| 1 | Brain Res. Mol. Brain Res. 2000 Mar 76: 132-41 |
|---|---|
| PMID | 10719223 |
| Title | New dopamine receptor, D2(Longer), with unique TG splice site, in human brain. |
| Abstract | Brain dopamine receptor agonists alleviate the signs of Parkinson's disease, while dopamine receptor antagonists alleviate hallucinations and delusions in psychosis. The dopamine type 2 receptor (or D2) is blocked by antipsychotic drugs, including even the "atypical" drugs such as clozapine or remoxipride, in direct relation to their clinical potencies. Compared to the long form of the D2 receptor (D2(Long)), the short form (D2(Short)) may be three times more sensitive to benzamide antipsychotic drugs. Hence, it is essential to identify additional variants of dopamine receptors for which more selective antipsychotic drugs can be found. Although no family linkage has been found between the D2 receptor and schizophrenia, there can be brain region abnormalities in the RNA transcript expression of dopamine receptors. Therefore, in order to identify variant dopamine D2 receptors, we searched for mutations in the RNA transcripts for the dopamine D2 receptor in the striatum of post-mortem brains from individuals who died with psychosis, including schizophrenia. A new splice variant of the D2 receptor, D2(Longer), with a unique TG splice site, was found in one control brain and in two psychotic brains. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Acta Pharmacol. Sin. 2003 Oct 24: 1001-5 |
| PMID | 14531942 |
| Title | Effects of phenothiazine drugs on serum levels of apolipoproteins and lipoproteins in schizophrenic subjects. |
| Abstract | To investigate the risk factors and clinical significance of blood-lipid metabolic disorder in schizophrenic patients caused by phenothiazine treatment for long term (from 1 month to 25 years). Serum levels of apolipoprotein AI (apoAI), apolipoprotein B (apoB), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and total cholesterol (TC) were measured in 120 chronic schizophrenia patients, 50 vascular dementia, and 100 normal controls by the enzyme method and immune fluoroscopy turbidimetric method. The patients with schizophrenia and vascular dementia had significantly lower content of apoAI, HDL-C, and apoAI/apoB than those in normal control (P<0.01). Their apoB and TG levels were higher than the healthy control group (P<0.01). The TG contents in the negative group and the vascular dementia group were obviously higher than the positive group (P<0.01) while there was no marked difference between the TC levels in the three groups and the normal control group (P>0.05). The chronic schizophrenic patients have a blood-lipid metabolic disorder by long-term intake of phenothiazine drugs. It is suggested that the traditional treatment with antipsychotic should reformed, and that drugs of degrading lipid and coagulation should be used to prevent and reduce the risk factors causing the onset of cardiovascular and cerebrovascular diseases and delay the development of the disturbance of intelligence and dementia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Acta Pharmacol. Sin. 2003 Oct 24: 1001-5 |
| PMID | 14531942 |
| Title | Effects of phenothiazine drugs on serum levels of apolipoproteins and lipoproteins in schizophrenic subjects. |
| Abstract | To investigate the risk factors and clinical significance of blood-lipid metabolic disorder in schizophrenic patients caused by phenothiazine treatment for long term (from 1 month to 25 years). Serum levels of apolipoprotein AI (apoAI), apolipoprotein B (apoB), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and total cholesterol (TC) were measured in 120 chronic schizophrenia patients, 50 vascular dementia, and 100 normal controls by the enzyme method and immune fluoroscopy turbidimetric method. The patients with schizophrenia and vascular dementia had significantly lower content of apoAI, HDL-C, and apoAI/apoB than those in normal control (P<0.01). Their apoB and TG levels were higher than the healthy control group (P<0.01). The TG contents in the negative group and the vascular dementia group were obviously higher than the positive group (P<0.01) while there was no marked difference between the TC levels in the three groups and the normal control group (P>0.05). The chronic schizophrenic patients have a blood-lipid metabolic disorder by long-term intake of phenothiazine drugs. It is suggested that the traditional treatment with antipsychotic should reformed, and that drugs of degrading lipid and coagulation should be used to prevent and reduce the risk factors causing the onset of cardiovascular and cerebrovascular diseases and delay the development of the disturbance of intelligence and dementia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Brain Res. 2003 Dec 994: 99-106 |
| PMID | 14642453 |
| Title | Increased auditory startle response and reduced prepulse inhibition of startle in transgenic mice expressing a double mutant form of amyloid precursor protein. |
| Abstract | Prepulse inhibition (PPI), a form of sensorimotor gating, occurs when an auditory startle response is markedly inhibited by a preceding sub-threshold stimulus (prepulse). Deficits in PPI have been demonstrated in patients with certain psychiatric disorders, such as schizophrenia, and in laboratory animals following specific pharmacological manipulations. Patients with Alzheimer's disease (AD) have not been tested in PPI, but have been shown to have abnormal sensory gating in another paradigm. Transgenic (TG) CRND8 mice, which model Alzheimer's disease, carry the Swedish and Indiana familial Alzheimer's disease mutations of the human amyloid precursor protein gene and show age-related increases in beta-amyloid (Abeta) production, as well as plaque deposition. The present experiment investigated auditory startle threshold and PPI in TGCRND8 mice at various ages. In two longitudinal studies, PPI was examined in male TGCRND8 mice and non-transgenic (non-TG) controls at 6-8 weeks of age (pre-plaque), and every 2 weeks thereafter until all mice were at least 16 weeks old (post-plaque). In a cross-sectional study, three different age sets of nai;ve TGCRND8 and non-TG mice were tested: 10-12, 12-14, and 15-17 weeks old. In all three studies, TGCRND8 mice consistently and robustly demonstrated an enhanced response to a range of auditory startle stimuli compared to non-TG mice. In addition, the TGCRND8 mice exhibited modest reductions in PPI, compared to non-TG controls. These PPI deficits were present at pre- and post-plaque time points and did not appear to intensify with age; thus, they do not seem to correlate with the known neuropathology of TGCRND8 mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Life Sci. 2003 Nov 74: 55-73 |
| PMID | 14575813 |
| Title | Behavioral and biochemical studies on chronic mild stress models in rats treated with a Chinese traditional prescription Banxia-houpu decoction. |
| Abstract | There is increasing evidence that psychological stress and depression trigger changes in various biochemical parameters in animals and in human subjects. In order to study these effects, the impact of chronic mild stress (CMS) on rats, and of the subsequent administration of Banxia-houpu decoction and fluoxetine, were studied regarding their effects on the following biochemical parameters: 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions, natural killer (NK) cell and lymphokine-activated killer (LAK) cell activities in spleen, serum lipid profiles including total cholesterol (TC), high density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc) and triglyceride (TG), liver superoxide dismutase (SOD) and nitric oxide synthase (NOS) activities, serum malondialdehyde (MDA), and interleukin-2 (IL-2) levels. The effects of drug administration on preference behavior for consumption of sucrose solution were also assessed. Rats subjected to CMS exhibited a reduction in sucrose intake, 5-HT, 5-HIAA, IL-2, TC, HDLc and LDLc levels, as well as, diminished NK cell and LAK cell activities. Conversely, liver SOD and NOS activities and serum TG and MDA levels were increased following CMS exposures. Administration of Banxia-houpu decoction and fluoxetine produced beneficial effects on the stressed rats by improving sucrose consumption. This behavioral change was accompanied by amelioration of numbers CMS-induced biochemical changes. Banxia-houpu decoction is a traditional Chinese prescription containing pinellia tuber, magnolia bark, hoelen, perilla herb and ginger rhizome, and has been used for centuries in China to treat mental diseases including depression and schizophrenia. However, the pharmacological profile of the decoction is different from that of fluoxetine. These findings suggest that the therapeutic actions of Banxia-houpu decoction are due to a combination of multiple biochemical effects, and may help to elucidate the mechanisms through which distinct biochemical parameters play a role in the etiology of depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Neurosci. Lett. 2004 Sep 368: 41-5 |
| PMID | 15342131 |
| Title | Association study of polymorphisms in the 5' upstream region of human DISC1 gene with schizophrenia. |
| Abstract | Disrupted-in-schizophrenia-1 (DISC1) is a gene in which a mutant truncation by a balanced t(1;11)(p42.1;q14.3) translocation is segregated with major psychiatric illness with a predominance of schizophrenic symptomatology in a large Scottish family. However, no functional polymorphisms have been detected that are associated with schizophrenia in general populations. As prior polymorphism searches in DISC1 have been focused on coding exons and flanking introns, the present study examined sequence variations in the 5' upstream region of DISC1. Screening of exon 1 through to approximately 1.0 kb upstream of exon 1 identified 6 polymorphisms, including 2 novel variants, -94C>A and -199(CG)(n). We tested these variants for associations with schizophrenia in the first set of a case (n = 198) and control (n = 198) panel, and found significant results with -274G>C (genotypic P = 0.01) and -215(TG)(n) (genotypic P = 0.039). However, we failed to replicate these associations in a second, larger independent patient (n = 532) and control (n = 519) sample. These results suggest that the genomic interval of DISC1 probably involved in transcriptional regulation does not display major genetic relevance in Japanese schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Neurosci. Lett. 2004 Sep 368: 41-5 |
| PMID | 15342131 |
| Title | Association study of polymorphisms in the 5' upstream region of human DISC1 gene with schizophrenia. |
| Abstract | Disrupted-in-schizophrenia-1 (DISC1) is a gene in which a mutant truncation by a balanced t(1;11)(p42.1;q14.3) translocation is segregated with major psychiatric illness with a predominance of schizophrenic symptomatology in a large Scottish family. However, no functional polymorphisms have been detected that are associated with schizophrenia in general populations. As prior polymorphism searches in DISC1 have been focused on coding exons and flanking introns, the present study examined sequence variations in the 5' upstream region of DISC1. Screening of exon 1 through to approximately 1.0 kb upstream of exon 1 identified 6 polymorphisms, including 2 novel variants, -94C>A and -199(CG)(n). We tested these variants for associations with schizophrenia in the first set of a case (n = 198) and control (n = 198) panel, and found significant results with -274G>C (genotypic P = 0.01) and -215(TG)(n) (genotypic P = 0.039). However, we failed to replicate these associations in a second, larger independent patient (n = 532) and control (n = 519) sample. These results suggest that the genomic interval of DISC1 probably involved in transcriptional regulation does not display major genetic relevance in Japanese schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Acta Psychiatr Scand 2004 Oct 110: 279-85 |
| PMID | 15352929 |
| Title | Serum lipids in schizophrenia and other functional psychoses: a general population northern Finland 1966 birth cohort survey. |
| Abstract | To compare fasting serum lipid concentrations of subjects with schizophrenia with a comparison group. The study sample consists of 5654 members of the northern Finland 1966 birth cohort who participated in the field study with blood samples after overnight fasting and clinical examination in 1997-98. Total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides (TG) and glucose were analyzed. Analysis of variance were used for comparing differences in lipids means between diagnostic categories. Mean fasting TC in subjects with schizophrenia was 20 mg/dl higher than in the comparison group. TC and TG levels in the group of other psychoses resembled the schizophrenia group. Blood lipid levels in subjects with schizophrenia and other functional psychoses were high. As these persons are at special risk for hyperlipidemia their lipid levels should be regularly monitored, and cholesterol lowering diet, as well as medication, should be considered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | BMC Genomics 2005 -1 6: 157 |
| PMID | 16280085 |
| Title | Genetic mapping of putative Chrna7 and Luzp2 neuronal transcriptional enhancers due to impact of a transgene-insertion and 6.8 Mb deletion in a mouse model of Prader-Willi and Angelman syndromes. |
| Abstract | Prader-Willi and Angelman syndrome (PWS and AS) patients typically have an approximately 5 Mb deletion of human chromosome 15q11-q13, of opposite parental origin. A mouse model of PWS and AS has a transgenic insertion-deletion (TGPWS/TGAS) of chromosome 7B/C subsequent to paternal or maternal inheritance, respectively. In this study, we define the deletion endpoints and examine the impact on expression of flanking genes. Using molecular and cytological methods we demonstrate that 13 imprinted and 11 non-imprinted genes are included in the TGPWS/TGAS deletion. Normal expression levels were found in TGPWS brain for genes extending 9.1- or 5.6-Mb centromeric or telomeric of the deletion, respectively. Our molecular cytological studies map the proximal deletion breakpoint between the Luzp2 and Siglec-H loci, and we show that overall mRNA levels of Luzp2 in TGPWS and TGAS brain are significantly reduced by 17%. Intriguingly, 5' Chrna7 shows 1.7-fold decreased levels in TGPWS and TGAS brain whereas there is a > or =15-fold increase in expression in neonatal liver and spleen of these mouse models. By isolating a Chrna7-TG fusion transcript from TGAS mice, we mapped the telomeric deletion breakpoint in Chrna7 intron 4. Based on the extent of the deletion, TGPWS/TGAS mice are models for PWS/AS class I deletions. Other than for the first gene promoters immediately outside the deletion, since genes extending 5.6-9.1 Mb away from each end of the deletion show normal expression levels in TGPWS brain, this indicates that the transgene array does not induce silencing and there are no additional linked rearrangements. Using gene expression, non-coding conserved sequence (NCCS) and synteny data, we have genetically mapped a putative Luzp2 neuronal enhancer responsible for approximately 33% of allelic transcriptional activity. The Chrna7 results are explained by hypothesizing loss of an essential neuronal transcriptional enhancer required for approximately 80% of allelic Chrna7 promoter activity, while the Chrna7 promoter is upregulated in B lymphocytes by the transgene immunoglobulin enhancer. The mapping of a putative Chrna7 neuronal enhancer inside the deletion has significant implications for understanding the transcriptional regulation of this schizophrenia-susceptibility candidate gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Schizophr. Res. 2005 Dec 80: 55-9 |
| PMID | 15964176 |
| Title | Serum lipid profiles and schizophrenia: effects of conventional or atypical antipsychotic drugs in Taiwan. |
| Abstract | This study investigated the relationships between serum lipid profiles and schizophrenia and the effects of conventional or atypical antipsychotic drugs on serum lipid profiles. During a 1-year period, fasting blood samples for serum lipid profiles were collected from 126 schizophrenic patients and 59 healthy control subjects. The serum lipid profiles were detected by enzymatic determination. Patients were assessed for disease severity at baseline and endpoint at 3 weeks using the Positive and Negative Syndrome Scale. At baseline, patients with acute-phase schizophrenia had lower high-density lipoprotein (HDL) levels, higher low-density lipoprotein (LDL) levels, and higher ratios of total cholesterol/high-density lipoprotein (TC/HDL) and LDL/HDL than healthy control subjects. At endpoint, after a 3-week treatment with antipsychotics, the blood samples of the 97 schizophrenic patients were assessed again. Responders to antipsychotic treatment (n = 68) but not nonresponders (n = 29) had significantly increased TC, triglyceride (TG), and very low-density lipoprotein (VLDL) levels and decreased ratio of LDL/HDL. Experimental findings also showed significantly increased TC, TG, HDL, and VLDL levels and decreased ratio of LDL/HDL in responders taking atypical antipsychotic drugs (n = 32), but not in patients treated with conventional antipsychotic drugs (n = 36). In conclusion, this study identified strong associations between dyslipidemia and acute-phase schizophrenia and dyslipidemia and responders taking atypical antipsychotics; both associations would increase the risk of developing diabetes and coronary heart disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Schizophr. Res. 2005 Dec 80: 55-9 |
| PMID | 15964176 |
| Title | Serum lipid profiles and schizophrenia: effects of conventional or atypical antipsychotic drugs in Taiwan. |
| Abstract | This study investigated the relationships between serum lipid profiles and schizophrenia and the effects of conventional or atypical antipsychotic drugs on serum lipid profiles. During a 1-year period, fasting blood samples for serum lipid profiles were collected from 126 schizophrenic patients and 59 healthy control subjects. The serum lipid profiles were detected by enzymatic determination. Patients were assessed for disease severity at baseline and endpoint at 3 weeks using the Positive and Negative Syndrome Scale. At baseline, patients with acute-phase schizophrenia had lower high-density lipoprotein (HDL) levels, higher low-density lipoprotein (LDL) levels, and higher ratios of total cholesterol/high-density lipoprotein (TC/HDL) and LDL/HDL than healthy control subjects. At endpoint, after a 3-week treatment with antipsychotics, the blood samples of the 97 schizophrenic patients were assessed again. Responders to antipsychotic treatment (n = 68) but not nonresponders (n = 29) had significantly increased TC, triglyceride (TG), and very low-density lipoprotein (VLDL) levels and decreased ratio of LDL/HDL. Experimental findings also showed significantly increased TC, TG, HDL, and VLDL levels and decreased ratio of LDL/HDL in responders taking atypical antipsychotic drugs (n = 32), but not in patients treated with conventional antipsychotic drugs (n = 36). In conclusion, this study identified strong associations between dyslipidemia and acute-phase schizophrenia and dyslipidemia and responders taking atypical antipsychotics; both associations would increase the risk of developing diabetes and coronary heart disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Georgian Med News 2006 May -1: 55-8 |
| PMID | 16783066 |
| Title | Risk factors for coronary heart disease in patients with schizophrenia. |
| Abstract | Cardiovascular disease is the leading cause of death worldwide. As many as half of these death may be attributed to the unhealthy cholesterol and lipid levels. Elevated cholesterol levels could contribute to the increase in cardiovascular morbidity and mortality. Association between the coronary artery disease and mental disorder is less studied and documented, but several studies have demonstrated, that mental disorders increases the risk of developing cardiac disease, in particular coronary artery disease. Cholesterol and other lipids level were measured in 40 patients (n=40). Cholesterol and LDL levels in patients with schizophrenia were significantly higher and HDL was significantly decreased. Cholesterol level 180-200 mg/dl were determined in 35%, 200-235 mg/dl in 17,5%, >235 mg/dl 12,5%. HDL->35 mg/dl revealed in 37,5%. LDL 130-159 mg/dl were determined in 10%, >160 mg/dl - 20%. Triglycerides (TG) from 150 mg/dl to 199 mg/dl were determined in 25%, from 200 mg/dl to 499 mg/dl in 12,5%. According to our study, patients with schizophrenia has some risk factors for cardiovascular heart disease such as, elevated levels of TG and LDL-c, smoking, lack of exercise, psychosocial factors (depression, social isolation and lack of social support, low socioeconomic status) and so on. We can conclude that all these patients with schizophrenia may belong to the risk group of cardiovascular disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Eur. J. Neurosci. 2007 Dec 26: 3237-52 |
| PMID | 18005073 |
| Title | Transgenic overexpression of adenosine kinase in brain leads to multiple learning impairments and altered sensitivity to psychomimetic drugs. |
| Abstract | The neuromodulator adenosine fulfills a unique role in the brain affecting glutamatergic neurotransmission and dopaminergic signaling via activation of adenosine A1 and A2A receptors, respectively. The adenosine system is thus ideally positioned to integrate glutamatergic and dopaminergic neurotransmission, which in turn could affect behavior and cognition. In the adult brain, adenosine levels are largely regulated by its key metabolic enzyme adenosine kinase (ADK), which may assume the role of an 'upstream regulator' of these two neurotransmitter pathways. To test this hypothesis, transgenic mice with an overexpression of ADK in brain (Adk-TG), and therefore reduced brain adenosine levels, were evaluated in a panel of behavioral and psychopharmacological assays to assess possible glutamatergic and dopaminergic dysfunction. In comparison to non-transgenic control mice, Adk-TG mice are characterized by severe learning deficits in the Morris water maze task and in Pavlovian conditioning. The Adk-TG mice also exhibited reduced locomotor reaction to systemic amphetamine, whereas their reaction to the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 was enhanced. Our results confirmed that ADK overexpression could lead to functional concomitant alterations in dopaminergic and glutamatergic functions, which is in keeping with the hypothesized role of ADK in the balance and integration between glutamatergic and dopaminergic neurotransmission. The present findings are of relevance to current pathophysiological hypotheses of schizophrenia and its pharmacotherapy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Neuropharmacology 2007 Feb 52: 634-45 |
| PMID | 17097694 |
| Title | The odour span task: a novel paradigm for assessing working memory in mice. |
| Abstract | Impoverished odour recognition and memory are amongst the earliest symptoms observed in mild cognitive impairment, Alzheimer's disease and schizophrenia, and have been advocated as early disease bio-markers. Although transgenic animals modelling disease pathologies continually emerge, there remains a paucity of tasks to examine olfactory working memory in mice. The present studies describe a mouse odour span task, which assesses the ability to remember increasing numbers of odours. Since caspase-3 is highly expressed throughout the olfactory system, we postulated that mice over-expressing this apoptogenic protein would exhibit impaired performance in the odour span task. Mice over-expressing human caspase-3 (TG) exhibited age-independent deficits in olfactory working memory (6-18 months) compared with wild-type littermates, requiring longer for task acquisition and exhibiting impaired asymptotic performance, with reduced span lengths, lower accuracy and increased error rates. These impairments appeared to be selective for working memory, as TG mice had no deficits in odour discriminatory ability or in locomotor measures. Importantly, nicotine, which improves working memory span in man, reversed the deficits exhibited by TG mice. In conclusion, the mouse odour span task can detect subtle changes in olfactory working memory induced by genetic manipulation and drug administration and therefore should be applied to animal models of neurological disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Mol. Psychiatry 2007 Oct 12: 966-74 |
| PMID | 17339875 |
| Title | More evidence supports the association of PPP3CC with schizophrenia. |
| Abstract | Calcineurin is a calcium/calmodulin-dependent protein phosphatase composed of two subunits, a regulatory subunit of calcineurin B (CNB) and a catalytic subunit of calcineurin A (CNA). PPP3CC is the gamma isoform of CNA located at the chromosome 8p21.3 region. To evaluate the association between PPP3CC and schizophrenia in the Taiwanese population, 10 single nucleotide polymorphism (SNP) markers across the gene were genotyped by the method of MALDI-TOF in 218 schizophrenia families with at least two affected siblings. One SNP (rs2272080) located around the exon 1 untranslated region was nominally associated with schizophrenia (P=0.024) and significantly associated with the expression of PPP3CC in lymphoblast cell line; the TT and TG genotype had significantly higher relative expression levels than the GG genotype (P=0.0012 and 0.015, respectively). In further endophenotype stratification, the single locus of rs2272080 and the haplotypes of both two-SNP haplotype (rs7833266-rs2272080) and seven-SNP haplotype (rs2461491-rs2469758-rs2461489-rs2469770-rs2449340-rs1482337-rs2252471) showed significant associations with the subgroup of schizophrenia with deficits of the sustained attention as tested by the continuous performance test (CPT, P<0.05) and the executive functioning as tested by the Wisconsin Card Sorting Test (WCST, P<0.05). The results suggest that PPP3CC gene may be a true susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Schizophr Bull 2007 May 33: 782-8 |
| PMID | 17387159 |
| Title | A controlled prospective study of toxoplasma gondii infection in individuals with schizophrenia: beyond seroprevalence. |
| Abstract | Toxoplasma gondii (TG) infection has been reported to be more frequent in schizophrenia. The interaction of the lifelong persisting parasite with the host's immune system involves T-cell/interferon-gamma-induced degradation of tryptophan and provides a challenge to the host well beyond a possible role in the etiology of schizophrenia. The hypothesis we tested in this study was that TG infection may be more frequent (serofrequency) and/or more intense (serointensity) in patients with schizophrenia or major depression compared with psychiatrically healthy controls. In addition, these measures are associated with the clinical course. We did a cross-sectional, prospective investigation of individuals with schizophrenia (n = 277) and major depression (n = 465) admitted to our department (2002-2005) and of healthy controls (n = 214), with all groups adjusted for age and geographic home region. Serofrequency was comparable between the groups, but serointensity was significantly higher in the patients. In individuals with schizophrenia, serointensity was significantly positively associated with C-reactive protein levels and leukocyte counts, and first-episode patients yielded significantly higher serotiters. Immunomodulatory medication was associated with decreased serotiters. In addition, the route of infection appears to differ between patients and controls. Thus, our results support increased host responses to TG infection in the patients, as well as increased titers in first-episode patients with schizophrenia; this may relate to the shifted T-helper 1/2 status described in these patients. Therefore, we suggest that TG infection, particularly in individuals with schizophrenia, is an important environmental factor in the interaction between psychiatric vulnerability, genetic background, immunomodulation, and the neurotransmitter systems. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Schizophr. Res. 2007 Jan 89: 91-100 |
| PMID | 17070017 |
| Title | Does antipsychotic polypharmacy increase the risk for metabolic syndrome? |
| Abstract | To determine whether the coprescribing of two or more antipsychotics, a relatively frequent practice with little data to support its safety and efficacy, is associated with an increased prevalence of metabolic syndrome. 364 newly admitted adults treated with second-generation antipsychotics underwent assessments evaluating antipsychotic polytherapy, and of the presence of metabolic syndrome and triglycerides/high-density lipoprotein cholesterol ratio>3.5 (TG/HDL), a sensitive marker of insulin resistance. The correlates of antipsychotic polytherapy and associations with metabolic syndrome and TG/HDL were determined by univariate comparisons and multiple logistic regression analyses. Antipsychotic polytherapy was present in 70 patients (19.2%) and was significantly more likely in patients with schizophrenia and those treated with clozapine, quetiapine or ziprasidone (p<0.0001). Compared with antipsychotic monotherapy, polytherapy was associated with elevated rates of metabolic syndrome (50.0% vs. 34.3%, p=0.015) and TG/HDL (50.7% vs. 35.0%, p=0.016). However, in logistic regression analyses, metabolic syndrome was significantly associated with higher body mass index (BMI), older age, a diagnosis of bipolar disorder or schizophrenia, and cotreatment with a first-generation antipsychotic (r(2): 0.25, p<0.0001). The TG/HDL marker of insulin resistance was associated with higher BMI, male sex, Caucasian race and absence of aripiprazole treatment (r(2): 0.14, p<0.0001). Antipsychotic polypharmacy dropped out of both multivariate models. Compared with patients receiving antipsychotic monotherapy, patients on antipsychotic polytherapy have higher rates of metabolic syndrome and lipid markers of insulin resistance. However, antipsychotic polytherapy is not independently associated with the prevalence of these abnormalities, which are related to known demographic, clinical and anthropometric risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Pharmacogenomics J. 2008 Jun 8: 228-36 |
| PMID | 17726453 |
| Title | Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. |
| Abstract | schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug x gene and drug x haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine- or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Psychiatry Res 2008 May 159: 245-9 |
| PMID | 18346794 |
| Title | Association study of a (TG)n dinucleotide repeat at chromosome 15q13.3 and schizophrenia in the Chinese population. |
| Abstract | Linkage studies have suggested that chromosome 15q13-q14 may harbor a susceptibility locus for schizophrenia. In the current study, the association between a (TG)n dinucleotide repeat polymorphism at D15S976 and schizophrenia was investigated using two independent samples from the Han Chinese population. In a population-based study, no significant difference was found between the genotype and allele frequency distributions in schizophrenia patients and control subjects. In a family-based study, no significant transmission disequilibrium from heterozygous parents to affected offspring was observed. Further analysis of the parent-of-origin effect found nominally significant allele-wise transmission disequilibrium through maternal transmissions, while 157bp and 159bp alleles showed significant individual allelic transmission disequilibrium from heterozygous mothers to affected offspring. Our results did not support the hypothesis that the (TG)n dinucleotide repeat polymorphism plays a major role in schizophrenia susceptibility in the Chinese population. Further studies are needed to elucidate the putative parent-of-origin effect and its role in schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Proc. Natl. Acad. Sci. U.S.A. 2008 Apr 105: 6133-8 |
| PMID | 18413613 |
| Title | The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia. |
| Abstract | The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (TG) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both TG and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 TG mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3' UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Behav Brain Funct 2008 -1 4: 2 |
| PMID | 18201382 |
| Title | Association between the PPP3CC gene, coding for the calcineurin gamma catalytic subunit, and bipolar disorder. |
| Abstract | Calcineurin is a neuron-enriched phosphatase that regulates synaptic plasticity and neuronal adaptation. Activation of calcineurin, overall, antagonizes the effects of the cyclic AMP activated protein/kinase A. Thus, kinase/phosphatase dynamic balance seems to be critical for transition to long-term cellular responses in neurons, and disruption of this equilibrium should induce behavioral impairments in animal models. Genetic animal models, as well as post-mortem studies in humans have implicated calcineurin dependent calcium and cyclic AMP regulated phosphorylation/dephosphorylation in both affective responses and psychosis. Recently, genetic association between schizophrenia and genetic variation of the human calcineurin A gamma subunit gene (PPP3CC) has been reported. Based on the assumption of the common underlying genetic factor in schizophrenia and bipolar affective disorder (BPAD), we performed association analysis of CC33 and CCS3 polymorphisms of the PPP3CC gene reported to be associated with schizophrenia in a French sample of 115 BPAD patients and 97 healthy controls. Carrying 'CT' or 'TT' genotypes of the PPP3CC-CC33 polymorphism increased risk to develop BPAD comparing to carry 'CC' genotype (OR = 1.8 [1.01-3.0]; p = 0.05). For the PPP3CC-CCS3 polymorphism, 'AG' or 'GG' carriers have an increased risk to develop BPAD than 'AA' carriers (OR = 2.8 [1.5-5.2]). The CC33 and CCS3 polymorphisms were observed in significant linkage disequilibrium (D' = 0.91, r2 = 0.72). Haplotype frequencies were significantly different in BPAD patients than in controls (p = 0.03), with a significant over-transmission of the 'TG' haplotype in BPAD patients (p = 0.001). We suggest that the PPP3CC gene might be a susceptibility gene for BPAD, in accordance with current neurobiological hypotheses that implicate dysregulation of signal-transduction pathways, such as those regulated by calcineurin, in the etiology of affective disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Schizophr. Res. 2008 Dec 106: 300-7 |
| PMID | 18973991 |
| Title | Changes in non-high-density lipoprotein cholesterol levels and triglyceride/high-density lipoprotein cholesterol ratios among patients randomized to aripiprazole versus olanzapine. |
| Abstract | Non-high-density lipoprotein cholesterol (non-HDL-C) and the triglyceride to high-density lipoprotein cholesterol ratio (TG:HDL-C) are predictors of cardiovascular risk. This post-hoc analysis assessed changes in these parameters during treatment with the atypical antipsychotics olanzapine or aripiprazole using pooled data from three randomized, long-term clinical studies in patients with schizophrenia. Data were pooled from one open-label and two double-blind (26- or 52-week) studies in patients randomized to olanzapine (5-20 mg/day) or aripiprazole (15-30 mg/day). Change from baseline in non-HDL-C levels between groups was analyzed in the Observed Case (OC) dataset at each time point and Last Observation Carried Forward (LOCF) dataset at endpoint using analysis of covariance, with treatment as main effect and baseline non-HDL-C as covariate. Differences between groups in median changes from baseline in TG:HDL-C were assessed with Kruskal-Wallis tests. This analysis included 546 patients (olanzapine, n=274; aripiprazole, n=272). Mean changes from baseline in non-HDL-C levels were significantly different (p<0.0001) with olanzapine versus aripiprazole at Weeks 26 (+13.0 versus -7.5 mg/dL) and 52 (+12.2 versus -8.1 mg/dL). Baseline TG:HDL-C was high in the olanzapine (3.73) and aripiprazole (3.79) groups. Differences in median changes from baseline in TG:HDL-C were significant with olanzapine versus aripiprazole at Weeks 26 (+0.22 versus -0.54; p<0.0001) and 52 (+0.24 versus -0.62; p=0.004). Long-term aripiprazole treatment is associated with improvements in lipid profiles of schizophrenia patients versus no improvement or worsening during olanzapine treatment. Consideration of cardiovascular risk is needed when prescribing antipsychotics, as is close monitoring for metabolic changes during treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Schizophr. Res. 2008 Aug 103: 104-9 |
| PMID | 18534821 |
| Title | Impact of antipsychotic treatment on nonfasting triglycerides in the CATIE Schizophrenia Trial phase 1. |
| Abstract | Recent literature documents a stronger association between nonfasting triglycerides (TG) and cardiovascular risk compared to fasting TG. Given concerns over antipsychotic effects on serum TG, this analysis explored changes in nonfasting TG in phase 1 of the CATIE schizophrenia Trial. Change in nonfasting TG, adjusted for baseline value, was compared between antipsychotic treatment groups using subjects with nonfasting laboratory assessments at baseline and 3 months. Among the 246 subjects there were significant treatment differences in 3-month change from baseline (p=0.009). The greatest increases in median and adjusted mean nonfasting TG levels were seen among those randomized to quetiapine (mean+54.7 mg/dl, median+26 mg/dl) and olanzapine (mean+23.4 mg/dl, median+26.5 mg/dl), while ziprasidone was neutral (mean+0.0 mg/dl, median+8 mg/dl), and decreases were seen with risperidone (mean -18.4 mg/dl, median -6.5 mg/dl) and perphenazine (mean -1.3 mg/dl, median -22 mg/dl). Pairwise comparisons indicated a significant between-group difference for perphenazine vs. olanzapine (p=0.002) and a trend for perphenazine vs. quetiapine (p=0.006). This analysis provides further evidence for differential antipsychotic metabolic liabilities, and confirms signals for the effects of olanzapine and quetiapine on serum TG seen in earlier CATIE analyses. Future consensus recommendations will clarify the role of nonfasting TG monitoring in routine clinical practice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Pharmacogenomics J. 2008 Jun 8: 228-36 |
| PMID | 17726453 |
| Title | Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. |
| Abstract | schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug x gene and drug x haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine- or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Neuroreport 2009 Nov 20: 1523-8 |
| PMID | 19829162 |
| Title | Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. |
| Abstract | Neuregulin 1 (NRG1) is a pleiotropic growth factor involved in diverse aspects of brain development and function. In schizophrenia, expression of the NRG1 type I isoform is selectively increased. However, virtually nothing is known about the roles of this isoform in brain. We have studied transgenic mice overexpressing type I NRG1(NRG1type 1-TG) using a series of behavioural tests. NRG1(type 1-TG) mice have a tremor, are impaired on the accelerating rotarod, and have reduced prepulse inhibition in the context of an increased baseline startle response. There is no overall anxiety or activity phenotype, although female NRG(1type 1-TG) mice show mild increases in anxiety on some measures. The pattern of results shows both similarities and differences to those reported in hypomorphic NRG1 mice, and may be relevant for interpreting the increased NRG1 type I expression observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | J. Neurosci. 2009 Jul 29: 8363-71 |
| PMID | 19571127 |
| Title | Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactions and decreased conduction velocities. |
| Abstract | Conduction velocity (CV) of myelinated axons has been shown to be regulated by oligodendrocytes even after myelination has been completed. However, how myelinating oligodendrocytes regulate CV, and what the significance of this regulation is for normal brain function remain unknown. To address these questions, we analyzed a transgenic mouse line harboring extra copies of the myelin proteolipid protein 1 (plp1) gene (plp1(TG/-) mice) at 2 months of age. At this stage, the plp1(TG/-) mice have an unaffected myelin structure with a normally appearing ion channel distribution, but the CV in all axonal tracts tested in the CNS is greatly reduced. We also found decreased axonal diameters and slightly abnormal paranodal structures, both of which can be a cause for the reduced CV. Interestingly the plp1(TG/-) mice showed altered anxiety-like behaviors, reduced prepulse inhibitions, spatial learning deficits and working memory deficit, all of which are schizophrenia-related behaviors. Our results implicate that abnormalities in the neuron-glia interactions at the paranodal junctions can result in reduced CV in the CNS, which then induces behavioral abnormalities related to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Pharmacopsychiatry 2009 Jan 42: 29-34 |
| PMID | 19153944 |
| Title | Effects of six second generation antipsychotics on body weight and metabolism - risk assessment and results from a prospective study. |
| Abstract | Due to the association of second generation antipsychotics (SGAs) with weight gain and alterations of glucose and lipid homeostasis, we aimed to group six commonly prescribed SGAs into classes of differing risks. Twenty-eight patients meeting the criteria for a diagnosis of schizophrenic disorder according to ICD-10 were assigned to monotherapy with olanzapine, clozapine, quetiapine, amisulpride, ziprasidone or risperidone. The levels of glucose and lipid metabolism were assessed before and after 28 days of treatment. Based on cluster analysis, olanzapine and clozapine were found to constitute a high-risk group for metabolic dysregulation while amisulpride, quetiapine, risperidone and ziprasidone could be assigned to a non-high-risk group. Subjects from the high-risk group displayed significant weight gain with concomitant increases of HOMA-IR, levels of insulin, total cholesterol, TG, LDL-C and leptin. No significant changes were observed in the non-high-risk group. The results of this study support the conclusion of the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes that certain SGAs are associated with a higher risk for weight gain, insulin resistance and dyslipidemia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | J Psychiatr Res 2009 Jul 43: 997-1002 |
| PMID | 19268968 |
| Title | In search of moderators and mediators of hyperglycemia with atypical antipsychotic treatment. |
| Abstract | Signal detection methods were used to identify values of metabolic variables that predict development of prediabetes or diabetes before (moderators) or associated with treatment (mediators), utilizing data from two multi-center clinical trials of patients with schizophrenia, treated for 6 months with olanzapine (OLZ) or ziprasidone (ZIP). At baseline, participants were often overweight/obese (63% with a body mass index >or=25.0kg/m(2)), dyslipidemic [more than one-third had elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations], and prediabetic (20%). Weight gain was significantly greater in OLZ-treated patients, as was accentuation of dyslipidemia. However, there were no significant correlations between weight gain and lipid changes from baseline to weeks 2, 4, 8 or to last observation. Type 2 diabetes developed in 4% and prediabetes in 18% of the population. Significant baseline predictors of diabetes were a HDL-C concentration <28mg/dL, or being >or=58-years-old if HDL-C concentration was >or=28mg/dL. Baseline plasma glucose concentration >or=92mg/dL was the only significant predictor of developing prediabetes, accounting for 60% of cases. Post-treatment increments in plasma TG concentrations >or=145mg/dL or >or=59mg/dL were significant predictors of diabetes (23%) or prediabetes (27%), respectively. If the increase in TG was <145mg/dL, rapid weight gain >or=6.1kg in 2 weeks predicted development of diabetes (18%). These findings provide a quantitative approach to identify those at greatest treatment-associated risk to develop glucose intolerance, and emphasize the need to address co-morbid medical disorders in these patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Folia Parasitol. 2010 Jun 57: 129-35 |
| PMID | 20608475 |
| Title | The diagnosis of a personality disorder increases the likelihood for seropositivity to Toxoplasma gondii in psychiatric patients. |
| Abstract | Individuals serologically positive for the chronic infection with the parasite Toxoplasma gondii (TG) display certain personality traits differently from uninfected individuals. Experimental data in mice demonstrate that TG infection modulates behaviour. However, psychiatric patients with a personality disorder have not yet been investigated systematically. In our sample containing 896 psychiatric inpatients with the primary diagnoses of schizophrenia, major depression, schizoaffective or bipolar disorder and 214 psychiatrically unaffected controls (same geographic region, sampled during same time period) we analysed for effects of the additional diagnosis of a personality disorder in the patients. Psychiatrically, a patient can meet the criteria of a personality disorder additionally to any of the mentioned primary diagnoses. We applied logistic regression and cross-table statistics, separated groups by the presence/absence of a personality disorder (ICD-10) and adjusted for age between groups. We found that among all patients the additional diagnosis of a personality disorder was significantly associated with TG infection. Furthermore, only in the patients with an additional personality disorder medium titre responses (1:16-1:64) were associated with chronic course and high C-reactive protein (CRP) levels whereas high titre response (>1:64) was associated with a more acute recurrent clinical course. In the older individuals only there was a preponderance of medium titre responses (1:16-1:64) among the patients with personality disorder compared to those without and controls. We conclude that TG infection and the host's response to it make a difference for the diagnosis of a personality disorder. Our data support that TG infection can modulate human behaviour and personality traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | PLoS ONE 2010 -1 5: e14185 |
| PMID | 21151609 |
| Title | Phenotypic characterization of transgenic mice overexpressing neuregulin-1. |
| Abstract | Neuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants. To assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (TG) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1? gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-TG lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both TG lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus. These findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Feb 34: 172-6 |
| PMID | 19879916 |
| Title | Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. |
| Abstract | Leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine family, regulates the neuronal phenotype and coordinates astrocyte, oligodendrocyte, microglia, and inflammatory cell responses. The LIF gene is located on 22q12.1-q12.2, a hot spot for schizophrenia. Three polymorphisms of the LIF gene (rs929271, rs737812, and rs929273) were examined in a case-control association study of 390 patients with schizophrenia and 410 age- and sex-matched controls. Effects of a risk genotype of LIF on cognitive domains were evaluated by the Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, and Wisconsin Card Sorting Test (WCST) in 355 healthy volunteers. The LIF gene showed significant associations with schizophrenia at rs929271 and a haplotype consisting of rs929271-rs737812. After stratification by subtype of schizophrenia, the hebephrenic, but not paranoid, type was associated with the LIF gene at rs929271 (allele, P=0.014) and the haplotype (permutation P=0.013). Having the T-allele and T-carrier genotypes (TT and TG) of rs929271 were risks for hebephrenic schizophrenia, and the odds ratios were 1.38 (95% CI: 1.21-1.56) and 1.54 (95%CI: 1.19-1.98), respectively. Subjects with T-carrier genotypes made significantly more errors on the WCST compared with those without (P=0.04). The present study indicated that the LIF gene variant may produce susceptibility to hebephrenic schizophrenia and deterioration of working memory function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Hum Psychopharmacol 2011 Aug 26: 440-3 |
| PMID | 21823168 |
| Title | Dose-dependent effects of olanzapine on QT intervals and plasma prolactin levels in Japanese patients with stable schizophrenia. |
| Abstract | There have been few reports regarding olanzapine (OLZ)-related QT prolongation and hyperprolactinemia. This study evaluated the dose-dependent effect of OLZ on QT interval and plasma prolactin (PRL) level in a single sample of patients with schizophrenia. Twenty-six subjects treated with varying starting doses of OLZ were enrolled in the study. Following baseline assessments, which included completion of the Brief Psychiatric Rating Scale (BPRS), measurements of Body Mass Index (BMI), QT interval, electrolytes, fasting plasma glucose, PRL, hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), and low density lipoprotein (LDL), the dose of OLZ was increased for each subject. The same parameters were evaluated following the increased dose treatment. A significant decrease was observed in BPRS score (p = 0.01) following treatment with an increased dose of OLZ. Significant increases were observed in BMI (p = 0.032), QTc (p = 0.031), and plasma PRL level (p = 0.028). The mean values of electrolytes, fasting plasma glucose, HbA1c, TC, TG, HDL and LDL treatment were unchanged by the switch to increased-dose OLZ treatment. We have demonstrated the dose-dependent effect of OLZ on the QT interval and the plasma PRL level of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Neuropsychopharmacology 2011 Jul 36: 1677-88 |
| PMID | 21471957 |
| Title | The association of schizophrenia risk D-amino acid oxidase polymorphisms with sensorimotor gating, working memory and personality in healthy males. |
| Abstract | There is evidence supporting a role for the D-amino acid oxidase (DAO) locus in schizophrenia. This study aimed to determine the relationship of five single-nucleotide polymorphisms (SNPs) within the DAO gene identified as promising schizophrenia risk genes (rs4623951, rs2111902, rs3918346, rs3741775, and rs3825251) to acoustic startle, prepulse inhibition (PPI), working memory, and personality dimensions. A highly homogeneous study entry cohort (n = 530) of healthy, young male army conscripts (n = 703) originating from the Greek LOGOS project (Learning On Genetics Of schizophrenia Spectrum) underwent PPI of the acoustic startle reflex, working memory, and personality assessment. The QTPHASE from the UNPHASED package was used for the association analysis of each SNP or haplotype data, with p-values corrected for multiple testing by running 10,000 permutations of the data. The rs4623951_T-rs3741775_G and rs4623951_T-rs2111902_T diplotypes were associated with reduced PPI and worse performance in working memory tasks and a personality pattern characterized by attenuated anxiety. Median stratification analysis of the risk diplotype group (ie, those individuals homozygous for the T and G alleles (TG+)) showed reduced PPI and working memory performance only in TG+ individuals with high trait anxiety. The rs4623951_T allele, which is the DAO polymorphism most strongly associated with schizophrenia, might tag a haplotype that affects PPI, cognition, and personality traits in general population. Our findings suggest an influence of the gene in the neural substrate mediating sensorimotor gating and working memory, especially when combined with high anxiety and further validate DAO as a candidate gene for schizophrenia and spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Behav. Brain Res. 2011 Nov 225: 305-10 |
| PMID | 21835207 |
| Title | Effects of antipsychotics on the behavioral deficits in human dominant-negative DISC1 transgenic mice with neonatal polyI:C treatment. |
| Abstract | Interactions of environmental and genetic factors may play a role in the pathoetiology of schizophrenia. We have recently developed a novel animal model of mental disorders such as schizophrenia by inducing abnormal immune response during the perinatal period in mice with overexpression of the human dominant-negative form of disrupted-in-schizophrenia 1 (DN-DISC1). In the present study, we investigated the effects of antipsychotics on the behavioral deficits in this animal model for mental disorders with gene-environment interaction. Neonatal DN-DISC1 transgenic (DN-DISC1 TG) mice were repeatedly injected with polyriboinosinic-polyribocytidylic acid (polyI:C) for 5 days from postnatal days 2 to 6. The behavioral analyses were performed in adulthood. Clozapine (3mg/kg) or haloperidol (1mg/kg) was administered orally once a day from 1 week before starting a series of behavioral experiments and continued until the end of the study. Cognitive impairment in polyI:C-treated DN-DISC1 TG mice was improved by repeated administration of clozapine while haloperidol had no effect. Both antipsychotics suppressed the augmentation of MK-801-induced hyperactivity in the model mice. Neither clozapine nor haloperidol ameliorated the impairments of social behaviors in polyI:C-treated DN-DISC1 TG mice. These results suggest that the polyI:C-treated DN-DISC TG mice are quite unique as an animal model for mental disorders. Furthermore, this mouse model may be useful for the screening of potential antipsychotic compounds that could be more effective than clozapine in ameliorating negative symptoms and cognitive impairment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Dec 35: 1927-32 |
| PMID | 21840365 |
| Title | Association of plasma retinol-binding protein-4, adiponectin, and high molecular weight adiponectin with metabolic adversities in patients with schizophrenia. |
| Abstract | Metabolic adversities are prevalent in patients with schizophrenia. Retinol-binding protein 4 (RBP4) and high molecular weight (HMW) adiponectin have been recently found to be associated with metabolic features in non-psychiatric population. The study aimed to evaluate the associations between metabolic features and RBP4, total adiponectin, and HMW adiponectin in patients with schizophrenia. We recruited 109 patients with schizophrenia treated with clozapine or haloperidol and evaluated their body mass index (BMI), waist circumference, blood pressure, and fasting triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose, insulin, RBP4, total adiponectin, and HMW adiponectin levels. We found that patients with metabolic syndrome (MS) had higher RBP4 level, and lower total adiponectin and HMW adiponectin levels than those without MS. There were no significant differences in metabolic features and adipocytokine levels between patients treated with clozapine and haloperidol. Most of the metabolic indexes were significantly correlated with the levels of adipocytokines. After adjusting the effects of age, gender, and BMI, marginal significant correlations existed between TG and RBP4 levels; HDL-C and total adiponectin and HMW adiponectin; insulin and HOMA-IR and HMW adiponectin. Receiver operating curve analysis showed that all of the three adipocytokines could differentiate patients with MS from those without MS. Meanwhile, total adiponectin and HMW adiponectin, but not RBP4, had the differentiating power for insulin resistance. Higher RBP4 and lower total adiponectin and HMW adiponectin levels were observed in schizophrenic patients with MS. Only HMW adiponectin is marginally correlated with insulin sensitivity. The finding that metabolic profiles, but not the antipsychotic types, are associated with adipocytokine levels should be confirmed in longitudinal studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | J Clin Psychiatry 2011 Dec 72: 1602-10 |
| PMID | 21813074 |
| Title | A 12-month randomized, open-label study of the metabolic effects of olanzapine and risperidone in psychotic patients: influence of valproic acid augmentation. |
| Abstract | Longitudinal data comparing the metabolic effects of olanzapine and risperidone with or without valproic acid supplementation in schizophrenic and bipolar patients are lacking. This study compares the metabolic effects of olanzapine and risperidone in a prospective, randomized, open-label trial in 160 patients with DSM-IV-TR schizophrenia, schizoaffective disorder, or bipolar disorder after 1, 3, 6, and 12 months' treatment. The study was conducted between 2000 and 2006. The primary analysis compared all patients randomized to olanzapine or risperidone; the primary outcome measure was changes in triglycerides (TG), and TG/high density lipoprotein cholesterol (HDL-C) ratio, a risk factor for ischemic cardiovascular disease. Secondary analyses included the effect of concomitant valproic acid. Significantly greater increases in weight (F(4,434) = 4.7), body mass index (BMI) (F(4,424) = 5.1), glycosylated hemoglobin (HgbA1c) (F(4,427) = 4.3), total cholesterol (F(4,429) = 4.4), TG (F(4,426) = 5.9), and TG/HDL-C ratio (F(4,426) = 4.3) (P < .005 for all drug × time interaction effects) were observed at all but the initial time points in the olanzapine- compared to the risperidone patients. Olanzapine/+valproic acid produced significantly greater increases in HgbA1c, BMI, weight, TG, and TG/HDL-C than olanzapine/-valproic acid at 3 and 6 months, while risperidone/+valproic acid produced significantly smaller increases in HgbA1c, BMI, and weight at 1, 3, and 6 months than risperidone/-valproic acid. The olanzapine/+valproic acid group had significantly greater BMI, and weight at 1, 3, and 6 months, and greater HgbA1c at 3 and 6 months, compared with the risperidone/+valproic acid group. There were too few patients treated with mood stabilizers other than valproic acid to analyze effects of any other mood stabilizer separately. Metabolic effects did not differ significantly by diagnostic category (schizophrenia/schizoaffective disorder vs bipolar disorder). Further study of the metabolic effects of adjunctive valproic acid is indicated, as valproic acid may produce markedly different metabolic effects when combined with various antipsychotic drugs. clinicaltrials.gov Identifier: NCT00179062. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Spectrochim Acta A Mol Biomol Spectrosc 2011 Oct 81: 489-97 |
| PMID | 21795104 |
| Title | New copper(II) complexes with dopamine hydrochloride and vanillymandelic acid: spectroscopic and thermal characterization. |
| Abstract | The dopamine derivatives participate in the regulation of wide variety of physiological functions in the human body and in medication life. Increase and/or decrease in the concentration of dopamine in human body reflect an indication for diseases such as schizophrenia and/or Parkinson diseases. The Cu(II) chelates with coupled products of dopamine hydrochloride (DO.HCl) and vanillymandelic acid (VMA) with 4-aminoantipyrine (4-AAP) are prepared and characterized. Different physico-chemical techniques namely IR, magnetic and UV-vis spectra are used to investigate the structure of these chelates. Cu(II) forms 1:1 (Cu:DO) and 1:2 (Cu:VMA) chelates. DO behave as a uninegative tridentate ligand in binding to the Cu(II) ion while VMA behaves as a uninegative bidentate ligand. IR spectra show that the DO is coordinated to the Cu(II) ion in a tridentate manner with ONO donor sites of the phenolic-OH, -NH and carbonyl-O, while VMA is coordinated with OO donor sites of the phenolic-OH and -NH. Magnetic moment measurements reveal the presence of Cu(II) chelates in octahedral and square planar geometries with DO and VMA, respectively. The thermal decomposition of Cu(II) complexes is studied using thermogravimetric (TG) and differential thermal analysis (DTA) techniques. The activation thermodynamic parameters, such as, energy of activation, enthalpy, entropy and free energy change of the complexes are evaluated and the relative thermal stability of the complexes are discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Eurasian J Med 2011 Apr 43: 39-44 |
| PMID | 25610158 |
| Title | The effects of atypical antipsychotic usage duration on serum adiponectin levels and other metabolic parameters. |
| Abstract | Although atypical antipsychotics are well-tolerated and effective treatment options for schizophrenia, they have metabolic side effects, including weight gain and increased risk of Type II Diabetes Mellitus (DM). Adiponectin, produced exclusively in adipocytes, is the most abundant serum adipokine. Low levels of adiponectin are correlated with DM, insulin resistance and coronary heart disease. Usage of atypical antipsychotics may create a risk of metabolic syndrome. The aim of this study was to evaluate the effects of antipsychotic usage on parameters related to development of metabolic syndrome. A total of 27 patients (n=27) (13 women and 14 men) were recruited from our out-patient psychiatry clinic. All patients had been treated with atypical antipsychotics for at least 3 months and were in remission. Patients were evaluated for levels of HDL (High Density Lipoprotein), LDL (Low Density Lipoprotein), TG (Triglyceride) total cholesterol and fasting blood glucose, body weight, BMI (Body Mass Index), waist circumference and serum adiponectin levels. Serum adiponectin levels were significantly lower (p:0.000) and body weights were significantly higher (p:0.003) in the patients who had been using atypical antipsychotics for longer than a year in comparison to patients who had been using atypical antipsychotics for one year or less. Our findings supported the hypothesis that the length of administration of atypical antipsychotics has an effect on metabolic changes. They also highlight the fact that when investigating metabolic changes generated by atypical antipsychotic effects, the length of time that the patient has been on the atypical antipsychotics should also be considered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Dec 35: 1927-32 |
| PMID | 21840365 |
| Title | Association of plasma retinol-binding protein-4, adiponectin, and high molecular weight adiponectin with metabolic adversities in patients with schizophrenia. |
| Abstract | Metabolic adversities are prevalent in patients with schizophrenia. Retinol-binding protein 4 (RBP4) and high molecular weight (HMW) adiponectin have been recently found to be associated with metabolic features in non-psychiatric population. The study aimed to evaluate the associations between metabolic features and RBP4, total adiponectin, and HMW adiponectin in patients with schizophrenia. We recruited 109 patients with schizophrenia treated with clozapine or haloperidol and evaluated their body mass index (BMI), waist circumference, blood pressure, and fasting triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose, insulin, RBP4, total adiponectin, and HMW adiponectin levels. We found that patients with metabolic syndrome (MS) had higher RBP4 level, and lower total adiponectin and HMW adiponectin levels than those without MS. There were no significant differences in metabolic features and adipocytokine levels between patients treated with clozapine and haloperidol. Most of the metabolic indexes were significantly correlated with the levels of adipocytokines. After adjusting the effects of age, gender, and BMI, marginal significant correlations existed between TG and RBP4 levels; HDL-C and total adiponectin and HMW adiponectin; insulin and HOMA-IR and HMW adiponectin. Receiver operating curve analysis showed that all of the three adipocytokines could differentiate patients with MS from those without MS. Meanwhile, total adiponectin and HMW adiponectin, but not RBP4, had the differentiating power for insulin resistance. Higher RBP4 and lower total adiponectin and HMW adiponectin levels were observed in schizophrenic patients with MS. Only HMW adiponectin is marginally correlated with insulin sensitivity. The finding that metabolic profiles, but not the antipsychotic types, are associated with adipocytokine levels should be confirmed in longitudinal studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | J Clin Psychiatry 2011 Dec 72: 1602-10 |
| PMID | 21813074 |
| Title | A 12-month randomized, open-label study of the metabolic effects of olanzapine and risperidone in psychotic patients: influence of valproic acid augmentation. |
| Abstract | Longitudinal data comparing the metabolic effects of olanzapine and risperidone with or without valproic acid supplementation in schizophrenic and bipolar patients are lacking. This study compares the metabolic effects of olanzapine and risperidone in a prospective, randomized, open-label trial in 160 patients with DSM-IV-TR schizophrenia, schizoaffective disorder, or bipolar disorder after 1, 3, 6, and 12 months' treatment. The study was conducted between 2000 and 2006. The primary analysis compared all patients randomized to olanzapine or risperidone; the primary outcome measure was changes in triglycerides (TG), and TG/high density lipoprotein cholesterol (HDL-C) ratio, a risk factor for ischemic cardiovascular disease. Secondary analyses included the effect of concomitant valproic acid. Significantly greater increases in weight (F(4,434) = 4.7), body mass index (BMI) (F(4,424) = 5.1), glycosylated hemoglobin (HgbA1c) (F(4,427) = 4.3), total cholesterol (F(4,429) = 4.4), TG (F(4,426) = 5.9), and TG/HDL-C ratio (F(4,426) = 4.3) (P < .005 for all drug × time interaction effects) were observed at all but the initial time points in the olanzapine- compared to the risperidone patients. Olanzapine/+valproic acid produced significantly greater increases in HgbA1c, BMI, weight, TG, and TG/HDL-C than olanzapine/-valproic acid at 3 and 6 months, while risperidone/+valproic acid produced significantly smaller increases in HgbA1c, BMI, and weight at 1, 3, and 6 months than risperidone/-valproic acid. The olanzapine/+valproic acid group had significantly greater BMI, and weight at 1, 3, and 6 months, and greater HgbA1c at 3 and 6 months, compared with the risperidone/+valproic acid group. There were too few patients treated with mood stabilizers other than valproic acid to analyze effects of any other mood stabilizer separately. Metabolic effects did not differ significantly by diagnostic category (schizophrenia/schizoaffective disorder vs bipolar disorder). Further study of the metabolic effects of adjunctive valproic acid is indicated, as valproic acid may produce markedly different metabolic effects when combined with various antipsychotic drugs. clinicaltrials.gov Identifier: NCT00179062. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Mar 35: 632-5 |
| PMID | 21256176 |
| Title | Weight gain and ghrelin level after olanzapine monotherapy. |
| Abstract | The present study aimed to explore the association between weight gain and ghrelin among schizophrenic patients under olanzapine treatment. The relationships among weight gain and adiponectin, fasting glucose, and lipid profile were also investigated. This case-control study recruited 66 schizophrenic patients from the Chung Shan Medical University Hospital in central Taiwan. All of them were undergoing olanzapine monotherapy and were categorized into weight gain (WG) and non-weight gain (NWG) groups. Subjects in the control group (CG) were recruited from a healthy community population based on a health survey (n=119). Multivariate logistic regression was used to explore the association of ghrelin with weight gain. The 66 schizophrenic patients had a mean age of 36.3±9.6 years, with 50% females. They received olanzapine treatment for a mean period of 8.3±7.5 years. The control group had a mean age of 38.9±9.3 years and 52.9% were females. Comparing fasting serum ghrelin levels, the WG group had the lowest mean value (822.3±253.1 pg/ml) while the control group had the highest mean value (1261.2±1639.7 pg/ml), with a significant difference between the two (p=0.01). In contrast, there was no difference in adiponectin levels among the three groups. The WG and NWG groups had higher diastolic blood pressure than the control group, but systolic blood pressure was the same in all three groups. There was no difference in the total cholesterol level although the WG and NWG groups had higher triglyceride (TG) and glucose levels than the control group. Weight gain after olanzapine treatment is associated with lower ghrelin level. Olanzapine is linked to elevated diastolic pressure, TG, and glucose, regardless of the weight gain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Cereb. Cortex 2012 Jul 22: 1520-9 |
| PMID | 21878485 |
| Title | Transgenic overexpression of the type I isoform of neuregulin 1 affects working memory and hippocampal oscillations but not long-term potentiation. |
| Abstract | Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1(TG-type I)) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes. Young NRG1(TG-type I) mice showed normal memory performance, but in older NRG1(TG-type I) mice, hippocampus-dependent spatial working memory was selectively impaired. Hippocampal slice preparations from NRG1(TG-type I) mice exhibited a reduced frequency of carbachol-induced gamma oscillations and an increased tendency to epileptiform activity. Long-term potentiation in NRG1(TG-type I) mice was normal. The results provide evidence that NRG1 type I impacts on hippocampal function and circuitry. The effects are likely mediated via inhibitory interneurons and may be relevant to the involvement of NRG1 in schizophrenia. However, the findings, in concert with those from other genetic and pharmacological manipulations of NRG1, emphasize the complex and pleiotropic nature of the gene, even with regard to a single isoform. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Eur Neuropsychopharmacol 2012 Aug 22: 596-606 |
| PMID | 22264868 |
| Title | Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments. |
| Abstract | Glycine N-methyltransferase (GNMT) affects cellular methylation capacity through regulating the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The product of its enzymatic reaction-sarcosine has antipsychotic effect in patients with schizophrenia. In this study, through RT-PCR and immunohistochemical staining, we demonstrated that GNMT expressed in various neurons located in the cerebral cortex, hippocampus, substantia nigra and cerebellum. Compared to the wild-type mice, Gnmt-/- mice had significantly lower level of sarcosine in the cerebral cortex. Real-time PCR identified genes involved in the methionine metabolism (Dnmt1 and Dnmt3a), ErbB (Nrg1 and ErbB4) and mTOR (Akt2, S6, S6k1 and S6k2) signaling pathways were dysregulated significantly in the cortex of Gnmt-/- mice. Acoustic startle reflex test demonstrated that Gnmt-/- mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine or sarcosine treatment. Furthermore, liver-specific-human-GNMT transgenic with Gnmt-/- (TG-GNMT/Gnmt-/-) mice were used to rule out that the phenotype was due to abnormal liver function. In summary, the neuropsychological abnormalities found in Gnmt-/- mice may represent an endophenotype of schizophrenia. GNMT plays an important role in maintaining normal physiological function of brain and TG-GNMT/Gnmt-/- mice are useful models for development of therapeutics for patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Mol Autism 2012 -1 3: 11 |
| PMID | 23110844 |
| Title | Vldlr overexpression causes hyperactivity in rats. |
| Abstract | Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients. We generated transgenic (TG) rats overexpressing Vldlr, and examined their histological and behavioral features. Spontaneous locomotor activity was significantly increased in TG rats, without detectable changes in brain histology. Additionally, TG rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function. Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-TG rats in the absence of neuroanatomical abnormalities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | J. Psychopharmacol. (Oxford) 2012 Sep 26: 1201-10 |
| PMID | 22234928 |
| Title | Comparative effectiveness of switching antipsychotic drug treatment to aripiprazole or ziprasidone for improving metabolic profile and atherogenic dyslipidemia: a 12-month, prospective, open-label study. |
| Abstract | We studied the effects of switching antipsychotic drug-treated patients with schizophrenia or bipolar disorder who evidenced adverse metabolic side effects as indicated by a triglyceride/high-density lipoprotein ratio (TG/HDL) ? 3.5 to aripiprazole (ARIP; 5-30 mg/day, n = 24) or ziprasidone (ZIP; 40-160 mg/day, n = 28). Anthropometric and metabolic measures, psychopathology, quality of life and motor adverse effects were assessed over a 52-week period with evaluations at baseline, 6, 12, 26 and 52 weeks. There were statistically significant improvements in body weight, body mass index (BMI), TG, HDL and TG/HDL which did not differ between treatments. However, numerous secondary measures including weight and BMI, and the proportion of patients who lost ? 7% or who no longer met criteria for obesity, favored ZIP over ARIP. Decreases in total cholesterol and increases in HDL-cholesterol also favored ZIP. On the other hand, decreases in TG/HDL ratio and reduction in HgbA1c favored ARIP. There were no significant time or group × time interaction effects for most psychopathology measures; however, Global Assessment of Functioning Scores favored ARIP at 6 and 12 months. We conclude that switching patients with evidence of metabolic side effects to either ARIP or ZIP may be beneficial for some, but not all metabolic measures, with minimal risk of worsening of psychopathology and possibly some benefit in that regard as well. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Eur. J. Neurosci. 2012 Sep 36: 2597-608 |
| PMID | 22697179 |
| Title | SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory. |
| Abstract | SREB2/GPR85, a member of the super-conserved receptor expressed in brain (SREB) family, is the most conserved G-protein-coupled receptor in vertebrate evolution. Previous human and mouse genetic studies have indicated a possible link between SREB2 and schizophrenia. SREB2 is robustly expressed in the hippocampal formation, especially in the dentate gyrus, a structure with an established involvement in psychiatric disorders and cognition. However, the function of SREB2 in the hippocampus remains elusive. Here we show that SREB2 regulates hippocampal adult neurogenesis, which impacts on cognitive function. Bromodeoxyuridine incorporation and immunohistochemistry were conducted in SREB2 transgenic (TG, over-expression) and knockout (KO, null-mutant) mice to quantitatively assay adult neurogenesis and newborn neuron dendritic morphology. Cognitive responses associated with adult neurogenesis alteration were evaluated in SREB2 mutant mice. In SREB2 TG mice, both new cell proliferation and new neuron survival were decreased in the dentate gyrus, whereas an enhancement of new neuron survival occurred in SREB2 KO mouse dentate gyrus. Doublecortin staining revealed dendritic morphology deficits of newly generated neurons in SREB2 TG mice. In a spatial pattern separation task, SREB2 TG mice displayed a decreased ability to discriminate spatial relationships, whereas SREB2 KO mice had enhanced abilities in this task. Additionally, SREB2 TG and KO mice had reciprocal phenotypes in a Y-maze working memory task. Our results indicate that SREB2 is a negative regulator of adult neurogenesis and consequential cognitive functions. Inhibition of SREB2 function may be a novel approach to enhance hippocampal adult neurogenesis and cognitive abilities to ameliorate core symptoms of psychiatric patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 405-13 |
| PMID | 22461181 |
| Title | Functional genetic variation at the NRGN gene and schizophrenia: evidence from a gene-based case-control study and gene expression analysis. |
| Abstract | Genome-wide association and follow-up studies have reported an association between schizophrenia and rs12807809 of the NRGN gene on chromosome 11q24.2. We investigated the association of five linkage disequilibrium-tagging SNPs and haplotypes that cover the NRGN gene with schizophrenia in a Japanese sample of 2,019 schizophrenia patients and 2,574 controls to determine whether rs12807809 is the most strongly associated variant for schizophrenia in the vicinity of the NRGN gene. We found that the rs12807809-rs12278912 haplotype of the NRGN gene was associated with schizophrenia (global P = 0.0042). The frequencies of the TG and TA haplotypes of rs12807809-rs12278912 in patients were higher (OR = 1.14, P = 0.0019) and lower (OR = 0.85, P = 0.0053), respectively, than in the controls. We did not detect any evidence of association of schizophrenia with any SNPs; however, two nominal associations of rs12278912 (OR = 1.10, P = 0.057) and rs2075713 (OR = 1.10, P = 0.057) were observed. Furthermore, we detected an association between the rs12807809-rs12278912 haplotype and NRGN expression in immortalized lymphoblasts derived from 45 HapMap JPT subjects (z = 2.69, P = 0.007) and confirmed the association in immortalized lymphoblasts derived from 42 patients with schizophrenia and 44 healthy controls (z = 3.09, P = 0.002). The expression of the high-risk TG haplotype was significantly lower than the protective TA haplotype. The expression was lower in patients with schizophrenia than in controls; however, this difference was not statistically significant. This study provides further evidence of the association of the NRGN gene with schizophrenia, and our results suggest that there is a link between the TG haplotype of rs12807809-rs12278912, decreased expression of NRGN and risk of developing schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Psychoneuroendocrinology 2012 Dec 37: 1901-11 |
| PMID | 22541717 |
| Title | Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome. |
| Abstract | At present there are strong indications of a shared vulnerability factor for schizophrenia (SZ), diabetes and the metabolic syndrome (metS). In this study we focus on an aberrantly activated monocyte/macrophage system as the shared factor. We measured in SZ patients (n=144), the serum levels of monocyte/macrophage cytokines/chemokines/adipokines CCL2, CCL4, IL-1?, TNF-?, IL-6, PTX3, leptin, adiponectin, PAI-1, OPG and ICAM-1 and compared these levels to healthy controls (HC) (n=138). Using multivariate analysis, we studied the effect of the presence of the disease SZ, the components of the metS including BMI, the levels of lipids (HDL cholesterol and triglycerides (TG)), diabetes (hyperglycemia) and the use of antipsychotic medication, on the serum levels of these immune compounds. We found all measured immune compounds with the exception of PAI-1 and OPG to be elevated in the SZ patient population. Multivariate analysis showed that elevations were linked to gender (ICAM-1, leptin, TNF-? and adiponectin), an increased BMI (leptin, adiponectin), hyperglycemia/diabetes (CCL4, and OPG), reduced HDL-cholesterol or increased levels of TG (adiponectin and PTX3) or the metS (CCL2, leptin and adiponectin). IL-1? and IL-6 were the only immune compounds raised in the serum of patients not affected by any of the included factors. Although many of the immune compounds were found linked to (components of) the metS, the most dominant linkage was found with the disease schizophrenia, confirming earlier reports on increased monocyte/macrophage activation as a key component for understanding the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Genet Test Mol Biomarkers 2012 Mar 16: 157-61 |
| PMID | 21988329 |
| Title | A polymerase chain reaction-restriction fragment length polymorphism method for screening ZNF804A gene polymorphism (rs1344706) in patients with schizophrenia: a significant association. |
| Abstract | The original ZNF804A rs1344706 risk variant was identified through genome-wide association studies as a risk factor for schizophrenia. Follow-up studies involving meta-analysis have confirmed that rs1344706 is a risk factor for schizophrenia as well as bipolar disorders. We describe here a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to genotype ZNF804A rs1344706 variant in patients with schizophrenia. We generated a 220 bp fragment through PCR and subsequently cleaved it by the restriction endonuclease BsaBI, creating two fragments of 114 and 106 bp. Upon change in the nucleotide from T to G, the 106 bp fragment is further cleaved by BsaBI, thus creating two fragments of 87 and 19 bp. As a result, when the 220 bp fragment is cleaved by BsaBI restriction endonuclease, the TT genotype yields two fragments of 114 and 106 bp, and TG genotype four fragments of 114, 106, 87, and 19 bp, and the GG genotype three fragments of 114, 87, and 19 bp. Thus, this is a simple, fast, and cost-effective method to genotype the ZNF804A rs1344706 risk variant. Using this method, we were able to replicate an association between ZNF804A rs1344706 variant and schizophrenia in a Turkish population. Stratification analysis of the population according to the gender showed an association that was statistically significant among overall schizophrenia and male schizophrenia and the risk T allele and TT genotype of the ZNF804A gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | J Clin Psychopharmacol 2012 Aug 32: 449-57 |
| PMID | 22722501 |
| Title | Metabolic effects of paliperidone extended release versus oral olanzapine in patients with schizophrenia: a prospective, randomized, controlled trial. |
| Abstract | Metabolic effects are generally more pronounced with second-generation than first-generation antipsychotics. This study was designed to compare long-term metabolic effects and efficacy of paliperidone extended release (ER) with those of oral olanzapine in patients with schizophrenia. In this 6-month, multicenter, prospective, randomized, controlled, open-label, parallel-group study, adults with schizophrenia were treated with paliperidone ER (6-9 mg/d; n = 239) or oral olanzapine (10-15 mg/d; n = 220). The primary outcome was mean change in the ratio of serum triglyceride level to high-density lipoprotein level (TG/HDL), a marker of insulin resistance. Other outcome measures included the Positive and Negative Syndrome Scale scores, measures of lipid and glucose metabolism, and body weight. Significant improvements in psychotic symptoms were observed with both treatments (P < 0.0001). The TG/HDL ratio was significantly higher at end point versus baseline with olanzapine compared with that of paliperidone ER. Mean end point change in TG/HDL ratio was 0.97 ± 2.72 [corrected] for olanzapine (P < 0.0001, reflecting worsening), with no significant change for paliperidone ER (-0.17 ± 2.51). Newly diagnosed impairment in TG and metabolic syndrome was more common with olanzapine (P < 0.05). Insulin resistance, as measured by the homeostasis model assessment of insulin resistance, worsened significantly with olanzapine (P = 0.0003), but not with paliperidone ER. Glucose sensitivity for insulin worsened significantly with olanzapine (P < 0.03), with no significant changes for paliperidone ER. End point increase in body weight was significantly higher with olanzapine than paliperidone ER (3.8 vs 1.2 kg; P = 0.0013). In summary, both paliperidone ER and olanzapine effectively treated schizophrenia; however, undesirable metabolic effects were significantly greater with olanzapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Mol. Biol. Rep. 2012 Jun 39: 6875-80 |
| PMID | 22311024 |
| Title | Association of thrombospondin 1 gene with schizophrenia in Korean population. |
| Abstract | Thrombospondin 1 (THBS1), a multi-domain glycoprotein, is secreted from astrocytes and promotes synaptogenesis. Increasing evidence has suggested that not only various markers for synaptic pathology, but also astrocytes are affected in schizophrenia. In this study, we investigated whether coding region single nucleotide polymorphisms (cSNPs) of the THBS1 gene were associated with schizophrenia and with the clinical symptoms of schizophrenia patients. We genotyped two cSNPs [rs2228261 (Asn470Asn) and rs2292305 (Thr523Ala)] using direct sequencing in 220 schizophrenia patients and 376 control subjects. In this study, rs2228261 revealed significant association with schizophrenia in both codominant (TT vs. CC, P = 0.009, OR = 2.10, 95% CI = 1.23-3.59) and recessive models (TT vs. CC/CT, P = 0.0012, OR = 2.28, 95% CI = 1.38-3.77). Also, rs2292305 was associated with schizophrenia in the recessive model (GG vs. AA/AG, P = 0.0052, OR = 2.05, 95% CI = 1.24-3.38). Additionally, in the analysis of the haplotype, the CA and TG haplotypes consisting of rs2228261 and rs2292305 were associated with schizophrenia in the dominant (P = 0.019, OR = 1.79, 95% CI = 1.10-2.90) and recessive models, respectively (P = 0.0086, OR = 0.51, 95% CI = 0.31-0.84). In further analysis according to the clinical symptoms, rs2292305 showed a weak association with the poor concentration symptoms of schizophrenia patients in the dominant model (AG/GG vs. AA, P = 0.024, OR = 2.04, 95% CI = 1.09-3.83). The results suggest that the THBS1 gene may contribute to the susceptibility of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Singapore Med J 2012 Jul 53: 488-92 |
| PMID | 22815019 |
| Title | Comparison of fasting blood sugar and serum lipid profile changes after treatment with atypical antipsychotics olanzapine and risperidone. |
| Abstract | This study aimed to compare the effects of the two most commonly prescribed atypical antipsychotics, olanzapine and risperidone, on fasting blood sugar and serum lipid profile of the recipients. A randomised, comparative, open clinical study was conducted on 60 schizophrenic patients. The patients were divided into two groups, one receiving olanzapine and the other receiving risperidone. The patients were assessed for changes in fasting blood sugar and serum lipid profile (triglycerides [TG], high-density lipoprotein [HDL], low-density lipoprotein [LDL], very-low-density lipoprotein [VLDL] and total cholesterol) eight weeks after starting treatment. The number of patients positive for fasting blood sugar and lipid profile criteria of metabolic syndrome was calculated by applying the modified National Cholesterol Education Programme Adult Treatment Panel III guidelines (NCEP ATP III) criteria at eight weeks. Patients treated with olanzapine showed a highly significant increase in the observed parameters, whereas those treated with risperidone showed a significant increase in fasting blood sugar, HDL and LDL levels, and a highly significant increase in other parameters. Intergroup comparison was insignificant except for TG, VLDL and total cholesterol levels. More men as compared to women fulfilled the NCEP ATP III criteria for metabolic syndrome in both groups. Olanzapine has a higher propensity to cause derangement of some parameters of lipid profile than risperidone. These parameters include TG, VLDL and total cholesterol levels. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | World J. Biol. Psychiatry 2012 Jan 13: 22-9 |
| PMID | 21375366 |
| Title | Impact of apolipoprotein A5 (APOA5) polymorphisms on serum triglyceride levels in schizophrenic patients under long-term atypical antipsychotic treatment. |
| Abstract | schizophrenic patients treated with clozapine or olanzapine often develop hypertriglyceridemia. The apolipoprotein A5 gene (APOA5), which affects VLDL production and lipolysis, has been implicated in the triglyceride (TG) metabolism. This study examined the association of common APOA5 genetic variants and TG levels in chronically institutionalized schizophrenic patients, on a stable dose of atypical antipsychotic (clozapine, olanzapine or risperidone. The TG levels in 466 schizophrenic patients treated with clozapine (n = 182), olanzapine (n = 89) or risperidone (n = 195) were measured. Patients were genotyped for the three APOA5 single nucleotide polymorphisms (SNPs) rs662799 (-1131T > C), rs651821 (3A > G) and rs2266788 (1891T > C). A gene × drug interaction with TG levels was observed. In single-marker-based analysis, the minor alleles of the two polymorphisms (-1131C and -3G) were observed to be associated with increased TGs in patients treated with risperidone, but not with clozapine or olanzapine. Haplotype analysis further revealed that carriers of the haplotype constructed with the three minor alleles had higher TG levels than those who did not carry this haplotype in patients taking risperidone (CGC((+/+)) vs. = 125.4 ± 59.1 vs. 82.2 ± 65.8, P = 0.015; CGC((-/+ )) vs. CGC((-/-)) = 113.7 ± 80.4 vs. 82.2 ± 65.8, P = 0.012). Our findings extend and add new information to the existing data regarding the association between APOA5 and TG regulation during long-term atypical antipsychotic treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Pharmacol. Biochem. Behav. 2013 Mar 104: 80-9 |
| PMID | 23290937 |
| Title | Dysregulation of brain adenosine is detrimental to the expression of conditioned freezing but not general Pavlovian learning. |
| Abstract | Glutamatergic and dopaminergic neurotransmission is modulated by adenosine, whose ambient level in the brain is in turn regulated by the metabolic enzyme, adenosine kinase (ADK). Brain adenosinergic tone can therefore be effectively reduced and increased by up- and down-regulation of ADK expression, respectively. Although changes in brain ADK levels can yield multiple behavioral effects, the precise functional significance of telencephalon (neocortical and limbic structures) adenosine remains ill-defined. Among the phenotypes identified in transgenic mice with brain-wide ADK overexpression (ADK(TG) mice) and reduced adenosinergic tone, working memory deficiency and potentiated response to systemic N-methyl-d-aspartate receptor blockade were exacerbated by the introduction of local ADK disruption (elevated adenosinergic tone) restricted to the telencephalon (ADK(TG):ADK(Tel-def) mice). These two phenotypes, which are central to schizophrenia cognitive/negative symptoms, appear to be regulated by adenosinergic activities within and outside the telencephalon in a complementary manner. Here, we extended this unique comparison between ADK(TG) mice ADK(TG):ADK(Tel-def) mice to another prominent phenotype previously documented in ADK(TG) mice - namely, impaired Pavlovian conditioned freezing. We found that ADK(TG):ADK(Tel-def) mice again were associated with a more severe phenotype while sharing a similar phenotype profile. Furthermore, we qualified that this Pavlovian phenotype did not translate into a general deficiency in associative learning, since no such deficit was evident in three other (aversive and appetitive) Pavlovian learning paradigms. The present study has thus identified a hitherto unknown function of brain adenosine: the execution of conditioned freezing behavior, which is dependent on the balance of adenosinergic changes between the telencephalon and the rest of the brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2013 Feb 30: 21-5 |
| PMID | 23450473 |
| Title | [Association between ESR1 gene polymorphisms and haplotypes with schizophrenia]. |
| Abstract | To assess the association between single nucleotide polymorphisms (SNPs) and haplotypes of estrogen receptor 1 (ESR1) gene with schizophrenia. Three SNPs (rs2234693, rs9340799 and rs3798759) were determined in 333 schizophrenic patients and 315 healthy subjects with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Allelic and genotypic frequencies and particular haplotypes were compared between the two groups using Chi-square test. The allelic and genotypic frequencies of rs2234693 and rs9340799 showed no significant difference between the two groups (P U+003E 0.05). However, a significant difference was detected in the frequencies of rs3798759 G allele and GG genotype between the two groups (P U+003C 0.01). Single factor analysis stratified by sex also found that frequencies of rs3798759 GG and TG genotypes and G allele were significantly higher in female schizophrenia patients compared with healthy females (P U+003C 0.05). Haplotypes C-A-G and C-G-G were more common in schizophrenia group (P U+003C 0.05). polymorphisms of rs3798759 may be a risk factor for female patients with schizophrenia, and haplotypes C-A-G and C-G-G may be risk factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | Schizophr Bull 2013 Jul 39: 867-71 |
| PMID | 22516148 |
| Title | Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. |
| Abstract | Gluten can cause extraintestinal manifestations with or without gastrointestinal symptoms and elevated antitissue transglutaminase 2 (tTG2) autoantibodies. Organ-specific gluten reaction involves immune response toward other transglutaminase (TG) isoforms including tTG3 (expressed in the skin, leading to dermatitis herpetiformis) and tTG6 (expressed in the brain, causing gluten ataxia). This analysis focuses on tTG6 antibodies, which have never been studied before in schizophrenia (SZ) and its relationships to tTG2 and to antigliadin antibodies. We previously showed an increased prevalence of tTG2 antibodies in gluten sensitive SZ patients compared with healthy controls (HC) that was not paralleled by an increased prevalence of antiendomysial antibody. To elucidate this discrepancy, we examined those tTG2 positive SZ patients for the presence of tTG6 antibody. We also searched for tTG6 antibodies in our sample of antigliadin (AGA) positive and AGA and tTG2 negative SZ patients. Seventy-four tTG2 positive SZ patients were compared with 148 age and gender-matched HC. Of the 74 tTG2 positive SZ patients, 16 were positive for tTG6 IgA for a prevalence of 22%. Only 4 HC were positive for tTG6 IgA for a prevalence of 2.7%. Among the AGA positive SZ patients, the prevalence of tTG6 IgA was 21.3% while 13.1% of the AGA and tTG2 negative SZ patients were positive for tTG6 IgA. The HC had a prevalence of 6%. Our results indicate a higher prevalence of tTG6 antibodies in SZ that may represent a biomarker useful to identify SZ patients who would benefit from a gluten-free diet. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | J Psychiatr Res 2013 Sep 47: 1215-21 |
| PMID | 23786914 |
| Title | Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. |
| Abstract | MicroRNAs (miRNAs) are small non-coding RNAs that act as potent regulators of gene expression. A recent GWAS reported the rs1625579 SNP, located downstream of miR-137, as the strongest new association with schizophrenia [Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:969-76.]. Prior to this GWAS finding, a schizophrenia imaging-genetic study found miR-137 target genes significantly enriched for association with activation in the dorsolateral prefrontal cortex (DLPFC) [Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, et al. Identifying gene regulatory networks in schizophrenia. Neuroimage 2010;53:839-47.]. We investigated the expression levels of miR-137 and three candidate target genes (ZNF804A, CACNA1C, TCF4) in the DLPFC of postmortem brain tissue from 2 independent cohorts: (1) 26 subjects (10 control (CTR), 7 schizophrenia (SZ), 9 bipolar disorder (BD)) collected at the UCI brain bank; and (2) 99 subjects (33 CTR, 35 SZ, 31 BD) obtained from the Stanley Medical Research Institute (SMRI). MiR-137 expression in the DLPFC did not differ between diagnoses. We also explored the relationship between rs1625579 genotypes and miR-137 expression. Significantly lower miR-137 expression levels were observed in the homozygous TT subjects compared to TG and GG subjects in the control group (30% decrease, p-value = 0.03). Moreover, reduced miR-137 levels in TT subjects corresponded to increased levels of the miR-137 target gene TCF4. The miR-137 expression pattern in 9 brain regions was significant for regional effect (ANOVA p-value = 1.83E-12), with amygdala and hippocampus having the highest miR-137 expression level. In conclusion, decreased miR-137 expression is associated with the SZ risk allele of rs1625579, and potential regulation of TCF4, another SZ candidate gene. This study offers additional support for involvement of miR-137 and downstream targets as mechanisms of risk for psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | 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 |
| 59 | J. Psychopharmacol. (Oxford) 2013 Apr 27: 401-3 |
| PMID | 23325369 |
| Title | Increases in triglyceride levels are associated with clinical response to clozapine treatment. |
| Abstract | Increases in serum triglyceride (TG) levels are associated with clinical response to clozapine treatment. Clozapine is the most efficacious therapy for treatment of refractory schizophrenia, although its use is well recognised to be associated with substantial metabolic dysfunction. Interestingly, there is some evidence that the therapeutic benefit of clozapine is associated with treatment-emergent weight gain and dyslipidaemia, specifically hypertriglyceridaemia. In this prospective observational study, we examine associations between therapeutic response to clozapine in 49 patients with treatment-resistant schizophrenia and lipid dysregulation. An increase in TG levels was strongly predictive of clinical improvement (B=9.33, t =3.56, df=4, p<0.001) and of improvement in positive PANSS scores (B=2.85, t=3.61, df=4, p=0.001) as well as negative PANSS scores (B=1.93, t=2.36, df=4, p=0.02), when controlling for potential confounds of weight gain, change in waist circumference, baseline antipsychotic polypharmacy and serum clozapine levels. This finding suggests that clozapine's therapeutic efficacy is linked to serum lipid changes. Hypertriglyceridaemia as a predictor of clinical response in patients treated with clozapine merits further investigation in order to better elucidate its effect on the pharmacological activity of clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2013 Feb 30: 21-5 |
| PMID | 23450473 |
| Title | [Association between ESR1 gene polymorphisms and haplotypes with schizophrenia]. |
| Abstract | To assess the association between single nucleotide polymorphisms (SNPs) and haplotypes of estrogen receptor 1 (ESR1) gene with schizophrenia. Three SNPs (rs2234693, rs9340799 and rs3798759) were determined in 333 schizophrenic patients and 315 healthy subjects with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Allelic and genotypic frequencies and particular haplotypes were compared between the two groups using Chi-square test. The allelic and genotypic frequencies of rs2234693 and rs9340799 showed no significant difference between the two groups (P U+003E 0.05). However, a significant difference was detected in the frequencies of rs3798759 G allele and GG genotype between the two groups (P U+003C 0.01). Single factor analysis stratified by sex also found that frequencies of rs3798759 GG and TG genotypes and G allele were significantly higher in female schizophrenia patients compared with healthy females (P U+003C 0.05). Haplotypes C-A-G and C-G-G were more common in schizophrenia group (P U+003C 0.05). polymorphisms of rs3798759 may be a risk factor for female patients with schizophrenia, and haplotypes C-A-G and C-G-G may be risk factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | Mol Brain 2013 -1 6: 35 |
| PMID | 23938054 |
| Title | Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. |
| Abstract | In autosomal recessive early-onset Parkinsonism (PARK2), the pathogenetic process from the loss of function of a ubiquitin ligase parkin to the death of dopamine neurons remains unclear. A dominant hypothesis attributes the neurotoxicity to accumulated substrates that are exempt from parkin-mediated degradation. Parkin substrates include two septins; SEPT4/CDCrel-2 which coaggregates with ?-synuclein as Lewy bodies in Parkinson's disease, and its closest homolog SEPT5/CDCrel-1/PNUTL1 whose overload with viral vector can rapidly eliminate dopamine neurons in rats. However, chronic effects of pan-neural overload of septins have never been examined in mammals. To address this, we established a line of transgenic mice that express the largest gene product SEPT4(54kDa) via the prion promoter in the entire brain. Histological examination and biochemical quantification of SEPT4-associated proteins including ?-synuclein and the dopamine transporter in the nigrostriatal dopamine neurons found no significant difference between Sept4(TG/+) and wild-type littermates. Thus, the hypothetical pathogenicity by the chronic overload of SEPT4 alone, if any, is insufficient to trigger neurodegenerative process in the mouse brain. Intriguingly, however, a systematic battery of behavioral tests revealed unexpected abnormalities in Sept4(TG/+) mice that include consistent attenuation of voluntary activities in distinct behavioral paradigms and altered social behaviors. Together, these data indicate that septin dysregulations commonly found in postmortem human brains with Parkinson's disease, schizophrenia and bipolar disorders may be responsible for a subset of behavioral abnormalities in the patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | Eur Rev Med Pharmacol Sci 2013 Aug 17: 2136-40 |
| PMID | 23893178 |
| Title | A twenty-four-week, open-label study on ziprasidone's efficacy and influence on glucolipid metabolism in patients with schizophrenia and metabolic disorder. |
| Abstract | The risks of antipsychotic drugs on metabolic syndrome (MS) present many challenges for psychiatrists. To evaluate the effectiveness and influences on glucolipid metabolism in patients with schizophrenia and metabolic disorders switched from clozapine to ziprasidone. schizophrenic patients with metabolic syndrome who had been treated with clozapine for ? 2 years were enrolled in the open-label study. All the patients were switched to ziprasidone from clozapine and followed up for 24-week. The primary endpoints included body mass index (BMI), fasting glucose (FG), triglycerides (TG), HDL cholesterol (HDL-c) and systolic pressure (SP)/diastolic pressure (DP). Secondary endpoints included scores on the Positive and Negative Syndrome Scale (PANSS) and treatment emergent symptom scale (TESS). A total of 213 cases satisfied the inclusion and exclusion criteria, but only 194 cases eventually completed the 24-week follow-up and were divided into ziprasidone group (n=68, complete substitution) and combined treatment group (n=126, partial substitution). In the ziprasidone group, TG at 4th and 24th week, BMI and HDL-c at 24th week were significantly improved (p < 0.05), while cognitive scores and total score of the PANSS at 4th and 24th week, negative factor, the factor of anxiety and depression at 24th week were significantly lower than those at the baseline (p < 0.05); In the combined group, cognitive factor scores (4 weekend, 24 weekends) and total score of PANSS (24 weeks) was significantly lower than baseline (p < 0.05). There was no significant difference in the TESS score (p > 0.05). Ziprasidone completely or partially substituting clozapine can improve both glucolipid metabolism disorders, and cognitive disorders and affective disorders of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | J. Hum. Genet. 2013 Oct 58: 700-5 |
| PMID | 23903071 |
| Title | Influence of the NRGN gene on intellectual ability in schizophrenia. |
| Abstract | Genome-wide association studies have reported an association between schizophrenia and rs12807809 of the neurogranin (NRGN) gene. We have recently found that an rs12807809-rs12278912 haplotype of the gene is associated with schizophrenia in a Japanese population and that the NRGN expression of the high-risk TG haplotype is lower than that of the protective TA haplotype in immortalized lymphoblasts. In this study, we investigated the influences of neurogranin genotypes (rs12807809 and rs12278912), haplotypes and diplotypes and genetic variant-diagnosis interactions on intellectual ability in 414 Japanese patients with schizophrenia and healthy subjects. We detected possible effects of the genome-wide screen-supported rs12807809, haplotypes, diplotypes and their genetic variant-diagnosis interactions on intellectual abilities at the threshold level of P<0.05. After applying Bonferroni correction for 13 genotype measures and setting P-values for significance (P<0.0039; 0.05/13), three effects remained significant: the rs12807809-rs12278912 diplotype-diagnosis interactions on performance intelligence quotient (CG/CG: P=3.9 × 10(-13); TA/TA: P=1.1 × 10(-7)) and TA/TA diplotype on performance intelligence quotient in patients with schizophrenia (P=8.2 × 10(-8)) remained significant. The intellectual abilities of the high-risk TG/TG diplotype of the neurogranin gene were lower compared to those with the non-risk TA/TA diplotype. Our findings suggest that the genetic risk variant in the neurogranin gene may be related to reduced intellectual ability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Neuropsychiatr Dis Treat 2013 -1 9: 595-603 |
| PMID | 23662058 |
| Title | Soccer practice as an add-on treatment in the management of individuals with a diagnosis of schizophrenia. |
| Abstract | Physical activity is an important aspect of good health for everyone; it is even more important for psychiatric patients who usually live an unhealthy lifestyle. In recent years, there has been growing focus on the use of soccer as a vehicle to improve the health of subjects with severe mental illness. The aim of this study was to investigate the effects of soccer practice on the self-reported health quality of life (SRHQL) and sports performance (SP) in psychotic subjects. Eighteen male patients with diagnosis of schizophrenia were randomized into either a trained (TG) or a control group (CG). The TG was trained for 12 weeks using two soccer training sessions per week. The CG did not perform any regular sports activity during the experimental period. Anthropometric measurements, SRHQL, personal time records in a 30 meter sprint test and slalom test running with a ball were evaluated before and after the experimental period. SRHQL was assessed using Short Form-12 questionnaire measuring physical and mental component summary scores. After the training period, the TG showed a relevant decrease by 4.6% in bodyweight (BW) and body mass index compared to baseline. Conversely, the CG showed an increased BW and body mass index by 1.8% from baseline to posttest. Moreover, after 12 weeks we found that control patients increased their BW significantly when compared to trained patients (? = 5.4%; P < 0.05). After the training period, comparing the baseline TG's Short Form-12-scores to posttest results, we found an improvement of 10.5% and 10.8% in physical component summary and mental component summary, respectively. In addition, performances on the 30 meter sprint test and slalom test running with a ball in the TG improved significantly (P < 0.01) from baseline to posttest when compared to CG. Soccer practice appears able to improve psychophysical health in individuals with diagnosis of schizophrenia. Indeed, our study demonstrated that programmed soccer physical activity could reduce antipsychotic medication-related weight gain and improve SRHQL and sports performance in psychotic subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | Zhong Nan Da Xue Xue Bao Yi Xue Ban 2013 Apr 38: 365-9 |
| PMID | 23645236 |
| Title | [Effects of ziprasidone and olanzapine on glucose and lipid metabolism in first-episode schizophrenia]. |
| Abstract | To investigate the effect of ziprasidone and olanzapine on glucose and lipid metabolism in first-episode schizophrenia. A total of 260 schizophrenics were assigned randomly to receive ziprasidone or olanzapine for 6 weeks. The weight was measured at baseline, week 2, 4 and 6. Fasting blood glucose (FBS), fasting insulin, high-density lipoprotein (HDL), total-cholesterol (TC) and triglycerides (TG) were measured at baseline and the end of 6-week treatment. Low-density lipoprotein (LDL) was measured in some patients at baseline and the end of 6-week treatment. Body mass index (BMI) and insulin resistance index (IRI) were counted. A total of 245 patients completed the trial, including 121 ziprasidone patients and 124 olanzapine patients. The average dose was 137.5 mg/d for ziprasidone and 19.5 mg/d for olanzapine. Patients treated with olanzapine had higher weight gain than those treated with ziprasidone [(4.55±3.37) kg vs (-0.83±2.05) kg, P<0.001]. After the treatment, FBS, fasting insulin, HDL, TC, TG, LDL and IRI levels were significantly increased in the olanzapine group (all P values<0.001 ). However, in the ziprasidone group, FBS decreased significantly and HDL and TG levels increased significantly after the 6-week treatment (all P values<0.05). The mean changes of FBS, fasting insulin, TC, TG, LDL and IRI were significantly different in the two groups (all P values<0.001). Ziprasidone has less glucose and lipid metabolic effect for first-episode schizophrenia patients in short-term treatment. However, olanzapine induces weight gain and dysfunction of glucose and lipid metabolism significantly, which is associated with increased risk of complications. When the doctors choose antipsychotics in the clinic, they should consider the side effects of the medication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 66 | Eur Rev Med Pharmacol Sci 2013 Aug 17: 2136-40 |
| PMID | 23893178 |
| Title | A twenty-four-week, open-label study on ziprasidone's efficacy and influence on glucolipid metabolism in patients with schizophrenia and metabolic disorder. |
| Abstract | The risks of antipsychotic drugs on metabolic syndrome (MS) present many challenges for psychiatrists. To evaluate the effectiveness and influences on glucolipid metabolism in patients with schizophrenia and metabolic disorders switched from clozapine to ziprasidone. schizophrenic patients with metabolic syndrome who had been treated with clozapine for ? 2 years were enrolled in the open-label study. All the patients were switched to ziprasidone from clozapine and followed up for 24-week. The primary endpoints included body mass index (BMI), fasting glucose (FG), triglycerides (TG), HDL cholesterol (HDL-c) and systolic pressure (SP)/diastolic pressure (DP). Secondary endpoints included scores on the Positive and Negative Syndrome Scale (PANSS) and treatment emergent symptom scale (TESS). A total of 213 cases satisfied the inclusion and exclusion criteria, but only 194 cases eventually completed the 24-week follow-up and were divided into ziprasidone group (n=68, complete substitution) and combined treatment group (n=126, partial substitution). In the ziprasidone group, TG at 4th and 24th week, BMI and HDL-c at 24th week were significantly improved (p < 0.05), while cognitive scores and total score of the PANSS at 4th and 24th week, negative factor, the factor of anxiety and depression at 24th week were significantly lower than those at the baseline (p < 0.05); In the combined group, cognitive factor scores (4 weekend, 24 weekends) and total score of PANSS (24 weeks) was significantly lower than baseline (p < 0.05). There was no significant difference in the TESS score (p > 0.05). Ziprasidone completely or partially substituting clozapine can improve both glucolipid metabolism disorders, and cognitive disorders and affective disorders of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 67 | Zhong Nan Da Xue Xue Bao Yi Xue Ban 2013 Apr 38: 365-9 |
| PMID | 23645236 |
| Title | [Effects of ziprasidone and olanzapine on glucose and lipid metabolism in first-episode schizophrenia]. |
| Abstract | To investigate the effect of ziprasidone and olanzapine on glucose and lipid metabolism in first-episode schizophrenia. A total of 260 schizophrenics were assigned randomly to receive ziprasidone or olanzapine for 6 weeks. The weight was measured at baseline, week 2, 4 and 6. Fasting blood glucose (FBS), fasting insulin, high-density lipoprotein (HDL), total-cholesterol (TC) and triglycerides (TG) were measured at baseline and the end of 6-week treatment. Low-density lipoprotein (LDL) was measured in some patients at baseline and the end of 6-week treatment. Body mass index (BMI) and insulin resistance index (IRI) were counted. A total of 245 patients completed the trial, including 121 ziprasidone patients and 124 olanzapine patients. The average dose was 137.5 mg/d for ziprasidone and 19.5 mg/d for olanzapine. Patients treated with olanzapine had higher weight gain than those treated with ziprasidone [(4.55±3.37) kg vs (-0.83±2.05) kg, P<0.001]. After the treatment, FBS, fasting insulin, HDL, TC, TG, LDL and IRI levels were significantly increased in the olanzapine group (all P values<0.001 ). However, in the ziprasidone group, FBS decreased significantly and HDL and TG levels increased significantly after the 6-week treatment (all P values<0.05). The mean changes of FBS, fasting insulin, TC, TG, LDL and IRI were significantly different in the two groups (all P values<0.001). Ziprasidone has less glucose and lipid metabolic effect for first-episode schizophrenia patients in short-term treatment. However, olanzapine induces weight gain and dysfunction of glucose and lipid metabolism significantly, which is associated with increased risk of complications. When the doctors choose antipsychotics in the clinic, they should consider the side effects of the medication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 68 | Psychiatr Q 2014 Dec 85: 487-96 |
| PMID | 25085446 |
| Title | No change of the lipid profile under the control of ApoE gene polymorphism in schizophrenics under paliperidone treatment. |
| Abstract | The present study tried to explore the effects of Paliperidone on the lipid profiles of schizophrenia patients. One hundred twenty-nine subjects diagnosed with schizophrenia were enrolled into this study and completed the lipid profile evaluation. Their blood samples were obtained on the morning following a 12-hours fast. Cholesterol and triglyceride (TG) levels in plasma were determined, and lipoproteins were determined by enzymatic methods. All participants provided written informed consent, and underwent additional venous blood withdrawal for DNA extraction for genetic study of the ApoE gene polymorphism. Under T test, TC, TG and HDL levels all declined after Paliperidone treatment although with no statistically significant difference. The ratios of TC/HDL declined after Paliperidone treatment, but without statistically significant difference. After GEE-I analysis, we found that ApoE4 genotype (? = 34.471; p < 0.001) had a positive effect on the total cholesterol (TC) level; female had positive effect on the high-density lipoprotein (HDL) level (? = 15.361; p = 0.003); and age had a positive effect on the TG level (? = 1.317; p = 0.030). Smoking (? = 0.961; p = 0.016) had a positive effect on the ratio of TC/HDL change. Lipid profiles were not increased after Paliperidone treatment under the control of ApoE gene polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 69 | Asian J Psychiatr 2014 Jun 9: 36-40 |
| PMID | 24813034 |
| Title | Paraoxonase 1 activity and lipid profile in schizophrenic patients. |
| Abstract | This study aimed to investigate the variations of paraoxonase 1 (PON1) activity and lipid profile in patients with schizophrenia and the association of this activity with the sociodemographic, clinical and therapeutical characteristics of this population. Our cross-sectional study included 140 schizophrenic patients and 119 control subjects aged respectively 37.3±10.4 and 41.4±10 years. PON1 activity was determined using Konelab 30? equipment (Thermo Electron Corporation). Plasma total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (c-HDL) and low-density lipoprotein cholesterol (c-LDL) concentrations were determined using Cobas 6000? (Roche Diagnostics), apolipoproteins (ApoA1, ApoB) and lipoprotein (a) (Lp(a)) were determined using Integra 400 plus (Roche Diagnostics). Compared to controls, patients had no significant decrease of PON1 activity and significantly lower ApoA1, c-HDL levels, and significantly higher levels of TG, ApoB, Lp(a) and TC/c-HDL and ApoB/ApoA1 ratios. Furthermore, PON1 activity was correlated with TG/c-HDL ratio. The lowest PON1 activity was noted in obese patients, in paranoid sub-type and in patients treated with combination of typical and atypical antipsychotics without significant difference. Moreover, it was associated with gender and cigarette smoking but not with alcohol consumption status. schizophrenic patients had a decrease in PON1 activity and perturbations in their lipid profiles that contribute to increase the risk of cardiovascular diseases. In addition, our results revealed that there was no association between the decrease of PON1 activity and any demographic or clinical characteristics. Therefore, such patients require specific care, particularly with regard to their lipid profile. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 70 | 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 |
| 71 | Psychopharmacology (Berl.) 2014 May 231: 2211-8 |
| PMID | 24448899 |
| Title | Metabolic syndrome in patients taking clozapine: prevalence and influence of catechol-O-methyltransferase genotype. |
| Abstract | Metabolic syndrome (MetS) has consistently been identified as an adverse effect of long-term treatment with atypical antipsychotics (AAPs) such as clozapine. Elevated serum homocysteine concentration has been found to act as an independent risk factor for MetS, and catechol-O-methyltransferase (COMT) catalyzes the homocysteine metabolism. We accordingly hypothesized that COMT dysregulation may confer the susceptibility to MetS induced by AAPs, potentially in a gender-specific manner, because the interaction effects of COMT and gender have been consistently reported. This study aimed at determining the prevalence and influence of COMT on MetS among a population undergoing long-term clozapine treatment. A total of 468 schizophrenia patients taking clozapine were divided into two groups, those experiencing MetS and non-MetS. We genotyped three functional variants (rs4633, rs4680, and rs4818) in COMT and measured the serum levels of fasting homocysteine, glucose, triglyceride (TG), and high-density lipoprotein cholesterol. MetS was found in 202/468 (43.2 %) of all the patients, with 40.2 % prevalence (138/343) in males and 51.2 % (64/125) in females. Patients with MetS had notably higher metabolic parameters than those without MetS. The mean levels of homocysteine in patients with MetS were significantly higher than those without MetS. We found a positive association between the rs4680 polymorphism and the serum triglyceride levels (corrected P?=?0.024). Further analysis revealed that the rs4680 Met allele was significantly associated with increased triglyceride levels among female patients (P?=?0.009), but not among males (P?=?0.07). Our findings suggest a potential association between rs4680 in COMT and elevated TG levels, particularly among female patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 72 | Psychiatry Res 2014 Jan 215: 9-13 |
| PMID | 24210662 |
| Title | Inverse association between 18-carbon trans fatty acids and intelligence quotients in smoking schizophrenia patients. |
| Abstract | This study aimed to investigate polyunsaturated (PUFA) and trans isomeric fatty acid status in schizophrenia patients. Fatty acid composition of plasma phospholipids (PL) and triacylglycerols (TG) was analyzed by gas chromatography in 29 schizophrenia patients and 15 healthy controls. We found no difference in PL n-3 fatty acid status between the two groups, while the values of 22:5n-6 were significantly higher in patients with schizophrenia than in controls. In TG, values of docosatrienoic acid (20:3n-3) and docosapentaenoic acid (20:5n-3) were significantly higher in schizophrenia patients than in controls. We found no difference in the trans fatty acid status between patients and controls. In smoking schizophrenia patients significant negative correlations were detected between Wechsler adult full-scale intelligence quotients and values of total trans fatty acids in PL lipids, whereas no such correlation was seen either in non-smoking schizophrenia patients, or in healthy controls. While data obtained in the present study fail to furnish evidence for n-3 PUFA supplementation to the diet of patients with schizophrenia, they indicate that in smoking schizophrenia patients high dietary exposure to trans fatty acids is associated with lower intelligence quotients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 73 | Schizophr Bull 2014 Sep 40: 963-72 |
| PMID | 24743863 |
| Title | Inflammatory molecular signature associated with infectious agents in psychosis. |
| Abstract | schizophrenia (SZ) is a devastating mental condition with onset in young adulthood. The identification of molecular biomarkers that reflect illness pathology is crucial. Recent evidence suggested immune and inflammatory cascades in conjunction with infection may play a role in the pathology. To address this question, we investigated molecular changes in cerebrospinal fluid (CSF) from antipsychotic-naïve patients with SZ and at risk mental status for psychosis (ARMS), in comparison with healthy controls (HCs). We measured 90 analytes using a broad multiplex platform focusing on immune and inflammatory cascades then selected 35 with our quality reporting criteria for further analysis. We also examined Toxoplasma gondii (TG) and herpes simplex virus 1 antibody levels in CSF. We report that expression of 15 molecules was significantly altered in the patient groups (SZ and ARMS) compared with HCs. The majority of these molecular changes (alpha-2-macroglobulin [?2M], fibrinogen, interleukin-6 receptor [IL-6R], stem cell factor [SCF], transforming growth factor alpha [TGF?], tumor necrosis factor receptor 2 [TNFR2], IL-8, monocyte chemotactic protein 2 [MCP-2/CCL8], testosterone [for males], angiotensin converting enzyme [ACE], and epidermal growth factor receptor) were consistent between SZ and ARMS patients, suggesting these may represent trait changes associated with psychotic conditions in general. Interestingly, many of these analytes (?2M, fibrinogen, IL-6R, SCF, TGF?, TNFR2, IL-8, MCP-2/CCL8, and testosterone [for males]) were exacerbated in subjects with ARMS compared with subjects with SZ. Although further studies are needed, we optimistically propose that these molecules may be good candidates for predictive markers for psychosis from an early stage. Lastly, reduction of IL-6R, TGF?, and ACE was correlated with positivity of TG antibody in the CSF, suggesting possible involvement of TG infection in the pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 74 | Psychiatr Q 2014 Dec 85: 487-96 |
| PMID | 25085446 |
| Title | No change of the lipid profile under the control of ApoE gene polymorphism in schizophrenics under paliperidone treatment. |
| Abstract | The present study tried to explore the effects of Paliperidone on the lipid profiles of schizophrenia patients. One hundred twenty-nine subjects diagnosed with schizophrenia were enrolled into this study and completed the lipid profile evaluation. Their blood samples were obtained on the morning following a 12-hours fast. Cholesterol and triglyceride (TG) levels in plasma were determined, and lipoproteins were determined by enzymatic methods. All participants provided written informed consent, and underwent additional venous blood withdrawal for DNA extraction for genetic study of the ApoE gene polymorphism. Under T test, TC, TG and HDL levels all declined after Paliperidone treatment although with no statistically significant difference. The ratios of TC/HDL declined after Paliperidone treatment, but without statistically significant difference. After GEE-I analysis, we found that ApoE4 genotype (? = 34.471; p < 0.001) had a positive effect on the total cholesterol (TC) level; female had positive effect on the high-density lipoprotein (HDL) level (? = 15.361; p = 0.003); and age had a positive effect on the TG level (? = 1.317; p = 0.030). Smoking (? = 0.961; p = 0.016) had a positive effect on the ratio of TC/HDL change. Lipid profiles were not increased after Paliperidone treatment under the control of ApoE gene polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 75 | Mol Brain 2014 -1 7: 74 |
| PMID | 25298178 |
| Title | Behavioral characterization of mice overexpressing human dysbindin-1. |
| Abstract | The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of-function is beneficial or detrimental. To answer this question and gain further insight into the pathophysiology and therapeutic potential of dysbindin-1, we developed transgenic mice expressing human DTNBP1 (Dys1A-TG) and analyzed their behavioral phenotypes. Dys1A-TG mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-TG mice. In addition, Dys1A-TG mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2, in the prefrontal cortex of Dys1A-TG mice. The present findings in Dys1A-TG mice support the role of dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-TG) or underexpression (Sandy) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of dysbindin-1 in vivo. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 76 | Eur. J. Clin. Pharmacol. 2014 Dec 70: 1433-41 |
| PMID | 25291992 |
| Title | Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients. |
| Abstract | Alterations in one-carbon metabolism (OCM) have been repeatedly reported in schizophrenia. However, there is a scarcity of studies addressing the effects of antipsychotics on selected OCM markers in schizophrenia and provided results are inconsistent. We recruited 39 first-episode schizophrenia (FES) patients and determined serum profile of total homocysteine (tHcy), folate, vitamin B12, lipoproteins and glucose at baseline and after 12 weeks of treatment with second-generation antipsychotics (SGA) including olanzapine and risperidone in monotherapy. After 12 weeks of treatment, all patients had significantly higher body mass index (BMI), serum levels of total cholesterol (TC), low-density lipoproteins (LDL), triglycerides (TG) and tHcy together with significantly lower levels of folate and vitamin B12. The analysis of differences between SGA revealed the same biochemical alterations in patients treated with olanzapine as in the whole group, while those receiving risperidone had no statistically significant changes in serum folate, vitamin B12 and TG. There was a significantly higher increase in BMI and TC in patients treated with olanzapine in comparison with those treated with risperidone. Patients receiving olanzapine had a higher decrease in vitamin B12 than those assigned to the treatment with risperidone. Changes in folate, vitamin B12, tHcy and TC levels were significant only in males, even after Bonferroni correction. Multiple regression analysis revealed that changes in tHcy levels are associated with gender and baseline metabolic parameters (BMI, glucose, TC, LDL and HDL) but not with selected SGA. These results indicate that SGA may influence OCM, especially in first-episode schizophrenia (FES) males. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 77 | Eur Neuropsychopharmacol 2014 Sep 24: 1524-33 |
| PMID | 25088904 |
| Title | Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice. |
| Abstract | Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with constitutive activity involved in cellular architecture, gene expression, cell proliferation, fate decision and apoptosis, among others. GSK-3 expression is particularly high in brain where it may be involved in neurological and psychiatric disorders such as Alzheimer?s disease, bipolar disorder and major depression. A link with schizophrenia is suggested by the antipsychotic drug-induced GSK-3 regulation and by the involvement of the Akt/GSK-3 pathway in dopaminergic neurotransmission. Taking advantage of the previous development of dominant negative GSK-3 transgenic mice (TG) showing a selective reduction of GSK-3 activity in forebrain neurons but not in dopaminergic neurons, we explored the relationship between GSK-3 and dopaminergic neurotransmission in vivo. In microdialysis experiments, local quinpirole (DA D2-R agonist) in dorsal striatum reduced dopamine (DA) release significantly less in TG mice than in wild-type (WT) mice. However, local SKF-81297 (selective DA D1-R agonist) in dorsal striatum reduced DA release equally in both control and TG mice indicating a comparable function of DA D1-R in the direct striato-nigral pathway. Likewise, systemic quinpirole administration - acting preferentially on presynaptic DA D2- autoreceptors to modulate DA release-reduced striatal DA release similarly in both control and TG mice. Quinpirole reduced locomotor activity and induced c-fos expression in globus pallidus (both striatal DA D2-R-mediated effects) significantly more in WT than in TG mice. Taking together, the present results show that dominant negative GSK-3 transgenic mice show reduced DA D2-R-mediated function in striatum and further support a link between dopaminergic neurotransmission and GSK-3 activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 78 | Eur. Psychiatry 2014 Mar 29: 167-71 |
| PMID | 23769679 |
| Title | Severity of psychosis syndrome and change of metabolic abnormality in chronic schizophrenia patients: severe negative syndrome may be related to a distinct lipid pathophysiology. |
| Abstract | Metabolic abnormality is common among schizophrenia patients. Some metabolic traits were found associated with subgroups of schizophrenia patients. We examined a possible relationship between metabolic abnormality and psychosis profile in schizophrenia patients. Three hundred and seventy-two chronic schizophrenia patients treated with antipsychotics for more than 2 years were assessed with the Positive and Negative Syndrome Scale. A set of metabolic traits was measured at scheduled checkpoints between October 2004 and September 2006. Multiple regressions adjusted for sex showed negative correlations between body mass index (BMI) and total score and all subscales; triglycerides (TG) was negatively correlated with total score and negative syndrome, while HDLC was positively correlated with negative syndrome. When sex interaction was concerned, total score was negatively correlated with BMI but not with others; negative syndrome was negatively correlated with BMI and positively with HDLC. No metabolic traits were correlated with positive syndrome or general psychopathology. Loss of body weight is a serious health problem in schizophrenia patients with severe psychosis syndrome, especially the negative syndrome. schizophrenia patients with severe negative syndrome may have a distinct lipid pathophysiology in comparison with those who were less severe in the domain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 79 | Psychiatry Investig 2014 Oct 11: 459-66 |
| PMID | 25395978 |
| Title | The effectiveness of cross-tapering switching to ziprasidone in patients with schizophrenia or schizoaffective disorder. |
| Abstract | Switching antipsychotics is one useful therapeutic option when the treatment of schizophrenia encounters suboptimal efficacy and intolerability issues. This study aimed to investigate the efficacy and tolerability of cross-tapering switching to ziprasidone from other antipsychotics. A total of 67 patients with schizophrenia or schizoaffective disorder were recruited in this 12-week, multicenter, non-comparative, open-label trial. Prior antipsychotics were allowed to be maintained for up to 4 weeks during the titration of ziprasidone. Efficacy was primarily measured using the 18-item Brief Psychotic Rating Scale (BPRS) at baseline, 4 weeks, 8 weeks, and 12 weeks. Efficacy was secondarily measured by the Clinical Global Impression-Severity (CGI-S) scale and the Global Assessment of Functioning (GAF) scale at each visit. Regarding the metabolic effects of switching to ziprasidone, weight, body mass index (BMI), waist-to-hip ratio (WHR), and lipid profile-including triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol levels-were measured at each follow-up visit. The BPRS scores were significantly improved at 12 weeks after switching to ziprasidone (F=5.96, df=2.11, p=0.003), whereas the CGI-S and GAF scores were not significantly changed. BMIs, WHRs, and TG levels were significantly decreased, with no significant changes in other lipid profiles. Cross-tapering switching to ziprasidone is effective for patients with schizophrenia spectrum disorders. Beyond the efficacy of the procedure, favorable metabolic profiles show that switching to ziprasidone may be helpful for maintenance therapy over an extended period. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 80 | Neuropsychopharmacology 2014 Aug 39: 2153-60 |
| PMID | 24625753 |
| Title | The impact of MIR137 on dorsolateral prefrontal-hippocampal functional connectivity in healthy subjects. |
| Abstract | A recent mega-analysis combining genome-wide association study data revealed that a variant of microRNA 137 (MIR137) exhibits the most significant association with schizophrenia. Other biological evidence also consistently suggests that MIR137 may have a pivotal role in the pathogenesis of schizophrenia. However, the underlying neural mechanism remains unclear. As the disrupted dorsolateral prefrontal cortex (DLPFC) coupling with the hippocampal formation (HF) has been widely observed in schizophrenia patients, DLPFC-HF dysconnectivity can therefore be thought of as a pivotal intermediate phenotype that links genetic variants of psychiatric risk genes to schizophrenia. This study used resting-state functional magnetic resonance imaging to test whether the MIR137 variant (rs1625579) impacts DLPFC-HF functional connectivity and cognitive performance in 290 young, healthy Han Chinese individuals. To identify functional connectivity between DLPFC and HF, a seed-based functional connectivity analysis was used. The association between DLPFC-HF connectivity and working memory performance was further examined in individuals with different MIR137 genotypes. The individuals who are homozygous for the MIR137 risk allele (TT), which confers a high risk for schizophrenia, exhibited significantly different DLPFC-HF functional connectivity compared with TG individuals. Moreover, the DLPFC-HF connectivity could predict the working memory performance in MIR137 TG individuals, but not in TT individuals. The current findings obtained in a large sample of healthy participants identified potential neural mechanisms linking MIR137 with the risk of developing schizophrenia via the intermediate phenotype of DLPFC-HF connectivity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 81 | Int. J. Neuropsychopharmacol. 2014 Aug 17: 1139-48 |
| PMID | 24565079 |
| Title | Metabolomic profiling of schizophrenia patients at risk for metabolic syndrome. |
| Abstract | Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia. However, SGAs cause metabolic disturbances that can manifest as metabolic syndrome (MetS) in a subset of patients. The causes for these metabolic disturbances remain unclear. We performed a comprehensive metabolomic profiling of 60 schizophrenia patients undergoing treatment with SGAs that puts them at high (clozapine, olanzapine), medium (quetiapine, risperidone), or low (ziprasidone, aripiprazole) risk for developing MetS, compared to a cohort of 20 healthy controls. Multiplex immunoassays were used to measure 13 metabolic hormones and adipokines in plasma. Mass spectrometry was used to determine levels of lipids and polar metabolites in 29 patients and 10 controls. We found that levels of insulin and tumor necrosis factor alpha (TNF-?) were significantly higher (p < 0.005) in patients at medium and high risk for MetS, compared to controls. These molecules are known to be increased in individuals with high body fat content and obesity. On the other hand, adiponectin, a molecule responsible for control of food intake and body weight, was significantly decreased in patients at medium and high risk for MetS (p < 0.005). Further, levels of dyacylglycerides (DG), tryacylglycerides (TG) and cholestenone were increased, whereas ?-Ketoglutarate and malate, important mediators of the tricarboxylic acid (TCA) cycle, were significantly decreased in patients compared to controls. Our studies suggest that high- and medium-risk SGAs are associated with disruption of energy metabolism pathways. These findings may shed light on the molecular underpinnings of antipsychotic-induced MetS and aid in design of novel therapeutic approaches to reduce the side effects associated with these drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 82 | Asian J Psychiatr 2014 Jun 9: 36-40 |
| PMID | 24813034 |
| Title | Paraoxonase 1 activity and lipid profile in schizophrenic patients. |
| Abstract | This study aimed to investigate the variations of paraoxonase 1 (PON1) activity and lipid profile in patients with schizophrenia and the association of this activity with the sociodemographic, clinical and therapeutical characteristics of this population. Our cross-sectional study included 140 schizophrenic patients and 119 control subjects aged respectively 37.3±10.4 and 41.4±10 years. PON1 activity was determined using Konelab 30? equipment (Thermo Electron Corporation). Plasma total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (c-HDL) and low-density lipoprotein cholesterol (c-LDL) concentrations were determined using Cobas 6000? (Roche Diagnostics), apolipoproteins (ApoA1, ApoB) and lipoprotein (a) (Lp(a)) were determined using Integra 400 plus (Roche Diagnostics). Compared to controls, patients had no significant decrease of PON1 activity and significantly lower ApoA1, c-HDL levels, and significantly higher levels of TG, ApoB, Lp(a) and TC/c-HDL and ApoB/ApoA1 ratios. Furthermore, PON1 activity was correlated with TG/c-HDL ratio. The lowest PON1 activity was noted in obese patients, in paranoid sub-type and in patients treated with combination of typical and atypical antipsychotics without significant difference. Moreover, it was associated with gender and cigarette smoking but not with alcohol consumption status. schizophrenic patients had a decrease in PON1 activity and perturbations in their lipid profiles that contribute to increase the risk of cardiovascular diseases. In addition, our results revealed that there was no association between the decrease of PON1 activity and any demographic or clinical characteristics. Therefore, such patients require specific care, particularly with regard to their lipid profile. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 83 | Pharmacogenomics J. 2015 Oct -1: -1 |
| PMID | 26503818 |
| Title | Complement 3 and metabolic syndrome induced by clozapine: a cross-sectional study and retrospective cohort analysis. |
| Abstract | Metabolic syndrome (MetS) is considered to be an adverse effect of long-term treatment with atypical antipsychotics, particularly clozapine. There is strong evidence that the activation of inflammatory pathways interferes with normal metabolism and contributes to the development of MetS. C3, which is an inflammation molecule, has been reported to be associated with MetS. Because C3 is a heritable trait, we accordingly hypothesized that the gene encoding C3 (C3) would be a candidate gene for inter-individual variation in clozapine-induced MetS. We recruited 576 schizophrenia patients taking clozapine and measured the serum levels of fasting metabolic parameters. We then examined C3 mRNA and genotyped seven polymorphisms in C3. The expression quantitative trait locus (eQTL) data available for tissues were extracted by the Genotype-Tissue Expression Portal. A total of 105 patients' medical records were retrospectively reviewed to obtain the metabolic parameters during the initial 2-year clozapine treatment. The relative expression levels of C3 mRNA in patients with MetS were significantly higher than in those without MetS (P=0.02). C3 single-nucleotide polymorphism (SNP) rs2277984 was marginally associated with MetS (allelic P=0.06, odds ratio=1.36, 95% confidence interval (CI): 1.07-1.72). We found a significant association of rs2277984 with fasting triglyceride (TG) levels (P=0.004). Further, eQTL analysis revealed that rs2277984 regulates C3 expression in the liver (P=0.002). Similar results were found in the retrospective cohort analysis. The receiver operating characteristic curve showed a significant effect of the rs2277984 G allele on the percentage change of TG levels, with an area under the curve of 0.71 (95% CI: 0.60-0.81). C3 is likely to enhance TG accumulation and to confer susceptibility to clozapine-induced MetS. The C3 SNP rs2277984 may be a potential biomarker for predicting MetS risk in patients receiving clozapine treatment.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.68. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 84 | PLoS ONE 2015 -1 10: e0136716 |
| PMID | 26401912 |
| Title | No Evidence of Association between Toxoplasma gondii Infection and Financial Risk Taking in Females. |
| Abstract | Past research linked Toxoplasma gondii (TG) infection in humans with neurological and mental disorders (e.g., schizophrenia, Alzheimer's disease and attention disorders), irregularities of the dopaminergic and testosterone system, and increased likelihood of being involved in traffic accidents. We test for an association between TG infection and financial decision-making (DM) using a case-control design in a sample of female Czech students (n = 79). We estimate each subject's risk attitude and loss aversion using an experimental economic task involving real monetary incentives. We find no significant evidence that either measure of decision-making is associated with TG infection. We were unable to find evidence of an association between TG infection and financial decision-making in females. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 85 | Korean J. Parasitol. 2015 Feb 53: 29-34 |
| PMID | 25748706 |
| Title | Seropositivity and serointensity of Toxoplasma gondii antibodies and DNA among patients with schizophrenia. |
| Abstract | The aim of this cross sectional case control study was to examine the serofrequency and serointensity of Toxoplasma gondii (TG) IgG, IgM, and DNA among patients with schizophrenia. A total of 101 patients with schizophrenia and 55 healthy controls from Sungai Buloh Hospital, Selangor, Malaysia and University Malaya Medical Center (UMMC) were included in this study. The diagnosis of schizophrenia was made based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The presence of TG infection was examined using both indirect (ELISA) and direct (quantitative real-time PCR) detection methods by measuring TG IgG and IgM and DNA, respectively. The serofrequency of TG IgG antibodies (51.5%, 52/101) and DNA (32.67%, 33/101) among patients with schizophrenia was significantly higher than IgG (18.2%, 10/55) and DNA (3.64%, 2/55) of the controls (IgG, P=0.000, OD=4.8, CI=2.2-10.5; DNA, P=0.000, OD=12.9, CI=2.17-10.51). However, the TG IgM antibody between patients with schizophrenia and controls was not significant (P>0.005). There was no significant difference (P>0.005) in both serointensity of TG IgG and DNA between patients with schizophrenia and controls. These findings have further demonstrated the strong association between the active TG infection and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 86 | Schizophr. Res. 2015 Oct 168: 381-7 |
| PMID | 26278336 |
| Title | Metabolic syndrome and aerobic fitness in patients with first-episode schizophrenia, including a 1-year follow-up. |
| Abstract | To compare the prevalence of metabolic syndrome (MetS) and metabolic abnormalities in patients with first-episode schizophrenia (FES) with sex- and age-matched healthy controls; to investigate changes in MetS during 1year of treatment; and to investigate predictors of MetS. Patients with FES (N=99) and healthy controls (N=50) were included in the study. MetS was defined according to IDF based on waist circumference (WC), blood pressure (BP), triglycerides (TG), high-density lipoprotein (HDL), and fasting-glucose. Data on physical activity, aerobic fitness, smoking, and dietary habits, sleeping disturbances, psychopathology and psychotropic medication were also obtained. Patients were assessed at baseline and at 1year follow-up. Compared with healthy controls patients with FES had a higher baseline prevalence of MetS (p=.07), and metabolic abnormalities: WC (p<.01), TG (p<.01), HDL (p=.017), and fasting glucose (p=.04). Patients with FES had significantly increased prevalence of MetS (p=.03), WC (p=.04), and TG (p=.01) during the study period. Antipsychotics and low physical activity were significantly correlated with the increase in metabolic abnormalities. In multivariate analyses low aerobic fitness was the most consistent and significant predictor of metabolic abnormalities and MetS. MetS and metabolic abnormalities are highly prevalent in patients with FES, and both increase significantly during 1year of treatment. Apart from confirming the metabolic adverse effects of antipsychotics, our study highlights that low aerobic fitness is a significant risk factor for MetS. Promoting a healthier lifestyle should be part of psychiatric treatment and rehabilitation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 87 | Mol. Psychiatry 2015 Dec 20: 1499-507 |
| PMID | 25623945 |
| Title | Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. |
| Abstract | Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in ?-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (TG) mice uncovered that the Pvalb/Gad1 TG mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 88 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Dec 168: 749-55 |
| PMID | 26408209 |
| Title | Common variants of HTR1A and SLC6A4 confer the increasing risk of Schizophrenia susceptibility: A population-based association and epistasis analysis. |
| Abstract | schizophrenia (SZ) is a complex psychiatric disorder strongly influenced by genetic variants, some of which are associated with mood disorders. The neurotransmitter 5-hydoxytryptamine (5-HT) and its related biochemical factors have been shown to play a significant role in maintaining mood balance. Recent studies evaluating the association between SZ and genetic polymorphisms in a serotonin transporter (encoded by SLC6A4) and serotonin receptor 1A (encoded by HTR1A) show conflicting results. In this study, we performed a case-control association analysis using 4,000 individuals with Chinese-Han ancestry. Of these participants, 1,000 were SZ cases and 3,000 were healthy controls. Thirty-six single nucleotide polymorphisms (SNPs) located in SLC6A4 and HTR1A were genotyped in our 4,000 study samples. Of those, 33 polymorphic SNPs with a minor allele frequency >0.05 were used for further analysis. We found that rs878567 in HTR1A (asymptotic P-value?=?3.89×10(-4) , corrected P-value?=?0.0106) was significantly associated with SZ. Further haplotype-based analyses revealed that a two-SNP haplotype, rs2054847-rs140701 (TG) in gene SLC6A4, was significantly associated with SZ (P-value?=?1.63×10(-4) and corrected P-value?=?0.002799). We did not identify any significant epistatic interactions between the two genes. Our findings provide supportive evidence that genetic polymorphisms in SLC6A4 and HTR1A may influence the risk of SZ in Han Chinese individuals. © 2015 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 89 | Rapid Commun. Mass Spectrom. 2015 Aug 29: 1491-500 |
| PMID | 26212164 |
| Title | Lipidomic analysis of p-chlorophenylalanine-treated mice using continuous-flow two-dimensional liquid chromatography/quadrupole time-of-flight mass spectrometry. |
| Abstract | Although serotonin deficiency is involved with various physiological disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia and depression, the serotonin-dependent pathomechanisms remain poorly understood, particularly from a lipidomics perspective. This study therefore aimed to identify novel lipid biomarkers associated with serotonin deficiency by lipid profiling of p-chlorophenylalanine (pCPA)-treated, serotonin-deficient mice using continuous-flow normal-phase/reversed-phase two-dimensional liquid chromatography/quadrupole time-of-flight mass spectrometry (NP/RP 2D LC/QTOFMS). Principal component analysis (PCA) was performed to distinguish significantly altered lipids between the pCPA-treated mice and control mice. Eighteen lipid biomarkers were associated with pCPA-induced serotonin deficiency. Specifically, lipid species of lysophosphatidylethanolamine (LPE), phosphatidylethanolamine (PE), sphingomyelin (SM), galactosylceramide (GalCer), glucotosylceramide (GluCer), lactosylceramide (LacCer) and triacylglycerol (TG) were down-regulated whereas glycerophosphocholine (PC) and phosphatidylinositol (PI) were up-regulated in the pCPA-treated mice compared with control mice. This work demonstrates the significant effects of serotonin deficiency on lipid metabolisms and will facilitate improved understanding of pathomechanisms in serotonin deficiency, particularly from a lipidomics perspective. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 90 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 Jan 56: 247-53 |
| PMID | 25283341 |
| Title | Dopaminergic activity and behaviour in SOCS2 transgenic mice: Revealing a potential drug target for schizophrenia. |
| Abstract | Alterations in immune function have been implicated in the aetiopathogenesis of schizophrenia. Specifically, the induction of inflammatory cytokines, which are important immunological factors in infection or inflammation, may be critical factors altering the normal course of brain development and increasing schizophrenia risk. Suppressor of cytokine signalling 2 (SOCS2) can negatively regulate the signalling of cytokines. The present study aimed to determine the behavioural phenotype of transgenic mice over-expressing SOCS2 (SOCS2 TG) in paradigms of relevance to schizophrenia. Both male and female SOCS2 TG mice displayed reduced locomotor hyperactivity after the administration of the dopamine releaser, amphetamine, compared to wildtype controls (WT). However, only male SOCS2 TG mice showed enhanced prepulse inhibition compared to WT. Dopamine D2 receptors mRNA expression was reduced and dopamine transporter mRNA expression was increased in the nucleus accumbens of female, but not male, SOCS2 TG mice, compared to WT. The role of hyperdopaminergia has long been implicated in the aetiology of schizophrenia. This study shows that over-expression of SOCS2 reduces the psychostimulant effects of amphetamine, enhances PPI, and alters mesolimbic dopaminergic activity. SOCS2 may provide a novel target in the development of treatments for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 91 | Schizophr. Res. 2015 Aug 166: 37-42 |
| PMID | 25982813 |
| Title | Free thyroxine levels are associated with cognitive abilities in subjects with early psychosis. |
| Abstract | Subjects with a psychotic disorder show mild to moderate cognitive impairment, which is an important determinant of functional outcome. The underlying biological process of cognitive impairment in psychosis is unclear. We aimed to explore whether hypothalamic-pituitary-thyroid axis hormones or thyroid autoimmunity modulate cognitive functioning in subjects with early psychosis. We studied 70 patients with a psychotic disorder (<3years of illness) and a control group of 37 healthy subjects (HS). Plasma levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroid-peroxidase (TPO-Abs) and thyroglobulin antibodies (TG-Abs) were determined. Cognitive assessment was performed with the MATRICS Cognitive Consensus Cognitive Battery. We also explored the relationship between thyroid variables and cognition in three subgroups of psychotic patients: psychosis not otherwise specified, affective psychosis (bipolar disorder or schizoaffective disorder) and non-affective psychosis (schizophrenia or schizophreniphorm disorder). In patients with early psychosis, higher FT4 levels (but not TSH or thyroid antibodies) were associated with better cognitive performance in attention/vigilance and overall cognition. The relationship between FT4 levels and the attention/vigilance domain remained significant in a multivariate analysis after adjusting for education level, age, gender, substance use, and benzodiazepine and antipsychotic treatments. We did not find a significant association between FT4 and cognitive performance in HS. In the exploratory analysis by psychotic subtypes, subjects with affective psychosis had increased FT4 levels and better cognitive profile than those with non-affective psychosis. Our study suggests that FT4 levels are associated with cognitive abilities (attention/vigilance and overall cognition) in individuals with early psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 92 | Acta Psychiatr Scand 2015 Oct 132: 293-300 |
| PMID | 25597473 |
| Title | Association between serum lipids and membrane fatty acids and clinical characteristics in patients with schizophrenia. |
| Abstract | Earlier reports indicate that patients with schizophrenia have altered lipid levels in serum and cell membranes. The purpose of this study was to determine the relationship between clinical characteristics and serum and membrane lipids. Fifty-five patients with schizophrenia and 51 healthy controls were included. The patients were characterized with Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Functioning (GAF). Serum lipids [high- and low-density lipoprotein cholesterol (HDL, LDL) and triglyceride (TG)] and erythrocyte polyunsaturated fatty acids (PUFA) were measured. Among the participants with schizophrenia, there was a significant correlation between serum triglyceride levels and PANSS-positive symptoms (r = 0.28, P = 0.04), GAF-S (r = -0.48, P = 0.001) and GAF-F (r = -0.32, P = 0.01), and between HDL level and GAF-S (r = 0.37, P = 0.008) and GAF-F (r = 0.28, P = 0.04). Long-chain PUFA were significantly associated with PANSS-negative symptoms (r = 0.52, P < 0.001), GAF-S (r = -0.32, P = 0.02), and GAF-F (r = -0.29, P = 0.04). The patients with schizophrenia had significantly higher TG (P < 0.001) and lower HDL (P < 0.001) levels than healthy controls. HDL was also lower in the subgroup (n = 11) not receiving antipsychotic medication (P = 0.02). The results suggest associations between lipid profile and clinical characteristics. This may indicate a role for lipid biology in schizophrenia pathophysiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 93 | J. Comp. Neurol. 2016 Aug 524: 2281-99 |
| PMID | 26669716 |
| Title | Immunocytochemical heterogeneity of somatostatin-expressing GABAergic interneurons in layers II and III of the mouse cingulate cortex: A combined immunofluorescence/design-based stereologic study. |
| Abstract | Many neurological diseases including major depression and schizophrenia manifest as dysfunction of the GABAergic system within the cingulate cortex. However, relatively little is known about the properties of GABAergic interneurons in the cingulate cortex. Therefore, we investigated the neurochemical properties of GABAergic interneurons in the cingulate cortex of FVB-TG(GadGFP)45704Swn/J mice expressing green fluorescent protein (GFP) in a subset of GABAergic interneurons (GFP-expressing inhibitory interneurons [GINs]) by means of immunocytochemical and design-based stereologic techniques. We found that GINs represent around 12% of all GABAergic interneurons in the cingulate cortex. In contrast to other neocortical areas, GINs were only found in cortical layers II and III. More than 98% of GINs coexpressed the neuropeptide somatostatin (SOM), but only 50% of all SOM?+?neurons were GINs. By analyzing the expression of calretinin (CR), calbindin (CB), parvalbumin, and various neuropeptides, we identified several distinct GIN subgroups. In particular, we observed coexpression of SOM with CR and CB. In addition, we found neuropeptide Y expression almost exclusively in those GINs that coexpressed SOM and CR. Thus, with respect to the expression of calcium-binding proteins and neuropeptides, GINs are surprisingly heterogeneous in the mouse cingulate cortex, and the minority of GINs express only one marker protein or peptide. Furthermore, our observation of overlap between the SOM?+?and CR?+?interneuron population was in contrast to earlier findings of non-overlapping SOM?+?and CR?+?interneuron populations in the human cortex. This might indicate that findings in mouse models of neuropsychiatric diseases may not be directly transferred to human patients. J. Comp. Neurol. 524:2281-2299, 2016. © 2015 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |