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Aim: Oral function in patients with schizophrenia has not been well-characterized. To address this, we performed a cross-sectional study of oral function in Japanese inpatients with schizophrenia., Methods: We measured oral function, including occlusal force, tongue-lip motor function, tongue pressure, and masticatory function in 130 Japanese inpatients with schizophrenia. We then compared the frequency of clinical signs of oral hypofunction among 63 non-elderly and 67 elderly inpatients with schizophrenia, as well as data from 98 elderly control participants from a previous Japanese study., Results: The frequency of reduced occlusal force was significantly higher in the elderly inpatients (76.2%) than in the non-elderly inpatients (43.9%) and elderly controls (43.9%). The frequency of decreased tongue-lip motor function in non-elderly inpatients (96.8%) and elderly inpatients (97.0%) was significantly higher than that in elderly controls (56.1%). The frequency of decreased tongue pressure in non-elderly inpatients (66.1%) and elderly inpatients (80.7%) was significantly higher than that in elderly controls (43.9%). Finally, the frequency of decreased masticatory function was highest in elderly inpatients (76.5%), followed by non-elderly inpatients (54.8%) and elderly controls (15.3%)., Conclusion: Oral function was decreased in both non-elderly and elderly Japanese inpatients with schizophrenia compared with elderly controls., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Aim: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case-control sample., Method: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD., Results: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit., Conclusion: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

The pathophysiology underlying major depressive disorder (MDD) and schizophrenia is related to endocrine system functions and includes changes in the blood levels of cortisol and insulin-like growth factor 1 (IGF-1). However, these hormones have not been investigated simultaneously in patients with MDD and schizophrenia. We investigated the differences in serum cortisol and IGF-1 levels among patients with MDD and schizophrenia and controls. We included 129 patients with MDD, 71 patients with schizophrenia, and 71 healthy volunteers. Blood tests were performed between 6:00 am and 11:00 am after fasting. Serum cortisol levels were significantly higher in patients with schizophrenia than in patients with MDD and controls. Serum cortisol levels were significantly higher in patients with MDD than in controls. Serum IGF-1 levels were higher in both patient groups than in controls, whereas there was no significant difference between patients with MDD and schizophrenia. Both cortisol and IGF-1 levels were positively correlated with the Hamilton Rating Scale for Depression score in patients with MDD, whereas cortisol level was positively correlated and IGF-1 level was negatively correlated with the Brief Psychiatric Rating Scale score in patients with schizophrenia. The differences in the level of these hormones suggest pathophysiological differences between these disorders., (© 2023. The Author(s).)

Background: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD)., Methods: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD., Results: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue., Conclusions: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

SETD1A has been identified as a substantial risk gene for schizophrenia. To further investigate the role of SETD1A in the genetic etiology of schizophrenia in the Japanese population, we performed resequencing and association analyses. First, we resequenced the SETD1A coding regions of 974 patients with schizophrenia. Then, we genotyped variants, prioritized via resequencing, in 2,027 patients with schizophrenia and 2,664 controls. Next, we examined the association between SETD1A and schizophrenia in 3,001 patients with schizophrenia and 2,664 controls. Finally, we performed a retrospective chart review of patients with prioritized SETD1A variants. We identified two novel missense variants (p.Ser575Pro and p.Glu857Gln) via resequencing. We did not detect these variants in 4,691 individuals via genotyping. These variants were not significantly associated with schizophrenia in the association analysis. Additionally, we found that a schizophrenia patient with the p.Glu857Gln variant had developmental delays. In conclusion, novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia. However, our study does not provide evidence for the contribution of these variants to the genetic etiology of schizophrenia in the Japanese population., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter., Methods: We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain., Results: SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes., Conclusion: These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression., Competing Interests: The authors have declared that no competing interests exist.

Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

Background: Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ., Methods: To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling., Results: Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal., Conclusions: The combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.

Whole-exome sequencing (WES) studies have shown that de-novo variants contribute to the genetic etiology of schizophrenia. WES studies of families with a monozygotic twin pair concordant or discordant for a disease may be fruitful for identifying de-novo pathogenic variants. Here, we performed WES in six individuals from one family (affected monozygotic twins, their unaffected parents, and two siblings) and identified three de-novo missense variants (CPT2 Ala283Thr, CPSF3 Val584Ile, and RNF148 Val210Ile) in the monozygotic twin pair concordant for schizophrenia. These three missense variants were not found in 1760 patients with schizophrenia or schizoaffective disorder or 1508 healthy controls. Our data do not support the role of the three missense variants in conferring risk for schizophrenia.

Background: Hyperprolactinemia is a troublesome adverse effect of antipsychotics. Aripiprazole (ARP), which is one of second-generation antipsychotics, has been reported to lower serum prolactin (PRL) levels. However, few studies have compared the effect of ARP on plasma PRL levels between monopharmacy and polypharmacy with antipsychotics., Methods: We conducted a large-scale investigation of the physical risk for inpatients with schizophrenia using a questionnaire covering demographic data, the number, dose and type of antipsychotics, and serum PRL levels., Results: Sufficient data to conduct an assessment of the effect on PRL levels between antipsychotic monopharmacy and polypharmacy were obtained from 316 of the inpatients. Serum PRL levels in ARP combination group were lower than non-ARP combination group, regardless of antipsychotic monopharmacy or polypharmacy., Conclusions: The present study suggests that ARP lowers serum PRL levels regardless of monopharamacy or polypharmacy with antipsychotics.

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Perineuronal nets comprise chondroitin sulfate moieties and their core proteins, and their neuropathological alterations have been implicated in schizophrenia. To explore the molecular mechanism of the perineuronal net impairments in schizophrenia, we measured the immunoreactivity of chondroitin sulfate moieties, major components of perineuronal nets, in three brain regions (postmortem dorsolateral prefrontal cortex, caudate nucleus, and hippocampus) of schizophrenia patients and control subjects. Immunoblotting for chondroitin 4-sulfate and chondroitin 6-sulfate moieties revealed a significant increase in intensity of a 180 kD band of chondroitin 4-sulfate immunoreactivity in the hippocampus of patients, although we detected no significant alteration in their immunoreactivities with any other molecular sizes or in other brain regions. The levels of immunoreactivity were not correlated with postmortem interval, age, or storage time. We failed to find such an increase in a similar molecular range of the chondroitin 4-sulfate immunoreactivity in the hippocampus of the rats chronically treated with haloperidol. These results suggest that the level alteration of the chondroitin 4-sulfate moiety might contribute to the perineuronal net abnormality found in patients with schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: Two single-nucleotide polymorphisms, rs3828611 and rs4704591, in the cardiomyopathy-associated protein 5 (CMYA5) gene have been extensively investigated for associations with schizophrenia in Asian populations, but with conflicting results. To assess the collective evidence across individual studies, we conducted an updated meta-analysis., Methods: We performed a random-effect model meta-analysis of the associations of rs3828611 and rs4704591 with schizophrenia using seven case-control samples from Asian populations (8074 patients and 8139 controls)., Results: The meta-analysis indicated that rs3828611 and rs4704591 were not significantly associated with schizophrenia (odds ratios [OR] = 0.93, 95% confidence interval [CI] = 0.85-1.01 and OR = 0.99, 95% CI = 0.93-1.05, respectively)., Conclusions: Our meta-analysis did not provide evidence supporting a contribution of CMYA5 rs3828611 and rs4704591 to schizophrenia susceptibility in Asian populations., (© 2017 John Wiley & Sons Australia, Ltd.)

Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Several previous studies have investigated an association between leukocyte telomere length (LTL) and schizophrenia (SCZ). However, results have been largely inconsistent, partially due to the relatively small sample sizes in each study and heterogeneity caused by various uncontrolled confounders (e.g., duration of illness or hospitalization, lifetime antipsychotic dose, and LTL assay methods). Here, we investigate the association of LTL with SCZ with the quantitative polymerase chain reaction method in independent cohorts consisting of 1241 patients with SCZ and 1042 controls (the largest independent sample in this field). Furthermore, we examined whether duration of hospitalization and lifetime antipsychotic dose had an effect on LTL in SCZ. In all samples, we observed significantly longer LTL in patients with SCZ relative to controls. In subgroup analyses, we observed that longer telomeres in SCZ were only visible in elderly patients and not in patients under 50 years old. Moreover, significantly longer LTL in elderly patients with SCZ was only specific to those with long-term hospitalization, but not outpatients or those with short-term hospitalization. This may be because the former received more appropriate lifestyle management. Meanwhile, lifetime antipsychotic dose had no effect on LTL. Our findings suggest that consideration of the effect of age and duration of hospitalization on LTL may improve our understanding of controversial results obtained in previous studies of telomeres in SCZ., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It has long been known that antipsychotic drugs (ATP) causes tachycardia, however details such as the differences between ATP are not well known. In recent years, the relationship between the rise in resting heart rate (RHR) and the increased risk of death in the general population has been garnering attention. In this study, we examined the difference in action on RHR between olanzapine (OLZ) and aripiprazole (ARP). The changes in the RHR on switching from OLZ to ARP and on increasing from the starting OLZ dose to the final one were evaluated in 19 outpatients (Study 1) and in 29 outpatients with schizophrenia (Study 2), respectively. To analyze the RHR, electrocardiographic measurements were obtained. At the same day, the Brief Psychiatric Rating Scale (BPRS) was evaluated, and fasting blood samples were drawn after an overnight fast of at least 8 h to examine electrolytes. Both Study 1 and 2 were conducted with the approval of the Gene Ethics Committee of Niigata University Graduate School of Medical and Dental Sciences, and the patients were treated at the outpatient psychiatric clinic at Niigata University Medical and Dental Hospital. All patients had been diagnosed with schizophrenia based on the DSM-IV-TR. In the Study 1, OLZ of 14.6 ± 9.2mg (mean ± standard deviation) was switched to ARP of 20.8 ± 8.1mg. Significant decreases were observed in the mean RHR after the switch to ARP (73.7 ± 9.7 vs 65.8 ± 10.9 beats/min, p = 0.008). In the Study 2, the starting OLZ dose was 7.2 ± 3.2mg and the increasing OLZ dose was 18.3 ± 7.4mg. Significant increases were observed in the mean RHR after increasing OLZ (69.7 ± 14.0 vs 75.6 ± 14.3 beats/min, p = 0.004). In this study, it was shown that OLZ has a stronger RHR enhancing effect compared to ARP and its effects are dose-dependent. If the increase in RHR increases the mortality rate of patients with schizophrenia, it may be necessary to further investigate the differences between ATP in terms of the effect on RHR of second-generation antipsychotics with a strong anticholinergic action or phenothiazine antipsychotics., Competing Interests: The authors have declared that no competing interests exist.

Background: Patients with schizophrenia have an increased prevalence of metabolic disturbances compared with the general population. However, the mechanisms underlying the metabolic side effects of antipsychotics are unknown. The aim of the present study was to compare the levels of high-density lipoprotein (HDL)-cholesterol in Japanese schizophrenia patients medicated with olanzapine, risperidone, or aripiprazole monotherapy., Methods: This study was a post-hoc analysis of a nationwide survey, which included 433 Japanese outpatients with schizophrenia and 674 inpatients. A brief questionnaire was compiled that covered demographic data, systolic blood pressure, diastolic blood pressure, and HDL-cholesterol after reviewing the relevant literature and guidelines. To compare demographic and clinical characteristics, analysis of variance was performed for continuous variables and the chi-square test was performed for categorical variables. For comparisons of HDL-cholesterol levels among the three antipsychotic groups, analysis of covariance was carried out with age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference as confounding variables after stratification by body mass index (BMI) for each outpatient group and inpatient group., Results: The mean age was 57.9 ± 14.0 years and the mean BMI was 23.4 ± 4.5 kg/m 2 . HDL-cholesterol levels when stratified by BMI differed significantly (p = 0.019) between the three antipsychotic groups after age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference in inpatients. A significant difference in HDL-cholesterol levels was only found in the overweight inpatient group, and no significant differences in HDL-cholesterol levels were found among the three antipsychotics for outpatients of all BMI stratifications or inpatients that were underweight or of normal weight. For post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group (p = 0.023)., Conclusions: This study reveals a difference in HDL-cholesterol levels in overweight Japanese inpatients with schizophrenia resulting from the use of different antipsychotics. In the post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group. Further studies incorporating more detailed evaluations, including diet and physical activity, are needed to clarify the differences in HDL-cholesterol according to antipsychotic use.

Aims: Although the relationship between body mass index and all-cause mortality is U-shaped, underweight has received comparatively less attention than obesity. There is only limited evidence to date regarding underweight among patients with schizophrenia. This is the first meta-analysis to address the prevalence of underweight in these patients., Methods: We conducted database searches (PubMed, PsycINFO) to identify studies examining underweight in patients with schizophrenia. In total, 17 studies (18 groups) with 45,474 patients were included; data were extracted independently by two authors. A meta-analysis was performed to calculate the pooled prevalence of underweight in patients., Results: The pooled prevalence of underweight was 6.2% (95% CI=4.5-8.6) for the 18 groups, which included 45,474 patients with schizophrenia. The heterogeneity was I 2 =98.9% (95% Cl=98.7-99.1%). Four studies with 4 groups, consisting of 30,014 individuals, focused on Japanese inpatients with schizophrenia. The pooled prevalence of underweight among inpatients in these 4 groups was 17.6% (95% CI=15.5-20.0). Fourteen studies were conducted with non-Japanese inpatients and included 14 groups of 15,460 patients with schizophrenia. The pooled prevalence of underweight in non-Japanese inpatients was 4.6% (95% CI=3.9-5.4). The proportion of underweight in the 18 groups significantly varied between Japanese inpatients and other patients., Conclusions: The results indicated that Japanese inpatients with schizophrenia have a high proportion of underweight. Future research should focus on evaluating interventions that target underweight., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Numerous studies have suggested that an immune system imbalance plays an important role in schizophrenia. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine. It plays multiple roles in various biological processes, including inflammation and neurogenesis. Furthermore, several exhaustive serum proteomic profiling studies have identified MIF as a potential biomarker of schizophrenia. Here, we investigate MIF protein levels in serum and postmortem prefrontal cortex in patients with schizophrenia and controls. Moreover, we investigate the association of two functional polymorphisms in the MIF gene promoter region (MIF-794CATT 5-8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) with schizophrenia., Methods: We measured serum MIF levels with an enzyme-linked immunosorbent assay (ELISA) (51 patients vs. 86 controls) and postmortem brain MIF levels with a western blotting assay (18 patients vs. 22 controls). Subsequently, we genotyped the MIF-794CATT 5-8 microsatellite with a fluorescence-based fragment assay and the MIF-173G/C SNP with a TaqMan SNP genotyping assay (1483 patients vs. 1454 controls)., Results: Serum MIF levels were significantly higher in patients with schizophrenia than in controls (p=0.00118), and were positively correlated with antipsychotic dose (Spearman's r=0.222, p=0.0402). In addition, an earlier age of onset was observed in patients with a high serum MIF level (≥40ng/mL) than those with a low serum MIF level (<40ng/mL) (p=0.0392). However, postmortem brain MIF levels did not differ between patients with schizophrenia and controls. The association study revealed that the CATT 6 -G haplotype was nominally significantly associated with schizophrenia (p=0.0338), and that the CATT 6 allele and CATT 6 -G haplotype were significantly associated with female adolescent-onset schizophrenia (AsOS) (corrected p=0.0222 and p=0.0147, respectively)., Conclusions: These results suggest that serum MIF level is a potential pharmacodynamic and/or monitoring marker of schizophrenia, and is related to a novel antipsychotic effect beyond dopamine antagonism. Furthermore, the MIF gene polymorphisms are associated with the risk for schizophrenia especially in adolescent females, and are potential stratification markers of schizophrenia. Further studies of MIF are warranted to elucidate the pathophysiology of schizophrenia and the effects of antipsychotics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Patients with schizophrenia have a higher prevalence of metabolic syndrome (MetS) than the general population. Minimizing weight gain and metabolic abnormalities in a population with an already high prevalence of obesity is of clinical and social importance. This randomized controlled trial investigated the effect of monthly nutritional education on weight change and metabolic abnormalities among patients with schizophrenia in Japan., Methods: From July 2014 to December 2014, we recruited 265 obese patients who had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder. Participants were randomly assigned to a standard care (A), doctor's weight loss advice (B), or an individual nutritional education group (C) for 12 months. The prevalence of MetS and body weight were measured at baseline and 12 months., Results: After the 12-month treatment, 189 patients were evaluated, and the prevalence of MetS based on the ATP III-A definition in groups A, B, and C was 68.9%, 67.2%, and 47.5%, respectively. Group C showed increased weight loss (3.2 ± 4.5 kg) over the 12-month study period, and the change in weight differed significantly from that of group A; additionally, 26.2% of the participants in group C lost 7% or more of their initial weight, compared with 8.2% of those in group A., Conclusion: Individual nutrition education provided by a dietitian was highly successful in reducing obesity in patients with schizophrenia and could be the first choice to address both weight gain and metabolic abnormalities induced by antipsychotic medications., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

Aim: Rare gene variations are thought to confer substantial risk for schizophrenia. We performed a three-stage study to identify rare variations that have a strong impact on the risk of developing schizophrenia., Methods: In the first stage, we prioritized rare missense variations using whole-exome sequencing (WES) data from three families, consisting of a proband, an affected sibling, and parents. In the second stage, we performed targeted resequencing of the PDCD11 coding region in 96 patients. In the third stage, we conducted an association study of rare PDCD11 variations with schizophrenia in a total of 1357 patients and 1394 controls., Results: Via WES, we identified two rare missense PDCD11 variations, p.(Asp961Asn) and p.(Val1240Leu), shared by two affected siblings within families. Targeted resequencing of the PDCD11 coding region identified three rare non-synonymous variations: p.(Asp961Asn), p.(Phe1835del), and p.(Arg1837His). The case-control study demonstrated no significant associations between schizophrenia and four rare PDCD11 variations: p.(Asp961Asn), p.(Val1240Leu), p.(Phe1835del), and p.(Arg1837His)., Conclusion: Our data do not support the role of rare PDCD11 variations in conferring substantial risk for schizophrenia in the Japanese population., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

Background: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome., Methods: We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals. We investigated 8 single-nucleotide polymorphisms identified on a GWAS., Results: We found that increased numbers of risk alleles at rs7188697 in NDRG4 and rs11970286 in PLN were the major predictors of an increased maximum QT interval over 24 hours in users of APs., Conclusions: It could be useful to perform a DNA-based analysis before the initiation of APs to reduce the risk of drug-induced torsades de pointes and SCD.

CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.

Aim: Rare variations are suggested to play a role in the genetic etiology of schizophrenia; to further investigate their role, we performed a three-stage study in a Japanese population., Methods: In the first stage, we performed whole-exome sequencing (WES) of two parent-affected offspring trios. In the second stage, we resequenced the FBXO18 coding region in 96 patients. In the third stage, we tested rare non-synonymous FBXO18 variations for association with schizophrenia in two independent populations comprising a total of 1376 patients and 1496 controls., Results: A rare frameshift variation (L116fsX) in the FBXO18 gene was recurrently identified by WES in both trios. Resequencing FBXO18 coding regions, we detected three rare non-synonymous variations (V15L, L116fsX, and V1006I). However, there were no significant associations between these rare FBXO18 variations and schizophrenia in the case-control study., Conclusion: Our present study does not provide evidence for the contribution of rare non-synonymous FBXO18 variations to the genetic etiology of schizophrenia in the Japanese population. However, to draw a definitive conclusion, further studies should be performed using sufficiently large sample sizes., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10 -9 , 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Background: Patients with schizophrenia have significantly shorter life expectancy than the general population, and a problem they commonly face is an unhealthy lifestyle, which can lead to obesity and metabolic syndrome. There is a very clear need to determine the prevalence of obesity, hypertension, hyperlipidemia, and diabetes mellitus which are components of metabolic syndrome in patients with schizophrenia, but there has been a paucity of large-scale studies examining this situation in Japan. The aim of our study was to address this need., Setting & Participants: We conducted a large-scale investigation of the prevalence of obesity, hypertension, hyperlipidemia, and diabetes mellitus using a questionnaire in 520 outpatient facilities and 247 inpatient facilities of the Japan Psychiatric Hospitals Association between January 2012 and July 2013. There were 7,655 outpatients and 15,461 inpatients with schizophrenia., Results: The outpatients had significantly higher prevalence of obesity, hypertension, hypertriglyceridemia, hyper-LDL cholesterolemia, and diabetes mellitus than the inpatients. The prevalence of hypo-HDL cholesterolemia was higher in inpatients than outpatients. Age-specific analysis showed the prevalence of obesity, hypertension, hypertriglyceridemia, hyper-LDL cholesterolemia, and diabetes mellitus among outpatients to be 2- to 3-fold higher than among inpatients. In individuals aged ≥60 years, the prevalence of obesity and DM among outpatients was about 3-fold higher than among inpatients., Conclusion: Japanese outpatients with schizophrenia were more likely to have physical risk such as obesity, hypertension, hyperlipidemia, and diabetes mellitus than inpatients. The physical risk to patients with schizophrenia may be affected by environmental parameters, such as type of care. The physical risk to Japanese patients with schizophrenia demands greater attention., Competing Interests: Toshiyuki Someya has received research support or honoraria from Asahi Kasei Pharma Corp., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan, K.K., GlaxoSmithKline K.K., Janssen Pharmaceutical K.K., Meiji Seika Pharma Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., MSD K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Shionogi & Co., Ltd., Tsumura & Co., and Yoshitomi Pharmaceutical Industries. Yutaro Suzuki has received research support or honoraria from Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. The other authors declare no potential conflicts of interest. Kazutaka Shimoda has received research support or honoraria from Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan, K.K., GlaxoSmithKline K.K., Meiji Seika Pharma Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Shionogi & Co., Ltd., Takeda Pharmaceutical Co., Ltd., Tsumura & Co., Yoshitomi Pharmaceutical Industries, Ltd., Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Janssen Pharmaceutical K.K., Kowa Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Mitsubishi Tanabe Pharma Corporation, Ltd., MSD K.K., Novartis Pharma K.K., and Ono Pharmaceutical Co., Ltd. Norio Yasui-Furukori has received research support or honoraria from Astellas Pharma Inc., Dainippon Sumitomo Pharma Co., Ltd., Eli Lilly Japan, K.K., GlaxoSmithKline K.K., Janssen Pharmaceutical K.K., Meiji Seika Pharma Co., Mochida Pharmaceutical Co. Ltd., MSD K.K., Otsuka Pharmaceutical Co. Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., and Yoshitomi Pharmaceutical Industries. Norio Sugawara has received grant or research support from the Grant-in-Aid for Young Scientists (B), Ministry of Education, Culture, Sports, Science and Technology, Japan Grant B., the Karoji Memorial Fund for Medical Research Grant, and the Senshin Medical Research Foundation. There are no patents, products in development, or marketed products to declare. This does not alter the authors’ adherence to PLOS ONE’s policies on sharing data and materials, as detailed online in the guide for authors. The other authors declare no potential conflicts of interest.

N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed.

Rare genomic variations inherited in multiplex schizophrenia families are suggested to play a role in the genetic etiology of the disease. To identify rare variations with large effects on the risk of developing schizophrenia, we performed whole-exome sequencing (WES) in two affected and one unaffected individual of a multiplex family with 10 affected individuals. We also performed follow-up resequencing of the unc-13 homolog B (Caenorhabditis elegans) (UNC13B) gene, a potential risk gene identified by WES, in the multiplex family and undertook a case-control study to investigate association between UNC13B and schizophrenia. UNC13B coding regions (39 exons) from 15 individuals of the multiplex family and 111 affected offspring for whom parental DNA samples were available were resequenced. Rare missense UNC13B variations identified by resequencing were further tested for association with schizophrenia in two independent case-control populations comprising a total of 1,753 patients and 1,602 controls. A rare missense variation (V1525M) in UNC13B was identified by WES in the multiplex family; this variation was present in five of six affected individuals, but not in eight unaffected individuals or one individual of unknown disease status. Resequencing UNC13B coding regions identified five rare missense variations (T103M, M813T, P1349T, I1362T, and V1525M). In the case-control study, there was no significant association between rare missense UNC13B variations and schizophrenia, although single-variant meta-analysis indicated that M813T was nominally associated with schizophrenia. These results do not support a contribution of rare missense UNC13B variations to the genetic etiology of schizophrenia in the Japanese population. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Patients with schizophrenia have a higher risk of metabolic syndrome (MetS). MetS prevalence varies with ethnicity. Although environmental factors, such as lack of physical activity and unbalanced diet, can lead to MetS, these may differ between outpatients and inpatients with schizophrenia. The Japanese mental health care system differs from that in other countries. However, few studies have investigated the prevalence of MetS in Japanese patients with schizophrenia. Therefore, we conducted a nationwide survey to clarify the prevalence of MetS in Japanese outpatients and inpatients with schizophrenia. We investigated the risk of MetS by questionnaire in 520 facilities for outpatients and 247 facilities for inpatients. There were 7655 outpatients and 15,461 inpatients with schizophrenia. MetS prevalence was based on the National Cholesterol Education Program Adult Treatment Panel III (ATP III-A) and the Japan Society for the Study of Obesity (JASSO). The overall MetS prevalence in outpatients using the ATP III-A definition was 34.2%, with 37.8% in men and 29.4% in women, compared with 13.0% in inpatients, with 12.3% in men and 13.9% in women. MetS prevalence in outpatients was approximately 2- to 3-fold higher than in inpatients. In conclusion, MetS prevalence in Japanese outpatients was approximately 3-fold higher than in inpatients. Therefore, we should pay more attention to the risk of physical disease in Japanese patients with schizophrenia, considering the difference in health characteristics between outpatients and inpatients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Olanzapine (OLZ) treatment is associated with a high risk of weight gain, and may cause abnormalities in glycolipid metabolism. Therefore, the underlying mechanism of OLZ-related weight gain is needed to clarify but not yet been adequately determined. In recent years, adipocytokines such as leptin, adiponectin, and tumor necrosis factor (TNF)-α, which play important roles in energy homeostasis, have been suggested as biomarkers of weight gain. Here, we determined if baseline plasma concentrations of leptin, adiponectin, and TNF-α predict weight gain following OLZ treatment., Methods: We recruited 31 schizophrenia outpatients (12 men and 19 women, 28.8 ± 10.2 years old) that were unmedicated or on another antipsychotic monotherapy medication. Baseline body mass index (BMI) and plasma levels of leptin, adiponectin, and TNF-α were obtained. All patients started or were switched to OLZ monotherapy for a maximum of 1 year. BMI was also obtained at the endpoint., Results: Mean BMI change following OLZ treatment was 2.1 ± 2.7 kg/m2. BMI change from baseline to endpoint negatively-correlated with baseline leptin levels in female patients (r = -0.514, P = 0.024), but not male patients. Baseline adiponectin or TNF-α levels were not correlated with BMI change., Conclusion: Baseline plasma leptin can have an effect on subsequent weight gain following OLZ treatment in female patients with schizophrenia.

Rare inherited variations in multiplex families with schizophrenia are suggested to play a role in the genetic etiology of schizophrenia. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in three families, each with two affected siblings. We also performed a three-stage follow-up case-control study in a Japanese population with a total of 2617 patients and 2396 controls. WES identified 15 rare truncating variations that were variously present in the two affected siblings in each family. These variations did not necessarily segregate with schizophrenia within families, and they were different in each family. In the follow-up study, four variations (NWD1 W169X, LCORL R7fsX53, CAMK2B L497fsX497, and C9orf89 Q102X) had a higher mutant allele frequency in patients compared with controls, although these associations were not significant in the combined population, which comprised the first-, second- and third-stage populations. These results do not support a contribution of the rare truncating variations identified in the three families to the genetic etiology of schizophrenia., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To clarify the prevalence of underweight and overweight/obesity, and laboratory data for nutritional status in Japanese outpatients and inpatients with schizophrenia., Design: Cross-sectional study., Setting: A questionnaire conducted in inpatient and outpatient facilities in Japan., Participants: The population of adult patients with schizophrenia in Japan (N=23,116)., Main Outcome Measures: The prevalence of underweight and undernutrition in Japanese inpatients and outpatients with schizophrenia., Results: We conducted a large-scale investigation of the prevalence of underweight and undernutrition in 520 outpatient facilities and 247 inpatient facilities belonging to the Japan Psychiatric Hospitals Association between January 2012 and July 2013. There were 7655 outpatients and 15,461 inpatients with schizophrenia. There was a significant difference in the distribution of three body mass index levels between outpatients and inpatients (p<0.001). The proportion of underweight inpatients with schizophrenia was significantly higher than that among outpatients (p<0.001). Age-specific analysis revealed that the proportion of underweight individuals aged ≥ 40 years was higher in inpatients than in outpatients and in the general Japanese population. The proportion of individuals with hypocholesterolaemia was significantly higher in inpatients with schizophrenia than in outpatients (p<0.001). There was a significant difference in the severity of underweight between outpatients and inpatients with schizophrenia; the proportion of severe underweight in inpatients was twofold higher than in outpatients., Conclusions: The prevalence of underweight and undernutrition in Japanese inpatients with schizophrenia was higher than in outpatients and the general population. Therefore, the physical risk of inpatients should be carefully considered in clinical practice., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Among the most important adverse effects of antipsychotics is abnormal glucose metabolism, which includes not only hyperglycemia but hyperinsulinemia and hypoglycemia. We have previously described five patients who experienced hypoglycemia during treatment with antipsychotics. Thus, an anamnesis of gastric surgery, which often causes dumping syndrome, and treatment with antipsychotics may synergistically induce hypoglycemia. We describe here a patient with schizophrenia under treatment of olanzapine and an anamnesis of gastric surgery, who experienced late dumping syndrome, hyperinsulinemia and overactivation of glucose-dependent insulinotropic polypeptide. Dumping syndrome, however, was improved after the patient was switched from olanzapine to quetiapine., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia.

Risperidone (RIS) is a frequently used efficacious psychotropic drug. However, it prolongs the QTc interval and may cause fatal arrhythmia. Little is known on the determinants of this RIS side effect. RIS is metabolized by CYP2D6, and is subject to drug efflux by P-glycoprotein (P-gp) encoded by the ATP-binding cassette subfamily B member 1 (ABCB1) gene. P-gp removes both RIS and its metabolite 9-OH-RIS from cardiac tissue. To investigate the effect of RIS metabolism and ABCB1 gene polymorphisms on QTc, steady-state plasma RIS and 9-OH-RIS levels, and QTc were measured. CYP2D6, ABCB1 C3435T and G2677T/A genotypes were determined in 66 schizophrenia patients on RIS. QTc was significantly longer in patients with ABCB1 3435CT+3435 TT than in those with 3435CC (P=0.006). ABCB1 G2677T/A genotype did not affect QTc. Multiple regression analysis showed that C/T or T/T genotypes at the ABCB1 C3435T locus, lower weight, and older age prolonged QTc. In summary, the T allele of the ABCB1 C3435T genotype should be considered in future diagnostic development efforts for RIS-associated QT.

Background: Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen; however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia., Methods: We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor (DRD2) gene/ankyrin-repeat containing kinase 1 (ANKK1) gene., Results: We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals (P<0.05) and the A1 allele of Taq1A genotype in DRD2/ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms., Conclusion: These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: We examined the difference between the effects of olanzapine (OLZ) and risperidone (RIS) on PR and QT intervals among patients with stable schizophrenia using a cohort analysis., Methods: Twenty-one subjects treated with OLZ were enrolled in the study. Following baseline assessments, which included PR and QT intervals, OLZ was switched to RIS for each subject. The same parameters were evaluated following the switch to RIS., Results: All patients who had been treated with OLZ were successfully switched to RIS. In all patients, we observed a significant decrease in PR interval (t = 2.397, P = 0.029) and no change in either QTc or RR interval. In female patients, the QTc interval was significantly decreased (t = 3.495, P = 0.008) following the switch, while in male patients, the QTc interval did not change. No patients showed a PR interval of >200 ms or a QTc interval of >500 ms., Conclusion: OLZ treatment has a greater prolonging effect on PR and QT intervals compared with RIS. Careful attention may need to be paid to the cardiac conduction system in addition to QT prolongation during OLZ treatment., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

Background: Genome-wide association studies (GWAS) and gene expression analyses have revealed that single nucleotide polymorphisms (SNPs) associated with multifactorial diseases, such as schizophrenia, are significantly more likely to be associated with expression quantitative trait loci (eQTL). It was recently suggested that an immune system imbalance plays an important role in the pathogenesis of schizophrenia. Interleukin-19 is a novel cytokine that may play multiple roles in immune regulation and various diseases., Method: We selected eight tag SNPs in the eQTL of the IL-19 gene. Seven of the SNPs are putative cis-acting SNPs. Then, we conducted a case-control study using two independent samples. The first sample comprised 567 schizophrenia patients and 710 controls, and the second sample comprised 677 schizophrenia patients and 667 controls., Result: We identified the TGAA haplotype as being significantly associated with schizophrenia (p=0.0036 and corrected p=0.0264), although a combined analysis of the TGAA haplotype with the replication samples exhibited a nominally significant difference (p=0.022 and corrected p=0.235)., Conclusions: These results suggest that the IL-19 gene might slightly contribute to the genetic risk of schizophrenia. Thus, further research on the association of eQTL SNPs with schizophrenia is warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: There is growing concern about the metabolic abnormalities in patients with schizophrenia., Aims: The aim of this study was to assess the attitudes of psychiatrists toward metabolic adverse events in patients with schizophrenia., Method: A BRIEF QUESTIONNAIRE WAS CONSTRUCTED TO COVER THE FOLLOWING BROAD AREAS: the psychiatrists' recognition of the metabolic risk of antipsychotic therapy, pattern of monitoring patients for physical risks, practice pattern for physical risks, and knowledge of metabolic disturbance. In March 2012, the questionnaire was mailed to 8,482 psychiatrists who were working at hospitals belonging to the Japan Psychiatric Hospitals Association., Results: The overall response rate was 2,583/8,482 (30.5%). Of the respondents, 85.2% (2,200/2,581) reported that they were concerned about prescribing antipsychotics that have a risk of elevating blood sugar; 47.6% (1,201/2,524) stated that their frequency of monitoring patients under antipsychotic treatment was based on their own experiences; and only 20.6% (5,22/2,534) of respondents answered that the frequency with which they monitored their patients was sufficient to reduce the metabolic risks., Conclusions: Psychiatrists practicing in Japan were generally aware and concerned about the metabolic risks for patients being treated with antipsychotics. Although psychiatrists should monitor their patients for metabolic abnormalities to balance these risks, a limited number of psychiatrists answered that the frequency with which they monitored patients to reduce the metabolic risks was sufficient. Promotion of the best practices of pharmacotherapy and monitoring is needed for psychiatrists treating patients with schizophrenia.

Objective: Interleukin-1 beta (IL-1β) has been implicated in the pathophysiology of schizophrenia. To assess whether the IL1B gene confers increased susceptibility to schizophrenia, we conducted case-control and family-based studies and an updated meta-analysis., Methods: We tested the association between IL1B and schizophrenia in 1229 case-control and 112 trio samples using 12 markers, including common tagging single nucleotide variations (SNVs) and a rare non-synonymous variation detected by resequencing the coding regions. We also performed a meta-analysis of rs16944 using a total of 8724 case-control and 201 trio samples from 16 independent populations., Results: We found no significant associations between any of the 12 SNVs examined and schizophrenia in either case-control or trio samples. Moreover, our meta-analysis results showed no significant association between the common SNV, rs16944, and schizophrenia., Conclusions: The present study does not support a role for IL1B in schizophrenia susceptibility.

Aims: In Europe and North America, schizophrenia patients treated with antipsychotic agents have a higher prevalence of obesity and metabolic syndrome compared with healthy individuals. In Japan, the prevalence of overweight/obesity in the general population is considerably lower than that in Europe and North America. The purpose of this study was to investigate the prevalence of underweight and overweight/obesity as well as laboratory data in Japanese inpatients with schizophrenia., Methods: The subjects were 333 inpatients with schizophrenia and 191 age- and sex-matched healthy volunteers. Overweight/obesity was defined as body mass index (BMI) ≥ 25 kg/m(2) , standard weight was defined as BMI ≥ 18.5 to <25 kg/m(2) and underweight was defined as BMI < 18.5 kg/m(2) ., Results: A significant difference in the prevalence of the three BMI levels was observed between schizophrenia patients and controls (P < 0.001). The prevalence of underweight was significantly higher in schizophrenia patients than that in controls (P < 0.001). The prevalence of hypoproteinemia (P < 0.001) and of hypocholesterolemia (P < 0.001) were significantly higher in schizophrenia patients than in controls. In schizophrenia patients, the prevalence of hypotriglyceridemia was significantly higher in the underweight group than in the standard weight group (P = 0.003) and in the overweight/obesity group (P < 0.001)., Conclusions: The prevalence of underweight in Japanese inpatients with schizophrenia may be higher compared with that in the general population. Therefore, the physical health of inpatients should be more carefully taken into account in clinical practice., (© 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.)