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Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies., (© 2023. The Author(s).)

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear., Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites., Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data., Study Selection: In total, 45 1H-MRS studies contributed data., Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor., Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL)., Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose., Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Objectives: Catecholamines, brain-derived neurotrophic factor (BDNF) and cytokines may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations between serum BDNF levels, plasma catecholamine metablolites, cytokines and the cognitive functions of patients with schizophrenia treated with atypical antipsychotic monotherapy., Methods: One hundred and forty-six patients with schizophrenia and 51 age- and sex-matched healthy controls were examined for peripheral biological markers and neurocognitive test., Results: There were positive correlations between serum BDNF levels and scores for verbal memory and attention and processing speed as well as between serum BDNF levels and negative symptoms. Furthermore, there was a negative correlation between the plasma homovanillic acid (HVA) level and motor function and a positive correlation between the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) level and attention and processing speed. There were no significant correlations between interleukin-6 or tumour necrosis factor alpha and cognitive function. Moreover, there were no significant correlations between the plasma levels of HVA, MHPG, cytokines and clinical symptoms., Conclusions: Serum BDNF levels are positively related to the impairment of verbal memory and attention, plasma HVA levels are positively related to motor function, and plasma MHPG levels are positively related to attention in patients with schizophrenia.

Objective: This study was designed to evaluate efficacy and safety of aripiprazole once-monthly (AOM) by verifying non-inferiority of AOM to oral aripiprazole in Asian patients with schizophrenia., Method: The study consisted of a screening phase and three phases: an oral conversion phase (≤12weeks), an oral stabilization phase (≤12weeks) and a 52-week double-blind phase. Patients meeting stabilization criteria for 4weeks during the oral stabilization phase were randomly assigned (1:1) to AOM (400mg) or oral aripiprazole (6-24mg/day). The primary endpoint was Kaplan-Meier estimated rate of non-exacerbation of psychotic symptoms/non-relapse at Week 26., Results: A total of 724 patients were screened, and 502 patients entered the oral stabilization phase. Of 455 patients randomized in the double-blind phase, 228 received AOM and 227 received oral aripiprazole. The non-exacerbation of psychotic symptoms/non-relapse rates at Week 26 were 95.0% (AOM) and 94.7% (oral aripiprazole) and the difference was 0.3% (95% CI: -3.9,4.5), thus non-inferiority of AOM compared to oral aripiprazole with respect to non-exacerbation of psychotic symptoms/non-relapse rate was shown with a margin of -3.9% which is well above the pre-defined non-inferiority limit (-15%). The proportions of patients meeting exacerbation of psychotic symptoms/relapse criteria and stabilization of psychotic symptoms/maintenance criteria were 6.6% and 92.5% in both groups. Discontinuation rates due to all reasons were 25.9% (AOM) and 33.5% (oral aripiprazole). AOM was well tolerated as well as oral aripiprazole., Conclusions: Non-inferiority of AOM to oral aripiprazole was established. AOM is efficacious in maintenance treatment of stabilized schizophrenia, with comparable efficacy and tolerability to oral aripiprazole., Clinical Trials Registration: JapicCTI-101175., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val(108/158)Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val(108/158)Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the χ(2) test. A significant association between the COMT Val(108/158)Met polymorphism and polydipsia was found (genotype distribution: χ(2) = 13.0, df = 2, p = 0.001; allele frequency: χ(2) = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val(108/158)Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings.

Objective: This study sought to examine whether switching polypharmacy therapy to monotherapy would improve the cognitive function and social function of patients with schizophrenia., Methods: Thirty-nine patients with schizophrenia who were receiving therapy with two antipsychotics were randomly divided into a switch to monotherapy group (switching group) and a polypharmacy continued group (continuing group). For the patients allocated to the switching group, the dose level of one of the two antipsychotic drugs was gradually reduced to zero. Psychotic symptoms, cognitive function and social function scale scores were assessed immediately before and 24 weeks after switching, and the time courses of these scores were compared between the two groups., Results: Compared with the continuing group, the switching group demonstrated significantly greater improvement in attention after switching (p = 0.02). Furthermore, the improvement in daily living (p = 0.038) and work skills (p = 0.04) was significantly greater in the switching group. In an analysis of the correlation among sub-items with respect to the degrees of improvement, a significant correlation was noted between improvement in executive function and improvement in daily living (r = -0.64, p = 0.005) and between improvement in work skills and improvement in attention (r = -0.51, p = 0.038)., Conclusion: In patients with schizophrenia receiving polypharmacy, switching to monotherapy resulted in improvements in attention. Furthermore, improvements in executive function led to improvements in daily living, and improvements in attention led to improvements in work skills. Thus, switching to monotherapy is a useful option., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Schizophrenia is a disease whose symptoms are shown to a little less than 1% at adolescence. Since the morbidity elucidation is not yet made many of psychiatry diseases including schizophrenia, a useful biological marker or image inspection, and a physiological inspection are not in diagnosis. About diagnosis of a psychiatric disorder, the symptoms study diagnostic method never must be used. Then, diagnosis needs to be made appropriately and carefully and differential diagnosis must also perform it exactly. It is because medical treatment may differ depending on diagnosis. If this is not made appropriately, it may lead to medication of an unnecessary and aimless antipsychotic. In this paper, diagnosis and differential diagnosis of schizophrenia, and clinical course were summarized.

We investigated the effects of the atypical antipsychotics risperidone, olanzapine, and aripiprazole on the cognitive functions of Japanese patients with schizophrenia with respect to dosage amounts and dosing schedules. We performed a cross-sectional survey using the Brief Assessment of Cognition in Schizophrenia - Japanese Language Version (BACS-J) to evaluate the neurocognitive functions of 101 schizophrenic patients who took the same dose of one of the three aforementioned antipsychotics for at least 3 months. The BACS-J composite score correlated negatively with the prescribed dosages of risperidone and olanzapine. In contrast, we did not find a correlation between the BACS-J composite score and the prescribed dosage of aripiprazole. Moreover, the primary scores for verbal learning, motor function, and attention and processing speed were significantly lower among the patients who were taking the prescribed dosage of risperidone. The scores for verbal learning and motor function were also significantly lower when correlated with the prescribed dosage of olanzapine. We did not find a correlation between any of the primary scores on the BACS-J and the prescribed dosage of aripiprazole. In fact, the results suggest there is no linear relationship between the dose of aripiprazole and cognitive impairment, which may be due to its unique pharmacological profile., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: We hypothesized that an excessive dose of antipsychotic drug and/or a larger number of antipsychotic drug worsens cognitive functions in schizophrenia patients. To confirm the hypothesis, we compared several cognitive functions in the patients taking a second-generation antipsychotic drug (SGA) only (SGA monotherapy group) with those in patients taking more than two kinds of antipsychotic drugs (polypharmacy group)., Methods: The cognitive functions of 136 chronic schizophrenia patients were evaluated using the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J)., Results: A significantly negative correlation was found between the composite score in the BACS-J and the chlorpromazine equivalence of doses of antipsychotic drugs in whole patients (r = -0.43, P < 0.001). Schizophrenia patients in the polypharmacy group had lower composite scores than those in the SGA monotherapy group in the BACS-J. No difference was observed in the composite score and the primary score in each item in the BACS-J between patients with first- plus second-generation antipsychotic drug (FGA + SGA group) and those with two kinds of SGA (SGA + SGA group)., Conclusion: These results suggest that an excessive dose of antipsychotic drugs regardless of FGA and SGA might cause the deterioration of cognitive functions in chronic Japanese schizophrenia patients.

The dopamine D3 receptor gene (DRD3) is considered being one of the candidate genes contributing to the development of tardive dyskinesia (TD). In a recent meta-analysis with mixed ethnicities, only a barely positive association was found between the functional DRD3 Ser9Gly polymorphism and TD in patients with schizophrenia (OR=1.17; 95% CI: 1.01-1.37; p=0.041). To further evaluate the controversial association between the polymorphism and TD using only Japanese subjects, we tested the association in a case-control design. We also conducted a meta-analysis including 8 studies with 3 East Asian populations (Japanese, Chinese, and Korean). In our Japanese case-control sample (43 with TD/157 without TD), we found no association between the DRD3 Ser9Gly polymorphism in schizophrenia and TD (genotype: p=0.92; allele: p=1.00). Furthermore, no significant difference in the mean AIMS score among the three genotypic groups was observed in our sample. The meta-analysis comprising 1291 East Asian subjects also showed no association between the polymorphism and TD; the Mantel-Haenszel pooled OR for TD among carriers of the DRD3 Ser9Gly of the eight Asian studies was 0.94 (95% CI: 0.78-1.12). Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to TD in East Asian populations. Given that the Ser9Gly variant may play a putative role in the DRD3 function, further studies on the DRD3 are warranted., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: We investigated the effects of aripiprazole on plasma levels of brain-derived neurotrophic factor (BDNF) and catecholamine metabolites in first-episode untreated schizophrenia patients., Methods: The subjects were 50 Japanese first-episode untreated schizophrenia patients who met the Diagnostic and Statistical Manual of Mental Disorders Text Revision criteria and were treated with aripiprazole monotherapy. Twenty-nine were males, and 21 were females. The age ranged from 21 to 42 years (mean ± SD; 30.8 ± 5.3 years). Plasma BDNF and catecholamine metabolites were measured by ELISA and HPLC, respectively. Psychiatric symptoms were evaluated using by Positive and Negative Syndrome Scale., Results: Treatment with aripiprazole for 8 weeks significantly increased plasma BDNF levels. It also changed plasma levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. A negative correlation was also observed between duration of psychosis and plasma BDNF levels. No correlation was observed however between plasma BDNF levels and the dose of aripiprazole., Conclusions: To the best of our knowledge, this is the first report showing that aripiprazole increases plasma BDNF levels in first-episode untreated schizophrenia patients. Furthermore, the BDNF Val66Met polymorphism was independent of the response to aripiprazole., (Copyright © 2011 John Wiley & Sons, Ltd.)

We investigated the effects of atypical antipsychotic drugs on GABA concentrations in early-stage, first-episode schizophrenia patients. Sixteen (8 males, 8 females; age, 30±11 years old) patients were followed up for six months. We also included 18 sex- and age-matched healthy control subjects. All patients were treated with atypical antipsychotic drugs (5 patients with risperidone, 5 patients with olanzapine, 4 patients with aripiprazole, and 2 patients with quetiapine). In all three regions measured (frontal lobe, left basal ganglia, and parieto-occipital lobe), no differences in GABA concentrations were observed in a comparison of pre-treatment levels and those six months after treatment. These results suggest that relatively short-term treatment with atypical antipsychotic drugs may not affect GABAergic neurotransmission; however, it is also possible that such treatment prevents further reductions in brain GABA levels in people with early-stage, first-episode schizophrenia., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Several investigations have reported that abnormalities in circadian rhythms might be related with the pathophysiology of psychiatric disorders, since many psychiatric patients have insomnia and sleep-awake disturbance. A recent animal study reported that Magel2, which encodes a member of the MAGE/necdin family of proteins, might be associated in the pathophysiology of psychiatric disorders. Magel2 gene knockout mice showed altered concentrations of both dopamine and serotonin in several parts of the brain compared with controls. In addition, the authors of that study detected a bilateral reduction in cortical volume in distinct regions of the Magel2 gene knockout mice brain, including focused regions in the parieto-temporal lobe of the cerebral cortex, the amygdala, the hippocampus, and the nucleus accumbens. These mice were also found to have hypoactivity and abnormalities in circadian rhythms. From this evidence, we considered Magel2 gene (MAGEL2) to be a good candidate gene for the pathophysiology of schizophrenia and mood disorder, and we conducted a case-control study among Japanese (731 schizophrenia patients, 465 MDD patients, 156 BP patients and 758 controls) using three tagging SNPs in MAGEL2 (rs850815, rs8920 and rs4480754), selected using the HapMap database. We did not find any association between MAGEL2 and schizophrenia, BP or MDD in allele/genotype-wise analysis or haplotype-wise analysis. Our results suggest that MAGEL2 may not play a role in the pathophysiology of schizophrenia and mood disorders in the Japanese population. A replication study using larger samples may be required for conclusive results, since our sample size was small and our study analyzed only three SNPs in MAGEL2.

In the present study, we longitudinally investigated the effects of risperidone, olanzapine, and aripiprazole on plasma levels of catecholamine metabolites and brain-derived neurotrophic factor (BDNF) in first-episode unmedicated schizophrenic patients. The subjects were 59 Japanese schizophrenic patients (35 males and 24 females; age range: 18-46 years; mean+/-SD: 25+/-16 years). The patients were treated with risperidone (n=32) in a dose range of 2-6 mg/day (mean+/-SD=3.4+/-1.9), olanzapine (n=18) in a dose range of 5-20 mg/day (mean+/-SD=12.1+/-5.8), or aripiprazole (n=9) in a dose range of 12-30 mg/day (mean+/-SD=22.8+/-10.1). All three drugs significantly decreased plasma homovanillic acid (HVA) levels within 8 weeks, although aripiprazole transiently raised this level before 8 weeks. All three drugs also significantly increased plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels within 8 weeks. On the other hand, none of them altered plasma BDNF levels. These results indicate that risperidone, olanzapine, and aripiprazole affect catecholaminergic systems in the brain, that the effects of aripiprazole on the dopaminergic systems seem to slightly different than those of risperidone and olanzapine, and that these atypical antipsychotic drugs might not alter BDNF levels, at least within 8 weeks of treatment.

Nitric oxide (NO) is involved in pathophysiology of psychiatric disorders such as depression and schizophrenia. We hypothesize that plasma levels of NO and its metabolites (NO(x)) are decreased in patients with schizophrenia. To examine the hypothesis, we compared plasma NO(x) levels between 30 schizophrenic patients (M/F: 18/12, age: 38 +/- 15 years) and age- and sex-matched 30 healthy controls (M/F: 18/12, age: 41 +/- 19 years), and we also examined the effects of risperidone on plasma NO(x) levels in schizophrenic patients. The baseline plasma NO(x) levels were significantly lower in the schizophrenia group (1.85 +/- 0.70 microM) than those in control group (3.37 +/- 2.27 microM). A significantly negative correlation was found between plasma NO(x) levels and PANSS-N scores before risperidone administration (rho = -0.385, p = 0.0416). Treatment with risperidone significantly increased the plasma NO(x) levels by 8 weeks (before; 1.85 +/- 0.70 microM, after; 2.25 +/- 1.00 microM, p = 0.0491). These results suggest that NO might be one of the candidates factors which are associated with the pathophysiology of negative symptoms of schizophrenia., (Copyright 2010 John Wiley & Sons, Ltd.)

Background: Pharmacogenomic approaches based on genomewide sets of single nucleotide polymorphisms (SNPs) are now feasible and offer the potential to uncover variants that influence drug response., Methods: To detect potential predictor gene variants for risperidone response in schizophrenic subjects, we performed a convergent analysis based on 1) a genomewide (100K SNP) SNP pharmacogenetic study of risperidone response and 2) a global transcriptome study of genes with mRNA levels influenced by risperidone exposure in mouse prefrontal cortex., Results: Fourteen genes were highlighted as of potential relevance to risperidone activity in both studies: ATP2B2, HS3ST2, UNC5C, BAG3, PDE7B, PAICS, PTGFRN, NR3C2, ZBTB20, ST6GAL2, PIP5K1B, EPHA6, KCNH5, and AJAP1. The SNPs related to these genes that were associated in the pharmacogenetic study were further assessed for evidence for association with schizophrenia in up to three case-control series comprising 1564 cases and 3862 controls in total (Japanese [JPN] 1st and 2nd samples and UK sample). Of 14 SNPs tested, one (rs9389370) in PDE7B showed significant evidence for association with schizophrenia in a discovery sample (p(allele) = .026 in JPN&#95;1st, two-tailed). This finding replicated in a joint analysis of two independent case-control samples (p(JPN&#95;2nd+UK) = .008, one-tailed, uncorrected) and in all combined data sets (p(all) = .0014, two-tailed, uncorrected and p(all) = .018, two-tailed, Bonferroni correction)., Conclusions: We identified novel candidate genes for treatment response to risperidone and provide evidence that one of these additionally may confer susceptibility to schizophrenia. Specifically, PDE7B is an attractive candidate gene, although evidence from integrated methodology, including pharmacogenomics, pharmacotranscriptomic, and case-control association approaches., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine whether statistical analyses of quantitative MR imaging data, including morphological changes, mean diffusivity (MD), and fractional anisotropy (FA), could provide useful biomarkers in early stage of first-episode schizophrenia., Materials and Methods: Twenty-three patients, who met all the criteria in the DSM-IV-TR category for schizophrenia excluding the duration of the disease (less than 6 months of follow-up), were examined by MR imaging during the initial consultation. Nineteen of the 23 patients were finally diagnosed to have schizophrenia after a 6-month follow-up, and they were included in this study as having been in the early stage of first-episode schizophrenia. Nineteen healthy volunteers also underwent MR imaging as age-matched controls. Three-dimensional spoiled gradient recalled acquisition with steady state (3D-SPGR) and diffusion tensor imaging (DTI) were performed at 3T. Image processing for voxel-based morphometry, a fully automatic technique for a computational analysis of differences in regional brain volume throughout the entire brain, was conducted using the Statistical Parametric Mapping 5 software package (SPM5). The 3D-SPGR images in the native space were bias-corrected; spatially normalized; segmented into gray matter, white matter, and cerebrospinal fluid images; and intensity-modulated using SPM5. A voxel-based analysis was conducted using both the MD and FA maps computed from DTI. The customized MD and FA template specific to this study was created from all participants. Thereafter, all the MD and FA maps in the native space were transformed onto the stereotactic space by registering each of the images to the customized MD and FA template. The two groups were compared using SPM5. Age and sex were treated as confounding covariates., Results: The patients demonstrated a significant increase in the MD of the left parahippocampal gyrus, left insula, and right anterior cingulate gyrus in comparison to the control subjects (FDR corrected p<0.05). No significant difference was observed in the correlation between the gray/white matter volume and FA., Conclusion: These findings suggest that structural abnormalities in the brain are present during the early stage of first-episode schizophrenia and MD might therefore be a sensitive marker for the detection of these abnormalities., (2009 Elsevier B.V. All rights reserved.)

Schizophrenic patients demonstrate a variety of cognitive deficits, including attention, executive functions, and working memory, even in the early stage of disease. In the present study, we examined the association between blood levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), or brain-derived neurotrophic factor (BDNF) and scores on the Wisconsin Card Sorting Test (WCST) in patients with early-stage schizophrenia. We also investigated the association between frontal GABA levels using 1H-magnetic resonance spectroscopy (MRS) at 3T and scores on the WCST in the same patients. Blood levels of BDNF and catecholamine metabolites and brain GABA levels using 1H-MRS were measured in 18 schizophrenic patients (nine males, nine females; age range 13-52 year). A significantly positive correlation was observed between plasma MHPG levels and %PEM (rho = -0.686, p = 0.0047). A trend toward negative correlation was found between frontal lobe GABA levels and the per cent of preservation error (%PEM) in the early stage of schizophrenia (rho = -0.420, p = 0.0836). These results suggest that noradrenergic neurons might be involved in neuropsychological functions in early-stage of schizophrenia., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Several lines of studies have shown the existence of an important inhibitory mechanism for the control of water intake involving adrenergic alpha2A receptors (ADRA2A). A human study using patients with schizophrenia demonstrated an exacerbation of polydipsia by the administration of clonidine, an ADRA2A-agonist, and a relief of polydipsia by mianserin, an ADRA2A-antagonist, suggesting the involvement of the central adrenergic system in the drinking behavior of patients with schizophrenia. Based on these findings we examined a possible association between the C-1291G polymorphism in the promoter region of the ADRA2A gene and polydipsia in schizophrenia using a Japanese case-control sample. Our sample includes 348 patients with schizophrenia (DSM-IV) (84 with polydipsia and 264 without polydipsia). No significant association between the ADRA2A C-1291G polymorphism and polydipsia was found. Our result suggests that the ADRA2A C-1291G polymorphism may not confer susceptibility to polydipsia in schizophrenia in our sample. Further studies with larger samples are warranted.

It has been suggested that hypoactivity of neuropeptide Y (NPY) may be involved in the pathophysiology of schizophrenia. A post-mortem study revealed a decreased level of NPY in the brain of patients with schizophrenia. An increased level of NPY after antipsychotic treatment was also reported in animal brain and cerebrospinal fluid of patients. Previously Itokawa et al. reported a positive association between the functional -485C>T polymorphism in the NPY gene and schizophrenia in a Japanese population. The aim of this study is to replicate their positive findings in an independent Japanese case-control sample. Our sample includes 260 patients with schizophrenia (DSM-IV) and 196 control subjects. No significant differences in distribution of genotype or allele frequencies between patients and controls were observed. Our results suggest that the NPY -485C>T polymorphism may not confer susceptibility to schizophrenia, at least in our sample. Further studies in larger samples are warranted.

An open-label study was performed to investigate the clinical efficacy and tolerability of olanzapine orally disintegrating tablets (Zyprexa Zydis) in ameliorating excitement symptoms in the acute phase of schizophrenia. Fifty-three patients meeting DSM-IV criteria for first-episode schizophrenia and treated with olanzapine monotherapy were evaluated with regard to their clinical improvement, behavioural response to medication, and extrapyramidal side effects using the Positive and Negative Syndrome Scale Excited Component (PANSS-EC), Nursing Assessment of Medication Acceptance (NAMA), and Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), respectively. Scores of PANSS-EC were significantly reduced after 3 days of olanzapine administration. A reduction in NAMA scores was also observed 7 days after administration of olanzapine. The DIEPSS score was unaffected by olanzapine administration. These results suggest that olanzapine orally disintegrating tablets are effective and well-tolerated for treatment excitement in the acute phase of schizophrenic patients. In addition, it is possible that adherence to medications is improved by using olanzapine orally disintegrating tablets.

Dysregulation in the dopaminergic system has been implicated in the pathophysiology of schizophrenia (SCZ). Dopamine D3 receptors (DRD3) concentrated in limbic regions of the brain (important for cognitive, emotional and endocrine function) may be particularly relevant to SCZ. A recent meta-analysis with mixed ethnicities reported a marginal significant association between the Ser9Gly homozygosity in the first exon of the DRD3 gene and SCZ. To further evaluate the controversial association between this polymorphism and SCZ, a case-control study and meta-analysis was conducted using the homogeneous Japanese population. In our Japanese case-control sample (246 cases/198 controls), we found an association between the DRD3 Ser9Gly polymorphism and SCZ (genotype: chi(2) = 9.76, d.f. = 2, p = 0.008; Ser allele versus Gly allele: chi(2) = 7.96, d.f. = 1, p = 0.0048; OR = 0.65; 95% CI = 0.48-0.88). However in a meta-analysis of nine Japanese case-control studies comprising 2056 subjects the association between DRD3 Ser9Gly polymorphism and SCZ did not persisted. The Mantel-Haenszel pooled OR for SCZ among carriers of the DRD3 Ser9Gly homozygosity (Ser/Ser homozygotes and Gly/Gly homozygotes) of the nine Japanese studies was 1.16 (95% CI 0.97-1.39), pointing to a non-significant effect of the DRD3 Ser9Gly homozygosity as a risk factor for SCZ. Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to SCZ in the Japanese population. Given that the Ser9Gly variant may play a putative role in DRD3 function, further studies on the DRD3 with linked variants are warranted.

Aims: Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics. We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes (DRD1-DRD5, AKT1 and GSK3beta) and serotonin receptor genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6 and HTR7) can be used to predict the efficacy of risperidone treatment for schizophrenia., Materials & Methods: A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale., Results: Among the 30 variants that we examined, two SNPs in DRD2 (-241A>G [rs1799978] and TaqIA [rs1800497]) and two SNPs in AKT1 (AKT1-SNP1 [rs3803300] and AKT1-SNP5 [rs2494732]) were significant predictors of treatment response to risperidone., Conclusion: These data suggest that the SNPs in DRD2 and AKT1 may influence the treatment response to risperidone in schizophrenia patients.

P-glycoprotein (P-gp), which is coded by the MDR1 gene, in the brain capillary endothelial cell limits the entry of many drugs including antipsychotics into the brain. The aim of this study is to examine whether a functional polymorphism, a C to T substitution at position 3435 in exon 26 of the MDR1 gene, is associated with susceptibility to polydipsia-hyponatremia in schizophrenia (SCZ) in a Japanese case-control sample. It has been reported that individuals homozygous for this polymorphism had significantly lower MDR1 expression levels and dysfunction of MDR1 (PNAS 97:3473-3478, 2000). Furthermore, the brain entry of risperidone and 9-hydroxyrisperidone has been shown to be greatly limited by P-gp (Int J Neuropsychopharmacol 7:415-419, 2004). In order to our knowledge, this is the first association study between the MDR1 polymorphism and polydipsia-hyponatremia in SCZ. Our sample includes 331 patients with SCZ (DSM-IV) (84 with polydipsics and 247 non-polydipsic controls). The common C3435T polymorphism of the MDR1 was genotyped for both groups and differences in genotype and allele frequency between cases and controls were evaluated using the chi(2)-test. A significant association between the MDR1 C3435T polymorphism and polydipsia was found (chi(2) = 4.43, d.f. = 1, P = 0.035; OR = 1.46; 95%CI = 1.03-2.07). Our results suggest that the MDR1 C3435T polymorphism may confer susceptibility to polydipsia in SCZ.

In the present study, we investigated the effects of risperidone treatment for 4 weeks on plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and brain-derived neurotrophic factor (BDNF) in 89 schizophrenic patients. We also compared the plasma levels of BDNF and MHPG between the schizophrenic group and 103 sex-and age-matched normal controls. In addition, we investigated the effects of two SNPs of the noradrenaline transporter (NAT) gene on plasma levels of MHPG, BDNF, and clinical improvement. The mean dose of risperidone was 3.8+/-1.4 mg/day. We demonstrated that treatment with risperidone increased plasma MHPG levels, and this increase was associated with an improvement of the negative symptoms of schizophrenia. In contrast, plasma BDNF did not change after 4 weeks of risperidone treatment, and the two SNPs in NAT did not influence the response to risperidone treatment or plasma MHPG and BDNF levels. These results suggest that the enhancement of noradrenergic neurons by risperidone, which occurs independently of the two SNPs of NAT, plays a role in the clinical efficacy of the drug.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that plays an important role in the development and maintenance of adult neurons and is important regulator of synaptic plasticity in human brain. It has been reported that there are alterations in BDNF levels in the brains of patients with schizophrenia. It has also been reported that transneuronal transfer of BDNF is dependent on neuronal activity, suggesting that BDNF plays an important role in neurotransmission. A single nucleotide polymorphism (SNP) in the BDNF gene that causes a valine to methionine substitution at codon 66 (Val66Met) has been demonstrated to affect human memory and hippocampal function. A possible positive association between the BDNF Val66Met polymorphism and schizophrenia has also been shown in Scottish and Spanish populations. Furthermore, the BDNF Val66Met polymorphism has been implicated in the age of onset of schizophrenia. In the present study, we attempted to replicate these findings in a Japanese case-control sample (211 patients with schizophrenia and 205 controls). We did not find an association between the BDNF Val66Met polymorphism and schizophrenia. An association between the Val66Met polymorphism and age of onset was not observed either. Furthermore, a meta-analysis including the present and previous Asian studies comparing 2059 patients with schizophrenia and 2765 controls also revealed no significant association between the BDNF Val66Met polymorphism and schizophrenia. Our results do not support a significant role for the BDNF Val66Met polymorphism in the development of schizophrenia in Asian populations.

A number of linkage studies have previously implicated the region of chromosome 13q34 in schizophrenia. Chumakov and colleagues (2002) identified a gene complex called G72 (now termed D-amino acid oxidase activator: DAOA)/G30 in this region and performed association analyses of the DAOA/G30 as well as the D-amino-acid oxidase (DAAO) gene with schizophrenia. DAAO oxidizes D-serine, a potent activator of the N-methyl-D-aspartate (NMDA) type glutamate receptor in the human brain whereas the DAOA protein is considered an activator of DAAO. The interaction of these two genes has thus been implicated in the NMDA receptor regulation pathway in schizophrenia. To date, several studies have shown a relatively consistent positive association between schizophrenia and DAOA/G30, but not with DAAO. The aim of our study was to further evaluate the contributions of these genes to the susceptibility to schizophrenia using two different sample sets. Our sample consisted of 168 matched case-control pairs as well as a family-based sample (n=113) for transmission disequilibrium test. Significant associations between the DAOA/G30 M-7 and M-18 polymorphisms and schizophrenia were observed in our case-control sample whereas no associations were observed for DAAO markers. We also observed significant or suggestive transmission disequilibrium for DAOA/G30 M-7, M-23, and M-24 to probands with schizophrenia in our family-based sample. Subsequent analysis of haplotypes made up of four DAOA/G30 markers, one marker selected from each of two linkage disequilibrium blocks that were observed in our sample as well as both ends (M-7 and M-25), were also associated with schizophrenia. Our data provide further evidence that the DAOA/G30 locus may play a role in the pathophysiology of schizophrenia. Although no direct link to genetic polymorphism in these genes and NMDA receptor function has been revealed, the present findings support previous reports implicating DAOA/G30 as susceptibility genes for schizophrenia. Further research is warranted to determine the functional variation underlying these findings and to relate this to the pathophysiology of schizophrenia.

The underlying pathophysiology of primary polydipsia in schizophrenia (SCZ) is poorly understood. Our previous study, however, suggested that this condition may have a genetic component [Shinkai et al 2003 Am J Med Genet 119B 7-12]. Orexins, also called hypocretins, play an important role in feeding and drinking behavior. Administration of orexin in rats has been shown to induce increased water intake with a longer-lasting effect than angiotensin II, which is also known as a potent dipsogen. Meerabux et al. [2005 Biol Psychiatry 58 401-407] reported an association between the 408Val allele of the orexin 1 receptor (HCRTR1) gene and polydipsia-hyponatremia in a sample of Japanese patients with SCZ. In the present study, we attempted to replicate the findings of Meerabux et al. in an independent Japanese case-control sample. Our sample included 312 patients with SCZ (DSM-IV) (65 with polydipsia and 247 without polydipsia). We also observed an association between the HCRTR1 Ile408Val polymorphism and polydipsia (genotype distribution: chi2 = 9.85, df = 2, P = 0.007). Meerabux et al. (2005) previously demonstrated an association between the 408Val allele of the HCRTR1 gene and polydipsia. In contrast with Meerabux et al. study, we found that the 408Ile allele was associated with polydipsia in our sample (chi2 = 8.00, df = 1, P = 0.0047; OR = 0.53; 95%CI = 0.34-0.83). How either allele contributes to the development of polydipsia in SCZ is unclear at this stage. It is possible that Ile408Val polymorphism is a non-functional marker that lies in linkage disequilibrium with an as-yet undetected functional variant. In any case, our results support the hypothesis that the HCRTR1 Ile408Val polymorphism may confer susceptibility to polydipsia in SCZ. Further studies examining the association between the orexin system and polydipsia in SCZ are warranted.

In the present study, we examined the effects of olanzapine on plasma levels of catecholamine metabolites, brain-derived neurotrophic factor, and cytokines (interleukin-2, interleukin-6 and tumor necrosis factor-alpha) using 32 olanzapine-treated schizophrenic patients and age and sex-matched 55 healthy individuals. Treatment with olanzapine for 8 weeks improved both positive and negative symptoms of schizophrenia. It also increased the plasma 3-methoxy-4-hydroxyphenylglycol levels, which were associated with the changes in the total scores of negative symptoms measured on the Positive and Negative Symptom Scale, and decreased the plasma homovanillic acid levels. In addition, treatment with olanzapine for 8 weeks reduced the plasma interleukin-2 levels. In contrast, olanzapine did not alter the plasma levels of brain-derived neurotrophic factor, interleukin-6, or tumor necrosis factor-alpha. These results suggest that olanzapine influences the dynamics of catecholamine and interleukin-2, which might be associated with its clinical efficacy.

The underlying pathophysiology of polydipsia in schizophrenia is poorly understood. Several studies, however, have suggested that there might be a genetic predisposition to polydipsia. In the present study, using a case-control sample that is independent from the previous family sample, we examined a possible association between polydipsia and functional polymorphisms in the genes of cytochrome P450 (CYP) 1A2 and 2D6, primarily important enzymes to the pharmacokinetics of antipsychotic drugs. Japanese patients with schizophrenia (63 polydipsics and 78 nonpolydipsics) were genotyped for two functional polymorphisms, the 734C/A polymorphism in the CYP1A2 gene and the 2D6*10 allele of the CYP2D6 gene. Neither of the polymorphisms was found to be associated with polydipsia nor was any evidence found that the two polymorphisms have an additive effect on the liability to polydipsia. Our results suggest that the CYP1A2 and CYP2D6 polymorphisms are not likely to play a major role in the development of polydipsia in schizophrenia, although further studies testing other alleles of CYP1A2 and CYP2D6 using different ethnic populations are warranted.

A possible role for oxidative stress in the pathophysiology of tardive dyskinesia (TD) has previously been proposed (reviewed in Andreassen and Jorgensen [O.A. Andreassen, H.A. Jorgensen, Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats Implications for tardive dyskinesia? Prog. Neurobiol. 61 (2000) 525-541]). Long-term administration of antipsychotics alters dopaminergic turnover, which results in increased formation of reactive oxygen species (ROS). This is hypothesized to lead to TD through neuronal toxicity as a consequence of oxidative stress. In the present study, the relationship between TD and a functional polymorphism of the gene coding for human glutathione S-transferase P1 (GSTP1), an important antioxidant enzyme involved in the detoxification of ROS, was studied in 225 chronic treatment-refractory patients with schizophrenia. An isoleucine (Ile) to valine (Val) substitution at codon 105 (Ile105Val) in the GSTP1 gene was genotyped. No significant difference in total AIMS scores was found among patients in the three genotype groups (chi(2)=1.47, d.f.=2, p=0.48). Moreover, no significant differences in genotype (chi(2)=0.05, d.f.=2, p=0.98) or allele frequencies (chi(2)=0.00, d.f.=1, p=1.00) were observed between subjects with and without TD. Our results suggest that the GSTP1 gene polymorphism does not confer increased susceptibility to TD, although further studies are warranted before a conclusion can be drawn.

The underlying pathophysiology of polydipsia in schizophrenia is poorly understood. However, several studies suggest there may be a genetic predisposition to polydipsia, including our previous study demonstrating familial concordance of polydipsia among first-degree relatives with schizophrenia. Antipsychotic medications may contribute to the development of polydipsia and studies show that dopamine D2 receptors are involved in drinking behaviour pathophysiology. Our hypothesis is that polymorphisms in the dopamine D2 receptor gene (DRD2) may confer susceptibility to polydipsia in schizophrenia. We tested for an association between polydipsia in schizophrenia and three functional polymorphisms of DRD2. The three polymorphisms, -141C Ins/Del, Ser311Cys, and TaqIA, were genotyped in patients with polydipsia (n = 64) and in those without polydipsia (n = 91). Of the three polymorphisms, TaqIA was significantly associated with polydipsia [genotype: chi2 = 6.59, df = 2, p = 0.037; allele: chi2 = 6.52, df = 1, p = 0.011, OR 1.81, 95% CI 1.15-2.86]. Haplotype analysis of the three markers found increased significance of the association (global, p = 0.00091). Although based on a relatively small portion of the sample, individual comparison of the common haplotypes showed that haplotype Ins-Cys-A1 was significantly less frequent in patients with polydipsia (p = 0.00082). The present data suggests polymorphisms in DRD2 may confer susceptibility to polydipsia in schizophrenia. To confirm our findings, further studies are warranted on larger samples using more extensive biological measures for diagnosing the polydipsia phenotype.

An open-label study was performed to investigate the clinical efficacy and mechanisms of risperidone liquid in ameliorating positive symptoms in the acute phase of schizophrenia. Eighty-eight patients (M/F: 50/38; age: 18-74 years;, mean +/- SD =32 +/- 16 years) meeting DSM-IV criteria for schizophrenia and treated with risperidone liquid (14 patients also used lorazepam) were evaluated with regard to their clinical improvement and extrapyramidal side effects using the positive and negative syndrome scale (PANSS) and the Simpson and Angus scale (SAS), while plasma concentrations of HVA and MHPG were analysed by HPLC-ECD before and 4 weeks after risperidone liquid administration. Patients showing a 50% or greater improvement in PANSS scores were defined as responders. An improvement in the PANSS scores related to excitement, hostility and poor impulse control was seen within 7 days after administration of risperidone liquid, and an improvement with regard to hallucinatory behaviour and uncooperativeness was seen within 14 days after its administration. Finally, 68% of patients were classified as responders 4 weeks after risperidone liquid administration. The scores of SAS were not changed after risperidone liquid administration. Pretreatment plasma homovanillic acid (HVA) levels in the responders (8.1 +/- 2.9 ng/ml) were higher than those in nonresponders (5.9 +/- 1.9 ng/ml). In addition, a negative correlation was seen between the changes in plasma HVA levels and the percentage of improvement in PANSS scores. On the other hand, there were no differences between pretreatment plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and those of nonresponders. These results suggest that risperidone liquid is effective and well tolerated for the treatment of acute phase schizophrenic patients, and that efficacy is related to its affects on dopaminergic activity, not noradrenergic activity., (Copyright 2005 John Wiley & Sons, Ltd.)

Objective: Recent studies have revealed positive associations between tardive dyskinesia (TD) and genetic polymorphisms of several cytochrome P450 (CYP) subfamilies that are involved in pharmacokinetic process of antipsychotic drugs. In the present study, we analyzed the relationship between TD and two polymorphisms of the CYP1A2 gene, 734C/A and -2964G/A, in a sample of Japanese patients with schizophrenia., Methods: We studied 199 Japanese patients with schizophrenia. We used the Abnormal Involuntary Movement Scale to evaluate TD. Two polymorphisms of the CYP1A2 gene, 734C/A and -2964 G/A were genotyped by means of polymerase chain reaction and restriction fragment length polymorphism analysis., Results: Neither the 734C/A nor the -2964G/A polymorphism was associated with TD [734C/A genotype: chi2=0.02, degrees of freedom (df)=2, P=1.00; allele: chi2=0.02, df=1, P=0.89; -2964G/A genotype: chi2=0.21, df=2, P=0.90; allele: chi2=0.15, df=1, P=0.70]. In addition, CYP1A2 haplotype was associated with TD (chi2=0.24, df=3, P=0.97). Furthermore, in both the subgroup of smokers and the subgroup of patients receiving high-dosage antipsychotics (chlorpromazine equivalent >1000 mg), neither the 734C/A nor the -2964G/A polymorphism was associated with TD., Conclusions: We did not find significant associations between the 734C/A and -2964G/A polymorphisms of CYP1A2 gene and TD in Japanese patients with schizophrenia. Our results suggest that these CYP1A2 gene polymorphisms may not contribute to TD susceptibility.

Objective: Oxidative stress such as free radical-mediated neuronal dysfunction may be involved in the pathophysiology of schizophrenia. The human glutathione peroxidase (GPX1) is a selenium-dependent enzyme, which plays an important role in the detoxification of free radicals. We therefore hypothesized that the GPX1 gene, which is located on chromosome 3p21.3, may be involved in the pathophysiology of schizophrenia. The aim of this study is to examine whether a potentially functional polymorphism, a proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) of the human GPX1 gene, is associated with susceptibility to schizophrenia., Methods: We genotyped the Pro197Leu polymorphism in a total of 113 nuclear families that had a proband with schizophrenia. Genetic association was tested using the transmission disequilibrium test (TDT), the sib transmission disequilibrium test (STDT), and the family-based association test (FBAT)., Results: The minor allele (Leu) frequency was calculated to be 0.282. We could not find significant transmission disequilibrium of the alleles for the Pro197Leu polymorphism in the GPX1 gene in association with the presence of schizophrenia in our family sample (TDT, chi2=0.03, degrees of freedom=1, P=0.86; combined TDT-STDT, Z'=-0.052, P=0.47; FBAT, Z=0.000, P=1.000)., Conclusion: The results of this study suggest that the GPX1 polymorphism is unlikely to be associated with susceptibility to schizophrenia.

Several lines of evidence suggest that tardive dyskinesia (TD) may be associated with altered dopaminergic neurotransmission. We hypothesized that deranged dopamine degradation enzyme activities might be related to the susceptibility to TD through altered dopaminergic neurotransmission in the central nervous system. In the present study, we investigated the relationship between the gene polymorphisms of three dopamine degradation enzymes and TD. We genotyped the valine/methionine polymorphism of codon 108/158 in the catechol-O-methyltransferase (COMT) gene, the 30-bp repeat polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, and the A/G polymorphism in intron 13 of the monoamine oxidase B (MAOB) gene in 206 Japanese patients with schizophrenia. No significant difference was found in total scores on the Abnormal Involuntary Movement Scale (AIMS) among the subject groups, sorted according to the COMT, MAOA and MAOB genotypes. Moreover, no significant difference was found in allele frequencies between patients with TD and patients without TD for any of the polymorphisms. As both COMT and MAO genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects, but none was observed. Our data, therefore, do not support the hypothesis that polymorphisms in COMT, MAOA, and MAOB genes are involved individually or in combination in the predisposition to TD., (Copyright 2004 Elsevier Ireland Ltd.)

Studies of schizophrenia show lack of agreement about the relationship of symptomatological and cognitive factors to insight. In this study, positive and negative symptomatology and cognitive function were assessed by the Positive and Negative Syndrome Scale (PANSS), the Wisconsin Card Sorting Test (WCST), and the Wechsler Adult Intelligence Scale Revised (WAIS-R) in male chronic schizophrenic patients in relation to level of insight measured with the Japanese version of the Schedule for the Assessment of Insight (SAI-J). Negative symptoms were significantly and negatively associated with overall insight, particularly with treatment compliance and recognition of mental illness. The present findings suggest that aspects of insight such as treatment compliance and recognition of mental illness are negatively associated with negative symptoms., (Copyright 2004 Elsevier Ireland Ltd.)

The purpose of the present study was to determine the characteristics of repeatedly secluded female inpatients. Fifty female inpatients in a typical mental hospital were retrospectively investigated from the viewpoint of their recent history of seclusion, age, psychiatric symptoms rated by the Positive and Negative Syndrome Scale, doses of antipsychotics, and serum prolactin levels. The patients were divided into three groups (none, once, twice or more) by the frequency of seclusion in the most recent year. The three groups were significantly different in terms of positive symptoms, general psychopathological symptoms and serum prolactin levels. Unexpectedly, the seclusion frequency was negatively associated with serum prolactin levels. The present findings suggest that repeatedly secluded female inpatients suffered from relatively low prolactin levels as well as more positive and psychopathological symptoms. Further prospective studies are warranted to confirm these findings and to investigate whether low prolactin levels are useful in predicting the risk of frequent seclusion in female inpatients.

NAD(P)H: quinone oxidoreductase (NQO1), an obligate two-electron reductase of quinones, prevents their participation in redox cycling and subsequent generation of reactive oxygen species (ROS). Reduced or negative activity of NQO1 would lead to an excess of neurotoxic compounds of cathecolamine o-quinones and ROS. Recently, there has been increasing evidence that catecholamine o-quinones and ROS might contribute to the development of schizophrenia. We investigated the genetic association between a functional polymorphism (Pro 187Ser) in the human NQO1 gene and schizophrenia (244 Japanese schizophrenic patients and 204 healthy controls). No significant differences in the allelic and genotypic distribution between patients and controls were observed. In addition, our results revealed no association between the genotypes of the polymorphism and any characteristics of patients such as gender, age at onset, family history or current neuroleptic dosage. Our results suggest that the NQO1 gene polymorphism does not confer increased susceptibility for schizophrenia in the present sample.

The pathophysiology of polydipsia in patients with schizophrenia is inadequately understood. This study aims to investigate the genetic influence on polydipsia in schizophrenia, and is comprised of a family study and an association study. First, we screened in-patients in 14 psychiatric hospitals and found a total of 36 pairs of a proband and his/her first-degree relative, both of whom were diagnosed with schizophrenia. Among these pairs, a significant familial concordance of polydipsia was found (Fisher's exact test, two-sided, P = 0.0014; odds ratio, 88.20; 95% confidence interval, 7.31-1064.34). These results indicate that genetic factors may underlie the pathophysiology of polydipsia in patients with schizophrenia. Subsequently, we examined the genetic association between polydipsia/water intoxication and the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism in patients with chronic schizophrenia (polydipsics: n = 65; non-polydipsics: n = 97) because several lines of evidence suggested that ACE might be involved in the development of polydipsia in schizophrenia. The D allele of ACE was found to be associated with a non-significant trend toward an increased risk of polydipsia (P = 0.086). Furthermore, a significant allelic association was found between the D allele of ACE and water intoxication (P = 0.0392). This significance remained after the data were adjusted for confounding variables by regression analysis. These results suggest that the ACE D allele may be a risk factor for polydipsia/water intoxication in patients with schizophrenia., (Copyright 2003 Wiley-Liss, Inc.)

We have previously reported that risperidone might improve negative symptoms in schizophrenia by influencing noradrenergic neurons. In the present study, we focused on the clinical efficacy and mechanisms of risperidone towards positive symptoms in the acute phase of schizophrenia. Thirty-four patients meeting DSM-IV criteria for schizophrenia and treated with risperidone alone were evaluated regarding their clinical improvement using the Positive and Negative Syndrome Scale (PANSS) before and 2 weeks after risperidone administration, and blood samples were also drawn at the same times. Plasma concentrations of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol were analysed by high-performance liquid chromatography with electrochemical detection. Plasma HVA levels in the responders to the risperidone treatment (more than 50% improvement in scores of positive symptoms in PANSS) were higher than those of non-responders before risperidone administration. Furthermore, there was a negative trend between changes in plasma HVA levels and improvement of total scores for positive symptoms in PANSS. These results suggest that higher levels of plasma HVA before risperidone administration might be a predictor of a good response to risperidone treatment, and the influence of risperidone on dopaminergic activity might be associated with its efficacy in treating symptoms of schizophrenia in the acute phase.

Lithium addition to neuroleptic treatment brought about some improvement in 6 schizophrenic inpatients. In 3 of them, however, enhancement of daily activity did not parallel improvement in psychiatric symptoms. This suggests that lithium addition may enhance daily activity independently of psychiatric symptoms, and that lithium effects should also be assessed from the viewpoint of daily activity.

An increasing amount of evidence suggests a possible implication of oxidative stress in the pathophysiology of schizophrenia. Oxidized low-density lipoproteins (oxLDL) have been reported to be capable of eliciting neurocytotoxicity. On the other hand, paraoxonase (PON1), an arylesterase, plays a role in protection against oxidative modifications of LDL and is considered to be one of the antioxidant enzymes. Thus, we investigated the genetic association between a functional polymorphism (Gln192Arg) of the human PON1 gene and schizophrenia in 244 patients and 177 controls. No significant association between the polymorphism and schizophrenia was observed. In addition, our results revealed that there was no association between the genotypes of the polymorphism and any demographic characteristics of patients such as gender, age, age at onset, or current neuroleptic dosage. Our results suggest that the Gln192Arg polymorphism of the PON1 gene may not be involved in the susceptibility to schizophrenia.