| 1 | J. Chem. Neuroanat. 2000 Dec 20: 259-69 |
|---|---|
| PMID | 11207424 |
| Title | Glutamate decarboxylase(65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain. |
| Abstract | Recent postmortem studies have been suggesting that a defect of GABAergic neurotransmission might occur in the corticolimbic system of subjects with schizophrenia and bipolar disorder. To explore this possibility, a method for immunolocalizing the 65 kdalton isoform of glutamate decarboxylase (GAD(65)) has been developed and applied to the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of 12 normal controls (CONs), 12 schizophrenics (SZs) and 5 manic depressive (MDs) subjects. A computer-assisted technique was employed under strictly blind conditions to determine the density of GAD(65)-IR terminals in apposition with pyramidal (PNs) and nonpyramidal (NPS) neurons and in neuropil (NPL) of layers II, III, V and VI of each cortical region. For SZs, no difference in the numerical density of GAD(65)-IR terminals in contact with either PNs or NPS or in NPL of layers II-VI in ACCx or PFCx was detected. There were also no differences in the size of either PNs and NPS that could have influenced the nature of these findings. Using a pixel count analysis, the size of IR terminals was, however, found to be increased in layers II (10.3%) and III (15.8%) of SZs, but only in subjects treated with neuroleptic drugs. For MDs, the density of GAD(65)-IR terminals was significantly reduced in all four layers of ACCx, but these differences were most significant in layers II (27.8%) and III (37.2%), whether or not the subjected were treated with neuroleptics. In PFCx, the MDs showed similar differences in terminal density for PNs and NPS but not neuropil in the four laminae examined. The MD group showed no differences in either the size of cell bodies or IR terminals. Age and PMI did not account for any of the differences between the CONs vs SZs and MDs. Overall, the results of this study, though preliminary, suggest that there may be complex changes in GABAergic terminals in SZ and MD, ones that may vary with respect to primary diagnosis and neuroleptic exposure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | J. Chem. Neuroanat. 2000 Dec 20: 259-69 |
| PMID | 11207424 |
| Title | Glutamate decarboxylase(65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain. |
| Abstract | Recent postmortem studies have been suggesting that a defect of GABAergic neurotransmission might occur in the corticolimbic system of subjects with schizophrenia and bipolar disorder. To explore this possibility, a method for immunolocalizing the 65 kdalton isoform of glutamate decarboxylase (GAD(65)) has been developed and applied to the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of 12 normal controls (CONs), 12 schizophrenics (SZs) and 5 manic depressive (MDs) subjects. A computer-assisted technique was employed under strictly blind conditions to determine the density of GAD(65)-IR terminals in apposition with pyramidal (PNs) and nonpyramidal (NPS) neurons and in neuropil (NPL) of layers II, III, V and VI of each cortical region. For SZs, no difference in the numerical density of GAD(65)-IR terminals in contact with either PNs or NPS or in NPL of layers II-VI in ACCx or PFCx was detected. There were also no differences in the size of either PNs and NPS that could have influenced the nature of these findings. Using a pixel count analysis, the size of IR terminals was, however, found to be increased in layers II (10.3%) and III (15.8%) of SZs, but only in subjects treated with neuroleptic drugs. For MDs, the density of GAD(65)-IR terminals was significantly reduced in all four layers of ACCx, but these differences were most significant in layers II (27.8%) and III (37.2%), whether or not the subjected were treated with neuroleptics. In PFCx, the MDs showed similar differences in terminal density for PNs and NPS but not neuropil in the four laminae examined. The MD group showed no differences in either the size of cell bodies or IR terminals. Age and PMI did not account for any of the differences between the CONs vs SZs and MDs. Overall, the results of this study, though preliminary, suggest that there may be complex changes in GABAergic terminals in SZ and MD, ones that may vary with respect to primary diagnosis and neuroleptic exposure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | J. Chem. Neuroanat. 2000 Dec 20: 259-69 |
| PMID | 11207424 |
| Title | Glutamate decarboxylase(65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain. |
| Abstract | Recent postmortem studies have been suggesting that a defect of GABAergic neurotransmission might occur in the corticolimbic system of subjects with schizophrenia and bipolar disorder. To explore this possibility, a method for immunolocalizing the 65 kdalton isoform of glutamate decarboxylase (GAD(65)) has been developed and applied to the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of 12 normal controls (CONs), 12 schizophrenics (SZs) and 5 manic depressive (MDs) subjects. A computer-assisted technique was employed under strictly blind conditions to determine the density of GAD(65)-IR terminals in apposition with pyramidal (PNs) and nonpyramidal (NPS) neurons and in neuropil (NPL) of layers II, III, V and VI of each cortical region. For SZs, no difference in the numerical density of GAD(65)-IR terminals in contact with either PNs or NPS or in NPL of layers II-VI in ACCx or PFCx was detected. There were also no differences in the size of either PNs and NPS that could have influenced the nature of these findings. Using a pixel count analysis, the size of IR terminals was, however, found to be increased in layers II (10.3%) and III (15.8%) of SZs, but only in subjects treated with neuroleptic drugs. For MDs, the density of GAD(65)-IR terminals was significantly reduced in all four layers of ACCx, but these differences were most significant in layers II (27.8%) and III (37.2%), whether or not the subjected were treated with neuroleptics. In PFCx, the MDs showed similar differences in terminal density for PNs and NPS but not neuropil in the four laminae examined. The MD group showed no differences in either the size of cell bodies or IR terminals. Age and PMI did not account for any of the differences between the CONs vs SZs and MDs. Overall, the results of this study, though preliminary, suggest that there may be complex changes in GABAergic terminals in SZ and MD, ones that may vary with respect to primary diagnosis and neuroleptic exposure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Biol. Psychiatry 2001 Sep 50: 395-406 |
| PMID | 11566156 |
| Title | The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects. |
| Abstract | A recent study reported a decreased density of nonpyramidal neurons (NPS) in layer II of the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of schizophrenic brain that was most pronounced in schizoaffective subjects. Our study assessed whether a decrease of NPS in ACCx may show a stronger covariation with affective disorder. A cohort consisting of 12 normal control (CONs), 11 schizophrenic, and 10 bipolar subjects matched for age and postmortem interval (PMI) has been analyzed. A two-dimensional technique was employed for counting cells in a large x,y sampling column that extended across layers I through VI of ACCx. There was a 27% reduction in the density of NPS in layer II of the bipolar group, whereas in the schizophrenic group, this density was 16.2% lower. There were no differences in NPS in layers III through VI of either the schizophrenic or bipolar group. Both groups also showed modest decreases of PNs in the deeper laminae; however, these differences were only significant in layer IV of the schizophrenic subjects. The density of glial cells was similar across the control, schizophrenic, and bipolar groups. An Abercrombie correction for cell size did not alter the nature of the results. Subjects both with and without neuroleptic exposure showed a lower density of NPS in layer II of bipolar subjects or PNS in deeper laminae of schizophrenic subjects. Overall, the findings reported here suggest that local circuit cells in layer II of ACCx may be decreased in bipolar disorder, whereas projection neurons in deeper laminae are decreased in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Biol. Psychiatry 2001 Sep 50: 395-406 |
| PMID | 11566156 |
| Title | The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects. |
| Abstract | A recent study reported a decreased density of nonpyramidal neurons (NPS) in layer II of the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of schizophrenic brain that was most pronounced in schizoaffective subjects. Our study assessed whether a decrease of NPS in ACCx may show a stronger covariation with affective disorder. A cohort consisting of 12 normal control (CONs), 11 schizophrenic, and 10 bipolar subjects matched for age and postmortem interval (PMI) has been analyzed. A two-dimensional technique was employed for counting cells in a large x,y sampling column that extended across layers I through VI of ACCx. There was a 27% reduction in the density of NPS in layer II of the bipolar group, whereas in the schizophrenic group, this density was 16.2% lower. There were no differences in NPS in layers III through VI of either the schizophrenic or bipolar group. Both groups also showed modest decreases of PNs in the deeper laminae; however, these differences were only significant in layer IV of the schizophrenic subjects. The density of glial cells was similar across the control, schizophrenic, and bipolar groups. An Abercrombie correction for cell size did not alter the nature of the results. Subjects both with and without neuroleptic exposure showed a lower density of NPS in layer II of bipolar subjects or PNS in deeper laminae of schizophrenic subjects. Overall, the findings reported here suggest that local circuit cells in layer II of ACCx may be decreased in bipolar disorder, whereas projection neurons in deeper laminae are decreased in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Mol. Psychiatry 2007 Apr 12: 385-97 |
| PMID | 17264840 |
| Title | Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection. |
| Abstract | Among the most consistent results of studies of post-mortem brain tissue from schizophrenia patients (SZP) is the finding that in this disease, several genes expressed by GABAergic neurons are downregulated. This downregulation may be caused by hypermethylation of the relevant promoters in affected neurons. Indeed, increased numbers of GABAergic interneurons expressing DNA methyltransferase 1 (DNMT1) mRNA have been demonstrated in the prefrontal cortex (PFC) of SZP using in situ hybridization. The present study expands upon these findings using nested competitive reverse transcription-polymerase chain reaction combined with laser-assisted microdissection to quantitate the extent of DNMT1 mRNA overexpression in distinct populations of GABAergic neurons obtained from either layer I or layer V of the PFC of SZP. In a cohort of eight SZP and eight non-psychiatric subject (NPS) post-mortem BA9 tissue samples, DNMT1 mRNA was found to be selectively expressed in GABAergic interneurons and virtually absent in pyramidal neurons. DNMT1 mRNA expression was approximately threefold higher in GABAergic interneurons microdissected from layer I of SZP relative to the same neurons microdissected from NPS. GABAergic interneurons obtained from layer V of the same samples displayed no difference in DNMT1 mRNA expression between groups. In the same samples, the GABAergic neuron-specific glutamic acid-decarboxylase(67) (GAD(67)) and reelin mRNAs were underexpressed twofold in GABAergic interneurons isolated from layer I of SZP relative to GABAergic interneurons microdissected from layer I of NPS, and unaltered in GABAergic interneurons of layer V. These findings implicate an epigenetically mediated layer I GABAergic dysfunction in the pathogenesis of schizophrenia, and suggest novel strategies for treatment of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Oct 31: 1444-8 |
| PMID | 17669576 |
| Title | Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder. |
| Abstract | Panic disorder is a common anxiety disorder characterized by sudden and recurrent panic attacks. Previous studies have indicated significant genetic contributions and a susceptibility locus for panic disorder has been mapped to human chromosome 7p 15. The receptor for Neuropeptide S (NPS) is located in the same genomic region while NPS is known to produce arousal and anxiolytic-like effects in rodents. Here we report that a coding polymorphism in the Neuropeptide S receptor (NPSR) is associated with panic disorder in male patients of Japanese ancestry. The polymorphism (Asn(107)Ile) results in a gain-of-function of the receptor protein by increasing the agonist sensitivity about tenfold. The allele representing the less active isoform (NPSR Asn(107)) was found under-represented in male panic disorder patients, indicating a potential protective function of the protein. Two unrelated groups of patients diagnosed with schizophrenia or attention-deficit/hyperactivity disorder (ADHD) showed no association of particular NPSR alleles with the disorders. These results provide evidence for a gender-specific effect of NPSR in the pathogenesis of panic disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Int J Psychophysiol 2008 Oct 70: 3-15 |
| PMID | 18511139 |
| Title | Auditory hallucinations and the mismatch negativity: processing speech and non-speech sounds in schizophrenia. |
| Abstract | In line with emerging research strategies focusing on specific symptoms rather than global syndromes in psychiatric disorders, we examined the functional neural correlates of auditory verbal hallucinations (AHs) in schizophrenia. Recent neuroimaging and behavioural evidence suggest a reciprocal relationship between auditory cortex response to external sounds versus that induced by AHs. The mismatch negativity (MMN), a well established event-related potential (ERP) index of auditory cortex function, was assessed in 12 hallucinating patients (HP), 12 non-hallucinating patients (NP) and 12 healthy controls (HC). The primary endpoints, MMN amplitudes and latencies recorded from anterior and posterior scalp regions, were measured in response to non-phonetic and phonetic sounds. While schizophrenia patients as a whole differed from HCs, no significant between-group differences were observed when patients were divided into hallucinated and non-hallucinated subgroups but, compared to NPS and HCs, whose MMN amplitudes were greatest in response to across phoneme change at frontal but not temporal sites, MMN amplitudes in HPs at frontal sites were not significantly different to any of the presented stimuli, while temporal MMNs in HPs were maximally sensitive to phonetic change. These findings demonstrate that auditory verbal hallucinations are associated with impaired pre-attentive processing of speech in fronto-temporal networks, which may involve defective attribution of significance that is sensitive to resource limitations. Overall, this research suggests that MMN may be a useful non-invasive tool for probing relationships between hallucinatory and neural states within schizophrenia and the manner in which auditory processing is altered in these afflicted patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Clin Neurophysiol 2008 Apr 119: 909-21 |
| PMID | 18261954 |
| Title | The right profile: mismatch negativity in schizophrenia with and without auditory hallucinations as measured by a multi-feature paradigm. |
| Abstract | To examine pre-attentive acoustic change detection in schizophrenia patients with and without auditory hallucinations via mismatch negativity (MMN) extracted from a multi-feature paradigm. This study examined the electroencephalograph (EEG)-derived MMN, recorded across 32 sites, in 12 hallucinating patients (HPs) with schizophrenia, 12 non-hallucinating patients (NPS) with schizophrenia and 12 healthy controls (HCs). MMN was recorded in response to a multi-feature MMN paradigm [Näätänen, R., et al., 2004. The mismatch negativity (MMN): towards the optimal paradigm. Clin. Neurophys. 115, 140-144] which employs frequency, duration, intensity, location and gap deviants. Differences in source localization were probed using standardized low resolution brain electromagnetic tomography (sLORETA). HPs showed significantly smaller MMNs to duration deviants compared to HCs and NPS, as well as smaller MMNs to intensity deviants compared to HCs. Regionalized differences between HCs and each of the patient groups were observed in response to frequency deviants. There were no significant group effects for location or gap deviants, or for MMN latency. Source localization using sLORETA showed no significant differences in MMN generator location across groups for any of the deviant stimuli. The often-reported robust MMN deficit to duration deviants may be specific to schizophrenia patients afflicted with auditory hallucinations. Furthermore, by using symptom-specific groups, novel deficits of pre-attentive auditory processing, such as that observed to intensity deviants in HPs, may be revealed. The differential responding observed between both groups of patients with schizophrenia has implications for automatic processing within the auditory cortex of hallucinating patients and suggests that care must be taken when recruiting participants in studies involving schizophrenia to ensure consistent, replicable results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Schizophr. Res. 2009 Jun 111: 115-22 |
| PMID | 19386473 |
| Title | An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes. |
| Abstract | Several lines of schizophrenia (SZ) research suggest that a functional downregulation of the prefrontal cortex GABAergic neuronal system is mediated by a promoter hypermethylation, presumably catalyzed by an increase in DNA-methyltransferase-1 (DNMT-1) expression. This promoter hypermethylation may be mediated not only by DNMT-1 but also by an entire family of de novo DNA-methyltransferases, such as DNA-methyltransferase-3a (DNMT-3a) and -3b (DNMT-3b). To verify the existence of an overexpression of DNMT-3a and DNMT-3b in the brain of schizophrenia patients (SZP), we compared their mRNA expression in Brodmann's area 10 (BA10) and in the caudate nucleus and putamen obtained from the Harvard Brain Tissue Resource Center (Belmont, MA) from both noNPSychiatric subjects (NPS) and SZP. Our results demonstrate that DNMT-3a and DNMT-1 are expressed and co-localize in distinct GABAergic neuron populations whereas DNMT-3b mRNA is virtually undetectable. We also found that unlike DNMT-1, which is frequently overexpressed in telencephalic GABAergic neurons of SZP, DNMT-3a mRNA is overexpressed only in layer I and II GABAergic interneurons of BA10. To ascertain whether these DNMT expression differences observed in brain tissue could also be detected in peripheral tissues, we studied whether DNMT-1 and DNMT-3a mRNAs were overexpressed in peripheral blood lymphocytes (PBL) of SZP. Both DNMT-1 and DNMT-3a mRNAs are expressed in the PBL and although DNMT-3a mRNA levels in the PBL are approximately 1/10 of those of DNMT-1, the comparison of the PBL content in NPS and SZP showed a highly significant 2-fold increase of both DNMT-1 and DNMT-3a mRNA in SZP. These changes were unaffected by the dose, the duration, or the type of antipsychotic treatment. The upregulation of DNMT-1 and to a lesser extent that of DNMT-3a mRNA in PBL of SZP supports the concept that this readily available peripheral cell type can express an epigenetic variation of specific biomarkers relevant to SZ morbidity. Hence, PBL studies may become useful to investigate a diagnostic epigenetic marker of SZ morbidity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Proc. Natl. Acad. Sci. U.S.A. 2010 Mar 107: 4407-11 |
| PMID | 20150511 |
| Title | Lower number of cerebellar Purkinje neurons in psychosis is associated with reduced reelin expression. |
| Abstract | Reelin is an extracellular matrix protein synthesized in cerebellar granule cells that plays an important role in Purkinje cell positioning during cerebellar development and in modulating adult synaptic function. In the cerebellum of schizophrenia (SZ) and bipolar (BP) disorder patients, there is a marked decrease ( approximately 50%) of reelin expression. In this study we measured Purkinje neuron density in the Purkinje cell layer of cerebella of 13 SZ and 17 BP disorder patients from the McLean 66 Cohort Collection, Harvard Brain Tissue Resource Center. The mean number of Purkinje neurons (linear density, neurons per millimeter) was 20% lower in SZ and BP disorder patients compared with noNPSychiatric subjects (NPS; n = 24). This decrease of Purkinje neuron linear density was unrelated to postmortem interval, pH, drugs of abuse, or to the presence, dose, or duration of antipsychotic medications. A comparative study in the cerebella of heterozygous reeler mice (HRM), in which reelin expression is down-regulated by approximately 50%, showed a significant loss in the number of Purkinje cells in HRM (10-15%) compared with age-matched (3-9 months) wild-type mice. This finding suggests that lack of reelin impairs GABAergic Purkinje neuron expression and/or positioning during cerebellar development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Neuropharmacology 2010 Jan 58: 166-72 |
| PMID | 19576911 |
| Title | Neuropeptide S attenuates neuropathological, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801. |
| Abstract | Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose-dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Int. J. Neuropsychopharmacol. 2012 Oct 15: 1205-15 |
| PMID | 22078257 |
| Title | The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response. |
| Abstract | Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Neuropsychopharmacology 2013 Jan 38: 138-66 |
| PMID | 22948975 |
| Title | The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. |
| Abstract | Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures, including multiple mRNAs that are downregulated in both inhibitory GABAergic and excitatory pyramidal neurons compared with non-psychiatric subjects (NPS). Several reports show increased expression of DNA methyltransferases in telencephalic GABAergic neurons. Accumulating evidence suggests a critical role for altered DNA methylation processes in the pathogenesis of SZ and related psychiatric disorders. The establishment and maintenance of CpG site methylation is essential during central nervous system differentiation and this methylation has been implicated in synaptic plasticity, learning, and memory. Atypical hypermethylation of candidate gene promoters expressed in GABAergic neurons is associated with transcriptional downregulation of the corresponding mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent reports indicate that the methylation status of promoter proximal CpG dinucleotides is in a dynamic balance between DNA methylation and DNA hydroxymethylation. Hydroxymethylation and subsequent DNA demethylation is more complex and involves additional proteins downstream of 5-hydroxymethylcytosine, including members of the base excision repair (BER) pathway. Recent advances in our understanding of altered CpG methylation, hydroxymethylation, and active DNA demethylation provide a framework for the identification of new targets, which may be exploited for the pharmacological intervention of the psychosis associated with SZ and possibly BP+. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Int. J. Neuropsychopharmacol. 2013 Oct 16: 1951-8 |
| PMID | 23680103 |
| Title | The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) influences age at onset of obsessive-compulsive disorder. |
| Abstract | Neuropeptide S (NPS) is a novel central acting neuropeptide that modulates several brain functions. NPS has shown strong anxiolytic-like effects and interactions with other central transmitter systems, including serotonin and glutamate. A coding variation (Asn107Ile) of the NPS receptor gene (NPSR1) was associated with panic disorder and schizophrenia. Based on these encouraging findings, the present study aimed at exploring a potential role of NPSR1 in obsessive?compulsive disorder (OCD). A sample of 232 OCD patients was successfully genotyped for the NPSR1 Asn107Ile variant (rs324981). Age at onset was taken into account to address the heterogeneity of the OCD phenotype. The NPSR1 genotype significantly affected age at onset of the OCD patients, with a mean age at onset approximately 4 yr earlier in homozygous carriers of the low-functioning Asn107 variant compared to patients with at least one Ile107 variant (p=0.032). Case?control analyses with 308 healthy control subjects reveal a highly significant association of the Asn107 variant with early onset OCD (odds ratio=2.36, p=0.0004) while late onset OCD or the OCD group as a whole were unrelated to the NPSR1 genotype. Based on our association finding relating NPSR1 genotype to early onset OCD, we suggest a differential role of the NPS system in OCD. In particular, the early onset OCD subtype seems to be characterized by a genetically driven low NPS tone, which might affect other OCD-related transmitter systems, including the serotonin and glutamate systems. In agreement with preclinical research, we suggest that NPS may be a promising pharmacological candidate with anti-obsessional properties. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Psychiatry Res 2013 Oct 209: 424-30 |
| PMID | 23598059 |
| Title | Are there differential deficits in facial emotion recognition between paranoid and non-paranoid schizophrenia? A signal detection analysis. |
| Abstract | This study assessed facial emotion recognition abilities in subjects with paranoid and non-paranoid schizophrenia (NPS) using signal detection theory. We explore the differential deficits in facial emotion recognition in 44 paranoid patients with schizophrenia (PS) and 30 non-paranoid patients with schizophrenia (NPS), compared to 80 healthy controls. We used morphed faces with different intensities of emotion and computed the sensitivity index (d') of each emotion. The results showed that performance differed between the schizophrenia and healthy controls groups in the recognition of both negative and positive affects. The PS group performed worse than the healthy controls group but better than the NPS group in overall performance. Performance differed between the NPS and healthy controls groups in the recognition of all basic emotions and neutral faces; between the PS and healthy controls groups in the recognition of angry faces; and between the PS and NPS groups in the recognition of happiness, anger, sadness, disgust, and neutral affects. The facial emotion recognition impairment in schizophrenia may reflect a generalized deficit rather than a negative-emotion specific deficit. The PS group performed worse than the control group, but better than the NPS group in facial expression recognition, with differential deficits between PS and NPS patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | J. Korean Med. Sci. 2014 May 29: 719-28 |
| PMID | 24851031 |
| Title | Patterns of antipsychotic prescription to patients with schizophrenia in Korea: results from the health insurance review & assessment service-national patient sample. |
| Abstract | This study aimed to analyze the patterns of antipsychotic prescription to patients with schizophrenia in Korea. Using the Health Insurance Review & Assessment Service-National Patients Sample (HIRA-NPS), which was a stratified sampling from the entire population under the Korean national health security system (2009), descriptive statistics for the patterns of the monopharmacy and polypharmacy, neuropsychiatric co-medications, and prescribed individual antipsychotic for patients with schizophrenia were performed. Comparisons of socioeconomic and clinical factors were performed among patients prescribed only with first- and second-generation antipsychotics. Of 126,961 patients with schizophrenia (age 18-80 yr), 13,369 were prescribed with antipsychotic monopharmacy and the rest 113,592 with polypharmacy. Two or more antipsychotics were prescribed to 31.34% of the patients. Antiparkinson medications (66.60%), anxiolytics (65.42%), mood stabilizers (36.74%), and antidepressants (25.90%) were co-medicated. Patients who were prescribed only with first-generation antipsychotics (n=26,254) were characterized by significantly older age, greater proportion of male, higher proportion of medicaid, higher total medical cost, lower self-payment cost, and higher co-medication rates of antiparkinson agents and anxiolytics than those who were prescribed only with second-generation antipsychotics (n=67,361). In this study, it has been reported substantial prescription rates of first-generation antipsychotics and antipsychotic polypharmacy and relatively small prescription rate of clozapine to patients with schizophrenia. Since this study has firstly presented the patterns of antipsychotic prescription to schizophrenic patients in Korean national population, the findings of this study can be compared with those of later investigations about this theme. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | J. Korean Med. Sci. 2014 May 29: 719-28 |
| PMID | 24851031 |
| Title | Patterns of antipsychotic prescription to patients with schizophrenia in Korea: results from the health insurance review & assessment service-national patient sample. |
| Abstract | This study aimed to analyze the patterns of antipsychotic prescription to patients with schizophrenia in Korea. Using the Health Insurance Review & Assessment Service-National Patients Sample (HIRA-NPS), which was a stratified sampling from the entire population under the Korean national health security system (2009), descriptive statistics for the patterns of the monopharmacy and polypharmacy, neuropsychiatric co-medications, and prescribed individual antipsychotic for patients with schizophrenia were performed. Comparisons of socioeconomic and clinical factors were performed among patients prescribed only with first- and second-generation antipsychotics. Of 126,961 patients with schizophrenia (age 18-80 yr), 13,369 were prescribed with antipsychotic monopharmacy and the rest 113,592 with polypharmacy. Two or more antipsychotics were prescribed to 31.34% of the patients. Antiparkinson medications (66.60%), anxiolytics (65.42%), mood stabilizers (36.74%), and antidepressants (25.90%) were co-medicated. Patients who were prescribed only with first-generation antipsychotics (n=26,254) were characterized by significantly older age, greater proportion of male, higher proportion of medicaid, higher total medical cost, lower self-payment cost, and higher co-medication rates of antiparkinson agents and anxiolytics than those who were prescribed only with second-generation antipsychotics (n=67,361). In this study, it has been reported substantial prescription rates of first-generation antipsychotics and antipsychotic polypharmacy and relatively small prescription rate of clozapine to patients with schizophrenia. Since this study has firstly presented the patterns of antipsychotic prescription to schizophrenic patients in Korean national population, the findings of this study can be compared with those of later investigations about this theme. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | J Am Assoc Nurse Pract 2014 Nov 26: 629-37 |
| PMID | 24715687 |
| Title | New findings: depression, suicide, and Toxoplasma gondii infection. |
| Abstract | This article provides an overview of the evidence of a potential pathophysiological relationship between depression, suicide, and the Toxoplasma gondii (T. gondii) infection. It discusses the role of inflammatory processes in depressive illness and the infection theory of psychiatric disease. It also provides guidelines for the screening, diagnosis, and treatment of depression for nurse practitioners (NPS). A narrative review was conducted of the literature from PubMed, PsycINFO, and Google Scholar. References of identified articles were also reviewed. Seropositivity of the obligate intracellular protozoan parasite, T. gondii is related to various mental health disorders including schizophrenia, suicide attempt, depression, and other neuropsychiatric diseases. Depressive symptoms have been linked to interferon-? (IFN-?) blocking T. gondii growth by inducing indoleamine-2,3-dioxygenase (IDO) activation and tryptophan depletion, which results in a decrease of serotonin production in the brain. Although exposure to T. gondii was considered unlikely to reactivate in immune-competent individuals, new findings report that this reactivation may be triggered by immune imbalance. NPS caring for patients with psychiatric illness need to understand the potential mechanisms associated with depression and the T. gondii infection in order to provide effective screening, treatment, and disease prevention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | BMJ Case Rep 2015 -1 2015: -1 |
| PMID | 25948854 |
| Title | A novel psychoactive substance poses a new challenge in the management of paranoid schizophrenia. |
| Abstract | Novel psychoactive substances (NPS), or 'legal highs' are becoming more commonly used as recreational substances in the UK. Their clinical effects are little known and vary considerably between substances. This case discusses a psychiatric inpatient who repeatedly used a stimulant NPS called 'el blanco' while on leave, precipitating relapses of his schizophrenia. The patient initially denied drug use, considering legal highs as different from drugs. The relationship between NPS use and mental state was eventually revealed on careful direct questioning. He recovered and was discharged following treatment with clozapine and education about NPS use. We suggest that specific questioning about NPS usage is added to routine psychiatric history taking and that patients using NPS should be educated about the substances' use. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | J. Psychopharmacol. (Oxford) 2015 Mar 29: 254-63 |
| PMID | 25586398 |
| Title | The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects. |
| Abstract | Cannabis use is associated with an increased risk of psychosis in vulnerable individuals. Cannabis containing high levels of the partial cannabinoid receptor subtype 1 (CB1) agonist tetrahydrocannabinol (THC) is associated with the induction of psychosis in susceptible subjects and with the development of schizophrenia, whereas the use of cannabis variants with relatively high levels of cannabidiol (CBD) is associated with fewer psychotic experiences. Synthetic cannabinoid receptor agonists (SCRAs) are full agonists and often more potent than THC. Moreover, in contrast to natural cannabis, SCRAs preparations contain no CBD so that these drugs may have a higher psychosis-inducing potential than cannabis. This paper reviews the general toxicity profile and the adverse effects of SCRAs with special emphasis on their psychosis-inducing risk. The review shows that, compared with the use of natural cannabis, the use of SCRAs may cause more frequent and more severe unwanted negative effects, especially in younger, inexperienced users. Psychosis and psychosis-like conditions seem to occur relatively often following the use of SCRAs, presumably due to their high potency and the absence of CBD in the preparations. Studies on the relative risk of SCRAs compared with natural cannabis to induce or evoke psychosis are urgently needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Small 2015 May 11: 2399-406 |
| PMID | 25604239 |
| Title | Highly Sensitive and Selective Field-Effect-Transistor NonEnzyme Dopamine Sensors Based on Pt/Conducting Polymer Hybrid Nanoparticles. |
| Abstract | Dopamine (DA), as one of catecholamine family of neurotransmitters, is crucially important in humans owing to various critical effects on biometric system such as brine circuitry, neuronal plasticity, organization of stress responses, and control of cardiovascular and renal organizations. Abnormal level of dopamine in the central nervous system causes several neurological diseases, e.g., schizophrenia, Parkinson's disease, and attention deficit hybperactivity disorder (ADHD)/attention deficit disorder (ADD). In this report, we suggest the fabrication of nonenzyme field effect transistor (FET) sensor composed of immobilized Pt particle decorated conducting-polymer (3-carboxylate polypyrrole) nanoparticles (Pt_CPPy) to detect dopamine. The hybrid nanoparticles (NPS) are produced by means of facile chemical reduction of pristine CPPyNP-contained Pt precursor (PtCl4 ) solution. The Pt_CPPys are then immobilized on an amine-functionalized (-NH2 ) interdigitated-array electrode substrate, through the formation of covalent bonds with amine groups (-CONH). The resulting Pt_CPPy-based FET sensors exhibit high sensitivity and selectivity toward DA at unprecedentedly low concentrations (100 × 10(-15) m) and among interfering biomolecules, respectively. Additionally, due to the covalent bonding involved in the immobilization process, a longer lifetime is expected for the FET sensor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Int J Psychiatry Clin Pract 2016 -1 20: 40-6 |
| PMID | 26442635 |
| Title | Mobility behaviour and driving status of patients with mental disorders - an exploratory study. |
| Abstract | Driving is an important activity of daily life and an integral part of mobility. However, impact of mental illness on road mobility is widely unexplored. Driving status in 1497 psychiatric inpatients (PPs) and a clinical control group of 313 neurological inpatients (NPS) was investigated using a brief questionnaire. 67% of PPs (89% NPS) reported to have a valid driver's licence and 77% of them (92% NPS) reported to regularly use their cars. Within driver's license holders, patients with organic mental disorder (32%), substance dependence (37%) and psychotic disorder (40%) had the lowest proportion of current drivers. Higher educational qualification (odds ratio [OR] from 2.978 to 17.036) and being married/partnered (OR 3.049) or divorced (OR 4.840) significantly advanced the probability of possession of a driving license. Predictive factors for driving cessation were being female, an older age, drawing a pension and having an organic mental disease or schizophrenic disorder. Mental disease has a negative impact on driving status and this is especially true for illnesses frequently being accompanied by distinct cognitive impairments. Factors predicting road mobility elucidate the strong relationship with psychosocial status indicating that recovery of driving competence should be an integral goal of treatment strategies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Mater Sci Eng C Mater Biol Appl 2016 Sep 66: 230-43 |
| PMID | 27207059 |
| Title | Aripiprazole loaded poly(caprolactone) nanoparticles: Optimization and in vivo pharmacokinetics. |
| Abstract | In the present investigation, a Quality by Design strategy was applied for formulation and optimization of aripiprazole (APZ) loaded PCL nanoparticles (APNPS) using nanoprecipitation method keeping entrapment efficiency (%EE) and particle size (PS) as critical quality attributes. Establishment of design space was done followed by analysis of its robustness and sensitivity. Characterization of optimized APNPS was done using DSC, FT-IR, PXRD and TEM studies and was evaluated for drug release, hemocompatibility and nasal toxicity. PS, zeta potential and %EE of optimized APNPS were found to be 199.2±5.65nm, -21.4±4.6mV and 69.2±2.34% respectively. In vitro release study showed 90±2.69% drug release after 8h. Nasal toxicity study indicated safety of developed formulation for intranasal administration. APNPS administered via intranasal route facilitated the brain distribution of APZ incorporated with the AUC0?8 in rat brain approximately 2 times higher than that of APNPS administered via intravenous route. Increase in Cmax was observed which might help in dose reduction along with reduction in dose related side effects. The results of the study indicate that intranasally administered APZ loaded PCL NPS can potentially transport APZ via nose to brain and can serve as a non-invasive alternative for the delivery of APZ to brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | J Psychiatr Ment Health Nurs 2016 Apr -1: -1 |
| PMID | 27037639 |
| Title | A systematic review of the effects of novel psychoactive substances 'legal highs' on people with severe mental illness. |
| Abstract | WHAT IS KNOWN ON THE SUBJECT?: Novel psychoactive substances (NPS) include synthetic drugs mimicking the effects of illicit drugs, e.g. synthetic cannabinoids, and herbs such as Salvia divinorum. NPS are substances that can trigger hallucinations and other effects altering the mind, and are currently uncontrolled by the United Nations' 1961 Narcotic Drugs/1971 Psychotropic Substances Conventions. NPS affect brain chemistry that induces the psychoactive effects, such as hallucinations and feeling 'high'. It is unknown what effects such drugs have on people with severe mental illness (i.e. psychotic illnesses). WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Our review demonstrates that little is known about the effects of various NPS on people with severe mental illness. Almost nothing is known about the long-term consequences of NPS use on the mental and physical health of SMI patients. Patients may lack understanding that NPS are psychoactive drugs that can impact on their mental and physical wellbeing. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Some patients might be reluctant or do not think it is relevant to disclose NPS use. Commonly used illicit drug screening is unlikely to detect the presence of NPS, therefore health and mental health professionals should directly enquire about NPS and actively encourage patients with severe mental illness to disclose any substance use. There was no significant patient and public involvement in the development and conduct of this study . Introduction Novel psychoactive substances (NPS) are synthetic substances that have been developed to produce altered states of consciousness and perceptions. People with severe mental illness (SMI) are more likely to use NPS than people without mental illness, but the short- and long-term effects of NPS are largely unknown. Method We systematically reviewed the literature about the effects of NPS on people with SMI. Results We included 12 case reports, 1 cross-sectional survey and 1 qualitative study. Participants included mostly males aged between 20 and 35 years. A variety of NPS were used, including synthetic cathinones and herbs such as Salvia. The most commonly reported effects of NPS were psychotic symptoms (in some cases novel in form and content to the patients' usual symptoms) and significant changes in behaviour, including agitation, aggression and violence. Patients' vital signs, such as blood pressure, pulse rate and temperature, were also commonly affected. Conclusion NPS potentially have serious effects on people with SMI, but our findings have limited generalizability due to a reliance on case studies. There is a paucity of evidence about the long-term effects of these substances. Further research is required to provide a better understanding about how different NPS affect patients' mental and physical health. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |