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Abstract 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

Abstract Aim The etiology of bipolar disorder (BD) remains unknown; however, lipid abnormalities in BD have received increasing attention in recent years. In this study, we examined the expression levels of enzyme proteins associated with the metabolic pathway of phosphoinositides (PIs) and their downstream effectors, protein kinase B (Akt1) and glycogen synthase kinase 3β (GSK3β), which have been assumed to be the targets of mood stabilizers such as lithium, in the postmortem brains of patients with BD. Methods The protein expression levels of phosphatidylinositol 4‐phosphate 5‐kinase type‐1 gamma (PIP5K1C), phosphatidylinositol 4‐kinase alpha (PIK4CA), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), Akt1, and GSK3β were measured using enzyme‐linked immunosorbent assays and multiplex fluorescent bead‐based immunoassays in the prefrontal cortex (PFC). Specifically, PTEN, Akt1, GSK3β, and PIP5K1C were measured in seven BD patients and 48 controls. Additionally, PIK4CA was analyzed in 10 cases and 34 controls. Results PTEN expression levels were markedly decreased in the PFCs of patients with BD, whereas those of Akt and GSK3β were prominently elevated. Moreover, patients medicated with lithium exhibited higher Akt1 expression levels and lower PTEN expression levels in comparison with the untreated group. Conclusion Our results suggest that the expression levels of Akt1/GSK3β and its upstream regulator PTEN are considerably altered.

Abstract 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.

BackgroundSchizophrenia 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. ObjectiveThis study aims to assess the efficacy of a novel tablet-based platform combining cognitive and eye movement measures for classifying schizophrenia. MethodsForty-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. ResultsCognitive and eye movement measures differed significantly between patients with schizophrenia and healthy controls (all 3 measures; P

Abstract Schizophrenia is a psychiatric disorder that is associated with various social dysfunctions, including shorter work hours. To measure the degree to which psychiatrists adhere to guidelines for pharmacological therapy of schizophrenia, we recently developed the individual fitness score (IFS) for adherence among psychiatrists in each patient. However, it remains unclear whether better adherence among psychiatrists is associated with higher patients’ social functional outcomes, such as work hours. In this study, we examined the relationship between adherence to guidelines among psychiatrists and work hours in patients with schizophrenia. To evaluate the association between adherence to guidelines for pharmacological therapy among psychiatrists for treating schizophrenia and work hours, we used the IFS and social activity assessment, respectively, in 286 patients with schizophrenia. The correlation between IFS values and work hours was investigated in the patients. The adherence among psychiatrists to guidelines was significantly and positively correlated with work hours in patients with schizophrenia (rho = 0.18, p = 2.15 × 10− 3). When we divided the patients into treatment-resistant schizophrenia (TRS) and nontreatment-resistant schizophrenia (non-TRS) groups, most patients with TRS (n = 40) had shorter work hours (0–15 h/week). Even after excluding patients with TRS, the positive correlation between adherence to guidelines among psychiatrists and work hours in patients with non-TRS (n = 246) was still significant (rho = 0.19, p = 3.32 × 10− 3). We found that work hours were longer in patients who received the guideline-recommended pharmacotherapy. Our findings suggest that widespread education and training for psychiatrists may be necessary to improve functional outcomes in patients with schizophrenia.

Abstract 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.

Abstract Aims Schizophrenia is a chronic relapsing psychiatric disorder that is characterized by many symptoms and has a high heritability. There were studies showing that the phospholipid abnormalities in subjects with schizophrenia (Front Biosci, S3, 2011, 153; Schizophr Bull, 48, 2022, 1125; Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933). Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in subjects with schizophrenia (Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933; Schizophr Res, 215, 2020, 493; J Psychiatr Res, 47, 2013, 636; Int J Mol Sci, 22, 2021). For exploring the signaling pathways contributing to the lipid changes in previous study (Sci Rep, 7, 2017, 6), we performed two types of transcriptome analyses in subjects with schizophrenia: an unbiased transcriptome analysis solely based on RNA‐seq data and a correlation analysis between levels of gene expression and lipids. Methods RNA‐Seq analysis was performed in the postmortem prefrontal cortex from 10 subjects with schizophrenia and 5 controls. Correlation analysis between the transcriptome and lipidome from 9 subjects, which are the same samples in the previous lipidomics study (Sci Rep, 7, 2017, 6). Results Extraction of differentially expressed genes (DEGs) and further sequence and functional group analysis revealed changes in gene expression levels in phosphoinositide 3‐kinase (PI3K)‐Akt signaling and the complement system. In addition, a correlation analysis clarified alterations in ether lipid metabolism pathway, which is not found as DEGs in transcriptome analysis alone. Conclusions This study provided results of the integrated analysis of the schizophrenia‐associated transcriptome and lipidome within the PFC and revealed that lipid‐correlated alterations in the transcriptome are enriched in specific pathways including ether lipid metabolism pathway.

Abstract Aim This study aimed to clarify the abnormalities in dopamine transporter (DAT) availability in drug‐naive adult patients with attention‐deficit/hyperactivity disorder (ADHD) and the relationship between ADHD symptoms and abnormalities in DAT availability. Methods Single‐photon emission tomography (SPECT) was performed using iodine‐123‐β‐carbomethoxy‐3β‐(4‐iodophenyltropane) (I‐123 β CIT) as a tracer to measure in vivo DAT availability in 20 drug‐naive patients with ADHD [mean age ± standard deviation (SD)]: 25 ± 3.44 years; male:female = 11:9] and 20 age‐ and sex‐matched healthy controls (HCs) (mean age ± SD: 23.9 ± 2.27 years). Comparisons of DAT availability between HCs and adult patients with ADHD and the association between symptom severity and DAT availability within the ADHD group were analyzed using Statistical Parametric Mapping 12. Results Drug‐naive adults with ADHD showed significantly reduced DAT availability in the bilateral nucleus accumbens compared with HCs. Correlation analyses revealed a negative correlation between the severity of inattentive symptoms in adult patients with ADHD and DAT availability in the bilateral heads of the caudate nucleus, indicating the association between severe inattentive symptoms and lower DAT availability in the caudate nucleus. Conclusion In drug‐naive adult patients with ADHD, DAT availability was reduced in the nucleus accumbens, an important part of the reward system. This finding indicates the importance of the DAT in the reward system in the pathogenesis of ADHD. Inattentiveness was associated with DAT availability in the caudate nucleus, suggesting involvement of the cortico‐striato‐thalamo‐cortical circuit.

Reports on polypharmacy strategies for patients with schizophrenia and major depressive disorder (MDD) are scarce. The nationwide Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project has been used to train psychiatrists on the guidelines for treatment of schizophrenia and MDD. This study aimed to determine whether the EGUIDE program enabled more appropriate evidence-based treatment of outpatients with schizophrenia and MDD. The types and doses of all psychotropics were analyzed in 174 and 147 patients with schizophrenia and MDD, respectively, in 2018 before the EGUIDE program and in 2019 and 2020 after the program. There were no significant differences in the rate of monopharmacy with antipsychotics for schizophrenia; however, the prescriptions of first-generation antipsychotics, anticholinergics, and benzodiazepines for schizophrenia decreased significantly after the program. There were also no significant differences in antidepressant monopharmacy rates for MDD; however, the prescriptions of benzodiazepines in patients with MDD decreased significantly after the program. Significant positive correlations were found between the number of psychotropic prescriptions and dosage of benzodiazepines. In conclusion, the EGUIDE project has improved the prescribing behavior for outpatients with schizophrenia and depression. Therefore, the guideline training program may be useful for regulating the prescribing behavior among physicians.

Abstract 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_mono group, monotherapy of the main drug at admission and discharge; (2) mono_poly group, monotherapy at admission and polypharmacy at discharge; (3) poly_poly group, polypharmacy at admission and discharge; and (4) poly_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_poly group than that in the mono_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).

Abstract Aim Delusions are a common symptom in schizophrenia. Some scales have been developed to measure delusional tendencies in healthy people, and nonpathological delusional thinking can occur even among these individuals. The existing scales measure the presence and frequency of delusional thoughts, distress levels, and confidence levels. However, these scales are limited because they do not consider the context of the delusions (i.e., where, with whom, and when). In this study, we developed a new scale that presents detailed scenes using illustrations and sentences and measures the tendency toward delusional interpretations. Methods Factor analysis was conducted to confirm the factor structure of the new scale. To examine the validity of the scale, we analyzed the correlations between delusional tendencies and related variables and verified the consistency between the current scale and previously developed tools. Results Factor analysis confirmed that the new scale has a two‐factor structure, including “internal attribution and paranoid tendency” and “external attribution tendency.” The new scale was found to have acceptable reliability and validity. The internal attribution and paranoid tendency factor was negatively correlated with self‐esteem and decentering. Furthermore, the internal attribution and paranoid tendency factor showed a moderate positive correlation with depressive state and anxiety tendency and a very weak positive correlation with experiences of bullying or harassment. Conclusion The correlations between the new scale and related variables confirmed the construct validity and replicated the results reported in previous studies. This new scale enables the measurement of delusional tendencies in healthy subjects based on the social context.

Abstract Aim Treatment guidelines are designed to assist patients and health care providers and are used as tools for making treatment decisions in clinical situations. The treatment guidelines of the Japanese Society of Mood Disorders establish treatment recommendations for each severity of depression. The individual fitness score (IFS) was developed as a simple and objective indicator to assess whether individual patients are practicing treatment by the recommendations of the depression treatment guidelines of the Japanese Society of Mood Disorders. Methods The EGUIDE project members determined the IFS through the modified Delphi method. In this article, the IFS was calculated based on the treatment of depressed patients treated and discharged between 2016 and 2020 at facilities participating in the EGUIDE project. In addition, we compared scores at admission and discharge. Results The study included 428 depressed patients (mild n = 22, moderate/severe n = 331, psychotic n = 75) at 57 facilities. The mean IFS scores by severity were statistically significantly higher at discharge than at admission with moderate/severe depression (mild 36.1 ± 34.2 vs. 41.6 ± 36.9, p = 0.49; moderate/severe 50.2 ± 33.6 vs. 55.7 ± 32.6, p = 2.1 × 10–3; psychotic 47.4 ± 32.9 versus 52.9 ± 36.0, p = 0.23). Conclusion We developed the IFS based on the depression treatment guideline, which enables us to objectively determine how close the treatment is to the guideline at the time of evaluation in individual cases. Therefore, the IFS may influence guideline‐oriented treatment behavior and lead to the equalization of depression treatment in Japan, including pharmacotherapy.

Abstract To disseminate, educate, and validate psychiatric clinical practice guidelines, the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project was launched in 2016. In this study, we investigated whether the web‐based courses offered by this project would be as effective as the face‐to‐face courses. We analyzed and compared survey answers about overall participant satisfaction with the course and answers regarding clinical knowledge of schizophrenia and major depressive disorder between 170 participants who took the web‐based courses in 2020 and 689 participants who took the face‐to‐face courses from 2016 to 2019. The web‐based course participants completed the survey questions about satisfaction with the web‐based courses. The web‐based courses were conducted using a combination of web services to make it as similar as possible to the face‐to‐face courses. The degree of satisfaction assessed by the general evaluation of the web‐based courses was higher than what was expected from the face‐to‐face courses. The degree of satisfaction was similar for the courses on schizophrenia and major depressive disorder. In addition, there were no significant differences in overall satisfaction and clinical knowledge between web‐based and face‐to‐face courses. In conclusion, the web‐based courses on clinical practice guidelines provided by the EGUIDE project were rated as more satisfying than the face‐to‐face course that the participants expected to take and no differences in the effectiveness of either course. The results suggest that, after the COVID‐19 pandemic, it would be possible to disseminate this educational material more widely by adopting web‐based courses additionally face‐to‐face courses.

Abstract 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.

Abstract Background Several guidelines recommend monotherapy in pharmacotherapy for schizophrenia and major depressive disorder. The content of regular prescriptions has been reported in several studies, but not enough research has been conducted on the content of pharmacotherapy, including pro re nata (PRN) medications. The purpose of this study was to evaluate the content of pharmacotherapy, including PRN medications, and to clarify the relationship with regular prescriptions. Methods We used data from the “Effectiveness of Guidelines for Dissemination And Education in psychiatric treatment” (EGUIDE) project to investigate the presence or absence of PRN psychotropic medications at discharge for each drug category. We compared the PRN psychotropic prescription ratio at discharge by diagnosis for each drug category. The antipsychotic monotherapy ratio and no prescription ratio of other psychotropics for schizophrenia at discharge and the antidepressant monotherapy ratio and no prescription ratio of other psychotropics for major depressive disorder at discharge were calculated for each regular prescription, including PRN psychotropic medications, as quality indicators (QIs). Spearman's rank correlation test was performed for QI values of regular prescriptions and the QI ratio between regular prescriptions and prescriptions including PRN medications for each diagnosis. Results The PRN psychotropic prescription ratio at discharge was 28.7% for schizophrenia and 30.4% for major depressive disorder, with no significant differences by diagnosis. The prescription ratios of PRN antipsychotic medications and PRN antiparkinsonian medications were significantly higher for schizophrenia. The prescription ratios of PRN anxiolytic and hypnotic and PRN antidepressant medications were significantly higher for patients with major depressive disorder. For both schizophrenia and major depressive disorder, the QI was lower for discharge prescriptions, including PRN medications, than for regular prescriptions. QI values for regular prescriptions and the QI ratio were positively correlated. Conclusions Considering PRN psychotropic medications, the monotherapy ratio and no prescription ratio of other psychotropics at discharge decreased in pharmacotherapy for schizophrenia and major depressive disorder. A higher ratio of monotherapy and no prescription of other psychotropics on regular prescriptions may result in less concomitant use of PRN psychotropic medications. Further studies are needed to optimize PRN psychotropic prescriptions.

Abstract The Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE) project, which is a nationwide dissemination and implementation program for clinical practice guidelines (CPGs) in the field of psychiatry, is currently ongoing. In the current study, a subjective assessment of the participants in the EGUIDE programs was assessed using a questionnaire. Then, the relationships between the subjective assessment, the characteristics of the participants, and the clinical knowledge of the CPGs were evaluated. More than 90% of the participants gave a high rating for the components of content, recommendation, knowledge, skill, and adherence, but not for the component of confidence. A positive correlation was found between years of professional experience and the score of confidence. These results suggest that it may be necessary to apply the knowledge and skills of CPGs obtained in the education programs into practice to increase confidence in the proper use of psychiatric therapies based on CPGs.

Abstract Aim Social functioning is influenced by various factors. Autistic traits could be one of the factors that affect social functioning. Methods In the present study, the relationship between autistic traits and social functioning among 755 healthy individuals was analyzed. Autistic traits were assessed with the autism‐spectrum quotient. Social functioning was assessed by the social functioning scale and the social activity assessment. Results The Autism‐Spectrum Quotient total score was significantly negatively correlated with the social functioning scale total and all subscales of the social functioning scale. All subscales of the Autism‐Spectrum Quotient except attention to detail were significantly negatively correlated with the social functioning scale total score. However, the Autism‐Spectrum Quotient was not correlated with the social activity assessment, which indicates labor functioning. Conclusion Autistic traits of healthy individuals had a negative impact on situations in real life through social functioning for daily life‐sustaining. The effect was not enough to affect labor functioning as indicated by working hours in healthy individuals. These findings should also be examined in individuals with autism spectrum disorder in future studies.

Abstract 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.

Abstract Aim Clozapine is currently the only effective drug for treatment‐resistant schizophrenia; nonetheless, its pharmacological mechanism remains unclear, and its administration is limited because of severe adverse effects. By comparing the binding proteins of clozapine and its derivative olanzapine, which is safer but less effective than clozapine, we attempted to clarify the mechanism of action specific to clozapine. Methods First, using the polyproline rod conjugates attached with clozapine or olanzapine, clozapine‐binding proteins in extracts from the cerebra of 7‐week‐old ICR mice were isolated and separated by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE) and analyzed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) to identify proteins. Second, the effect of clozapine on tubulin polymerization was determined turbidimetrically. Finally, the cellular effects of clozapine were observed in HeLa cells by immunofluorescence microscopy. Results Alpha and β tubulins were the most abundant clozapine‐binding proteins. We also found that clozapine directly binds with α and β tubulin heterodimers to inhibit their polymerization to form microtubules and disturbs the microtubule network, causing mitotic arrest in HeLa cells. Conclusion These results suggest that α and β tubulin heterodimers are targeted by the clozapine and the microtubules are involved in the etiology of schizophrenia.

IntroductionAttention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder whose primary symptoms are hyperactivity, impulsivity, and inattention. Historically, ADHD was recognized as a disease of childhood and adolescence. However, many patients are known to have persistent symptoms into adulthood. Many researchers consider the neuropathology of ADHD to be based on abnormalities in multiple parallel and intersecting pathways rather than a single anatomical area, but such alterations remain to be clarified.MethodsUsing diffusion tensor imaging, we investigated differences in the global network metrics estimated by graph theory and the degree of connectivity between adjacent voxels within a white matter (WM) fascicle defined by the density of the diffusing spins (connectometry) between 19 drug-naive Japanese patients with adult ADHD and 19 matched healthy controls (HCs). In adult patients with ADHD, we examined the relationships between the symptomatology of ADHD and global network metrics and WM abnormalities.ResultsCompared with HCs, adult patients with ADHD showed a reduced rich-club coefficient and decreased connectivity in widely distributed WMs such as the corpus callosum, the forceps, and the cingulum bundle. Correlational analyses demonstrated that the general severity of ADHD symptoms was associated with several global network metrics, such as lower global efficiency, clustering coefficient, small worldness, and longer characteristic path length. The connectometry revealed that the severity of hyperactive/impulsive symptoms was associated with overconnectivity in the corticostriatal, corticospinal, and corticopontine tracts, the inferior fronto-occipital fasciculus, and the extreme capsule but dysconnectivity in the cerebellum. The severity of inattentive symptoms was associated with dysconnectivity in the intracerebellar circuit and some other fibers.ConclusionThe results of the present study indicated that patients with treatment-naive adult ADHD showed disrupted structural connectivity, which contributes to less efficient information transfer in the ADHD brain and pathophysiology of ADHD.Trial registrationUMIN Clinical Trials Registry (UMIN-CTR) UMIN000025183, Registered: 5 January 2017.

Abstract 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.

Abstract 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.

Background Clinical practice guidelines for schizophrenia and major depressive disorder have been published. However, these have not had sufficient penetration in clinical settings. We developed the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project as a dissemination and education programme for psychiatrists. Aims The aim of this study is to assess the effectiveness of the EGUIDE project on the subjective clinical behaviour of psychiatrists in accordance with clinical practice guidelines before and 1 and 2 years after participation in the programmes. Method A total of 607 psychiatrists participated in this study during October 2016 and March 2019. They attended both 1-day educational programmes based on the clinical practice guidelines for schizophrenia and major depressive disorder, and answered web questionnaires about their clinical behaviours before and 1 and 2 years after attending the programmes. We evaluated the changes in clinical behaviours in accordance with the clinical practice guidelines between before and 2 years after the programme. Results All of the scores for clinical behaviours in accordance with clinical practice guidelines were significantly improved after 1 and 2 years compared with before attending the programmes. There were no significant changes in any of the scores between 1 and 2 years after attending. Conclusions All clinical behaviours in accordance with clinical practice guidelines improved after attending the EGUIDE programme, and were maintained for at least 2 years. The EGUIDE project could contribute to improved guideline-based clinical behaviour among psychiatrists.

In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups—low rate group (LG), medium rate group (MG), and high rate group (HG)—according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, and first-generation antipsychotics (FGAs) use. The anticholinergic prescription rate varied considerably among hospitals, ranging from 0 to 66.7%, and it was significantly higher in patients with antipsychotic monotherapy, antipsychotic polypharmacy, and normal and high doses of antipsychotics in HG than in those LG and MG. The anticholinergics prescription rate in patients with second-generation antipsychotic monotherapy in HG was also significantly higher than in those LG and MG; however, the difference was no longer significant in patients with FGA monotherapy. Conclusively, in addition to high antipsychotic doses, antipsychotic polypharmacy, and FGA use, hospital characteristics influence the prescribing of anticholinergic drugs.

Abstract 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.

Background: Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. We aimed to test the role of betaine in schizophrenia pathophysiology, and to evaluate its potential as a novel psychotherapeutic. Methods: Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. Findings: The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations in the brain. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine (PCP) treatments. Betaine also showed a prophylactic effect on behavioral abnormality induced by PCP. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with “betaine deficit-oxidative stress pathology”. We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. Interpretation: The present study revealed the role of betaine in psychiatric pathophysiology and underscores the potential benefit of betaine in a subset of schizophrenia. Fund: This study was supported by the Strategic Research Program for Brain Sciences from AMED (Japan Agency for Medical Research and Development) under Grant Numbers JP18dm0107083 and JP19dm0107083 (TY), JP18dm0107129 (MM), JP18dm0107086 (YK), JP18dm0107107 (HY), JP18dm0107104 (AK) and JP19dm0107119 (KH), by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05433 (AH.-T), JP18H05428 (AH.-T and TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). In addition, this study was supported by the Collaborative Research Project of Brain Research Institute, Niigata University under Grant Numbers 2018–2809 (YK) and RIKEN Epigenetics Presidential Fund (100214–201801063606-340120) (TY). Keywords: Schizophrenia, Chdh, DNA methylation, Postmortem brain, Carbonyl stress, iPS cell

Perforation of the larynx is very rare but may result in severe airway complications that include pneumothorax, pneumonia, mediastinitis, and retropharyngeal abscess. If conservative treatment fails, aggressive treatments including reconstructive surgery with pedicle flap are considered. Negative pressure wound therapy has been used for large skin defects, necrotizing fasciitis, pharyngocutaneous fistula, stoma dehiscence, osteoradionecrosis of the mandible, chyle fistula, flap failure, and lymphangioma in the field of head and neck surgery. We report a case of false vocal cord perforation with abscess successfully treated by negative pressure wound therapy after abscess treatment. The result suggests that negative pressure wound therapy can be an alternative or adjunctive approach for larynx perforation when the perforation is difficult to close after conservative therapy.

Abstract Certain butterflies utilize plant-acquired alkaloids for their own chemical defense and/or for producing male sex pheromone; a trait known as pharmacophagy. Males of the danaine butterfly, Parantica sita, have been reported to ingest pyrrolizidine alkaloids (PAs) as adults to produce two PA-derived sex pheromone components, viz. danaidone (major) and 7R-hydroxydanaidal. We found, however, that not all PAs that can be precursors for the pheromone serve for mating success of males. Here we show that although the sex pheromone is regarded as a requisite for successful mating, uptake of specific PA(s) (lycopsamine-type PAs) is also imperative for the males to achieve copulation. The increase in the levels of two biogenic amines, octopamine and/or serotonin, in the brain and thoracic ganglia of males fed with specific PA(s) suggested that these alkaloids most likely enhance male mating activity. The results can present new evidence for the evolutionary provenance of pharmacophagous acquisition of PAs in PA-adapted insects.

BackgroundAfter the 3.11 complex disaster, fear of radioactive contamination and forced evacuation influenced a number of residents to seek psychiatric care.ObjectivesThis study assessed the sequential changes in the number of new outpatients and patients with acute stress disorder (ASD), post-traumatic stress disorder (PTSD), adjustment disorder, and depression after the Fukushima disaster.MethodsWe distributed questionnaires to 77 psychiatric institutions to determine the number of new outpatients between March and June in 2010, 2011, and 2012.FindingsThere were 771, 1000, and 733 new patients in 2010, 2011, and 2012, respectively. We observed a statistically significant increase in new patients with ASD or PTSD and a significant decrease in patients with depression in 2011, which returned to predisaster levels in 2012.ConclusionsThere were time- and disease-dependent changes in the numbers of psychiatric care-seeking individuals after the 3.11 complex disaster in Fukushima.

Background: Cytogenomic mutations and chromosomal abnormality are implicated in the neuropathology of several brain diseases. Cell heterogeneity of brain tissues makes their detection and validation difficult, however. In the present study, we analyzed gene dosage alterations in brain DNA of schizophrenia patients and compared those with the copy number variations (CNVs) identified in schizophrenia patients as well as with those in Asian lymphocyte DNA and attempted to obtain hints at the pathological contribution of cytogenomic instability to schizophrenia. Results: Brain DNA was extracted from postmortem striatum of schizophrenia patients and control subjects (n = 48 each) and subjected to the direct two color microarray analysis that limits technical data variations. Disease-associated biases of relative DNA doses were statistically analyzed with Bonferroni's compensation on the premise of brain cell mosaicism. We found that the relative gene dosage of 85 regions significantly varied among a million of probe sites. In the candidate CNV regions, 26 regions had no overlaps with the common CNVs found in Asian populations and included the genes (i.e., ANTXRL, CHST9, DNM3, NDST3, SDK1, STRC, SKY) that are associated with schizophrenia and/or other psychiatric diseases. The majority of these candidate CNVs exhibited high statistical probabilities but their signal differences in gene dosage were less than 1.5-fold. For test evaluation, we rather selected the 10 candidate CNV regions that exhibited higher aberration scores or larger global effects and were thus confirmable by PCR. Quantitative PCR verified the loss of gene dosage at two loci (1p36.21 and 1p13.3) and confirmed the global variation of the copy number distributions at two loci (11p15.4 and 13q21.1), both indicating the utility of the present strategy. These test loci, however, exhibited the same somatic CNV patterns in the other brain region. Conclusions: The present study lists the candidate regions potentially representing cytogenomic CNVs in the brain of schizophrenia patients, although the significant but modest alterations in their brain genome doses largely remain to be characterized further. [ABSTRACT FROM AUTHOR]

Exposure to environmental chemicals with estrogenic activity during the early stage of pregnancy can seriously affect embryonic development and the maintenance of pregnancy. To estimate the metabolism and pharmacodynamics of a xenoestrogen, bisphenol A, in a reproductive organ, the metabolite of bisphenol A was analyzed after incubating a rat uterine sac in buffer solutions containing the chemical. When the inner or the outer side of the uterine sac was exposed to bisphenol A, the concentration of the parent chemical was decreased in buffer solution and then, only one metabolite, bisphenol A-glucuronide, was observed only in the outer, that is, the maternal, side. A small amount of the parent chemical could pass through the uterine sac without being modified. Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) was shown by immunohistochemical staining analysis to be distributed in epithelial cells of the endometrium, oviduct, and uterine glands. Based on measurements of enzyme activity and on Western blot analysis, UGT activity toward bisphenol A and UGT protein were identified in the microsomal fractions prepared from rat uterus. UGT isoforms, such as UGT1A1, 1A2, 1A5, 1A6, and 1A7, were expressed, and MRP-1 (multidrug resistance-associated protein) and MRP-3, which are well-known to be transporters of various drug-glucuronides, were detected in the rat uterus by reverse transcription-PCR. These results elucidate the rat uterine barrier system by showing that most bisphenol A perfused into the uterus was glucuronidated in the epithelium, resulting in transport of glucuronides to the maternal side. [ABSTRACT FROM AUTHOR]