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Aim: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis., Methods: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS)., Results: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS., Conclusion: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: Genome-wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD-associated loci., Methods: The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders., Results: A meta-analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10 -8 ) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over-represented in categories including long-term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling., Conclusion: The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population., Methods: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%., Results: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05)., Conclusion: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: Clinical studies reported that patients with schizophrenia are at a higher risk of developing dementia than people without schizophrenia. However, early neuropathological studies have shown that the incidence of Alzheimer's disease (AD) in schizophrenia patients does not differ from that in controls. These inconsistent results may be attributable to the inclusion of non-AD dementia, but there have been few clinicopathological studies in older patients with schizophrenia based on the current neuropathological classification. This study aimed to investigate the neuropathological basis of incident dementia in older patients with schizophrenia., Methods: We systematically examined 32 brains of old patients with schizophrenia using standardized pathological methods. The severity of dementia-related neuropathologies was analyzed using standardized semiquantitative assessments. After excluding patients who fulfilled the neuropathological criteria, clinicopathological variables were compared between patients with and without incident dementia to identify potential differences., Results: Seven patients fulfilled the pathological criteria for AD (n = 3), argyrophilic grain disease (AGD) (n = 2), dementia with Lewy bodies (n = 1), and AGD/progressive supranuclear palsy (n = 1). Among 25 patients for whom a neuropathological diagnosis was not obtained, 10 had dementia, but the clinicopathological findings did not differ from the remaining 15 patients without dementia., Conclusion: Two types of older schizophrenia patient present dementia: patients with co-existing neurodegenerative disease and patients who do not meet pathological criteria based on the current classification. To understand the neurobiological aspects of incident dementia in older patients with schizophrenia, further clinicopathological studies are needed that do not simply analyze incident dementia as a comorbidity of conventional dementia-related neuropathologies., (© 2023 The Authors. Psychiatry and Clinical Neurosciences © 2023 Japanese Society of Psychiatry and Neurology.)

Mental disorders are considered as one of the major healthcare issues worldwide owing to their significant impact on the quality of life of patients, causing serious social burdens. However, it is hard to examine the living brain-a source of psychiatric symptoms-at the cellular, subcellular, and molecular levels, which poses difficulty in determining the pathogenesis and pathophysiology of mental disorders. Recently, induced pluripotent stem cell (iPSC) technology has been used as a novel tool for research on mental disorders. We believe that the iPSC-based studies will address the limitations of other research approaches, such as human genome, postmortem brain study, brain imaging, and animal model analysis. Notably, studies using integrated iPSC technology with genetic information have provided significant novel findings to date. This review aimed to discuss the history, current trends, potential, and future of iPSC technology in the field of mental disorders. Although iPSC technology has several limitations, this technology can be used in combination with the other approaches to facilitate studies on mental disorders., (© 2023 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: The aims of the present study were: (i) to examine the association between schizophrenia (SCZ) and 47, XXY or 47, XXX in a large case-control sample; and (ii) to characterize the clinical features of patients with SCZ with these X chromosome aneuploidies., Methods: To identify 47, XXY and 47, XXX, array comparative genomic hybridization (aCGH) was performed in 3188 patients with SCZ and 3586 controls. We examined the association between 47, XXY and 47, XXX and SCZ in males and females separately using exact conditional tests to control for platform effects. Clinical data were retrospectively examined for patients with SCZ with X chromosome aneuploidies., Results: Of the analyzed samples, 3117 patients (97.8%) and 3519 controls (98.1%) passed our quality control. X chromosome aneuploidies were exclusively identified in patients: 47, XXY in seven patients (0.56%), 47, XXX in six patients (0.42%). Statistical analysis revealed a significant association between SCZ and 47, XXY (P = 0.028) and 47, XXX (P = 0.011). Phenotypic data were available from 12 patients. Treatment-resistance to antipsychotics and manic symptoms were observed in six patients each (four with 47, XXY and two with 47, XXX for both), respectively. Statistical analysis revealed that treatment-resistance to antipsychotics, mood stabilizer use, and manic symptoms were significantly more common in patients with 47, XXY than in male patients without pathogenic copy number variations., Conclusion: These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment-resistance and manic symptoms., (© 2022 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: Eating disorders (EDs) are complex, multifactorial psychiatric conditions. Previous studies identified pathogenic copy number variations associated with NDDs (NDD-CNVs) in ED patients. However, no statistical evidence for an association between NDD-CNVs and EDs has been demonstrated. Therefore, we examined whether NDD-CNVs confer risk for EDs., Methods: Using array comparative genomic hybridization (aCGH), we conducted a high-resolution CNV analysis of 71 severe female ED patients and 1045 female controls. According to the American College of Medical Genetics guidelines, we identified NDD-CNVs or pathogenic/likely pathogenic CNVs in NDD-linked loci. Gene set analysis was performed to examine the involvement of synaptic dysfunction in EDs. Clinical data were retrospectively examined for ED patients with NDD-CNVs., Results: Of the samples analyzed with aCGH, 70 severe ED patients (98.6%) and 1036 controls (99.1%) passed our quality control filtering. We obtained 189 and 2539 rare CNVs from patients and controls, respectively. NDD-CNVs were identified in 10.0% (7/70) of patients and 2.3% (24/1036) of controls. Statistical analysis revealed a significant association between NDD-CNVs and EDs (odds ratio = 4.69, P = 0.0023). NDD-CNVs in ED patients included 45,X and deletions at KATNAL2, DIP2A, PTPRT, RBFOX1, CNTN4, MACROD2, and FAM92B. Four of these genes were related to synaptic function. In gene set analysis, we observed a nominally significant enrichment of rare exonic CNVs in synaptic signaling in ED patients (odds ratio = 2.55, P = 0.0254)., Conclusion: Our study provides the first preliminary evidence that NDD-CNVs may confer risk for severe EDs. The pathophysiology may involve synaptic dysfunction., (© 2022 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Objective: Medications for the treatment of bipolar disorder (BD) could affect patients' cognitive function. Patients with BD present with neurocognitive impairment even in a remission state. Little research is available on the daily functioning, especially driving performance, of stable outpatients with BD under pharmacological treatment., Methods: In total, 58 euthymic outpatients with BD undergoing real-world pharmacotherapy and 80 sex- and age-matched healthy controls (HCs) were enrolled. Three driving tasks using a driving simulator-road-tracking, car-following, and harsh-braking-and three cognitive tasks-Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test-were evaluated. Symptom assessment scales-Young Mania Rating Scale, Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-evaluation Scale, and Stanford Sleepiness Scale-were also completed., Results: Car-following and road-tracking performance were significantly impaired in patients with BD compared with HCs after adjusting for demographic variables, but these performances generally overlapped. Broad neurocognitive functions were significantly lower in the patients with BD compared to HCs, but car-following performance was significantly negatively correlated with sustained attention only. Although most patients received multiple medications rather than monotherapy, no relationship between prescriptions and driving performance was found., Conclusion: Euthymic patients with BD under steady-state pharmacotherapy had impaired driving performance compared with HCs, but the overlapping distributions of driving performance suggested that driving performance is not always deteriorated in patients with BD. Therefore, attentional function may be a useful clinical feature for judging driving aptitude in patients with BD., (© 2022 The Authors Psychiatry and Clinical Neurosciences © 2022 Japanese Society of Psychiatry and Neurology.)

The underlying pathologies of psychiatric disorders, which cause substantial personal and social losses, remain unknown, and their elucidation is an urgent issue. To clarify the core pathological mechanisms underlying psychiatric disorders, in addition to laboratory-based research that incorporates the latest findings, it is necessary to conduct large-sample-size research and verify reproducibility. For this purpose, it is critical to conduct multicenter collaborative research across various fields, such as psychiatry, neuroscience, molecular biology, genomics, neuroimaging, cognitive science, neurophysiology, psychology, and pharmacology. Moreover, collaborative research plays an important role in the development of young researchers. In this respect, the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium and Cognitive Genetics Collaborative Research Organization (COCORO) have played important roles. In this review, we first overview the importance of multicenter collaborative research and our target psychiatric disorders. Then, we introduce research findings on the pathophysiology of psychiatric disorders from neurocognitive, neurophysiological, neuroimaging, genetic, and basic neuroscience perspectives, focusing mainly on the findings obtained by COCORO. It is our hope that multicenter collaborative research will contribute to the elucidation of the pathological basis of psychiatric disorders., (© 2021 The Authors Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: A Japanese individual with schizophrenia harboring a novel exonic deletion in RELN was recently identified by genome-wide copy-number variation analysis. Thus, the present study aimed to generate and analyze a model mouse to clarify whether Reln deficiency is associated with the pathogenesis of schizophrenia., Methods: A mouse line with a novel RELN exonic deletion (Reln-del) was established using the CRISPR/Cas9 method to elucidate the underlying molecular mechanism. Subsequently, general behavioral tests and histopathological examinations of the model mice were conducted and phenotypic analysis of the cerebellar granule cell migration was performed., Results: The phenotype of homozygous Reln-del mice was similar to that of reeler mice with cerebellar atrophy, dysplasia of the cerebral layers, and abrogated protein levels of cerebral reelin. The expression of reelin in heterozygous Reln-del mice was approximately half of that in wild-type mice. Conversely, behavioral analyses in heterozygous Reln-del mice without cerebellar atrophy or dysplasia showed abnormal social novelty in the three-chamber social interaction test. In vitro reaggregation formation and neuronal migration were severely altered in the cerebellar cultures of homozygous Reln-del mice., Conclusion: The present results in novel Reln-del mice modeled after our patient with a novel exonic deletion in RELN are expected to contribute to the development of reelin-based therapies for schizophrenia., (© 2020 The Authors Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Kraepelin expected that the neuropathological hallmark of schizophrenia would be identified when he proposed the concept of dementia praecox 120 years ago. Although a variety of neuropathological findings have been reported since then, a consensus regarding the pathology of schizophrenia has not been established. The discrepancies have mainly been ascribed to limitations in the disease definition of schizophrenia that accompanies etiological heterogeneity and to the incompleteness of the visualization methodology and technology for biochemical analyses. However, macroscopic structural changes in the schizophrenia brain, such as volumetric changes of brain regions, must entail structural changes to cells composing the brain. This paper overviews neuropathology of schizophrenia and also summarizes recent application of synchrotron radiation nanotomography (nano-CT) to schizophrenia brain tissues. Geometric parameters of neurites determined from the 3-D nano-CT images of brain tissues indicated that the curvature of neurites in schizophrenia cases is significantly higher than that of controls. The schizophrenia case with the highest curvature carried a frameshift mutation in the glyoxalase 1 gene and exhibited treatment resistance. Controversies in the neuropathology of schizophrenia are mainly due to the difficulty in reproducing histological findings reported for schizophrenia. Nano-CT visualization using synchrotron radiation and subsequent geometric analysis should shed light on this long-standing question about the neuropathology of schizophrenia., (© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology.)

Aims: Recent studies have revealed that the interplay between polygenic risk scores (PRS) and large copy number variants (CNV; >500kb) is essential for the etiology of schizophrenia (SCZ). To replicate previous findings, including those for smaller CNV (>10kb), the PRS between SCZ patients with and without CNV were compared., Methods: The PRS were calculated for 724 patients with SCZ and 1178 healthy controls (HC), genotyped using array-based comparative genomic hybridization and single nucleotide polymorphisms chips, and comparisons were made between cases and HC, or between subjects with and without 'clinically significant' CNV., Results: First, we replicated the higher PRS in patients with SCZ compared to that in HC (without taking into account the CNV). For clinically significant CNV, as defined by the American College of Medical Genetics ('pathogenic' and 'uncertain clinical significance, likely pathogenic' CNV), 66 patients with SCZ carried clinically significant CNV, whereas 658 SCZ patients had no such CNV. In the comparison of PRS between cases with/without the CNV, despite no significant difference in PRS, significant enrichment of the well-established risk CNV (22q11.2 deletion and 47,XXY/47,XXX) was observed in the lowest decile of PRS in SCZ patients with the CNV., Conclusion: Although the present study failed to replicate the significant difference in PRS between SCZ patients with and without clinically significant CNV, SCZ patients with well-established risk CNV tended to have a lower PRS. Therefore, we speculate that the CNV in SCZ patients with lower PRS may contain 'genuine' risk; PRS is a possible tool for prioritizing clinically significant CNV because the power of the CNV association analysis is limited due to their rarity., (© 2019 The Author. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Although automobile driving is necessary for many people, including patients with mental disorders, the influence of psychotropic drugs on driving performance remains unclear and requires scientific verification. Therefore, the objective of this study was to conduct a review of the literature in order to aid the development of a valid evaluation method regarding the influence of medication on driving performance. We conducted a literature search using two sets of terms on PubMed. One set was related to psychotropic drugs, and the other to driving tests. We excluded reviews and case studies and added literature found on other sites. A total of 121 relevant reports were found. The experiments were roughly divided into on-the-road tests (ORT) and driving simulators (DS). Although highway driving tests in ORT are most often used to evaluate driving performance, DS are becoming increasingly common because of their safety and low cost. The validity of evaluation methods for alcohol should be verified; however, we found that there were few validated tests, especially for DS. The scenarios and measurement indices of each DS were different, which makes it difficult to compare the results of DS studies directly. No evaluation indices, except for SD of lateral position, were sufficiently validated. Although highway ORT are the gold standard, DS were shown to have an increasing role in evaluating driving performance. The reliability of DS needs to be established, as does their validation with alcohol in order to accumulate more high-quality evidence., (© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.)

Aim: Although the effects of psychotropics on driving ability have received much attention, little research is available on driving performance of stable outpatients with depression undergoing real-world treatment. This observational study investigated driving performance, cognitive functions, and depressive symptomatology of partly remitted outpatients with depression under daily-practice psychopharmacologic treatment., Methods: Seventy stable outpatients with depression and 67 healthy volunteers were enrolled. Patients' prescriptions were not controlled in order to capture the real-world treatment environment. Participants underwent three driving tasks - road-tracking, car-following, and harsh-braking - using a driving simulator, and three cognitive tasks - Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test. The Symptom Assessment Scale - Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-Evaluation Scale, and Stanford Sleepiness Scale were also completed., Results: Although many patients received various pharmacologic treatments, there were no significant differences in the three driving tasks between outpatients with depression and healthy controls. Difficulty of maintaining set in the Wisconsin Card Sorting Test was significantly increased in patients with depression. Results on the Social Adaptation Self-Evaluation Scale were significantly associated with road-tracking and car-following performance, in contrast to results on the Hamilton Depression Rating Scale and the Beck Depression Inventory-II., Conclusion: We conclude that partly remitted depressive patients under steady-state pharmacologic treatment do not differ from healthy controls with respect to driving performance, which seems to be more affected by psychosocial functioning than by pharmacologic agents. This, however, should be investigated systematically in an off/on study., (© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.)

Aim: Rapid eye movement sleep behavior disorder (RBD) and psychiatric symptoms often antedate the clinical diagnosis of Parkinson's disease or dementia with Lewy bodies. The purpose of this study was to investigate RBD and its relevance to Lewy body disease (LBD) in patients with late-onset psychiatric disorders., Methods: Study subjects included 19 patients with late-onset psychiatric disorders who exhibited REM sleep without atonia (RWA), which is a hallmark of RBD on polysomnography, at our psychiatric ward. Clinical profiles and radiological findings by cardiac [ 123 I]-metaiodobenzylguanidine ([ 123 I]-MIBG) scintigraphy and imaging for the dopamine transporter (DAT) were compared between patients with and without RBD symptoms. The correlations between the percentage of RWA in the total rapid eye movement sleep (%RWA) and radiological findings were also investigated., Results: Nine patients reported RBD symptoms only on specific questioning, but clinical profiles, including the prevalence of antipsychotropic usage, did not differ when compared to the remaining 10 patients without RBD (incidental RWA group). The median %RWA was significantly higher in the definite RBD group than in the incidental RWA group. Although the cardiac [ 123 I]-MIBG uptake was significantly lower in the definite RBD group than in the incidental RWA group, there was overlap in the specific binding ratio on DAT scan., Conclusion: The severity of %RWA was highly correlated with the value of cardiac [ 123 I]-MIBG uptake, but not with specific binding ratio on DAT scan. Clinical history of RBD and cardiac [ 123 I]-MIBG scintigraphy are helpful for an early differential diagnosis of LBD from late-onset psychiatric disorders, even before parkinsonism or dementia appears., (© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.)

Aim: Although the association between maternal depression and bonding failure during pregnancy and after delivery has been investigated, the causal relationships remain unclear., Methods: A total of 751 women (mean [SD] age, 32.1 [4.4] years) completed the Mother-Infant Bonding Questionnaire and the Edinburgh Postnatal Depression Scale during early pregnancy before week 25 (T1), during late pregnancy around week 36 (T2), and at 5 days after delivery (T3). We created a structural regression model to clarify the relationships between depressive mood and bonding failure during pregnancy and at 5 days after delivery. The model was tested with structural equation modeling., Results: Our non-recursive model fit the data well, and we found that: (i) during T2, bonding failure predicted depressive mood (P < 0.01, r = 0.23); (ii) at T3, bonding failure predicted depressive mood (P < 0.05, r = 0.31); (iii) during T1, depressive mood was correlated with bonding failure (P < 0.01, r = 0.45); (iv) depressive mood during T1 predicted depressive mood during T2 (P < 0.01, r = 0.58); (v) depressive mood during T2 predicted depressive mood at T3 (P < 0.01, r = 0.45); (vi) bonding failure during T1 predicted bonding failure during T2 (P < 0.01, r = 0.84); and (vii) bonding failure during T2 predicted bonding failure at T3 (P < 0.01, r = 0.44). The determinant coefficients of depressive mood and bonding failure at T3 were 0.41 and 0.28, respectively., Conclusion: Our large-scale cohort study indicates that bonding failure predicts depressive mood during pregnancy and 5 days after delivery. These findings suggest that protection and support for pregnant women with depressive mood and bonding failure may prevent both issues during pregnancy and the early stage after delivery., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

Aim: Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder., Methods: We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed., Results: Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls., Conclusion: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease., (© 2016 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning., Methods: A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants' current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ., Results: Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were -16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls., Conclusion: These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline., (© 2016 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: Short sleep duration is a risk factor for cardiovascular diseases. Cerebral blood flow and its regulation are affected by pathological conditions commonly observed in the elderly population, such as dementia, atherosclerosis, diabetes mellitus (DM), stroke, and hypertension. The purpose of this study was to examine the influence of sleep duration on cortical oxygenated hemoglobin (OxyHb) using near-infrared spectroscopy (NIRS)., Methods: Seventy-three individuals (age, 70.1 ± 3.9 years, 51 men and 22 women) participated in this study. Cortical OxyHb levels were measured with NIRS. We evaluated age, body mass index (BMI), smoking status, alcohol intake, sleep duration, hypertension, DM, and hyperlipidemia using a questionnaire. Blood pressure was measured using plethysmography., Results: Peak OxyHb and area under the NIRS curve significantly decreased in participants with sleep duration <7 h compared with those with sleep duration ≥7 h (0.136 ± 0.212 mM·mm vs 0.378 ± 0.342 mM·mm, P = 0.001; 112.0 ± 243.6 vs 331.7 ± 428.7, P  = 0.012, respectively). Sleep duration was significantly correlated with peak OxyHb level and area under the NIRS curve (r = 0.378, P  = 0.001; r = 0.285, P  = 0.015, respectively). Multiple regression analysis, including age, BMI, sex, smoking status, alcohol intake, sleep duration, hypertension, DM, and hyperlipidemia revealed that sleep duration was the only significant independent factor associated with peak OxyHb and area under the NIRS curve (β = 0.343, P  = 0.004; β = 0.244, P  = 0.049, respectively), and smoking status was independently correlated with time to the peak OxyHb (β = -0.319, P  = 0.009)., Conclusion: Sleep duration may be an important factor that influences cortical oxygenation in the elderly population., (© 2016 The Authors. Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology.)

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was published in 2013, and its official Japanese version was published in 2014. The Japanese Government uses classifications from the 10th revision of the I nternational C lassification of D iseases (ICD-10) to categorize disorders and determine treatment fees. However, since the publication of the DSM-III, the use of the DSM system has become prevalent in research and educational settings in Japan. In addition to traditional psychiatry, both the ICD and the DSM are taught by many Japanese medical schools, and virtually all clinical research and trials refer to the DSM to define targeted disorders. Amid the current backdrop in which the reputation of the DSM-5 is being established, the editorial board of P sychiatry and C linical N eurosciences has asked Japanese experts across 12 specialties to examine the structure of the DSM-5, including the following categories: Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders, Major Depression, Bipolar Disorders, Obsessive-Compulsive Disorders, Somatic Symptom Disorder, Eating Disorders, Substance-Related and Addictive Disorders, Gender Dysphoria, and Neurocognitive Disorders. Although opinions were only obtained from these selected experts, we believe that we have succeeded, to a certain extent, in presenting views that are representative of each specialty., (© 2016 The Authors. Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology.)

Schizophrenia, a debilitating disease with 1% prevalence in the general population, is characterized by major neuropsychiatric symptoms, including delusions, hallucinations, and deficits in emotional and social behavior. Previous studies have directed their investigations on the mechanism of schizophrenia towards neuronal dysfunction and have defined schizophrenia as a 'neuron-centric' disorder. However, along with the development of genetics and systematic biology approaches in recent years, the crucial role of glial cells in the brain has also been shown to contribute to the etiopathology of schizophrenia. Here, we summarize comprehensive data that support the involvement of glial cells (including oligodendrocytes, astrocytes, and microglial cells) in schizophrenia and list several acknowledged glia-related genes or molecules associated with schizophrenia. Instead of purely an abnormality of neurons in schizophrenia, an additional 'glial perspective' provides us a novel and promising insight into the causal mechanisms and treatment for this disease., (© 2015 The Authors. Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology.)

Aim: Results from this randomized, placebo-controlled study of aripiprazole augmentation to antidepressant therapy (ADT) in Japanese patients with major depressive disorder (MDD) (the Aripiprazole Depression Multicenter Efficacy [ADMIRE] study) revealed that aripiprazole augmentation was superior to ADT alone and was well tolerated. In subgroup analyses, we investigated the influence of demographic- and disease-related factors on the observed responses. We also examined how individual symptom improvement was related to overall improvement in MDD., Methods: Data from the ADMIRE study were analyzed. Subgroup analyses were performed on the primary outcome measures: the mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from the end of selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI) treatment to the end of the randomized treatment., Results: Changes in the MADRS total scores were consistently greater with aripiprazole than placebo in each of the subgroups. Efficacy was not related to sex, age, number of adequate ADT trials in the current episode, MDD diagnosis, number of depressive episodes, duration of the current episode, age at first depressive episode, time since the first depressive episode, type of SSRI/SNRI, or severity at the end of SSRI/SNRI treatment phase. Compared to placebo, aripiprazole resulted in significant and rapid improvement on seven of the 10 MADRS items, including sadness., Conclusion: These post-hoc analyses indicated that aripiprazole was effective for a variety of Japanese patients with MDD who had exhibited inadequate responses to ADT. Additionally, we suggest that aripiprazole significantly and rapidly improved the core depressive symptoms., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

Aim: Postnatal depression has demonstrated long-term consequences on child cognitive and emotional development; however, the link between maternal and child pathology has not been clearly identified. We conducted a prospective study using self-rating questionnaires to clarify the association between bonding disorder and maternal mood during pregnancy and after childbirth., Methods: A total of 389 women participated in this study and completed questionnaires. Participants were asked to complete the Edinburgh Postnatal Depression Scale (EPDS) and the Mother-to-Infant Bonding Scale four times during pregnancy and the postpartum period., Results: We found statistically significant weak to moderate correlations (r = 0.14-0.39) between the EPDS and Mother-to-Infant Bonding Scale scores at each testing period. Women who experienced low mood tended to have stronger bonding disorder. Furthermore, the effectiveness of attachment between the mother and child was closely related to the mood of the mother as measured by the EPDS., Conclusion: We observed different patterns of bonding and maternal mood. Distinct subtypes regarding maternal mood and formation of mother-to-infant attachment suggests that analysis of bonding disorder should be performed considering the course of maternal depressive symptoms., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

Autism spectrum disorder is a neurodevelopmental disorder present in 1% of the population, characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Approximately 10% of the autism spectrum disorder population is thought to have large chromosomal rearrangements. Copy-number variations (CNV) alter the genome structure either by duplication or deletion of a chromosomal region. The association between CNV and autism susceptibility has become more apparent through the use of methods based on comparative genomic hybridization in screening CNV. The nature of the high CNV rate in the human genome is partly explained by non-allelic homologous recombination between flanking repeated sequences derived from multiple copies of transposons or mobile genetic elements. There are hotspots for CNV in the human genome, such as 16p11.2 and 22q11.2. Genes involved in CNV are supposed to have copy-number dose-dependent effects on the behavior of affected individuals. Animal models give insight into the possible interactions between core genetic loci and additional factors contributing to the phenotypes of each individual. If affected genes code for cellular signaling molecules, reducing the dosage in the intracellular signaling pathway may result in the malfunction of the nervous system. The genetic background of autism spectrum disorder is highly heterogenic and most common or rare CNV do not lead to autism spectrum disorders in the majority of cases, but may occasionally increase the risk of developing an autism spectrum disorder., (© 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.)

Aims: The purpose of this study was to predict the outcome of cognitive behavior therapy (CBT) by trainees for major depressive disorder (MDD) based on the Parental Bonding Instrument (PBI). The hypothesis was that the higher level of care and/or lower level of overprotection score would predict a favorable outcome of CBT by trainees., Methods: The subjects were all outpatients with MDD treated with CBT as a training case. All the subjects were asked to fill out the Japanese version of the PBI before commencing the course of psychotherapy. The difference between the first and the last Beck Depression Inventory (BDI) score was used to represent the improvement of the intensity of depression by CBT. In order to predict improvement (the difference of the BDI scores) as the objective variable, multiple regression analysis was performed using maternal overprotection score and baseline BDI score as the explanatory variables., Results: The multiple regression model was significant (P = 0.0026) and partial regression coefficient for the maternal overprotection score and the baseline BDI was -0.73 (P = 0.0046) and 0.88 (P = 0.0092), respectively. Therefore, when a patient's maternal overprotection score of the PBI was lower, a better outcome of CBT was expected., Conclusion: The hypothesis was partially supported. This result would be useful in determining indications for CBT by trainees for patients with MDD., (© 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.)

Aims: The aim of this study was to analyze the relation between treatment response and the duration of untreated illness (DUI) in 133 outpatients with the first major depressive disorder (MDD) episode., Methods: A logistic regression was performed with DUI, sex, age at onset, and score for 17 items on the Hamilton Depression Rating Scale at the time of start of fluvoxamine treatment as the explanatory variables, and the response and the remission as the outcome variables., Results: Regression analysis showed significant association between the response and DUI (P < 0.0001), and between the remission and DUI (P < 0.0001), respectively. The remission rate gradually decreased with longer DUI., Conclusion: Early treatment of first depressive episodes is important because a shorter DUI implied better remission outcomes.

Aims: The purpose of the present study was to examine the extent of the effects of psychopathological symptoms and cognitive function on quality of life (QOL) in patients with chronic schizophrenia., Methods: Data were obtained using the Japanese Schizophrenia Quality of Life Scale (JSQLS), Positive and Negative Syndrome Scale (PANSS), Wisconsin Card-Sorting Test (WCST) Keio version, and Continuous Performance Test (CPT) for 52 schizophrenia patients., Results: Stepwise regression analysis showed that PANSS depression/anxiety factors predicted JSQLS psychosocial conditions and motivation/energy, and that WCST Categories Achieved predicted JSQLS symptoms/side-effects., Conclusions: Psychopathological symptoms and cognitive function affect subjective QOL in patients with schizophrenia. If the final goal is treatment that improves QOL in a manner that patients themselves are aware of, clinicians probably need to consider a treatment strategy that improves depression/anxiety symptom.