cathodal transcranial direct-current stimulation (tDCS) applied to the left primary motor cortex. Animal and human research indicates that excitability shifts following anodal and cathodal tDCS are related to molecular long-term potentiation and long-term depression. To test motor-cortical excitability before and after tDCS, well-established single- and paired-pulse transcranial magnetic stimulation protocols were applied. Our analysis revealed increased glutamate-mediated intracortical facilitation in met-heterozygotes compared to val-homozygotes at baseline. Following cathodal tDCS, schizophrenia met-heterozygotes had reduced gamma-amino-butyric-acid-mediated short-interval intracortical inhibition, whereas healthy met-heterozygotes displayed the opposite effect. The BDNF-Val66Met-polymorphism did not influence single-pulse motor-evoked potential amplitudes after tDCS. These preliminary findings support the notion of an association of the BDNF-Val66Met-polymorphism with observable alterations in plasticity following cathodal tDCS in schizophrenia patients. This indicates a complex interaction between inhibitory intracortical interneuron-networks, cortical plasticity, and the BDNF-Val66Met-polymorphism. Further replication and validation need to be dedicated to this question to confirm this relationship. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 593 | Transl Psychiatry 2015 -1 5: e498 |
| PMID | 25603414 |
| Title | Analyzing the influence of BDNF heterozygosity on spatial memory response to 17?-estradiol. |
| Abstract | The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate neuronal synchrony and cognitive function. What is unknown is whether disruptions to the aforementioned estradiol-parvalbumin pathway alter learning and memory, and whether BDNF may mediate these events. Wild-type (WT) and BDNF heterozygous (+/-) mice were ovariectomized (OVX) at 5 weeks of age and simultaneously received empty, estradiol- or progesterone-filled implants for 7 weeks. At young adulthood, mice were tested for spatial and recognition memory in the Y-maze and novel-object recognition test, respectively. Hippocampal protein expression of BDNF and GABAergic interneuron markers, including parvalbumin, were assessed. WT OVX mice show impaired performance on Y-maze and novel-object recognition test. Estradiol replacement in OVX mice prevented the Y-maze impairment, a Behavioral abnormality of dorsal hippocampal origin. BDNF and parvalbumin protein expression in the dorsal hippocampus and parvalbumin-positive cell number in the dorsal CA1 were significantly reduced by OVX in WT mice, while E2 replacement prevented these deficits. In contrast, BDNF(+/-) mice showed either no response or an opposite response to hormone manipulation in both behavioral and molecular indices. Our data suggest that BDNF status is an important biomarker for predicting responsiveness to estrogenic compounds which have emerged as promising adjunctive therapeutics for schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 594 | World J. Biol. Psychiatry 2015 Jan 16: 45-56 |
| PMID | 25560300 |
| Title | The role of genetic variation across IL-1?, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain. |
| Abstract | Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1?, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associated with antipsychotic-induced weight gain (AIWG). Nineteen polymorphisms were genotyped using Taqman(®) assays in 188 schizophrenia patients on antipsychotic treatment for up to 14 weeks. Mean weight change (%) from baseline was compared across genotypic groups using analysis of covariance (ANCOVA). Epistatic effects between cytokine polymorphisms and BDNF Val66Met were tested using Model-Based Multifactor Dimensionality Reduction. In European patients, IL-1? rs16944*GA (P = 0.013, Pcorrected = 0.182), IL-1? rs1143634*G (P = 0.001, Pcorrected = 0.014), and BDNF Val66Met (Val/Val, P = 0.004, Pcorrected = 0.056) were associated with greater AIWG, as were IL-1? rs4849127*A (P = 0.049, Pcorrected = 0.784), and IL-1? rs16944*GA (P = 0.012, Pcorrected = 0.192) in African Americans. BDNF Val66Met interacted with both IL-1? rs13032029 (Val/Met+ TT, PPerm = 0.029), and IL-6 rs2069837 (Val/Val+ AA, PPerm = 0.021) in Europeans, in addition to IL-1? rs16944 (Val/Val+ GA, PPerm = 0.006) in African Americans. SNPs across IL-1? and BDNF Val66Met may influence AIWG. Replication of these findings in larger, independent samples is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 595 | Eur. Psychiatry 2015 Feb 30: 198-204 |
| PMID | 25543333 |
| Title | Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders. |
| Abstract | Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) have essential roles in synaptic plasticity which is involved in pathogenesis and treatment of psychiatric disorders. However, it is not clear whether they act simultaneously during illness states in major psychiatric disorders. BDNF and GDNF serum levels were measured concomitantly by enzyme-linked immunosorbent assay (ELISA) method in 171 patients diagnosed with schizophrenia (n=33), bipolar disorder-manic episode (n=39), bipolar/unipolar depression (n=64, 24/40) and obsessive-compulsive disorder (n=35) according to DSM-IV, and 78 healthy volunteers. SCID-I and SCID non-patient version were used for clinical evaluation of the patients and healthy volunteers, respectively. Correlations between the two trophic factor levels, and illness severity scores, duration of illness and medication dosages were studied across different illnesses. While patients had equally lower BDNF levels in all diagnoses, GDNF levels were significantly higher in mania and lower in schizophrenia compared to healthy controls. BDNF levels were negatively correlated to illness severity scores in affective episodes (mania and depression). Longer duration of illness (>5 years) had an impact on lower GDNF levels in schizophrenia. BDNF levels and antipsychotic drug dosages in schizophrenia, and GDNF levels and antidepressant drug dosages in obsessive-compulsive disorder were positively correlated. Our data confirmed the evidence of equally deficient neuronal support by BDNF in all major psychiatric illnesses, but suggested a diverse glial functioning between schizophrenia and mania. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 596 | Neurodegener Dis 2015 -1 15: 38-44 |
| PMID | 25531449 |
| Title | Is schizophrenia a neurodegenerative disease? Evidence from age-related decline of brain-derived neurotrophic factor in the brains of schizophrenia patients and matched nonpsychiatric controls. |
| Abstract | Brain-derived neurotrophic factor (BDNF) protein levels decline in the brain during senescence and are also shown to be reduced in schizophrenia patients. BDNF is present in both the gray and white matters of the brain. It is unclear whether BDNF abnormalities in schizophrenia are specific to gray and/or white matter. We hypothesized that the age-related BDNF decline is abnormal and contributes to the reduced BDNF in schizophrenia. We tested this hypothesis by measuring BDNF protein levels in postmortem gray and white matter, using the prefrontal cortex (PFC) and the genu of the corpus callosum as regions of interests, from 20 schizophrenia patients and 20 matched nonpsychiatric controls. Samples were selected across the adult lifespan--from 20 to 80 years of age. PFC gray matter BDNF protein levels were significantly lower in older age in both nonpsychiatric comparisons and patients, while BDNF in white matter did not decrease significantly with age in either group. PFC BDNF was linearly lower from 20 to 80 years of age in nonpsychiatric comparisons. In schizophrenia, the age effect was similarly linear in younger patients but a decline did not occur in older patients. PFC BDNF does not follow a normative linear age effect in schizophrenia patients as they grow older, which may represent a 'floor effect' due to earlier decline or a survivor cohort of older patient donors who are less susceptible to a schizophrenia-related pathological aging process. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 597 | Psychiatry Res 2015 Feb 225: 501-8 |
| PMID | 25529262 |
| Title | Effect of Ramadan fasting on anthropometric, metabolic, inflammatory and psychopathology status of Egyptian male patients with schizophrenia. |
| Abstract | Ramadan fasting is believed to be beneficial. We assessed a random sample of 100 Egyptian male schizophrenia outpatients using the Positive and Negative Syndrome Scale (PANSS) and dietary, anthropometric, clinical, and laboratory measures at baseline (T1) before Ramadan of 2014 and during the fourth week of Ramadan (T2). The metabolic syndrome was identified in 31 patients and these showed a reduction of high-density lipoprotein cholesterol (HDLc) and brain-derived neurotrophic factor (BDNF) concentrations and increase in the levels of dietary intakes, body mass index (BMI), waste circumference, systolic and diastolic blood pressure, all PANSS subscales, glucose, insulin, HOMA-IR, total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-c), white blood cells, granulocytes, lymphocytes, monocytes, fibrinogen and high-sensitivity C-reactive protein (hs-CRP). In a multiple regression analysis, total energy intake and body mass index (BMI) emerged as the main independent predictors of deterioration in most inflammatory and psychopathology parameters. These findings did not support our hypothesis but suggested that Ramadan fasting has a negative impact on schizophrenia patients, especially those with metabolic syndrome. This could draw attention to the need in the psycho-education management of such patients to focus more on nutrition education for safe fasting. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 598 | Int. J. Neuropsychopharmacol. 2015 Apr 18: -1 |
| PMID | 25522392 |
| Title | Primate phencyclidine model of schizophrenia: sex-specific effects on cognition, brain derived neurotrophic factor, spine synapses, and dopamine turnover in prefrontal cortex. |
| Abstract | Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits. The effects of repeated phencyclidine treatment on spine synapse number, dopamine turnover and BDNF expression in dorsolateral prefrontal cortex, and working memory accuracy were examined in pre-adult monkeys. One week following phencyclidine treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in dorsolateral prefrontal cortex than adult male monkeys. Further studies indicated that in juvenile males, a cognitive deficit existed at 4 weeks following phencyclidine treatment, and this impairment was associated with decreased dopamine turnover, decreased brain derived neurotrophic factor messenger RNA, and a loss of dendritic spine synapses in dorsolateral prefrontal cortex. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after phencyclidine treatment and no alteration in dopamine turnover or brain derived neurotrophic factor messenger RNA or spine synapse number in dorsolateral prefrontal cortex. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number, and cognitive performance. As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate phencyclidine model and highlight its potential usefulness in understanding the deficits in dorsolateral prefrontal cortex in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 599 | Mol Med Rep 2015 Apr 11: 2927-34 |
| PMID | 25503442 |
| Title | WSKY, a traditional Chinese decoction, rescues cognitive impairment associated with NMDA receptor antagonism by enhancing BDNF/ERK/CREB signaling. |
| Abstract | Warm?supplementing kidney yang (WSKY) is an herbal prescription that has been used in Traditional Chinese Medicine for the treatment of psychiatric conditions. A previous study by our group found that WSKY significantly improved cognitive function of schizophrenia patients. In the present study, the effects of WSKY on cognitive function and their underlying mechanisms were investigated. WSKY was administered to an MK?801?induced rat model of chronic schizophrenia for 14 days. Memory performance was assessed using the Morris water maze (MWM) test. The expression of brain?derived neurotrophic factor (BDNF), activation of cAMP response element binding protein (pCREB/CREB) and activation of extracellular signal?regulated kinase (pERK/ERK) in the hippocampus was detected using western blot analysis. In the acquisition phase of the MWM test, the escape latency was significantly increased in the MK?801?treated group compared with the normal control group (P<0.01). Treatment with WSKY for 14 days at doses of 100 or 250 mg/kg rescued this cognitive impairment (P<0.05). In the probe test, 250 mg/kg WSKY treatment increased the time spent in the target quadrant (P<0.05) and number of platform crossings (P<0.01). Western blot analysis demonstrated that the levels of BDNF expression in the hippocampus of rats without behavioral tests were elevated following 14 days of WSKY treatment, and the effect of WSKY treatment on hippocampal BDNF expression was presented in an inverted U?shaped dose?response pattern. The pERK1/2 in the hippocampus was significantly enhanced following 100 mg/kg (P<0.01) and 250 mg/kg (P<0.01) WSKY treatment, while only 250 mg/kg WSKY increased the phosphorylation of CREB (P<0.01). The results of the present study indicated that WSKY enhances cognitive performance via the upregulation of BDNF/ERK/CREB signaling, and that WSKY has potential therapeutic implications for cognitive impairment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 600 | Schizophr. Res. 2015 Sep 167: 35-41 |
| PMID | 25476119 |
| Title | DNA-methyltransferase1 (DNMT1) binding to CpG rich GABAergic and BDNF promoters is increased in the brain of schizophrenia and bipolar disorder patients. |
| Abstract | The down regulation of glutamic acid decarboxylase67 (GAD1), reelin (RELN), and BDNF expression in brain of schizophrenia (SZ) and bipolar (BP) disorder patients is associated with overexpression of DNA methyltransferase1 (DNMT1) and ten-eleven translocase methylcytosine dioxygenase1 (TET1). DNMT1 and TET1 belong to families of enzymes that methylate and hydroxymethylate cytosines located proximal to and within cytosine phosphodiester guanine (CpG) islands of many gene promoters, respectively. Altered promoter methylation may be one mechanism underlying the down-regulation of GABAergic and glutamatergic gene expression. However, recent reports suggest that both DNMT1 and TET1 directly bind to unmethylated CpG rich promoters through their respective Zinc Finger (ZF-CXXC) domains. We report here, that the binding of DNMT1 to GABAergic (GAD1, RELN) and glutamatergic (BDNF-IX) promoters is increased in SZ and BP disorder patients and this increase does not necessarily correlate with enrichment in promoter methylation. The increased DNMT1 binding to these promoter regions is detected in the cortex but not in the cerebellum of SZ and BP disorder patients, suggesting a brain region and neuron specific dependent mechanism. Increased binding of DNMT1 positively correlates with increased expression of DNMT1 and with increased binding of MBD2. In contrast, the binding of TET1 to RELN, GAD1 and BDNF-IX promoters failed to change. These data are consistent with the hypothesis that the down-regulation of specific GABAergic and glutamatergic genes in SZ and BP disorder patients may be mediated, at least in part, by a brain region specific and neuronal-activity dependent DNMT1 action that is likely independent of its DNA methylation activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 601 | Psychoneuroendocrinology 2015 Jan 51: 201-8 |
| PMID | 25462893 |
| Title | The interplay between BDNF and oxidative stress in chronic schizophrenia. |
| Abstract | Neurodegenerative processes may be involved in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF), the most widely distributed neurotrophin and oxidative stress (OS) may be critical for several pathological manifestations of neurodegenerative disorders. Accumulating evidence suggests that both BDNF and OS may be involved in the pathophysiology of schizophrenia. However, the possible interaction between BDNF and OS has been under-investigated. Serum BDNF, plasma malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were analyzed using established procedures in 164 chronic medicated schizophrenia and 50 healthy controls. schizophrenic symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) with cognitive and depressive factors derived from the five factor model of the PANSS. Compared to the control group, the patients exhibited a significant decrease in BDNF levels, in the activities of SOD and GSH-Px but a significant increase in MDA levels. In patients, but not in controls, we observed a significant negative correlation between BDNF and SOD. Furthermore, the interaction between BDNF and CAT was associated with the PANSS cognitive factor, and the interaction between BDNF and GSH-Px with the PANSS depressive factor. Both decreased BDNF levels and OS may be implicated in the pathophysiology of chronic schizophrenia. Their inverse association only in the schizophrenia group may reflect a pathological mechanism involving an interaction of oxidative damage and neurotrophin dysfunction. Moreover, OS may interact with the BDNF system to influence the clinical symptoms and cognitive impairment in schizophrenia, which is line with the neurodevelopmental hypothesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 602 | J Psychiatr Res 2015 Jan 60: 49-55 |
| PMID | 25455509 |
| Title | Smoking and BDNF Val66Met polymorphism in male schizophrenia: a case-control study. |
| Abstract | Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 ± 1.7 vs. Met/Val: 2.2 ± 1.7 vs. Val/Val: 2.0 ± 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smoker's response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 603 | Neuroscience 2015 Jan 284: 297-310 |
| PMID | 25445195 |
| Title | Brain-derived neurotrophic factor heterozygous mutant rats show selective cognitive changes and vulnerability to chronic corticosterone treatment. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin involved in neurodevelopment, neuroprotection and synaptic plasticity. It is also implicated in a range of psychiatric disorders such as schizophrenia, depression and post-traumatic stress disorder. Stress during adolescence/young adulthood can have long-term psychiatric and cognitive consequences, however it is unknown how altered BDNF signaling is involved in such effects. Here we investigated whether a congenital deficit in BDNF availability in rats increases vulnerability to the long-term effects of the stress hormone, corticosterone (CORT). Compared to wildtype (WT) littermates, BDNF heterozygous (HET) rats showed higher body weights and minor developmental changes, such as reduced relative brain and pituitary weight. These animals furthermore showed deficits in short-term spatial memory in the Y-maze and in prepulse inhibition and startle, but not in object-recognition memory. CORT treatment induced impairments in novel-object recognition memory in both genotypes but disrupted fear conditioning extinction learning in BDNF HET rats only. These results show selective behavioral changes in BDNF HET rats, at baseline or after chronic CORT treatment and add to our understanding of the role of BDNF and its interaction with stress. Importantly, this study demonstrates the utility of the BDNF HET rat in investigations into the pathophysiology of various psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 604 | Biol. Psychiatry 2015 Mar 77: 589-96 |
| PMID | 25444166 |
| Title | Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice. |
| Abstract | Prenatal stress (PRS) is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that PRS induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ, including the gene for brain-derived neurotrophic factor (BDNF). Studying adult offspring of pregnant mice subjected to PRS, we explored the long-term effects of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1, ten-eleven-translocation hydroxylases, methyl CpG binding protein 2, histone deacetylases, and histone methyltransferases and demethylase in the frontal cortex and hippocampus. We also measured the expression of BDNF. Adult PRS offspring demonstrate behavioral abnormalities suggestive of SZ and molecular changes similar to changes seen in postmortem brains of patients with SZ. This includes a significant increase in DNA methyltransferase 1 and ten-eleven-translocation hydroxylase 1 in the frontal cortex and hippocampus but not in cerebellum; no changes in histone deacetylases, histone methyltransferases and demethylases, or methyl CpG binding protein 2, and a significant decrease in BDNF messenger RNA variants. The decrease of the corresponding BDNF transcript level was accompanied by an enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at BDNF gene regulatory regions. In addition, the expression of BDNF transcripts (IV and IX) correlated positively with social approach in both PRS mice and nonstressed mice. Because patients with psychosis and PRS mice show similar epigenetic signature, PRS mice may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 605 | Proc. Natl. Acad. Sci. U.S.A. 2015 Jun 112: 6807-13 |
| PMID | 25385582 |
| Title | DNA methylation of BDNF as a biomarker of early-life adversity. |
| Abstract | Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the BDNF gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 606 | Psychiatry Clin. Neurosci. 2015 May 69: 243-58 |
| PMID | 25296946 |
| Title | Psychopharmacology of atypical antipsychotic drugs: From the receptor binding profile to neuroprotection and neurogenesis. |
| Abstract | The original definition of atypical antipsychotic drugs (APD) was drugs that are effective against positive symptoms in schizophrenia with no or little extrapyramidal symptoms (EPS). However, atypical APD have been reported to be more effective for cognitive dysfunction and negative symptoms in schizophrenia than typical APD, which expands the definition of 'atypicality'. This article provides a critical review of the pharmacology of atypical APD, especially from the viewpoint of receptor binding profiles and neurotransmitter regulations as well as neuroprotection and neurogenesis. A variety of serotonin (5-HT) receptors, such as 5-HT2A / 2C , 5-HT1A , 5-HT6 and 5-HT7 receptors, may contribute to the mechanisms of action of 'atypicality'. The dopaminergic modulations, including a low affinity for dopamine D2 receptors and a partial D2 receptor agonistic action, and glutamatergic regulations may also be involved in the pharmacological backgrounds of 'atypicality'. Atypical APD, but not typical APD, may facilitate cortical neuroprotection and hippocampal neurogenesis, which might be a part of the action mechanisms of atypical APD. The facilitation of cortical neuroprotection and hippocampal neurogenesis induced by atypical APD might be mediated by an increase in the Ser9 phosphorylation of glycogen synthase kinase-3? (GSK-3?). The stimulation of 5-HT1A receptors and/or the blockade of 5-HT2 receptors, which is characteristic of atypical APD, might increase Ser9 phosphorylation of GSK-3?. Moreover, atypical APD increase brain-derived neurotrophic factor (BDNF) levels. BDNF increases Ser9 phosphorylation of GSK-3? and has neuroprotective and neurogenic effects, as in the case of atypical APD. These findings suggest that GSK-3? might play a role in the action mechanisms of atypical APD, in both the 5-HT-dependent and BDNF-dependent mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 607 | J Psychiatr Res 2015 Jan 60: 22-8 |
| PMID | 25282282 |
| Title | Decreased cortical thickness in drug naïve first episode schizophrenia: in relation to serum levels of BDNF. |
| Abstract | This study was to examine cortical thickness in drug naïve, first episode schizophrenia patients, and to explore its relationship with serum levels of brain-derived neurotrophic factor (BDNF). Forty-five drug naive schizophrenia patients and 28 healthy controls were enrolled in the study. Freesurfer was used to parcellate cortical regions, and vertex-wise group analysis was used for whole brain cortical thickness. The clusters for the brain regions that demonstrated group differences were extracted, and the mean values of thickness were calculated. Serum levels of BDNF were measured using enzyme-linked immunosorbent assay (ELISA). After controlling for age and gender, significantly thinner cortical thickness was found in left insula and superior temporal gyrus in the patient group compared with the healthy control group (HC group) (p's < 0.001). Lower serum levels of BDNF were also found in the patient group compared with the HC group (p = 0.001). Correlation analysis showed a significant positive relationship between thickness of left insula and serum levels of BDNF within the HC group (r = 0.396, p = 0.037) but there was no such relationship within the patient group (r = 0.035, p = 0.819). Cortical thinning is present in drug naïve, first episode schizophrenia patients, indicating neurodevelopmental abnormalities at the onset of schizophrenia. Left insula might be an imaging biomarker in detecting the impaired protective role of neurotrophic factor for the brain development in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 608 | Mol. Psychiatry 2015 Sep 20: 1108-19 |
| PMID | 25266124 |
| Title | Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. |
| Abstract | It has been postulated that schizophrenia (SZ) is related to a lower expression of brain-derived neurotrophic factor (BDNF). In the past few years, an increasing number of divergent clinical studies assessing BDNF in serum and plasma have been published. It is now possible to verify the relationship between BDNF levels and severity of symptoms in SZ as well as the effects of antipsychotic drugs on BDNF using meta-analysis. The aims of this study were to verify if peripheral BDNF is decreased in SZ, whether its levels are correlated with positive and negative symptomatology and if BDNF levels change after antipsychotic treatment. This report consists of two distinct meta-analyses of peripheral BDNF in SZ including a total of 41 studies and more than 7000 participants: (1) peripheral BDNF levels in serum and plasma were moderately reduced in SZ compared with controls. Notably, this decrease was accentuated with the disease duration. However, the extent of peripheral BDNF level decrease did not correlate with the severity of positive and negative symptoms. (2) In plasma, but not serum, peripheral BDNF levels are consistently increased after antipsychotic treatment irrespective of the patient's response to medication. In conclusion, there is compelling evidence that there are decreased levels of peripheral BDNF in SZ, in parallel to previously described reduced cerebral BDNF expression. It remains unclear whether these systemic changes are causally related to the development of SZ or if they are merely a pathologic epiphenomenon. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 609 | World J. Biol. Psychiatry 2015 Apr 16: 171-9 |
| PMID | 25264289 |
| Title | Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders. |
| Abstract | Suicide is a serious public health concern, and it is partly genetic. The brain-derived neurotrophic factor (BDNF) gene has been a strong candidate in genetic studies of suicide (Dwivedi et al., Arch Gen Psychiatry 2010;60:804-815; Zai et al., Prog Neuropsychopharmacol Biol Psychiatry 2012;34:1412-1418) and BDNF regulates the expression of the dopamine D3 receptor. We examined the role of the BDNF and DRD3 genes in suicide. We analysed four tag single-nucleotide polymorphisms (SNPs) in BDNF and 15 SNPs in the D3 receptor gene DRD3 for possible association with suicide attempt history in our Canadian sample of schizophrenia (SCZ) patients of European ancestry (N = 188). In this sample, we found a possible interaction between the BDNF Val66Met and DRD3 Ser9Gly SNPs in increasing the risk of suicide attempt(s) in our SCZ sample. Specifically, a larger proportion of SCZ patients who were carrying at least one copy of the minor allele at each of the Val66Met and Ser9Gly functional markers have attempted suicides compared to patients with other genotypes (Bonferroni P < 0.05). However, we could not replicate this finding in samples from other psychiatric populations. Taken together, the results from the present study suggest that an interaction between BDNF and DRD3 may not play a major role in the risk for suicide attempt, though further studies, especially in SCZ, are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 610 | Psychol Med 2015 Mar 45: 841-54 |
| PMID | 25162472 |
| Title | Peripheral BDNF: a candidate biomarker of healthy neural activity during learning is disrupted in schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptogenesis and synaptic plasticity underlying learning. However, a relationship between circulating BDNF levels and brain activity during learning has not been demonstrated in humans. Reduced brain BDNF levels are found in schizophrenia and functional neuroimaging studies of probabilistic association learning in schizophrenia have demonstrated reduced activity in a neural network that includes the prefrontal and parietal cortices and the caudate nucleus. We predicted that brain activity would correlate positively with peripheral BDNF levels during probabilistic association learning in healthy adults and that this relationship would be altered in schizophrenia. Twenty-five healthy adults and 17 people with schizophrenia or schizo-affective disorder performed a probabilistic association learning test during functional magnetic resonance imaging (fMRI). Plasma BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA). We found a positive correlation between circulating plasma BDNF levels and brain activity in the parietal cortex in healthy adults. There was no relationship between plasma BDNF levels and task-related activity in the prefrontal, parietal or caudate regions in schizophrenia. A direct comparison of these relationships between groups revealed a significant diagnostic difference. This is the first study to show a relationship between peripheral BDNF levels and cortical activity during learning, suggesting that plasma BDNF levels may reflect learning-related brain activity in healthy humans. The lack of relationship between plasma BDNF and task-related brain activity in patients suggests that circulating blood BDNF may not be indicative of learning-dependent brain activity in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 611 | Psychopharmacology (Berl.) 2015 Jan 232: 223-32 |
| PMID | 24994553 |
| Title | Altered BDNF is correlated to cognition impairment in schizophrenia patients with tardive dyskinesia. |
| Abstract | Long-term antipsychotic treatment for schizophrenia is often associated with the emergence of tardive dyskinesia (TD), which is linked to greater cognitive impairment. Brain-derived neurotrophic factor (BDNF) plays a critical role in cognitive function, and schizophrenia patients with TD have lower BDNF levels than those without TD. This study examines the BDNF levels, the cognitive function, and the association of BDNF with cognitive function in schizophrenia patients with or without TD. We recruited 83 male chronic patients with (n=35) and without TD (n=48) meeting DSM-IV criteria for schizophrenia and 52 male control subjects. We examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and BDNF levels for all subjects. Positive and Negative Symptom Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were assessed in patients. BDNF levels were lower in patients with than those without TD (p<0.05). RBANS total score (p<0.01) and subscales of immediate memory, visuospatial/constructional performance, and attention were lower in patients with than those without TD (all p<0.05). BDNF levels were positively associated with immediate memory in patients without TD, but negatively in TD patients (both p<0.05). Multiple regression analysis confirmed that in either TD or non-TD group, BDNF was an independent contributor to immediate memory (both p<0.05). BDNF may be involved in the pathophysiology of TD. While the associations between BDNF and cognition in both TD and non-TD patients suggest a close relationship between BDNF and cognition, the different directions may implicate distinct mechanisms between TD and non-TD patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 612 | Psychiatr Q 2015 Nov -1: -1 |
| PMID | 26603624 |
| Title | Cognitive Impairment in Schizophrenia: Interplay of BDNF and Childhood Trauma? A Review of Literature. |
| Abstract | Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 613 | J. Mol. Neurosci. 2015 May 56: 205-11 |
| PMID | 25529856 |
| Title | Genetic variability testing of neurodevelopmental genes in schizophrenic patients. |
| Abstract | This study investigated the associations between single nucleotide polymorphisms in the neurodevelopmental Disrupted In schizophrenia 1 (DISC1 ), neuregulin 1 (NRG1), brain-derived neurotrophic factor (BDNF) and NOTCH4 genes and the clinical symptoms and the occurrence of treatment-resistant schizophrenia in the Slovenian population. We included 138 schizophrenia patients, divided into treatment-responsive and treatment-resistant group and 94 healthy blood donors. All subjects were genotyped for eight polymorphisms (DISC1 rs6675281, DISC1 rs821616, NRG1 rs3735781, NRG1 rs3735782, NRG1 rs10503929, NRG1 rs3924999, BDNF rs6265, NOTCH rs367398) and investigated for associations with clinical variables. NOTCH4 rs367398 AA/AG was significantly associated with worse Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) score. NOTCH4 rs367398 was not statistically significantly associated with the occurrence of treatment-resistant schizophrenia after the correction for multiple testing. Our data indicate that NOTCH4 polymorphism can influence clinical symptoms in Slovenian patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 614 | Prilozi 2015 -1 36: 53-67 |
| PMID | 26076775 |
| Title | Pharmacogenetics and antipsychotic treatment response. |
| Abstract | (Full text is available at http://www.manu.edu.mk/prilozi). Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients. Key words: Pharmacogenetics, antipsychotics, schizophrenia, biomarkers, CYP450, P-glycoprotein, seroto-nergic receptors, dopaminergic receptors, COMT, BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 615 | Neuropsychiatr Dis Treat 2015 -1 11: 865-72 |
| PMID | 25848285 |
| Title | Decreased serum levels of brain-derived neurotrophic factor in schizophrenic patients with deficit syndrome. |
| Abstract | Brain-derived neurotrophic factor (BDNF) is a well-established neurotrophin that plays a role in the pathophysiology of numerous psychiatric disorders. Many studies have investigated the serum BDNF levels in patients with schizophrenia. However, there are restricted data in the literature that compare the serum BDNF levels in patients with deficit and nondeficit syndromes. In this study, we aimed to compare the serum BDNF levels between schizophrenic patients with deficit or nondeficit syndrome and healthy controls. After fulfilling the inclusion and exclusion criteria, 58 patients with schizophrenia and 36 healthy controls were included in the study. The patients were grouped as deficit syndrome (N=23) and nondeficit syndrome (N=35) according to the Schedule for the Deficit Syndrome. Three groups were compared in terms of the sociodemographic and clinical variants and serum BDNF levels. The groups were similar in terms of age, sex, body mass index, and smoking status. The serum BDNF levels in patients with deficit syndrome were significantly lower than those in healthy controls. In contrast, the serum BDNF levels in patients with nondeficit syndrome were similar to those in healthy controls. This study suggests that decreased BDNF levels may play a role in the pathophysiology of schizophrenic patients with deficit syndrome. Nonetheless, additional studies using a larger patient sample size are needed to investigate the serum BDNF levels in schizophrenic patients with deficit syndrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 616 | Int Clin Psychopharmacol 2015 May 30: 158-66 |
| PMID | 25756551 |
| Title | Improvement in verbal memory following SSRI augmentation of antipsychotic treatment is associated with changes in the expression of mRNA encoding for the GABA-A receptor and BDNF in PMC of schizophrenic patients. |
| Abstract | Verbal memory impairment in schizophrenia is associated with abnormalities in gamma-aminobutyric acid (GABA)-ergic and brain-derived neurotrophic factor (BDNF) systems. Recent evidence from animal and clinical studies that adding fluvoxamine to antipsychotics alters the expression of transcripts encoding for the GABA-A receptor and BDNF led us to postulate that fluvoxamine augmentation may improve memory in schizophrenia. To test this, we examined the effect of add-on fluvoxamine on verbal memory and other cognitive functions and related it to the expression of mRNA coding for the GABA-A receptor and BDNF in peripheral mononuclear cells (PMC) of schizophrenic patients. Twenty-nine patients completed a 6-week study in which fluvoxamine (100 mg/day) was added to ongoing antipsychotic treatment. Verbal memory, abstraction working memory, object and face recognition, and psychomotor speed and clinical symptoms were assessed at baseline and after 3 and 6 weeks of treatment. Blood samples were taken at baseline and weeks 1, 3, and 6 and PMC was assayed for the GABA-A beta3 receptor and BDNF mRNA by quantitative real-time reverse transcription-PCR. Associative and logical verbal memory improved significantly and showed a significant correlation with changes in PMC BDNF and GABA-A beta3 receptor mRNA, which increased during treatment. Abstraction and object recognition improved, but this did not correlate with PMC measures. Negative and positive symptoms improved significantly; the latter showed significant correlations with changes in PMC measures. Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 617 | Psychoneuroendocrinology 2015 Jan 51: 201-8 |
| PMID | 25462893 |
| Title | The interplay between BDNF and oxidative stress in chronic schizophrenia. |
| Abstract | Neurodegenerative processes may be involved in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF), the most widely distributed neurotrophin and oxidative stress (OS) may be critical for several pathological manifestations of neurodegenerative disorders. Accumulating evidence suggests that both BDNF and OS may be involved in the pathophysiology of schizophrenia. However, the possible interaction between BDNF and OS has been under-investigated. Serum BDNF, plasma malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were analyzed using established procedures in 164 chronic medicated schizophrenia and 50 healthy controls. schizophrenic symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) with cognitive and depressive factors derived from the five factor model of the PANSS. Compared to the control group, the patients exhibited a significant decrease in BDNF levels, in the activities of SOD and GSH-Px but a significant increase in MDA levels. In patients, but not in controls, we observed a significant negative correlation between BDNF and SOD. Furthermore, the interaction between BDNF and CAT was associated with the PANSS cognitive factor, and the interaction between BDNF and GSH-Px with the PANSS depressive factor. Both decreased BDNF levels and OS may be implicated in the pathophysiology of chronic schizophrenia. Their inverse association only in the schizophrenia group may reflect a pathological mechanism involving an interaction of oxidative damage and neurotrophin dysfunction. Moreover, OS may interact with the BDNF system to influence the clinical symptoms and cognitive impairment in schizophrenia, which is line with the neurodevelopmental hypothesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 618 | Schizophr Bull 2016 May -1: -1 |
| PMID | 27217270 |
| Title | Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis. |
| Abstract | Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (?7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 619 | Schizophr. Res. 2016 May -1: -1 |
| PMID | 27209525 |
| Title | BDNF and other biological markers are associated with schizophrenia onset and positive symptoms: A different approach. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 620 | Psychiatry Res 2016 May 242: 54-60 |
| PMID | 27262086 |
| Title | BDNF serum levels in schizophrenic patients during treatment augmentation with sarcosine (results of the PULSAR study). |
| Abstract | Finding a relationship between schizophrenia symptoms severity and initial level of BDNF and its changes during augmentation of antipsychotic treatment with sarcosine. 57 individuals with schizophrenia with predominantly negative symptoms completed a 6-month RCT prospective study. The patients received 2g of sarcosine (n=27) or placebo (n=30) daily. At the beginning, after 6 weeks and 6 months BDNF levels were measured. Severity of symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for schizophrenia (CDSS). BDNF serum levels were stable after 6 weeks and 6 months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group comparing to placebo, however there was no correlations between serum BDNF concentrations and PANSS scores in all assessments. Initial serum BDNF concentrations cannot be used as a predictor of the improvement resulting from adding sarcosine. Our results indicate that either BDNF is not involved in the NMDA-dependent mechanism of sarcosine action or global changes in BDNF concentrations induced by amino-acid cannot be detected in blood assessments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 621 | Expert Opin. Ther. Targets 2016 May -1: 1-13 |
| PMID | 27167520 |
| Title | Synaptic alterations associated with depression and schizophrenia: potential as a therapeutic target. |
| Abstract | In recent years, the concept of 'synaptopathy' has been extended from neurodegenerative and neurological disorders to psychiatric diseases. According to this nascent line of research, disruption in synaptic structure and function acts as the main determinant of mental illness. Therefore, molecular systems and processes crucial for synaptic activity may represent promising therapeutic targets. We review data on synaptic structural alterations in depression and schizophrenia and on specific molecular systems and/or mechanisms important for the maintenance of proper synaptic function. Specifically, we examine the involvement of the neuroligin system, the local protein translation, and the neurotrophin BDNF by reviewing clinical and preclinical studies, with particular attention to results provided by using animal models based on the role of stress in psychiatric diseases. Finally, we also discuss the impact of pharmacological treatment on these molecular systems/mechanisms. The relevance of synaptic dysfunctions in psychiatric diseases is undoubted and the potential to normalize, ameliorate, and shape such alterations by acting on molecular systems crucial to ensure synaptic function property is fascinating. However, future studies are required to elucidate several open issues. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 622 | Nutrition 2016 Feb 32: 174-8 |
| PMID | 26706021 |
| Title | Beneficial action of resveratrol: How and why? |
| Abstract | Flavonoid resveratrol modulates the transcription factor NF-?B; inhibits the cytochrome P450 isoenzyme CYP1 A1; suppresses the expression and activity of cyclooxygenase enzymes; and modulates Fas/Fas-ligand-mediated apoptosis, p53, mammalian target of rapamycin, and cyclins and various phosphodiesterases. This increases the cytosolic cAMP that activates Epac1/CaMKK?/AMPK/SIRT1/PGC-1? pathway, which in turn facilitates increased oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-?, interluekin-17 (IL-17), and other proinflammatory molecules, and thus is of benefit in autoimmune diseases. In addition, resveratrol inhibits expression of hypoxia-inducible factor-1? and vascular endothelial growth factor, explaining its effective action against cancer. Brain-derived neurotrophic factor (BDNF) that is involved in the pathogenesis of obesity, type 2 diabetes mellitus, and metabolic syndrome is also altered in depression, schizophrenia, bipolar disorder, and autism. We noted that BDNF protects against cytotoxic actions of alloxan, streptozotocin, and benzo(a)pyrene. Resveratrol prevents bisphenol A-induced autism, type 2 diabetes mellitus, and metabolic syndrome, suggesting that it may augment BDNF synthesis and action. We also observed that BDNF levels are low in type 2 diabetes mellitus and that BDNF enhances production of antiinflammatory lipid, lipoxin A4, whose levels are low in diabetes mellitus. Thus, resveratrol may augment production of lipoxin A4. Resveratrol alters gut microbiota and influences stem cell proliferation and differentiation. These pleiotropic actions of resveratrol may explain the multitude of its actions and benefits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 623 | Behav Pharmacol 2016 Mar -1: -1 |
| PMID | 26960162 |
| Title | GM1 ganglioside reverses the cognitive deficits induced by MK801 in mice. |
| Abstract | Cognitive deficits are core symptoms of schizophrenia, but effective treatments are still lacking. Previous studies have reported that the brain-derived neurotrophic factor (BDNF) signaling is closely involved in learning and memory. Monosialotetrahexosylganglioside (GM1) is a ganglioside with wide-ranging pharmacologic effects that enhances the BDNF signaling cascade. This study aimed to assess the effects of GM1 on schizophrenia-related cognitive impairments. A brief disruption of N-methyl-D-aspartate receptors with MK801 was used to generate the animal model for cognitive deficits in schizophrenia. It was found that MK801-treated mice showed significant deficits in memory ability compared with control mice in different behavior tests, and this was accompanied by decreased hippocampal BDNF signaling pathway. Consecutive administration of GM1 fully restored the MK801-induced cognitive deficits and the impaired BDNF signaling in the hippocampus. Furthermore, a BDNF system inhibitor abolished the effects of GM1 in the MK801 model. Taken together, our results show that GM1 could reverse the MK801-induced cognitive deficits, suggesting a potential usefulness of GM1 in treating the schizophrenia-related cognitive impairments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 624 | Schizophr Bull 2016 Jun -1: -1 |
| PMID | 27262112 |
| Title | BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity. |
| Abstract | Reduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNF(Val66Met) (hBDNF(Val66Met)) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the long-term effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30ms and 100ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100ms ISI identified that, irrespective of CORT treatment, the hBDNF(Val/Met) genotype was associated with significantly reduced PPI. In contrast, PPI was not different between hBDNF(Met/Met) and hBDNF(Val/Val) genotype mice. At the 30ms ISI, CORT treatment selectively disrupted sensorimotor gating of hBDNF(Val/Met) heterozygote mice but not hBDNF(Val/Val) or hBDNF(Met/Met) mice. Analysis of startle reactivity revealed that chronic CORT reduced startle reactivity of hBDNF(Val/Val) male mice by 51%. However, this was independent of the effect of CORT on PPI. In summary, we provide evidence of a distinct BDNF(Val66Met) heterozygote-specific phenotype using the sensorimotor gating endophenotype of schizophrenia. These data have important implications for clinical studies where, if possible, the BDNF(Val/Met) heterozygote genotype should be distinguished from the BDNF(Met/Met) genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 625 | Front Aging Neurosci 2016 -1 8: 10 |
| PMID | 26869919 |
| Title | Molecular Pathways Bridging Frontotemporal Lobar Degeneration and Psychiatric Disorders. |
| Abstract | The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD), which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia (SCZ), can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review, we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF) and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN) genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 626 | Psychiatry Res 2016 May 242: 34-38 |
| PMID | 27254652 |
| Title | Effects of repetitive transcranial magnetic stimulation over supplementary motor area in patients with schizophrenia with obsessive-compulsive-symptoms: A pilot study. |
| Abstract | In patients with schizophrenia, obsessive-compulsive symptoms (OCS) are associated with lower rates of quality of life and polypharmacy. No previous controlled studies have tested the efficacy of repetitive transcranial magnetic stimulation (rTMS) on the treatment of OCS in this population. The present study examined the therapeutic effects of rTMS applied to the supplementary motor area (1Hz, 20min, 20 sessions) on OCS and general symptoms in patients with schizophrenia or schizoaffective disorder, and whether this intervention can produce changes in plasma levels of brain derived neurotrophic factor (BDNF). A double-blind randomized controlled trial was conducted. Active and sham rTMS were delivered to 12 patients (6 on each group). Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Brief Psychiatric Rating Scale (BPRS) scores, as well as BDNF levels, were assessed before, after, and 4 weeks after treatment. rTMS did not significantly change the outcomes after treatment and on the follow-up (Y-BOCS: Wald's X(2)=3.172; p=0.205; BPRS: X(2)=1.629; p=0.443; BDNF: X(2)=2.930; p=0.231). There seemed to be a trend towards improvement of BPRS scores 4 weeks after rTMS treatment comparing with sham (Cohen's d=0.875, with 32.9% statistical power). No side effects were reported. Future studies with larger sample sizes are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 627 | Ann Gen Psychiatry 2016 -1 15: 1 |
| PMID | 26770258 |
| Title | Serum levels of brain-derived neurotrophic factor (BDNF), proBDNF and plasma 3-methoxy-4-hydroxyphenylglycol levels in chronic schizophrenia. |
| Abstract | We investigated the serum levels of brain-derived neurotrophic factor (BDNF), proBDNF and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with chronic schizophrenia. Sixty-eight patients who met the DSM-IV-TR criteria and had a chronic schizophrenia (CS) duration of ??5 years were enrolled. Their serum brain-derived BDNF and proBDNF levels were measured by enzyme-linked immunosorbent assays, and their plasma MHPG levels were analyzed by high-performance liquid chromatography with electrochemical detection. The plasma MHPG levels were significantly lower in the CS group (3.9? ± ?1.8 ng/ml) compared to those in the group of 32 age- and sex-matched healthy controls (5.1? ± ?2.4 ng/ml). The serum BDNF levels were significantly lower in the CS group (8.9? ± ?4.8 ng/ml) compared to the control group (12.2.1? ± ?6.8 ng/ml). No correlation was observed between plasma MHPG and BDNF in the CS group. These results suggest that hypo-activity of noradrenergic neurons and decreased BDNF secretion exist in chronic schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 628 | Neurosci. Lett. 2016 May -1: -1 |
| PMID | 27235578 |
| Title | Elevation of Ser9 phosphorylation of GSK3? is required for HERV-W env-mediated BDNF signaling in human U251 cells. |
| Abstract | Human endogenous retrovirus W family (HERV-W) envelope (env) is known to be associated with neurological and psychiatric disorders, such as multiple sclerosis and schizophrenia. Previous studies showed that overexpression of HERV-W env could induce brain-derived neurotrophic factor (BDNF) gene expression. In human and rat cells, BDNF-mediated signal transduction might be modulated by glycogen synthase kinase 3? (GSK3?). Both BDNF and GSK3? are schizophrenia-related genes. In this paper, we investigated whether GSK3? was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3? at Ser9 (p-GSK3? (Ser9)) and the ratio of p-GSK3? (Ser9) to total GSK3? (p<0.05) in U251 cells. Overexpression of HERV-W env led to a 36% reduction in GSK3? activity compared to control (p<0.05). The levels of ?-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p<0.05). These data suggested that overexpression of HERV-W env might activate the GSK3? signaling pathway in U251 cells. Further, knockdown of GSK3? reduced the expression of total GSK3?, p-GSK3? (Ser9), and the ratio of p-GSK3? (Ser9) to total GSK3? by 29%, 50%, and 31%, respectively (p<0.05). Levels of ?-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p<0.05). Interestingly, GSK3? activity increased (p<0.05). Knockdown of GSK3? also decreased mRNA and protein expression of BDNF by 36% and 48% respectively (p<0.05). These results indicated that phosphorylation of GSK3? at Ser9 might be involved in HERV-W env-induced BDNF expression, and will hopefully improve our understanding of the role of HERV-W env in neurological and psychiatric diseases (schizophrenia, etc). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 629 | Eur Neuropsychopharmacol 2016 Apr -1: -1 |
| PMID | 27133030 |
| Title | Genetic blockade of adenosine A2A receptors induces cognitive impairments and anatomical changes related to psychotic symptoms in mice. |
| Abstract | schizophrenia is a chronic severe mental disorder with a presumed neurodevelopmental origin, and no effective treatment. schizophrenia is a multifactorial disease with genetic, environmental and neurochemical etiology. The main theories on the pathophysiology of this disorder include alterations in dopaminergic and glutamatergic neurotransmission in limbic and cortical areas of the brain. Early hypotheses also suggested that nucleoside adenosine is a putative affected neurotransmitter system, and clinical evidence suggests that adenosine adjuvants improve treatment outcomes, especially in poorly responsive patients. Hence, it is important to elucidate the role of the neuromodulator adenosine in the pathophysiology of schizophrenia. A2A adenosine receptor (A2AR) subtypes are expressed in brain areas controlling motivational responses and cognition, including striatum, and in lower levels in hippocampus and cerebral cortex. The aim of this study was to characterize A2AR knockout (KO) mice with complete and specific inactivation of A2AR, as an animal model for schizophrenia. We performed behavioral, anatomical and neurochemical studies to assess psychotic-like symptoms in adult male and female KO and wild-type (WT) littermates. Our results show impairments in inhibitory responses and sensory gating in A2AR KO animals. Hyperlocomotion induced by d-amphetamine and MK-801 was reduced in KO animals when compared to WT littermates. Moreover, A2AR KO animals show motor disturbances, social and cognitive alterations. Finally, behavioral impairments were associated with enlargement of brain lateral ventricles and decreased BDNF levels in the hippocampus. These data highlight the role of adenosine in the pathophysiology of schizophrenia and provide new possibilities for the therapeutic management of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 630 | Biochim. Biophys. Acta 2016 Apr -1: -1 |
| PMID | 27105834 |
| Title | Relationship between ST8SIA2, polysialic acid and its binding molecules, and psychiatric disorders. |
| Abstract | Polysialic acid (polySia, PSA) is a unique and functionally important glycan, particularly in vertebrate brains. It is involved in higher brain functions such as learning, memory, and social behaviors. Recently, an association between several genetic variations and single nucleotide polymorphisms (SNPs) of ST8SIA2/STX, one of two polysialyltransferase genes in vertebrates, and psychiatric disorders, such as schizophrenia (SZ), bipolar disorder (BD), and autism spectrum disorder (ASD), was reported based on candidate gene approaches and genome-wide studies among normal and mental disorder patients. It is of critical importance to determine if the reported mutations and SNPs in ST8SIA2 lead to impairments of the structure and function of polySia, which is the final product of ST8SIA2. To date, however, only a few such forward-directed studies have been conducted. In addition, the molecular mechanisms underlying polySia-involved brain functions remain unknown, although polySia was shown to have an anti-adhesive effect. In this report, we review the relationships between psychiatric disorders and polySia and/or ST8SIA2, and describe a new function of polySia as a regulator of neurologically active molecules, such as brain-derived neurotrophic factor (BDNF) and dopamine, which are deeply involved in psychiatric disorders. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 631 | Schizophr. Res. 2016 Jan 170: 41-7 |
| PMID | 26603468 |
| Title | BDNF polymorphisms are associated with schizophrenia onset and positive symptoms. |
| Abstract | Numerous studies have showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis and pathophysiology of schizophrenia. The purposes of this study were to investigate the potential association of BDNF gene polymorphisms with susceptibility to schizophrenia and the psychopathological symptoms in patients with schizophrenia in a Han Chinese population. Four polymorphisms (rs6265, rs12273539, rs10835210 and rs2030324) of the BDNF gene were analyzed in a case-control study of 1887 Han Chinese individuals (844 patients and 1043 controls). We assessed 825 patients for psychopathology using the Positive and Negative Syndrome Scale. In single marker analyses the BDNF rs10835210 mutant A allele was significantly associated with schizophrenia. Haplotype analyses revealed higher frequencies of haplotypes containing the mutant A allele of the rs10835210 in schizophrenia than controls. We also found that this polymorphism rs10835210 was associated with positive symptoms, and the patients carrying the mutational allele A showed more positive symptoms. These findings suggest the role of these BDNF gene variants in both susceptibility to schizophrenia and in clinical symptom severity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 632 | Brain Behav. Immun. 2016 Mar -1: -1 |
| PMID | 27002704 |
| Title | Environmental enrichment rescues the effects of early life inflammation on markers of synaptic transmission and plasticity. |
| Abstract | Environmental enrichment (EE) has been successful at rescuing the brain from a variety of early-life psychogenic stressors. However, its ability to reverse the behavioral and neural alterations induced by a prenatal maternal infection model of schizophrenia is less clear. Moreover, the specific interactions between the components (i.e. social enhancement, novelty, physical activity) of EE that lead to its success as a supportive intervention have not been adequately identified. In the current study, standard housed female Sprague-Dawley rats were administered either the inflammatory endotoxin lipopolysaccharide (LPS; 100?g/kg) or pyrogen-free saline (equivolume) on gestational day 15. On postnatal day 50, offspring were randomized into one of three conditions: EE (group housed in a large multi-level cage with novel toys, tubes and ramps), Colony Nesting (CN; socially-housed in a larger style cage), or Standard Care (SC; pair-housed in standard cages). Six weeks later we scored social engagement and performance in the object-in-place task. Afterwards hippocampus and prefrontal cortex (n=7-9) were collected and evaluated for excitatory amino acid transporter (EAAT) 1-3, brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor type 2 (TrkB) gene expression (normalized to GAPDH) using qPCR methods. Overall, we show that gestational inflammation downregulates genes critical to synaptic transmission and plasticity, which may underlie the pathogenesis of neurodevelopmental disorders such as schizophrenia and autism. Additionally, we observed disruptions in both social engagement and spatial discrimination. Importantly, behavioral and neurophysiological effects were rescued in an experience dependent manner. Given the evidence that schizophrenia and autism may be associated with infection during pregnancy, these data have compelling implications for the prevention and reversibility of the consequences that follow immune activation in early in life. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 633 | Cell. Mol. Life Sci. 2016 Apr 73: 1503-14 |
| PMID | 26450419 |
| Title | Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice. |
| Abstract | Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we characterize the regulation of BDNF expression by STEP61, utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP61 expression was associated with the inhibition of CREB-dependent BDNF transcription. Similarly, both genetic and pharmacologic inhibition of STEP prevented the PCP-induced reduction in BDNF expression in vivo and normalized PCP-induced hyperlocomotion and cognitive deficits. These results suggest a mechanism by which STEP61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 634 | Schizophr Bull 2016 Mar -1: -1 |
| PMID | 26980143 |
| Title | Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons. |
| Abstract | In the cortex of subjects with schizophrenia, expression of glutamic acid decarboxylase 67 (GAD67), the enzyme primarily responsible for cortical GABA synthesis, is reduced in the subset of GABA neurons that express parvalbumin (PV). This GAD67 deficit is accompanied by lower cortical levels of other GABA-associated transcripts, including GABA transporter-1, PV, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B, somatostatin, GABAA receptor ?1 subunit, and KCNS3 potassium channel subunit mRNAs. In contrast, messenger RNA (mRNA) levels for glutamic acid decarboxylase 65 (GAD65), another enzyme for GABA synthesis, are not altered. We tested the hypothesis that this pattern of GABA-associated transcript levels is secondary to the GAD67 deficit in PV neurons by analyzing cortical levels of these GABA-associated mRNAs in mice with a PV neuron-specific GAD67 knockout. Using in situ hybridization, we found that none of the examined GABA-associated transcripts had lower cortical expression in the knockout mice. In contrast, PV, BDNF, KCNS3, and GAD65 mRNA levels were higher in the homozygous mice. In addition, our behavioral test battery failed to detect a change in sensorimotor gating or working memory, although the homozygous mice exhibited increased spontaneous activities. These findings suggest that reduced GAD67 expression in PV neurons is not an upstream cause of the lower levels of GABA-associated transcripts, or of the characteristic behaviors, in schizophrenia. In PV neuron-specific GAD67 knockout mice, increased levels of PV, BDNF, and KCNS3 mRNAs might be the consequence of increased neuronal activity secondary to lower GABA synthesis, whereas increased GAD65 mRNA might represent a compensatory response to increase GABA synthesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 635 | Proc. Natl. Acad. Sci. U.S.A. 2016 Mar 113: E1944-52 |
| PMID | 26976569 |
| Title | Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress. |
| Abstract | Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 636 | Brain Behav. Immun. 2016 Jan 51: 169-75 |
| PMID | 26407757 |
| Title | Interaction of BDNF with cytokines in chronic schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-?, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-? levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-? levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-? may interact with BNDF causing cognitive impairment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 637 | Behav. Brain Res. 2016 May 305: 181-5 |
| PMID | 26965573 |
| Title | Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure. |
| Abstract | Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 638 | Int. J. Dev. Neurosci. 2016 May 50: 39-46 |
| PMID | 26952695 |
| Title | Schneiderian first rank symptoms in schizophrenia: A developmental neuroscience evaluation. |
| Abstract | Self disorders in schizophrenia have been suggested to have distinct neurobiological underpinnings. Using comprehensive neuro-scientific assessments including a neurophysiological, a neurochemical and a neuropsychological marker, this study assesses disordered-"self" in schizophrenia. Twenty schizophrenia patients with first rank symptoms (FRS;FRS+), 20 patients without FRS (FRS-) and 20 healthy controls (HC) were assessed for psychopathology, especially on specially designed FRS score sheets with a narrow and a broad definition. Resting state electroencephalography was acquired using 256-electrodes; gamma spectral-power was measured in 8 regions of interest. Serum BDNF and self-monitoring were also assessed. Comparative and correlation analysis were conducted in addition to a step-wise discriminant function analysis. FRS+ group with greater positive symptom score and a lower negative symptom score, showed significantly increased gamma spectral power, especially on right hemispheric regions, along with lower BDNF levels and lower scores on self-monitoring compared to FRS- and HC. Serum BDNF levels and gamma spectral power in the region corresponding right inferior parietal lobule were identified as predictors that most accurately classified the defined groups. schizophrenia patients satisfying the criteria of presence of first rank symptoms represent a distinct neurodevelopmental subgroup with associated features of predominantly positive symptoms, significantly lower neurotrophin levels, aberrant resting state brain activity in the heteromodal association cortex and performing poorer on self-monitoring tasks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 639 | Epigenetics 2016 Jan 11: 11-23 |
| PMID | 26889735 |
| Title | BDNF rs6265 methylation and genotype interact on risk for schizophrenia. |
| Abstract | Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val(66)Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 640 | Med. Hypotheses 2016 Mar 88: 18-21 |
| PMID | 26880628 |
| Title | Cortical gray matter loss in schizophrenia: Could microglia be the culprit? |
| Abstract | Cortical gray matter loss in schizophrenia remains a great therapeutic difficulty. Each psychotic episode causes irreversible cortical gray matter loss, that causes the patients to never regain their previous state of functioning. Microglial cells are part of the innate immune system and their functions, among others, include phagocytosis and release of neurotrophic factors. They have a key impact on developmental and plasticity-induced removal of neuronal precursors, live-but-stressed neurons and synapses, while also stimulating synaptic growth and development. We hypothesize that microglia are the culprit for the cortical gray matter loss in schizophrenia through abnormal synaptic pruning, phagocytosis of stressed neurons and lacking neurotrophic factor release. Furthermore, we propose a research that could validate the hypotheses using serum samples of first-episode early-onset patients. By measuring the serum levels of milk fat globule-EGF factor 8 (MFG-E8), subcomponent in the classical pathway of complement activation (C1q), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6) and interleukin-10 (IL-10), we could gain an insight into the state of microglial activation during various stages of the disease. If this hypothesis is valid, new targeted drugs could be developed in order to reduce the deterioration of cortical gray matter, thereby possibly improving negative symptoms and cognitive deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 641 | Eur. Psychiatry 2016 Mar 33: 45-53 |
| PMID | 26854986 |
| Title | BDNF Val66Met and clinical response to antipsychotic drugs: A systematic review and meta-analysis. |
| Abstract | The polymorphic brain-derived neurotrophic factor (BDNF) gene has been postulated to be involved in inter-individual variability response to antipsychotic drugs. To perform a qualitative and quantitative synthesis of studies evaluating the influence of BDNF genetic variation on clinical response to antipsychotics. The review protocol was published in the PROSPERO database (Reg. n(o) CRD42015024614). A comprehensive search was performed through PubMed, Web of Knowledge and Cochrane databases up to July 2015. The methodological quality of identified studies was assessed using the MINORS criteria. Publication bias was estimated and potential sources of heterogeneity were investigated via meta-regression, subgroup and sensitivity analyses. Nine studies including a total of 2461 antipsychotic-treated patients fulfilled inclusion criteria for meta-analysis of BDNF Val66Met. Using the random-effects model, the pooled results showed no significant association with antipsychotic response for the dominant (Met carriers vs Val/Val, OR: 0.93, 95% CI: 0.72-1.19, P=0.55), codominant (Met/Met vs Val/Val, OR: 0.82, 95% CI: 0.59-1.15, P=0.25), recessive (Met/Met vs Val carriers, OR: 0.81, 95% CI 0.60-1.10, P=0.18) or the allelic contrast (Met vs Val, OR: 0.92, 95% CI 0.76-1.10, P=0.34). Visual inspection of funnel plots and further evaluation with Egger's test did not suggest evidence of publication bias. Despite lack of significant heterogeneity in most comparisons, no evidence of association also emerged in the subgroup and sensitivity analyses conducted. The present meta-analysis excludes a clinically relevant effect of BDNF Val66Met on antipsychotic drug response per se. Nevertheless, further investigation is still needed to clarify in well-designed, large sample-based studies, the impact of BDNF haplotypes containing the Val66Met polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 642 | Med. Sci. Monit. 2016 -1 22: 397-402 |
| PMID | 26851233 |
| Title | DNA Methylation of BDNF Gene in Schizophrenia. |
| Abstract | BACKGROUND Although genetic factors are risk factors for schizophrenia, some environmental factors are thought to be required for the manifestation of disease. Epigenetic mechanisms regulate gene functions without causing a change in the nucleotide sequence of DNA. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic transmission and plasticity. It has been suggested that BDNF may play a role in the pathophysiology of schizophrenia. It is established that methylation status of the BDNF gene is associated with fear learning, memory, and stressful social interactions. In this study, we aimed to investigate the DNA methylation status of BDNF gene in patients with schizophrenia. MATERIAL AND METHODS The study included 49 patients (33 male and 16 female) with schizophrenia and 65 unrelated healthy controls (46 male and 19 female). Determination of methylation pattern of CpG islands was based on the principle that bisulfite treatment of DNA results in conversion of unmethylated cytosine residues into uracil, whereas methylated cytosine residues remain unmodified. Methylation-specific PCR was performed with primers specific for either methylated or unmethylated DNA. RESULTS There was no significant difference in methylated or un-methylated status for BDNF promoters between schizophrenia patients and controls. The mean duration of illness was significantly lower in the hemi-methylated group compared to the non-methylated group for BDNF gene CpG island-1 in schizophrenia patients. CONCLUSIONS Although there were no differences in BDNF gene methylation status between schizophrenia patients and healthy controls, there was an association between duration of illness and DNA methylation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 643 | Curr Neuropharmacol 2016 -1 14: 41-7 |
| PMID | 26813121 |
| Title | Metabotropic Glutamate 2/3 Receptors and Epigenetic Modifications in Psychotic Disorders: A Review. |
| Abstract | schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as "major psychosis"; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group developed an epigenetic model of schizophrenia originated by Prenatal Restraint Stress (PRS) paradigm in mice. PRS mice developed some behavioral alterations observed in schizophrenic patients and classic animal models of schizophrenia, i.e. deficits in social interaction, locomotor activity and prepulse inhibition. They also showed specific changes in promoter DNA methylation activity of genes related to schizophrenia such as reelin, BDNF and GAD67, and altered expression and function of mGlu2/3 receptors in the frontal cortex. Interestingly, behavioral and molecular alterations were reversed by treatment with mGlu2/3 agonists. Based on these findings, we speculate that pharmacological modulation of these receptors could have a great impact on early phase treatment of psychosis together with the possibility to modulate specific epigenetic key protein involved in the development of psychosis. In this review, we will discuss in more details the specific features of the PRS mice as a suitable epigenetic model for major psychosis. We will then focus on key proteins of chromatin remodeling machinery as potential target for new pharmacological treatment through the activation of metabotropic glutamate receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 644 | Transl Psychiatry 2016 -1 6: e711 |
| PMID | 26756904 |
| Title | Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs. |
| Abstract | We have recently reported that mice born from dams stressed during pregnancy (PRS mice), in adulthood, have behavioral deficits reminiscent of behaviors observed in schizophrenia (SZ) and bipolar (BP) disorder patients. Furthermore, we have shown that the frontal cortex (FC) and hippocampus of adult PRS mice, like that of postmortem chronic SZ patients, are characterized by increases in DNA-methyltransferase 1 (DNMT1), ten-eleven methylcytosine dioxygenase 1 (TET1) and exhibit an enrichment of 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) at neocortical GABAergic and glutamatergic gene promoters. Here, we show that the behavioral deficits and the increased 5MC and 5HMC at glutamic acid decarboxylase 67 (Gad1), reelin (Reln) and brain-derived neurotrophic factor (BDNF) promoters and the reduced expression of the messenger RNAs (mRNAs) and proteins corresponding to these genes in FC of adult PRS mice is reversed by treatment with clozapine (5 mg kg(-1) twice a day for 5 days) but not by haloperidol (1 mg kg(-1) twice a day for 5 days). Interestingly, clozapine had no effect on either the behavior, promoter methylation or the expression of these mRNAs and proteins when administered to offspring of nonstressed pregnant mice. Clozapine, but not haloperidol, reduced the elevated levels of DNMT1 and TET1, as well as the elevated levels of DNMT1 binding to Gad1, Reln and BDNF promoters in PRS mice suggesting that clozapine, unlike haloperidol, may limit DNA methylation by interfering with DNA methylation dynamics. We conclude that the PRS mouse model may be useful preclinically in screening for the potential efficacy of antipsychotic drugs acting on altered epigenetic mechanisms. Furthermore, PRS mice may be invaluable for understanding the etiopathogenesis of SZ and BP disorder and for predicting treatment responses at early stages of the illness allowing for early detection and remedial intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 645 | Neuropeptides 2016 Apr 56: 1-8 |
| PMID | 26706181 |
| Title | Effects of phenytoin and lamotrigine treatment on serum BDNF levels in offsprings of epileptic rats. |
| Abstract | The role of brain-derived neurotrophic factor (BDNF) is to promote and modulate neuronal responses across neurotransmitter systems in the brain. Therefore, abnormal BDNF signaling may be associated with the pathophysiology of schizophrenia. Low BDNF levels have been reported in brains and serums of patients with psychotic disorders. In the present study, we investigated the effects of antiepileptic drugs on BDNF in developing rats. Pregnant rats were treated with phenytoin (PHT), lamotrigine (LTG) and folic acid for long-term, all through their gestational periods. Experimental epilepsy (EE) model was applied in pregnant rats. Epileptic seizures were determined with electroencephalography. After birth, serum BDNF levels were measured in 136 newborn rats on postnatal day (PND) 21 and postnatal day 38. In postnatal day 21, serum BDNF levels of experimental epilepsy group were significantly lower compared with PHT group. This decrease is statistically significant. Serum BDNF levels increased in the group LTG. This increase compared with LTG+EE group was statistically significant. In the folic acid (FA) group, levels of serum BDNF decreased statistically significantly compared to the PHT group. On postnatal day 38, no significant differences were found among the groups for serum BDNF levels. We concluded that, the passed seizures during pregnancy adversely affect fetal brain development, lowering of serum BDNF levels. PHT use during pregnancy prevents seizure-induced injury by increasing the levels of BDNF. About the increase level of BDNF, LTG is much less effective than PHT, the positive effect of folic acid on serum BDNF levels was not observed. LTG increase in BDNF is much less effective than PHT, folic acid did not show a positive effect on serum BDNF levels. Epilepsy affects fetal brain development during gestation in pregnant rats, therefore anti-epileptic therapy should be continued during pregnancy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 646 | Schizophr Res Cogn 2016 Mar 3: 1-7 |
| PMID | 26705516 |
| Title | Neuroscience-informed Auditory Training in Schizophrenia: A Final Report of the Effects on Cognition and Serum Brain-Derived Neurotrophic Factor. |
| Abstract | We previously reported the interim effects in a per protocol analysis of a randomized controlled trial of an innovative neuroscience-informed computerized cognitive training approach in schizophrenia. Here we report the effects of training on behavioral outcome measures in our final sample using an intent-to-treat analysis. We also report the effects on serum brain-derived neurotrophic factor (BDNF). Eighty-seven clinically stable participants with schizophrenia were randomly assigned to either targeted auditory training (AT, N=46) or a computer games control condition (CG, N=41). Participants were assessed on neurocognition, symptoms and functional outcome at baseline and after 50 hours of intervention delivered over 10 weeks. Serum BDNF was assessed at baseline, at 2 weeks, and at 10 weeks. After the intervention, AT participants showed significant gains in global cognition, speed of processing, verbal learning, and verbal memory, relative to CG participants, with no changes in symptoms or functioning. At baseline, schizophrenia participants had significantly lower-than-normal serum BDNF. AT participants showed a significant increase in serum BDNF compared to CG participants, and "normalized" levels by post training. Participants with chronic schizophrenia made significant cognitive gains after 50 hours of intensive computerized training delivered as a stand-alone treatment, but no improvement in symptoms or functioning. Serum BDNF levels were significantly increased, and may serve as a peripheral biomarker for the effects of training. Future research must focus on: 1) Methods of integrating cognitive training with psychosocial treatments; 2) A deeper understanding of underlying neurophysiology in order to enhance critical mechanisms of action. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 647 | Behav. Brain Res. 2016 Mar 300: 123-34 |
| PMID | 26704217 |
| Title | Possible contribution of epigenetic changes in the development of schizophrenia-like behavior in vasopressin-deficient Brattleboro rats. |
| Abstract | schizophrenia-like symptoms were detected in vasopressin-deficient (di/di) Brattleboro rats, and it was also suggested that schizophrenia might have an epigenetic component. We aimed to clarify if epigenetic changes contribute to schizophrenia-like behavior of this strain. Behavioral (locomotion by telemetry, cognition by novel object recognition, social recognition and social avoidance test, attention by pre-pulse inhibition) and epigenetic differences were compared between wild type and di/di animals. DNA methyltransferase1 (DNMT1), DNMT3a, as well as COMT, GAD, VGLUT1, 5HT2A, BDNF mRNA levels in prefrontal brain region and hippocampus were studied by qRT-PCR. Histone3 (H3) and H4 acetylation (Ac) were studied by western-blot followed by region specific examination of H3 lysine9 (K9) acetylation by immunohistochemistry. Impaired cognitive, social and attention behavior of di/di rats confirmed schizophrenia-like symptoms in our local colony. The pan-AcH3 immunoreactivity was lower in prefrontal region and elevated in the hippocampus of di/di animals. We found lower immunopositive cell number in the dorsal peduncular prefrontal cortex and the ventral lateral septum and increased AcH3K9 immunoreactivity in CA1 region of di/di animals. There were no major significant alterations in the studied mRNA levels. We confirmed that Brattleboro rat is a good preclinical model of schizophrenia. Its schizophrenia-like behavioral alteration was accompanied by changes in H3 acetylation in the prefrontal region and hippocampus. This may contribute to disturbances of many schizophrenia-related substances leading to development of schizophrenia-like symptoms. Our studies confirmed that not a single gene, rather fine changes in an array of molecules are responsible for the majority of schizophrenia cases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 648 | World J. Biol. Psychiatry 2016 Mar 17: 129-39 |
| PMID | 26700405 |
| Title | Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning. |
| Abstract | Objectives Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results The frequency of the haplotype C-C (rs645649-rs582262) was significantly increased in patients compared to controls (P?=?0.0043), while the haplotype T-C-C-T-C-A (rs3763180-rs10484320-rs4960155-rs9379002-rs9405890-rs1475157) was more frequent in controls (P?=?3.1?×?10(-5)). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P?=?0.005). Conclusions Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 649 | Nord J Psychiatry 2016 May 70: 267-71 |
| PMID | 26548545 |
| Title | Serum levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in depressed patients with schizophrenia. |
| Abstract | Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are neurotrophins-proteins that induce the survival, development, and function of neurons. Their role in the development of schizophrenia and mood disorders is widely studied. This study was aimed to determine whether depression affects levels of BDNF and NT-3 in patients with schizophrenia. Data for 53 Caucasian adult hospitalized patients with chronic paranoid schizophrenia was compared with 27 healthy subjects. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and positive, negative and general sub-scores, the Calgary Depression Scale for schizophrenia (CDSS), the Hamilton Depression Rating Scale (HDRS), and the Clinical Global Impressions scale (CGI). Patients were defined as depressed (SHZ-DEP) with scores CDSS?>?6 and HDRS?>?7, otherwise they were included into the non-depressed group (SHZ-nonDEP). In total, 17 patients (32.1%) with schizophrenia met criteria for depression. SHZ-DEP patients had higher scores in HDRS, CDSS, PANSS total, PANSS negative, PANSS general and CGI (p?BDNF or NT-3 levels between patients with schizophrenia and controls. BDNF levels were lower in SHZ-DEP compared to SHZ-nonDEP: 18.82?±?5.95 versus 22.10?±?5.31?ng/mL, p?=?0.045. NT-3 levels were higher in SHZ-DEP compared to SHZ-nonDEP: 133.31?±?222.19 versus 56.04?±?201.28 pg/mL, p?=?0.033. There were no differences in neurotrophin levels between patients with schizophrenia and controls. We found lower BDNF and higher NT-3 serum levels in depressed patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 650 | Dev Neurobiol 2016 May 76: 519-32 |
| PMID | 26215537 |
| Title | Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine. |
| Abstract | Neonatal N-methyl-D-aspartate (NMDA) receptor blockade in rodents triggers schizophrenia (SCZ)-like alterations during adult life. SCZ is influenced by gender in age of onset, premorbid functioning, and course. Estrogen, the hormone potentially driving the gender differences in SCZ, is known to present neuroprotective effects such as regulate oxidative pathways and the expression of brain-derived neurotrophic factor (BDNF). Thus, the aim of this study was to verify if differences in gender and/or estrous cycle phase during adulthood would influence the development of behavioral and neurochemical alterations in animals neonatally administered ketamine. The results showed that ketamine-treated male (KT-male) and female-in-diestrus (KTF-diestrus, the low estrogen phase) presented significant deficits in prepulse inhibition of the startle reflex and spatial working memory, two behavioral SCZ endophenotypes. On the contrary, female ketamine-treated rats during proestrus (KTF-proestrus, the high estradiol phase) had no behavioral alterations. This correlated with an oxidative imbalance in the hippocampus (HC) of both male and KTF-diestrus female rats, that is, decreased levels of GSH and increased levels of lipid peroxidation and nitrite. Similarly, BDNF was decreased in the KTF-diestrus rats while no alterations were observed in KTF-proestrus and male animals. The changes in the HC were in contrast to those in the prefrontal cortex in which only increased levels of nitrite in all groups studied were observed. Thus, there is a gender difference in the adult rat HC in response to ketamine neonatal administration, which is based on the estrous cycle. This is discussed in relation to neuropsychiatric conditions and in particular SCZ. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 519-532, 2016. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 651 | Cell. Mol. Neurobiol. 2016 Jan 36: 1-10 |
| PMID | 26134309 |
| Title | Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism and Risk of Schizophrenia: A Meta-analysis of Case-Control Studies. |
| Abstract | According to evidences from previous family and association studies, it has been claimed that genetic factors are involved in the neuropathogenesis of schizophrenia disorder. Whether the Val66Met variant of brain-derived neurotrophic factor (BDNF) gene plays any roles in the pathogenesis of this syndrome or could be a potential biomarker for prognosis of this disorder has been a long-standing controversial issue. We performed a meta-analysis restricted to case-control studies and searched Pubmed, PsychInfo, and Google scholar using keywords including 'association,' 'Val66Met,' 'BDNF,' and 'schizophrenia' published up to May 1, 2015. A total of 39 studies for schizophrenia were combined by fixed- and random-effects models. The pooled results from the schizophrenia sample indicated no significant evidence for the association of Val/Val and Val/Met genotypes of BDNF gene with schizophrenia, but it was observed that there is an association between Met/Met polymorphism and schizophrenia in Asian, European, and Chinese populations, this means that the risk of schizophrenia in Asian, European, and Chinese populations with Met/Met genotype is, respectively, 9, 26, and 9%. There was a significant association between BDNF Val66Met polymorphism and schizophrenia in our meta-analysis study. We cannot rule out the possibility that other polymorphisms in the BDNF gene are involved in the pathophysiology of schizophrenia. In addition, more studies should be conducted on the polymorphisms in other genes to elucidate their possible roles in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 652 | Schizophr Bull 2016 Jan 42: 142-51 |
| PMID | 26130821 |
| Title | BDNF and NGF Signalling in Early Phases of Psychosis: Relationship With Inflammation and Response to Antipsychotics After 1 Year. |
| Abstract | Previous studies have indicated systemic deregulation of the proinflammatory or anti-inflammatory balance in individuals with first-episode psychosis (FEP) that persists 12 months later. To identify potential risk/protective factors and associations with symptom severity, we assessed possible changes in plasma levels of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and their receptors in peripheral blood mononuclear cells (PBMCs). Expression of the 2 forms of BDNF receptors (active TrkB-FL and inactiveTrkB-T1) in PBMCs of FEP patients changed over time, TrkB-FL expression increasing by 1 year after diagnosis, while TrkB-T1 expression decreased. The TrkB-FL/TrkB-T1 ratio (hereafter FL/T1 ratio) increased during follow-up in the nonaffective psychosis group only, suggesting different underlying pathophysiological mechanisms in subgroups of FEP patients. Further, the expression of the main NGF receptor, TrkA, generally increased in patients at follow-up. After adjusting for potential confounders, baseline levels of inducible isoforms of nitric oxide synthase, cyclooxygenase, and nuclear transcription factor were significantly associated with the FL/T1 ratio, suggesting that more inflammation is associated with higher values of this ratio. Interestingly, the FL/T1 ratio might have a role as a predictor of functioning, a regression model of functioning at 1 year suggesting that the effect of the FL/T1 ratio at baseline on functioning at 1 year depended on whether patients were treated with antipsychotics. These findings may have translational relevance; specifically, it might be useful to assess the expression of TrkB receptor isoforms before initiating antipsychotic treatment in FEPs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 653 | Acta Neuropsychiatr 2016 Feb 28: 1-10 |
| PMID | 25877668 |
| Title | Transcranial direct current stimulation and neuroplasticity genes: implications for psychiatric disorders. |
| Abstract | Transcranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders. A systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms. Synthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials. Taking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 654 | Psychiatry Res 2016 May 242: 54-60 |
| PMID | 27262086 |
| Title | BDNF serum levels in schizophrenic patients during treatment augmentation with sarcosine (results of the PULSAR study). |
| Abstract | Finding a relationship between schizophrenia symptoms severity and initial level of BDNF and its changes during augmentation of antipsychotic treatment with sarcosine. 57 individuals with schizophrenia with predominantly negative symptoms completed a 6-month RCT prospective study. The patients received 2g of sarcosine (n=27) or placebo (n=30) daily. At the beginning, after 6 weeks and 6 months BDNF levels were measured. Severity of symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for schizophrenia (CDSS). BDNF serum levels were stable after 6 weeks and 6 months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group comparing to placebo, however there was no correlations between serum BDNF concentrations and PANSS scores in all assessments. Initial serum BDNF concentrations cannot be used as a predictor of the improvement resulting from adding sarcosine. Our results indicate that either BDNF is not involved in the NMDA-dependent mechanism of sarcosine action or global changes in BDNF concentrations induced by amino-acid cannot be detected in blood assessments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 655 | Ann Gen Psychiatry 2016 -1 15: 1 |
| PMID | 26770258 |
| Title | Serum levels of brain-derived neurotrophic factor (BDNF), proBDNF and plasma 3-methoxy-4-hydroxyphenylglycol levels in chronic schizophrenia. |
| Abstract | We investigated the serum levels of brain-derived neurotrophic factor (BDNF), proBDNF and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with chronic schizophrenia. Sixty-eight patients who met the DSM-IV-TR criteria and had a chronic schizophrenia (CS) duration of ??5 years were enrolled. Their serum brain-derived BDNF and proBDNF levels were measured by enzyme-linked immunosorbent assays, and their plasma MHPG levels were analyzed by high-performance liquid chromatography with electrochemical detection. The plasma MHPG levels were significantly lower in the CS group (3.9? ± ?1.8 ng/ml) compared to those in the group of 32 age- and sex-matched healthy controls (5.1? ± ?2.4 ng/ml). The serum BDNF levels were significantly lower in the CS group (8.9? ± ?4.8 ng/ml) compared to the control group (12.2.1? ± ?6.8 ng/ml). No correlation was observed between plasma MHPG and BDNF in the CS group. These results suggest that hypo-activity of noradrenergic neurons and decreased BDNF secretion exist in chronic schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 656 | Curr Neuropharmacol 2016 -1 14: 41-7 |
| PMID | 26813121 |
| Title | Metabotropic Glutamate 2/3 Receptors and Epigenetic Modifications in Psychotic Disorders: A Review. |
| Abstract | schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as "major psychosis"; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group developed an epigenetic model of schizophrenia originated by Prenatal Restraint Stress (PRS) paradigm in mice. PRS mice developed some behavioral alterations observed in schizophrenic patients and classic animal models of schizophrenia, i.e. deficits in social interaction, locomotor activity and prepulse inhibition. They also showed specific changes in promoter DNA methylation activity of genes related to schizophrenia such as reelin, BDNF and GAD67, and altered expression and function of mGlu2/3 receptors in the frontal cortex. Interestingly, behavioral and molecular alterations were reversed by treatment with mGlu2/3 agonists. Based on these findings, we speculate that pharmacological modulation of these receptors could have a great impact on early phase treatment of psychosis together with the possibility to modulate specific epigenetic key protein involved in the development of psychosis. In this review, we will discuss in more details the specific features of the PRS mice as a suitable epigenetic model for major psychosis. We will then focus on key proteins of chromatin remodeling machinery as potential target for new pharmacological treatment through the activation of metabotropic glutamate receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |