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Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal 'trajectory' of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors., (© 2024. The Author(s).)

Background: Schizophrenia is a complex mental disorder characterized by significant cognitive and neurobiological alterations. Impairments in cognitive function and eye movement have been known to be promising biomarkers for schizophrenia. However, cognitive assessment methods require specialized expertise. To date, data on simplified measurement tools for assessing both cognitive function and eye movement in patients with schizophrenia are lacking., Objective: This study aims to assess the efficacy of a novel tablet-based platform combining cognitive and eye movement measures for classifying schizophrenia., Methods: Forty-four patients with schizophrenia, 67 healthy controls, and 41 patients with other psychiatric diagnoses participated in this study from 10 sites across Japan. A free-viewing eye movement task and 2 cognitive assessment tools (Codebreaker task from the THINC-integrated tool and the CognitiveFunctionTest app) were used for conducting assessments in a 12.9-inch iPad Pro. We performed comparative group and logistic regression analyses for evaluating the diagnostic efficacy of the 3 measures of interest., Results: Cognitive and eye movement measures differed significantly between patients with schizophrenia and healthy controls (all 3 measures; P<.001). The Codebreaker task showed the highest classification effectiveness in distinguishing schizophrenia with an area under the receiver operating characteristic curve of 0.90. Combining cognitive and eye movement measures further improved accuracy with a maximum area under the receiver operating characteristic curve of 0.94. Cognitive measures were more effective in differentiating patients with schizophrenia from healthy controls, whereas eye movement measures better differentiated schizophrenia from other psychiatric conditions., Conclusions: This multisite study demonstrates the feasibility and effectiveness of a tablet-based app for assessing cognitive functioning and eye movements in patients with schizophrenia. Our results suggest the potential of tablet-based assessments of cognitive function and eye movement as simple and accessible evaluation tools, which may be useful for future clinical implementation., (©Kentaro Morita, Kenichiro Miura, Atsuhito Toyomaki, Manabu Makinodan, Kazutaka Ohi, Naoki Hashimoto, Yuka Yasuda, Takako Mitsudo, Fumihiro Higuchi, Shusuke Numata, Akiko Yamada, Yohei Aoki, Hiromitsu Honda, Ryo Mizui, Masato Honda, Daisuke Fujikane, Junya Matsumoto, Naomi Hasegawa, Satsuki Ito, Hisashi Akiyama, Toshiaki Onitsuka, Yoshihiro Satomura, Kiyoto Kasai, Ryota Hashimoto. Originally published in JMIR Mental Health (https://mental.jmir.org), 30.05.2024.)

Background: To examine whether the "Effectiveness of Guideline for Dissemination and Education in psychiatric treatment (EGIUDE)" project affects the rate of prescriptions of hypnotic medication and the type of hypnotic medications prescribed among psychiatrists, for schizophrenia and major depressive disorder in Japan., Methods: The EGUIDE project is a nationwide prospective study of evidence-based clinical guidelines for schizophrenia and major depressive disorder in Japan. From 2016 to 2021, clinical and prescribing data from patients discharged from hospitals participating in the EGUIDE project were used to examine hypnotic medication prescriptions The prescribing rate of hypnotics and the prescribing rate of each type of hypnotic (benzodiazepine receptor agonist, nonbenzodiazepine receptor agonist, melatonin receptor agonist, and orexin receptor antagonist) were compared among patients who had been prescribed medication by psychiatrists participating in the EGUIDE project and patients who had been prescribed medication by nonparticipating psychiatrists. Multivariate logistic regression analysis was performed to examine the effect of the EGUIDE project on the prescription of hypnotic medications., Results: A total of 12,161 patients with schizophrenia and 6,167 patients with major depressive disorder were included. Psychiatrists participating in the EGUIDE project significantly reduced the rate of prescribing hypnotic medication and benzodiazepine receptor agonists for both schizophrenia (P < 0.001) and major depressive disorder (P < 0.001) patients., Conclusion: This is the first study to investigate the educational effects of guidelines for the treatment of psychiatric disorders on psychiatrists in terms of prescribing hypnotic medications to patients. The EGUIDE project may play an important role in reducing hypnotic medication prescription rates, particularly with respect to benzodiazepine receptor agonists. The results suggest that the EGUIDE project may result in improved therapeutic behavior., (© 2024. The Author(s).)

Establishing a brain biomarker for schizophrenia is strongly desirable not only to support diagnosis by psychiatrists but also to help track the progressive changes in the brain over the course of the illness. A brain morphological signature of schizophrenia was reported in a recent study and is defined by clusters of brain regions with reduced volume in schizophrenia patients compared to healthy individuals. This signature was proven to be effective at differentiating patients with schizophrenia from healthy individuals, suggesting that it is a good candidate brain biomarker of schizophrenia. However, the longitudinal characteristics of this signature have remained unclear. In this study, we examined whether these changes occurred over time and whether they were associated with clinical outcomes. We found a significant change in the brain morphological signature in schizophrenia patients with more brain volume loss than the natural, age-related reduction in healthy individuals, suggesting that this change can capture a progressive morphological change in the brain. We further found a significant association between changes in the brain morphological signature and changes in the full-scale intelligence quotient (IQ). The patients with IQ improvement showed preserved brain morphological signatures, whereas the patients without IQ improvement showed progressive changes in the brain morphological signature, suggesting a link between potential recovery of intellectual abilities and the speed of brain pathology progression. We conclude that the brain morphological signature is a brain biomarker that can be used to evaluate progressive changes in the brain that are associated with cognitive impairment due to schizophrenia., (© 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.)

Abnormalities in visual exploration affect the daily lives of patients with schizophrenia. For example, scanpath length during free-viewing is shorter in schizophrenia. However, its origin and its relevance to symptoms are unknown. Here we investigate the possibility that abnormalities in eye movements result from abnormalities in visual or visuo-cognitive processing. More specifically, we examined whether such abnormalities reflect visual salience in schizophrenia. Eye movements of 82 patients and 252 healthy individuals viewing natural and/or complex images were examined using saliency maps for static images to determine the contributions of low-level visual features to salience-guided eye movements. The results showed that the mean value for orientation salience at the gazes of the participants with schizophrenia were higher than that of the healthy control subjects. Further analyses revealed that orientation salience defined by the L + M channel of the DKL color space is specifically affected in schizophrenia, suggesting abnormalities in the magnocellular visual pathway. By looking into the computational stages of the visual salience, we found that the difference between schizophrenia and healthy control emerges at the earlier stage, suggesting functional decline in early visual processing. These results suggest that visual salience is affected in schizophrenia, thereby expanding the concept of the aberrant salience hypothesis of psychosis to the visual domain., (© 2024. The Author(s).)

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection., (© 2023. The Author(s).)

Patients with schizophrenia can exhibit intelligence decline, which is an important element of cognitive impairment. Previous magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have altered gray matter structures and functional connectivity associated with intelligence decline defined by a difference between premorbid and current intelligence quotients (IQs). However, it has remained unclear whether white matter microstructures are related to intelligence decline. In the present study, the indices of diffusion tensor imaging (DTI) obtained from 138 patients with schizophrenia and 554 healthy controls were analyzed. The patients were classified into three subgroups based on intelligence decline: deteriorated (94 patients), preserved (42 patients), and compromised IQ (2 patients) groups. Given that the DTI of each subject was acquired using either one of two different MRI scanners, we analyzed DTI indices separately for each scanner group. In the comparison between the deteriorated IQ group and the healthy controls, differences in some DTI indices were noted in three regions of interest irrespective of the MRI scanners, whereas differences in only one region of interest were noted between the preserved IQ group and the healthy controls. However, the comparisons between the deteriorated and preserved IQ groups did not show any reproducible differences. Together with the previous findings, it is thought that gray matter structures and functional connectivity are more promising as markers of intelligence decline in schizophrenia than white matter microstructures., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: This study aims to examine the real-world effectiveness of education regarding clinical guidelines for psychiatric disorders using 'the Effectiveness of guidelines for dissemination and education in psychiatric treatment (EGUIDE)' project., Methods: The EGUIDE project is a nationwide prospective implementation study of two clinical practice guidelines, i.e., the Guideline for Pharmacological Therapy of Schizophrenia and the Treatment Guidelines for Major Depressive Disorders, in Japan. Between 2016 and 2019, 782 psychiatrists belonging to 176 hospitals with psychiatric wards participated in the project and attended lectures on clinical practice guidelines. The proportions of guideline-recommended treatments in 7405 patients with schizophrenia and 3794 patients with major depressive disorder at participating hospitals were compared between patients under the care of psychiatrists participating in the project and those not participating in the project. Clinical and prescribing data on the patients discharged from April to September each year from participating hospitals of the project were also analyzed., Results: The proportions of three quality indicators (antipsychotic monotherapy regardless of whether other psychotropics medication, antipsychotic monotherapy without other psychotropics and no prescription of anxiolytics or hypnotics) for schizophrenia were higher among participating psychiatrists than among nonparticipating psychiatrists. As similar results were obtained in major depressive disorder, the effectiveness of the project for the dissemination of guideline-recommended treatment has been replicated., Conclusion: This strategy of providing education regarding the clinical guidelines for psychiatric disorders was effective in improving the treatment-related behavior of psychiatrists. The use of this education-based strategy might contribute to resolving the mental health treatment gap., (© 2023 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aims: Schizophrenia is a psychiatric disorder presenting a lack of insight. Although insight changes over time, longitudinal studies of insight in schizophrenia are scarce. Furthermore, most previous studies on insight and intelligence have not measured full-scale IQ and have not been able to examine the relationship between detailed dimensions of cognitive function and insight. In this study, we assessed insight at two time points and assessed dimensions of cognitive function., Methods: A total of 163 patients with schizophrenia participated in the study. We evaluated insight at two time points to understand the patterns of change and examined the association between insight and clinical variables. Additionally, we examined the relationship between the dimensions of cognitive function and insight., Results: The patients were divided into three groups based on their change in insight over time: stable at a low level of insight (poor insight), stable at a high level of insight (good insight), and changed in insight over time (unstable insight). Those in the poor insight group had lower general intelligence scores than those in the good insight and unstable insight groups. Regarding cognitive function, verbal comprehension was associated with the level of insight at baseline and follow-up. Regarding psychiatric symptoms, the poor insight group exhibited more severe symptoms than the other two groups, especially regarding positive symptoms., Conclusions: Our classification of patients based on changes in insight revealed that poor insight patients had impaired cognitive function, especially verbal comprehension, and more severe positive symptoms than good insight or unstable insight patients., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Clinician adherence to guideline recommendations in the pharmacological therapy of schizophrenia is important for favorable patient outcomes. To evaluate whether prescriptions followed the guidelines for pharmacological therapy of schizophrenia, we recently developed a summary indicator of multiple quality indicators: the individual fitness score (IFS). It is unclear whether adherence to the guidelines is related to patient outcomes. Here, we investigated correlations between the IFS values and psychotic symptoms in patients with schizophrenia., Methods: We assessed whether patients' current prescriptions adhered to the guideline recommendations using the IFS in 47 patients with treatment-resistant schizophrenia (TRS) and 353 patients with non-TRS (total n = 400), respectively. We investigated correlations between the IFS and total scores and scores on the 5 subscales of the Positive and Negative Syndrome Scale (PANSS). Furthermore, we explored correlations between over 2-year longitudinal changes in IFS values and changes in psychotic symptoms in some patients (n = 77)., Results: We found significant negative correlation between the IFS and PANSS total score in all patients with schizophrenia (β = -0.18, P = 9.80 × 10-5). The IFS was significantly and nominally negatively correlated with the PANSS total score in patients with non-TRS (Spearman's rho = -0.15, P = 4.40 × 10-3) and patients with TRS (rho = -0.37, P = .011), respectively. The IFS was also significantly and nominally negatively correlated with several factors, such as the negative and depressed factors, in patients with non-TRS and patients with TRS, respectively (P < .05). Furthermore, the change in IFS values was marginally negatively correlated with the changes in PANSS total scores and scores on the positive and depressed factors (P < .05)., Conclusions: These findings suggest that efforts to improve clinician adherence to guideline recommendations for pharmacological therapy of schizophrenia, as assessed by the IFS, may lead to better outcomes in patients with schizophrenia., (© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.)

Background: Individuals with schizophrenia (SCZ) and bipolar disorder (BD) display cognitive impairments, but the impairments in those with SCZ are more prominent, supported by genetic overlap between SCZ and cognitive impairments. However, it remains unclear whether cognitive performances differ between individuals at high and low genetic risks for SCZ or BD., Methods: Using the latest Psychiatric Genomics Consortium (PGC) data, we calculated PGC3 SCZ-, PGC3 BD-, and SCZ v. BD polygenic risk scores (PRSs) in 173 SCZ patients, 70 unaffected first-degree relatives (FRs) and 196 healthy controls (HCs). Based on combinations of three PRS deciles, individuals in the genetic SCZ, genetic BD and low genetic risk groups were extracted. Cognitive performance was assessed by the Brief Assessment of Cognition in Schizophrenia., Results: SCZ-, BD-, SCZ v. BD-PRSs were associated with case-control status ( R 2 = 0.020-0.061), and SCZ-PRS was associated with relative-control status ( R 2 = 0.023). Furthermore, individuals in the highest decile for SCZ PRSs had elevated BD-PRSs [odds ratio (OR) = 6.33] and SCZ v. BD-PRSs (OR = 1.86) compared with those in the lowest decile. Of the three genetic risk groups, the low genetic risk group contained more HCs, whereas the genetic BD and SCZ groups contained more SCZ patients ( p < 0.05). SCZ patients had widespread cognitive impairments, and FRs had cognitive impairments that were between those of SCZ patients and HCs ( p < 0.05). Cognitive differences between HCs in the low genetic risk group and SCZ patients in the genetic BD or genetic SCZ groups were more prominent (Cohen's d > -0.20) than those between HCs and SCZ patients in the no genetic risk group. Furthermore, SCZ patients in the genetic SCZ group displayed lower scores in verbal fluency and attention than those in the genetic BD group ( d > -0.20)., Conclusions: Our findings suggest that cognitive impairments in SCZ are partially mediated through genetic loadings for SCZ but not BD.

Aim: Eye movements and cognitive functions are significantly impaired in patients with schizophrenia. The authors aimed to develop promising clinical diagnostic markers that fit practical digital health applications in psychiatry using eye movement and cognitive function data from 1254 healthy individuals and 336 patients with schizophrenia., Methods: Multivariate analyses using logistic regression were performed to confirm net performance of eye movements and cognitive functions scored using the Wechsler Adult Intelligence Scale, Third Edition, and Wechsler Memory Scale-Revised. The authors then examined the discrimination performance of pairs containing an eye movement and a cognitive function measure to search the pairs that would be effective in practical application for the discrimination according to the diagnostic criterion between the groups., Results: Multivariate analyses confirmed that eye movements and cognitive functions were effective modalities for discriminating between patients with schizophrenia and healthy controls. The discriminant analyses of the pairs demonstrated that seven eye movement measures and seven scores from cognitive function tests showed high discrimination performance when paired with one measure from the other modality. Moreover, seven pairs of digit-symbol coding or symbol-search and eye movement measures had high and robust discrimination performance., Conclusion: Seven pairs of an eye movement and a cognitive function measure were effective, robust, and less time-consuming in assisting with clinical diagnosis by categorizing healthy individuals or patients with schizophrenia. These findings may help develop an objective auxiliary diagnosis method working even on portable devices, which facilitates the consistency of diagnosis, earlier intervention, and shared decision-making., (© 2023 The Authors. Psychiatry and Clinical Neurosciences © 2023 Japanese Society of Psychiatry and Neurology.)

Background: Although several guidelines recommend monotherapy with antipsychotics for the treatment of schizophrenia, patients who receive long-acting injectable antipsychotics (LAIs) are frequently treated with oral antipsychotics (OAPs). In the present study, we investigated the detailed use of psychotropic medications among patients throughout Japan with schizophrenia who received LAIs or OAPs., Methods: The present study used data from the project for the Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment from 94 facilities in Japan. The LAI group included patients who received any LAI, and the non-LAI group included patients who took only OAP medications at discharge. The participants of this study were 2518 schizophrenia patients (263 in the LAI group and 2255 in the non-LAI group) who received inpatient treatment and had prescription information at discharge between 2016 and 2020., Results: This study revealed significantly higher rates of polypharmacy antipsychotics, number of antipsychotics, and chlorpromazine equivalents in the LAI group than in the non-LAI group. In contrast, the LAI group showed lower rate of concomitant use of hypnotic and/or antianxiety medication than the non-LAI group., Conclusions: Presenting these real-world clinical results, we want to encourage clinicians to keep monotherapy in mind for the treatment of schizophrenia, especially by reducing concomitant use of antipsychotics in the LAI group and reducing hypnotic and/or antianxiety medication in the non-LAI group., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Polypharmacy of additional psychotropics alongside the main treatment drug (antipsychotics in schizophrenia and antidepressants in major depressive disorder) is common in Japan. Our goal is to align psychotropic prescription in Japan with international standards, while reducing the differences between facilities. To achieve this goal, we aimed to compare prescriptions at the time of hospital admission and discharge., Methods: Data on prescriptions at admission and discharge from 2016 to 2020 were collected. We divided the patients into four groups: (1) mono&#95;mono group, monotherapy of the main drug at admission and discharge; (2) mono&#95;poly group, monotherapy at admission and polypharmacy at discharge; (3) poly&#95;poly group, polypharmacy at admission and discharge; and (4) poly&#95;mono group, polypharmacy at admission and monotherapy at discharge. We compared the changes in dosage and number of psychotropics among the four groups., Results: For both schizophrenia and major depressive disorder, the patients who received monotherapy with the main drug at admission were likely to receive main drug monotherapy at discharge and vice versa. For schizophrenia, the polypharmacy was prescribed more often in the mono&#95;poly group than that in the mono&#95;mono group. The prescription was not changed at all for more than 10% of the patients., Conclusions: It is critical to avoid a polypharmacy regimen to ensure that guideline-compliant treatment is provided. We expect higher rates of monotherapy with the main drug after the EGUIDE lectures., Trial Registration: The study protocol was registered in the University Hospital Medical Information Network Registry (UMIN000022645)., (© 2023. The Author(s).)

Schizophrenia is a psychiatric disorder that presents with hallucinations, delusions, thought disorders, and cognitive dysfunctions. Antipsychotic monotherapy is effective in the treatment of schizophrenia. In recent years, the main antipsychotics used have been second-generation antipsychotics, also called atypical antipsychotics, which have a slightly lower incidence of side effects. When monotherapy of two or more antipsychotics fails to produce sufficient improvement, a diagnosis of treatment-resistant schizophrenia is made, and clozapine is used.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

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.)

Aims: The Guidelines for the Pharmacotherapy of Schizophrenia were established to improve the quality of medical care, and the EGUIDE project was conducted to train clinicians on guideline usage. A quality indicator (QI) was established to measure the prevalence of the guidelines, and a survey was conducted, which revealed a gap between the guidelines and actual clinical practice (evidence-practice-gap). The purpose of this study was to develop an individual fitness score (IFS) formula that expresses the degree to which prescribers adhere to the Guidelines for Pharmacological Therapy of Schizophrenia in a simple manner, and to determine the validity of this formula from a survey of the prescriptions of the EGUIDE project participants'., Methods: To establish appropriate scores, members discussed the proposed formula and then voted on them. The IFS formula developed was set up so that antipsychotic monotherapy would be given 100 points, with points deducted if concomitant or adjunctive antipsychotic medications were used, and a minimum score of 0. To validate this formula, prescriptions of hospitalized schizophrenic patients at admission and at discharge were scored and compared., Result: IFS points vary and ranged from 0 to100. The average pre-admission score for all subjects was 45.6, and the average score at discharge was 54, those were significantly higher during discharge., Conclusions: We developed an IFS formula, a tool to easily visualize the degree to which current prescriptions conform to the guidelines for the pharmacological treatment of schizophrenia., (© 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Although clozapine is effective for treatment-resistant schizophrenia (TRS), the rate of clozapine prescription is still low. Whereas antipsychotic monotherapy is recommended in clinical practice guidelines, the rate of antipsychotic polypharmacy is still high. There is little evidence on whether a clozapine prescription influences changes in the rate of monotherapy and polypharmacy, including antipsychotics and other psychotropics. We therefore hypothesized that the rate of antipsychotic monotherapy in patients with TRS who were prescribed clozapine would be higher than that in patients with schizophrenia who were not prescribed clozapine., Methods: We assessed 8306 patients with schizophrenia nationwide from 178 institutions in Japan from 2016 to 2019. We analyzed the psychotropic prescription data at discharge in patients diagnosed with TRS and with no description of TRS (ND-TRS) based on the diagnosis listed in the discharge summary., Results: The rate of antipsychotic monotherapy in the TRS with clozapine group (91.3%) was significantly higher than that in the TRS without clozapine group (45.9%; P &lt; 2.0 × 10-16) and the ND-TRS without clozapine group (54.7%; P &lt; 2.0 × 10-16). The rate of antipsychotic monotherapy without any other concomitant psychotropics in the TRS with clozapine group (26.5%) was significantly higher than that in the TRS without clozapine group (12.6%; P = 1.1 × 10-6) and the ND-TRS without clozapine group (17.0%; P = 5.9 × 10-6)., Conclusions: Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

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.)

Schizophrenia was initially defined as "dementia praecox" by E. Kraepelin, which implies progressive deterioration. However, recent studies have revealed that early effective intervention may lead to social and functional recovery in schizophrenia. In this review, we provide an overview of current concepts in schizophrenia and pathophysiological hypotheses. In addition, we present recent findings from clinical and basic research on schizophrenia. Recent neuroimaging and neurophysiological studies have consistently revealed specific biological differences in the structure and function of the brain in those with schizophrenia. From a basic research perspective, to determine the essential pathophysiology underlying schizophrenia, it is crucial that findings from all lines of inquiry-induced pluripotent stem cell (iPSC)-derived neural cells from patients, murine models expressing genetic mutations identified in patients, and patient clinical data-be integrated to contextualize the analysis results. However, the findings remain insufficient to serve as a diagnostic tool or a biomarker for predicting schizophrenia-related outcomes. Collaborations to conduct clinical research based on the patients' and their families' values are just beginning, and further development is expected., (© 2022 The Authors. Psychiatry and Clinical Neurosciences © 2022 Japanese Society of Psychiatry and Neurology.)

Despite previous neuroimaging studies demonstrating morphological abnormalities of the thalamus and other subcortical structures in patients with schizophrenia, the potential role of the thalamus and its subdivisions in the pathophysiology of this illness remains elusive. It is also unclear whether similar changes of these structures occur in individuals at high risk for psychosis. In this study, magnetic resonance imaging was employed with the Multiple Automatically Generated Templates (MAGeT) brain segmentation algorithm to determine volumes of the thalamic subdivisions, the striatum (caudate, putamen, and nucleus accumbens), and the globus pallidus in 62 patients with schizophrenia, 38 individuals with an at-risk mental state (ARMS) [4 of whom (10.5%) subsequently developed schizophrenia], and 61 healthy subjects. Cognitive function of the patients was assessed by using the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). Thalamic volume (particularly the medial dorsal and ventral lateral nuclei) was smaller in the schizophrenia group than the ARMS and control groups, while there were no differences for the striatum and globus pallidus. In the schizophrenia group, the reduction of thalamic ventral lateral nucleus volume was significantly associated with lower BACS score. The pallidal volume was positively correlated with the dose of antipsychotic treatment in the schizophrenia group. These results suggest that patients with schizophrenia, but not those with ARMS, exhibit volume reduction in specific thalamic subdivisions, which may underlie core clinical features of this illness., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The decision to initiate clozapine treatment should be made on an individual basis and may be closely related to the early detection of treatment-resistant schizophrenia (TRS), although there is evidence that the early use of clozapine results in a better response to treatment. Therefore, we investigated the relationship between the examination rate of TRS and the prescription rate of clozapine., Methods: After attending a 1-day educational program on schizophrenia based on the "Guidelines for the Pharmacological Treatment of Schizophrenia," we asked the participating facilities to submit records of whether or not TRS was evaluated for each patient. We calculated the clozapine prescription rate from the schizophrenic patients prescribed clozapine and all of the schizophrenic patients. Forty-nine facilities in 2017 were included in the study., Results: There were dichotomous distributions in the examination rate of TRS and a non-normal distribution in the prescription rate of clozapine. There was a significant correlation between the prescription rate of clozapine and the examination rate of TRS (r s  = 0.531, P = 1.032 × 10 -4 ). A significant difference was found in the prescription rate of clozapine between the three groups of facilities according to the examination rate of TRS., Conclusion: As a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of Neuropsychopharmacology.)

Recent literature examining associations between cognitive function, clinical features, and violence in patients with schizophrenia has been growing; however, the results are inconsistent. Reports on social function and personality are limited. These studies are yet to be reflected in risk assessment tools and management plans. The aim of this study is to provide a resource for risk assessment and intervention studies by conducting multifaceted well-established assessments in a large population. Data from 355 patients with schizophrenia (112 patients with a history of violence; 243 patients without a history of violence) and 1265 healthy subjects were extracted from a large database of individuals with mental disorders in a general psychiatric population in Japan. The associations between violence in patients with schizophrenia and intellectual function, cognitive function (memory function, executive function, attentional function, verbal learning, processing speed, social cognition), clinical variables, personality traits, social function, and quality of life (QOL) were analyzed. Compared with healthy subjects, the schizophrenia group had broadly impaired cognitive function and social cognition, and their personality traits showed similar differences as those reported previously. Patients with schizophrenia with a history of violence showed significantly more impaired visual memory function (P = 1.9 × 10 -5 , Cohen's d = 0.34), longer hospitalization (P = 5.9 × 10 -4 , Cohen's d = 0.38), more severe excited factor on Positive and Negative Syndrome Scale (P = 1.6 × 10 -4 , Cohen's d = 0.47), higher self-transcendence personality construct on the Temperament and Character Inventory (P = 1.8 × 10 -4 , Cohen's d = 0.46), and shorter total working hours per week (P = 4.8 × 10 -4 , Cohen's d = 0.53) than those with schizophrenia without a history of violence. New findings, including impaired visual memory, a high self-transcendence personality trait, and shorter total working hours, could be focused on in future interventional research., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although several guidelines indicate that daily pharmacotherapy is an important part of the treatment of schizophrenia and major depressive disorder, there are few reports regarding pro re nata (PRN) prescriptions. The purpose of this study is to clarify the characteristics of patients receiving psychotropic PRN prescription for the treatment of schizophrenia and major depressive disorder., Method: We used data from 'the effectiveness of guideline for dissemination and education in psychiatric treatment' (EGUIDE) project to evaluate the presence or absence of psychotropic PRN prescription at the time of discharge, the age and sex of patients receiving PRN prescription for each diagnosis, and the association between PRN prescription and regular daily psychotropics., Results: The psychotropic PRN prescription ratio was 29.9% among 2617 patients with schizophrenia and 31.1% among 1248 patients with major depressive disorder at discharge. In schizophrenia, the psychotropic PRN prescription ratio was 21.6% for patients aged 65 years or older, which was lower than that of all other age groups. In major depressive disorder, the psychotropic PRN prescription ratio was 34.2% for female patients, which was significantly higher than that for male patients (25.5%). In schizophrenia, there was an association between psychotropic PRN prescription and regular use of multiple psychotropic medications., Conclusions: Psychotropic PRN prescription was less common in elderly patients with schizophrenia and more common in female patients with major depressive disorder. In schizophrenia, psychotropic PRN prescription led to polypharmacy of psychotropics. Further studies are needed to accumulate evidence and to provide education on appropriate PRN prescriptions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Study Objectives: To investigate the proportion of inpatients with schizophrenia and major depressive disorder prescribed hypnotic medication, and the association between such medication and the use of other antipsychotic agents., Methods: This was a nationwide cross-sectional study performed as part of the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment' (EGUIDE) project. Data from 2146 inpatients with schizophrenia and 1031 inpatients with major depressive disorder were analyzed. All types and dosages of psychotropic drugs were recorded and the data at the time of discharge were analyzed. Associations between the use of hypnotic medication and other antipsychotic agents were evaluated using multivariate logistic regression analyses., Results: The proportions of schizophrenia patients who were prescribed any and two or more hypnotic agents were 55.7% and 17.6%, respectively, and the corresponding proportions for patients with major depressive disorder were 63.6% and 22.6%, respectively. In schizophrenia patients, multivariate logistic regression analyses showed that two or more antipsychotics, anticholinergic drugs, anxiolytics, and mood stabilizers/antiepileptic drugs were positively associated with the use of any hypnotic agent. In patients with major depressive disorder, multivariate logistic regression analyses revealed that two or more antidepressants, two or more antipsychotics, anxiolytics, and mood stabilizers/antiepileptic drugs were positively associated with the use of any hypnotic agent., Conclusions: Prescription of hypnotic agents was found to be highly frequent among inpatients with psychiatric disorders. Prescription of two or more main antipsychotic agents was commonly associated with the use of hypnotic medication for both schizophrenia and major depressive disorder., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi + Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD., (© 2021. The Author(s).)

An increasing body of evidence suggests that impaired synapse development and function are associated with schizophrenia; however, the underlying molecular pathophysiological mechanism of the disease remains largely unclear. We conducted a family-based study combined with molecular and cellular analysis using induced pluripotent stem cell (iPSC) technology. We generated iPSCs from patients with familial schizophrenia, differentiated these cells into neurons, and investigated the molecular and cellular phenotypes of the patient's neurons. We identified multiple altered synaptic functions, including increased glutamatergic synaptic transmission, higher synaptic density, and altered splicing of dopamine D2 receptor mRNA in iPSC-derived neurons from patients. We also identified patients' specific genetic mutations using whole-exome sequencing. Our findings support the notion that altered synaptic function may underlie the molecular and cellular pathophysiology of schizophrenia, and that multiple genetic factors cooperatively contribute to the development of schizophrenia., (© 2021. The Author(s).)

Background: Monopharmacy with antipsychotics and antidepressants is the first-line treatment for schizophrenia and major depressive disorder (MDD) in most clinical guidelines, while polypharmacy with psychotropic agents in the treatment of schizophrenia is common in clinical practice. There are no detailed data on the prescription patterns for inpatients with mental illness with reliable diagnoses made by treating psychiatrists., Methods: We gathered prescription data at discharge from 2177 patients with schizophrenia and 1238 patients with MDD from October 2016 to March 2018., Results: The patients with schizophrenia aged between 60 and 79 were prescribed lower doses of antipsychotics and hypnotics/anxiolytics than those aged between 40 and 59. There were significant differences between the prescription rate of antipsychotics in the patients with schizophrenia and that of antidepressants in the patients with MDD. The frequency of concomitant drugs such as anti-Parkinson drugs, anxiolytics/hypnotics and mood stabilizers in the subjects with schizophrenia prescribed antipsychotic polypharmacy was significantly higher than that with monotherapy. For the patients with schizophrenia, olanzapine, risperidone, aripiprazole, quetiapine, and blonanserin were the five most prescribed antipsychotics. For the patients with MDD, mirtazapine, duloxetine, escitalopram, trazodone and sertraline were the five most prescribed antidepressants., Conclusions: Our results showed the use of high doses of antipsychotics, high percentages of antipsychotic polypharmacy and concurrent use of hypnotics/anxiolytics in patients with schizophrenia. Notably, these data were collected before intensive instruction regarding the guidelines; therefore, we need to assess the change in the prescription pattern post guideline instruction., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Impairments in intelligence are more severe in patients with schizophrenia (SCZ) than in patients with bipolar disorder (BD) despite clinical and genetic similarities between the disorders. Genetic loci differentiating SCZ from BD, that is, SCZ-specific risk, have been identified. Polygenetic [risk] scores (PGSs) for SCZ-specific risk are higher in SCZ patients than in healthy controls (HCs). However, the influence of genetic risk on impaired intelligence is poorly understood. Here, we investigated whether SCZ-specific risk could predict impairments in intelligence in SCZ patients and HCs., Methods: Large-scale genome-wide association study datasets related to SCZ vs BD, childhood intelligence (CHI), and adulthood intelligence (n = 12 441-282 014) were utilized to compute PGSs. PGSs derived from the genome-wide association studies were calculated for 130 patients with SCZ and 146 HCs. Premorbid and current intelligence and the decline were measured in SCZ patients and HCs. Correlations between PGSs and intelligence functions were investigated., Results: High PGSs for SCZ-specific risk were correlated with low premorbid intelligence in SCZ patients and HCs (β = -0.17, P = 4.12 × 10-3). The correlation was still significant after adjusting for diagnostic status (β = -0.13, P = .024). There were no significant correlations between PGSs for SCZ-specific risk and current intelligence or intelligence decline (P > .05). PGSs for CHI were lower in SCZ patients than in HCs (R2 = 0.025, P = .025), while the PGSs for CHI were not significantly correlated with premorbid and current intelligence, the decline, or the PGSs for SCZ-specific risk (P > .05)., Conclusions: These findings suggest that genetic factors differentiating SCZ from BD might affect the pathogenesis of SCZ and/or pathological differences between SCZ and BD via the impairment of premorbid intelligence, that is, crystallized intelligence, while genetic factors for CHI might affect the pathogenesis of SCZ but not via impairments in intelligence., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Abnormal eye movements are often associated with psychiatric disorders. Eye movements are sensorimotor functions of the brain, and aging and sex would affect their characteristics. A precise understanding of normal eye movements is required to distinguish disease-related abnormalities from natural differences associated with aging or sex. To date, there is no multicohort study examining age-related dependency and sex effects of eye movements in healthy, normal individuals using large samples to ensure the robustness and reproducibility of the results. In this study, we aimed to provide findings showing the impact of age and sex on eye movement measures. The present study used eye movement measures of more than seven hundred healthy individuals from three large independent cohorts. We herein evaluated eye movement measures quantified by using a set of standard eye movement tests that have been utilized for the examination of patients with schizophrenia. We assessed the statistical significance of the effects of age and sex and its reproducibility across cohorts. We found that 4-18 out of 35 eye movement measures were significantly correlated with age, depending on the cohort, and that 10 of those, which are related to the fixation and motor control of smooth pursuit and saccades, showed high reproducibility. On the other hand, the effects of sex, if any, were less reproducible. The present results suggest that we should take age into account when we evaluate abnormalities in eye movements., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of Neuropsychopharmacology.)

Background: To implement clinical practice guidelines (CPGs), it is necessary for psychiatrists to deepen their understanding of the CPGs. The Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project is a nationwide dissemination and implementation study of two sets of CPGs for schizophrenia and major depressive disorder (MDD)., Methods: A total of 413 psychiatrists (n = 212 in 2016; n = 201 in 2017) learned the two CPGs in the education program of the EGUIDE project, and clinical knowledge of these CPGs was evaluated at baseline and after the programs. To improve the correct answer rate for clinical knowledge after the programs, we revised the lecture materials associated with items that had a low correct answer rate in 2016 and used the revised lecture materials with the CPGs in 2017. The rates of correct answers after the programs between the 2016 and 2017 groups were compared., Results: The correct answer rate of one item on the schizophrenia CPG and one item on the MDD CPG tended to be improved (S-D5 and D-C6) and that of one on the MDD CPG was significantly improved (D-D3, P = 0.0008) in the 2017 group compared to those in the 2016 group., Conclusions: We reported improvements in clinical knowledge of CPGs after the EGUIDE program in the 2017 group following revision of the lecture materials based on results from the 2016 group. These attempts to improve the degree of understanding of CPGs may facilitate the successful dissemination and implementation of psychiatric guidelines in everyday practice., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of Neuropsychopharmacology.)

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Schizophrenia affects various aspects of cognitive and behavioural functioning. Eye movement abnormalities are commonly observed in patients with schizophrenia (SZs). Here we examined whether such abnormalities reflect an anomaly in inhibition of return (IOR), the mechanism that inhibits orienting to previously fixated or attended locations. We analyzed spatiotemporal patterns of eye movement during free-viewing of visual images including natural scenes, geometrical patterns, and pseudorandom noise in SZs and healthy control participants (HCs). SZs made saccades to previously fixated locations more frequently than HCs. The time lapse from the preceding saccade was longer for return saccades than for forward saccades in both SZs and HCs, but the difference was smaller in SZs. SZs explored a smaller area than HCs. Generalized linear mixed-effect model analysis indicated that the frequent return saccades served to confine SZs' visual exploration to localized regions. The higher probability of return saccades in SZs was related to cognitive decline after disease onset but not to the dose of prescribed antipsychotics. We conclude that SZs exhibited attenuated IOR under free-viewing conditions, which led to restricted scene scanning. IOR attenuation will be a useful clue for detecting impairment in attention/orienting control and accompanying cognitive decline in schizophrenia.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood., Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia., Design, Setting, and Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244., Main Outcomes and Measures: Interregional profiles of group difference in cortical thickness between cases and controls., Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders., Conclusions and Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

Previous studies have indicated associations between several OLIG2 gene single-nucleotide polymorphisms (SNPs) and susceptibility to schizophrenia among Caucasians. Consistent with these findings, postmortem brain and diffusion tensor imaging studies have indicated that the schizophrenia-risk-associated allele (A) in the OLIG2 SNP rs1059004 predicts lower OLIG2 gene expression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients and reduced white matter (WM) integrity of the corona radiata in normal brains among Caucasians. In an effort to replicate the association between this variant and WM integrity among healthy Japanese, we found that the number of A alleles was positively correlated with WM integrity in some fiber tracts, including the right posterior limb of the internal capsule, and with mean blood flow in a widespread area, including the inferior frontal operculum, orbital area, and triangular gyrus. Because the A allele affected WM integrity in opposite directions in Japanese and Caucasians, we investigated a possible association between the OLIG2 gene SNPs and the expression level of OLIG2 transcripts in postmortem DLPFCs. We evaluated rs1059004 and additional SNPs in the 5' upstream and 3' downstream regions of rs1059004 to cover the broader region of the OLIG2 gene. The 2 SNPs (rs1059004 and rs9653711) had opposite effects on OLIG2 gene expression in the DLPFC in Japanese and Caucasians. These findings suggest ethnicity-dependent opposite effects of OLIG2 gene SNPs on WM integrity and OLIG2 gene expression in the brain, which may partially explain the failures in replicating associations between genetic variants and psychiatric phenotypes among ethnicities., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample., Method: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls., Results: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression., Conclusion: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Background: Guideline for Pharmacological Therapy for Schizophrenia was published by the Japanese Society of Neuropsychopharmacology in 2015. "Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE)" project aimed to standardize medical practice using quality indicators (QIs) as indices to evaluate the quality of medical practice. In this study, we have reported the quality indicator values of prescription before the beginning of the guideline lectures in the EGUIDE project to ascertain the baseline status of treating patients with schizophrenia., Methods: A cross-sectional, retrospective case record survey was conducted, involving 1164 patients with schizophrenia at the time of discharge. We checked all types and dosage of psychotropic drugs., Results: Forty-three percent of patients had antipsychotic polypharmacy, and substantial concomitant medication was observed (antidepressants; 8%, mood stabilizers: 37%, anxiolytics or hypnotics: 68%)., Conclusions: In the results obtained in this study, we plant to report changes in the effectiveness of education in the EGUIDE project near the future., (© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.)

Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense variant was found to be located in the RhoGAP domain and was determined to be relevant to the association between ARHGAP10 and the active form of RhoA. We evaluated ARHGAP10 protein expression in the brains of reporter mice and generated a mouse model to mimic the patient case. The model exhibited abnormal emotional behaviors, along with reduced spine density in the medial prefrontal cortex (mPFC). In addition, primary cultured neurons prepared from the mouse model brain exhibited immature neurites in vitro. Furthermore, we established induced pluripotent stem cells (iPSCs) from this patient, and differentiated them into tyrosine hydroxylase (TH)-positive neurons in order to analyze their morphological phenotypes. TH-positive neurons differentiated from the patient-derived iPSCs exhibited severe defects in both neurite length and branch number; these defects were restored by the addition of the Rho-kinase inhibitor, Y-27632. Collectively, our findings suggest that rare ARHGAP10 variants may be genetically and biologically associated with SCZ and indicate that Rho signaling represents a promising drug discovery target for SCZ treatment.

Aim: Matrix metalloproteinase-9 (MMP-9) has been shown to modulate synaptic plasticity and may contribute to the pathophysiology of schizophrenia. This study investigated the peripheral levels of MMP-9 and its association with cognitive functions in patients with schizophrenia to see the possible involvement of MMP-9 in pathophysiology of schizophrenia, especially in cognitive decline., Methods: We measured the plasma levels of MMP-9 in 257 healthy controls and 249 patients with schizophrenia, including antipsychotic drug-free patients. We also explored the possible association between plasma MMP-9 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition (WAIS- III), the Wechsler Memory Scale-Revised (WMS-R), and the Rey Auditory Verbal Learning Test (AVLT)., Results: We found that the plasma levels of MMP-9 were significantly higher in patients with schizophrenia, including antipsychotic drug-free patients, than in healthy controls. We found a significant negative association between plasma MMP-9 levels and cognitive performance in controls and patients with schizophrenia., Conclusion: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased MMP-9 levels are associated with cognitive impairment., (© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.)

Background: The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected first-degree relatives and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses., Methods: To calculate PRSs for 5 psychiatric disorders (SCZ, bipolar disorder [BIP], major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder) and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target participants [SCZ patients, FRs, and healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders and investigated their effect on risk in Japanese SCZ patients and unaffected first-degree relatives., Results: The PRSs obtained from European SCZ and BIP patients were higher in Japanese SCZ patients than in HCs. Furthermore, PRSs differentiating SCZ patients from European BIP patients were higher in Japanese SCZ patients than in HCs. Interestingly, PRSs related to European autism spectrum disorder were lower in Japanese first-degree relatives than in HCs or SCZ patients. The PRSs of autism spectrum disorder were positively correlated with a young onset age of SCZ., Conclusions: These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected first-degree relatives may help protect against SCZ development., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Eye movements are indispensable for the collection of visual information in everyday life. Many findings regarding the neural basis of eye movements have been accumulated from neurophysiological and psychophysical studies. In the field of psychiatry, studies on eye movement characteristics in mental illnesses have been conducted since the early 1900s. Participants with schizophrenia are known to have characteristic eye movements during smooth pursuit, saccade control, and visual search. Recently, studies evaluating eye movement characteristics as biomarkers for schizophrenia have attracted considerable attention. In this article, we review the neurophysiological basis of eye movement control and eye movement characteristics in schizophrenia. Furthermore, we discuss the prospects for eye movements as biomarkers for mental illnesses., (© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.)

Aim: Eye movement abnormalities are often associated with psychiatric illness. Subjects with either schizophrenia or autism spectrum disorder (ASD) have been reported to show eye movement abnormalities. However, it is still unclear whether eye movement abnormalities in schizophrenia and in ASD have common features. This study aimed to understand the similarities/differences in eye movement abnormalities of subjects with schizophrenia and those with ASD., Methods: We analyzed 75 eye movement characteristics of 83 subjects with schizophrenia, 17 subjects with ASD and 255 healthy controls that were collected during fixation, smooth pursuit and free viewing tasks using analysis of covariance with the covariates age and sex., Results: We found significant effects across groups on 21 eye movement characteristics, of which 4 characteristics had large effect sizes. Post hoc multiple comparisons indicated significant differences between the subjects with schizophrenia and healthy controls across all 21 characteristics. On the other hand, no significant difference between the ASD group and healthy control group was found. Instead, the subjects with ASD showed significant differences from the subjects with schizophrenia in 5 eye movement characteristics during the free viewing and smooth pursuit eye movements., Conclusions: The present results suggest that eye movement abnormalities in the subjects with ASD are different from those with schizophrenia and that the tasks in this study are suitable to detect eye movement abnormality in schizophrenia. Thus, the eye movement examinations used here may distinguish subjects with schizophrenia from those with ASD., (© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.)