Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1002/npr2.12370

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Background

There is a rising interest in perinatal mental health studies, and proper psychometric tools to assess autistic traits among this population in Japan are vital.

Objective

This study aimed to clarify the optimal factor structure of the AQ as part of a perinatal mental health research project.

Methods

We used the Japanese version of the AQ (AQ-J) to measure autistic-like traits in pregnant women. Participants were 4,287 Japanese women who were pregnant or who had given birth within the last month. We performed exploratory factor analysis (EFA) using the first sample group (n = 2,154) to obtain factor structures for the final item selections. We performed confirmatory factor analysis (CFA) using the second sample group (n = 2,133) to obtain a model with good fit, then compared the model to all previously proposed models to determine the best-fitting model.

Results

The EFA analysis identified a model consisting of 25 items distributed across three factors. Cronbach’s alpha for the total 25-item AQ-J, 9-item “Social interaction” factor, 11-item “Non-verbal communication” factor, and 5-item “Restricted interest” factor was 0.829, 0.829, 0.755, and 0.576, respectively. McDonald’s omega and its 95% confidence interval were 0.826 (0.821–0.836), 0.835 (0.821–0.837), 0.755 (0.744–0.766), and 0.603 (0.556–0.596), respectively. CFA confirmed that the three-factor structure had an acceptable fit (goodness of fit index: 0.900, comparative fit index: 0.860, root mean square error of approximation: 0.066). These findings indicated that the three-factor model was better than the 13 existing models.

Conclusion

The findings are discussed in relation to the adequacy of the AQ-J for assessing autistic traits in perinatal women. We recommend the use of this 25-item, three-factor AQ-J model for this population owing to its superiority to all previous models.

DOI： 10.3389/fpsyt.2023.1275043

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BACKGROUND: Major depressive disorder (MDD) is linked to an increased risk of diabetes; however, the underlying pathomechanism remains unknown. Although insulin-like growth factor 1 (IGF-1) is involved in the pathogenesis of both insulin resistance (IR) and MDD, no studies have investigated the relationship between IGF-1 and IR in patients with MDD. METHODS: We recruited 120 patients with MDD (84 non-remitting patients and 36 remitting patients) and 99 control participants. Blood samples were collected after overnight fasting to investigate associations between serum and clinical factors, such as serum IGF-1 levels and homeostasis model assessment-insulin resistance (HOMA-IR). RESULTS: Serum IGF-1 levels were higher in patients with non-remitting MDD than in control participants and patients with remitting MDD (P = 0.001 and P = 0.007, respectively). There were no significant differences in HOMA-IR between the three groups. HOMA-IR was positively correlated with serum IGF-1 levels in patients with non-remitting MDD (R = 0.355; P= 0.001) but not in control participants or patients with remitting MDD. A stepwise multiple regression analysis with various clinical factors revealed a positive association of serum IGF-1 levels and body mass index with HOMA-IR in patients with non-remitting MDD. LIMITATIONS: This is a cross-sectional study and therefore we cannot draw firm conclusions about causal associations. CONCLUSIONS: Serum IGF-1 levels may play a role in IR in patients with MDD who fail to achieve remission. Further studies, including longitudinal studies, are needed to determine the relationship between high serum IGF-1 levels and subsequent IR and diabetes risk.

DOI： 10.1016/j.jad.2023.10.009

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Abstract

This study aimed to determine how paternal and maternal parenting before adolescence affects adult attachment to a partner during the perinatal period, using three different models of attachment. We used the Parental Bonding Instrument (PBI) and the Relationship Questionnaire (RQ) to examine perceived parenting practices and adult attachment styles, respectively. The participants included 4586 Japanese women who were pregnant or who had given birth, up until one month after childbirth. We performed structural equation modeling analysis between PBI and RQ scores with three different category models, including the four-category model (secure, fearful, preoccupied, and dismissive attachment) as Model 1, the two-category model (model of the self and others) as Model 2, and the single-category model (total attachment style) as Model 3. Models 1 and 2 showed a good fit. Both path models showed a significant association between adult attachment style and perceived paternal and maternal parenting before adolescence, where high care and low overprotection from both paternal and maternal parents predicted adult attachment. Our findings indicate that attachment styles are best described using the four-category and two-category models, and suggest that both paternal and maternal overprotection and care influence adult attachment with a partner during the perinatal period.

DOI： 10.1038/s41598-023-42674-1

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Abstract

Background

Although several studies have found significant relationships between autistic traits and depression/anxiety, the relationships between autistic traits and postpartum depression/anxiety remain unclear. Moreover, few studies have examined the relationships between autistic traits and mother–infant bonding while considering depression or anxiety.

Methods

This study used a cross-sectional data analysis design. Participants were 2692 women who completed the Autism-Spectrum Quotient (AQ), Hospital Anxiety and Depression Scale (HADS), and Mother-to-Infant Bonding Scale (MIBS) at 1 month postpartum. We performed path analysis that included parity, the five AQ subscales (social skills, attention switching, attention to detail, communication, and imagination), both HADS subscales (anxiety and depression), and the two MIBS subscales (lack of affection and anger and rejection).

Results

Our path analysis revealed that higher scores for social skills, attention switching, communication, and imagination were associated with higher scores for depression. Higher scores for social skills, attention switching, attention to detail, and communication were associated with higher scores for anxiety. Moreover, difficulties in social skills and imagination were associated with failure of maternal–infant bonding. However, more attention to detail was associated with better maternal–infant bonding.

Conclusions

This study suggests that maternal autistic traits are related to anxiety and depression to a certain degree, but only slightly related to maternal–infant bonding at 1 month postpartum. To improve autistic women’s quality of life and that of their newborns, perinatal mental health issues such as anxiety, depression, and maternal–fetal bonding difficulties should be appropriately addressed.

DOI： 10.1186/s12888-023-04970-y

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Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5-12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

DOI： 10.1038/s41380-023-02096-x

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Language：Japanese   Publisher：(有)科学評論社  

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Introduction

Chronic pain remains a health problem that is difficult to treat adequately. Its unknown cause and complex comorbidity with other illnesses, including mental disorders, amplify the severity of symptoms, which consequently decreases the quality of life of patients long term. In our clinical practice, we coincidentally found evidence that methylphenidate (MPH) effectively managed chronic pain in an adult patient with attention deficit hyperactivity disorder (ADHD). The effectiveness of MPH in the treatment of ADHD is well-established; however, its utility in treating pain remains unclear.

Case presentation

We present a rare case of a 43-year-old male patient with 15 years of chronic idiopathic pain symptoms that did not adequately respond to standard pain management, such as acetaminophen, non-opioid analgesics, and muscle relaxers. Pain also persisted after treatments with antidepressants and an epidural block. Furthermore, symptoms worsened following several sessions of modified electroconvulsive therapy. After a thorough assessment at our child and adolescent psychiatric outpatient clinic, we confirmed a diagnosis of adult ADHD with a predominantly inattentive type. Considering this newly established diagnosis, we prescribed osmotic-release oral system (OROS) methylphenidate. Within 1 month of treatment at a dose of 18 mg/day of OROS-MPH, the patient’s chronic pain unexpectedly improved dramatically, and the patient no longer experienced pain symptoms. The dosage of OROS-MPH was titrated monthly, reaching 72 mg/day as a maintenance dose, and ADHD symptoms improved after 4 months of treatment. The patient was followed up regularly for 7 years during his OROS-MPH treatment. No adverse effects were reported, including stimulant addiction. He was stable overall and functioned well in his daily activities. His pain never recurred.

Conclusion

This case report suggests that MPH may be potentially effective in treating chronic pain. Further studies are needed to confirm whether MPH improved chronic pain simultaneously with or separately from the improvement in ADHD. Moreover, elucidating the anatomical sites and molecular pharmacological mechanisms related to the action of MPH in pain modulation and perception is essential. Such sites include the descending dopaminergic pain pathway and higher cortical areas. Furthering our understanding may reinforce the justification for treating chronic pain using MPH.

DOI： 10.3389/fpsyt.2023.1091399

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

DOI： 10.1038/s41598-023-28449-8

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Abstract

The parental bonding instrument (PBI) is often used to examine the perceptions of children and adolescents regarding parenting practices. Previous studies have investigated the factor structure of the PBI. However, although it is important to examine the relationships between the perceived parenting practices and perinatal mental health, few studies have included perinatal women. We aimed to accurately clarify which PBI factor structure was useful in assessing perinatal women (n = 4633). Furthermore, we evaluated the measurement invariance between primipara and multipara groups, and between the paternal and maternal PBI forms. Our exploratory and confirmatory factor analyses revealed that a three-factor PBI structure was most plausible for perinatal women. Moreover, we found complete invariance (residual invariance) of the PBI ratings across primipara and multipara women for the paternal and maternal forms. In contrast, we found weak invariance (metric invariance) of the PBI ratings across the paternal and maternal forms. Our participants tended to rate fathers as less caring and less overprotective than mothers. This three-factor structure shows measurement invariance in perinatal women and can be used to accurately determine how the perceived parenting style before adolescence influences women’s mental health in the perinatal period.

DOI： 10.1038/s41598-022-22017-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/pcn.13494

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DOI： 10.1002/pcn5.36

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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.

DOI： 10.1016/j.biopsych.2022.04.003

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Protein kinases are responsible for protein phosphorylation and are involved in important signal transduction pathways; however, a considerable number of poorly characterized kinases may be involved in neuronal development. Here, we considered cyclin G-associated kinase (GAK) as a candidate regulator of neurite outgrowth and synaptogenesis by examining the effects of the selective GAK inhibitor SGC-GAK-1. SGC-GAK-1 treatment of cultured neurons reduced neurite length and decreased synapse number and phosphorylation of neurofilament 200-kDa subunits relative to the control. In addition, the related kinase inhibitor erlotinib, which has distinct specificity and potency from SGC-GAK-1, had no effect on neurite growth, unlike SGC-GAK-1. These results suggest that GAK may be physiologically involved in normal neuronal development, and that decreased GAK function and the resultant impaired neurite outgrowth and synaptogenesis may be related to neurodevelopmental disorders.

DOI： 10.1186/s13041-022-00951-6

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DOI： 10.1002/pcn5.28

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DOI： 10.1002/pcn5.24

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s11064-022-03599-9

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

DOI： 10.1016/j.psychres.2022.114481

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DOI： 10.1111/febs.16322

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BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter. METHODS: We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain. RESULTS: SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes. CONCLUSION: These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.

DOI： 10.1371/journal.pone.0265738

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PURPOSE: There is little evidence regarding the effects of dental status on body mass index (BMI) in inpatients with schizophrenia. Thus, we performed a cross-sectional study to explore the associations between the number of remaining teeth and BMI in Japanese inpatients with schizophrenia. PATIENTS AND METHODS: We performed multiple regression analysis to assess the effects of potential predictors (age, sex, number of remaining teeth, number of antipsychotics prescribed, chlorpromazine equivalent dose, and antipsychotic type) on BMI in 212 inpatients with schizophrenia. We then compared the number of remaining teeth between inpatients with schizophrenia and the Japanese general population (3283 individuals) from the Japan Dental Diseases Survey 2016, using an analysis of covariance with age and sex as covariates. RESULTS: Multiple regression analysis showed that the number of remaining teeth and the number of antipsychotics prescribed were significantly correlated with BMI (standardized regression coefficient = 0.201 and 0.235, respectively). In the analysis of covariance, inpatients with schizophrenia had significantly fewer remaining teeth compared with the Japanese general population (mean 14.8 [standard deviation: 10.9] vs mean 23.0 [standard deviation: 8.1]). CONCLUSION: These results suggested that tooth loss and antipsychotic polypharmacy affect BMI in inpatients with schizophrenia, and that inpatients with schizophrenia lose more teeth compared with the general population.

DOI： 10.2147/NDT.S387724

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<title>Abstract</title><sec>
<title>Background</title>
Beneficial effects of napping on cognition have been suggested in cross-sectional studies. This study aimed to clarify longitudinal associations between cognitive decline and sleep characteristics, particularly daytime napping, over a 5-year period in older adults.


</sec><sec>
<title>Methods</title>
Study participants were 389 community-dwelling individuals aged ≥65 years living in Ojiya City, Niigata, Japan. Baseline and follow-up examinations were conducted in 2011–2013 and 2016–2018, respectively. Trained nurses visited and interviewed participants to collect the following information at baseline and follow-up: demographic characteristics, disease history, lifestyle habits including bedtime, sleeping hours, and daytime nap duration, and cognitive function. The assessment of cognitive function was performed using the revised Hasegawa’s dementia scale (HDS-R), with cognitive decline defined as a change in the HDS-R of ≤ − 3 over 5 years. Odds ratios (ORs) for cognitive decline were calculated using multiple logistic regression analysis.


</sec><sec>
<title>Results</title>
Mean age of participants was 74.6 years (SD 6.4), and the cumulative incidence of cognitive decline was 106/389 (27.3%). The adjusted OR for 1–29 min daytime napping was significantly lower compared to that for no napping (OR = 0.47, 95%CI: 0.23–0.96). Earlier bedtime was associated with cognitive decline (adjusted P for trend = 0.0480).


</sec><sec>
<title>Conclusion</title>
Short daytime napping (&lt; 30 min) reduces the risk of cognitive decline over 5 years for community-dwelling older people. A future study will be necessary to confirm the effect of short napping on the reduction of risk for clinically diagnosed dementia.


</sec>

DOI： 10.1186/s12877-021-02418-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

<bold>Objective</bold>: We conducted this non-randomized prospective interventional study to clarify the relationship between improved attention-deficit hyperactivity disorder (ADHD) symptoms and regional brain activity.

<bold>Methods</bold>: Thirty-one adult patients underwent near-infrared spectroscopy examinations during a go/no-go task, both before and 8 weeks after atomoxetine administration.

<bold>Results</bold>: Clinical symptoms, neuropsychological results of the go/no-go task, and bilateral lateral prefrontal activity significantly changed. A positive correlation was observed between right dorsolateral prefrontal cortex activity and Conners’ Adult ADHD Rating Scales scores. Before atomoxetine administration, no correlations between prefrontal cortex activity and clinical symptoms were observed in all cases. When participants were divided into atomoxetine-responder and non-responder groups, a positive correlation was observed between prefrontal cortex activity and clinical symptoms in the non-responder group before treatment but not in the responder group, suggesting that non-responders can activate the prefrontal cortex without atomoxetine.

<bold>Conclusions</bold>: Individuals with increased ADHD symptoms appear to recruit the right dorsolateral prefrontal cortex more strongly to perform the same task than those with fewer symptoms. In clinical settings, individuals with severe symptoms are often observed to perform more difficultly when performing the tasks which individuals with mild symptoms can perform easily. The atomoxetine-responder group was unable to properly activate the right dorsolateral prefrontal cortex when necessary, and the oral administration of atomoxetine enabled these patients to activate this region. In brain imaging studies of heterogeneous syndromes such as ADHD, the analytical strategy used in this study, involving drug-responsivity grouping, may effectively increase the signal-to-noise ratio.

DOI： 10.3389/fnhum.2021.755025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

Purpose: Identification of pregnant women with bonding difficulties is important to provide early intervention. However, few studies have examined the utility of self-report questionnaires that assess mother-infant bonding as screening tools for bonding difficulties. This longitudinal study aimed to identify pregnant women with bonding difficulties using the Japanese version of the Mother-to-Infant Bonding Scale (MIBS-J) and to estimate its optimal cutoff points in the peripartum period. Patients and Methods: A total of 1301 pregnant women completed the MIBS-J and Hospital Anxiety and Depression Scale (HADS) at three time points: first trimester (T1; approximately 12-15 weeks gestation), third trimester (T2; approximately 30-34 weeks gestation), and postpartum (T3; approximately 4 weeks postpartum). A two-step cluster analysis was conducted to classify pregnant women based on their MIBS-J subscale scores at the three time points. Based on the cluster analysis results, receiver operating characteristic curve analysis was performed to estimate the optimal cutoff scores for the MIBS-J total score at each time point. Results: The two-step cluster analysis produced two clusters: Cluster 1 (n = 824) and Cluster 2 (n = 477). Both the MIBS-J and HADS scores were significantly higher in Cluster 2 than in Cluster 1 at all time points. The MIBS-J tentative cutoff points were 3/4, 3/4, and 2/3 at T1, T2, and T3, respectively. Conclusion: We identified two distinct groups across the perinatal period: pregnant women with bonding difficulties and pregnant women with normal bonding. Our findings suggest the usefulness of the MIBS-J as a screening tool to identify bonding difficulties during pregnancy.

DOI： 10.2147/ndt.s336819

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AIM: This study aimed to detect how the perceived parenting practices before adolescence affect maternal-infant bonding in the perinatal period, considering factors such as depression, anxiety and parity. METHODS: We used the Parental Bonding Instrument (PBI) to examine the perceived parenting practices. Participants included 1301 pregnant women who completed the Hospital Anxiety and Depression Scale (HADS) and Mother-to-Infant Bonding Scale (MIBS) at three time points: early pregnancy (approximately 12-15 weeks), late pregnancy (approximately 30-34 weeks) and postpartum (4 weeks after childbirth). We performed a path analysis with factors including parity, PBI subscales (paternal care, paternal overprotection, maternal care and maternal overprotection), HADS and MIBS. RESULTS: Perceived paternal or maternal low care parenting predicted higher HADS and MIBS scores in early pregnancy. Moreover, perceived maternal low care parenting predicted higher HADS scores at postpartum and higher MIBS scores in late pregnancy. Perceived paternal or maternal overprotective parenting predicted higher HADS scores in the pregnancy period. Furthermore, perceived maternal overprotective parenting predicted higher MIBS scores in late pregnancy. Being primipara predicted higher HADS scores at postpartum and higher MIBS scores in early pregnancy and at postpartum. Being multipara predicted higher MIBS scores in late pregnancy. CONCLUSION: This study suggests that perceived negative parenting before adolescence has indirect effects (via anxiety and depression) and direct effects on maternal-infant bonding in the perinatal period. This article is protected by copyright. All rights reserved.

DOI： 10.1111/pcn.13289

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

BACKGROUND: Atomoxetine (ATX) is used as a first-line, non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD), although no studies have systematically examined the relationship between plasma concentration and clinical efficacy. We conducted this non-randomized prospective interventional study to examine the relationship between plasma concentration of ATX and clinical efficacy. METHODS: Forty-three ADHD pediatric patients received ATX, and the steady-state through plasma concentration of the last daily dose that was maintained for at least 4 weeks were determined by high-performance liquid chromatography. RESULTS: The receiver operating characteristic curve suggested that when plasma concentration exceeded 64.60 ng/mL, scores on the ADHD-Rating Scale improved by 50% or more (P = .14). Although 6 of the 8 final responders were unresponsive at the initial dose (.72 ± .04 mg/kg [mean ± standard deviation]), they responded after increasing the ATX dose to the final dose (1.52 ± .31 mg/kg). Excluding 7 outlier participants, the concentration was 83.3 ± 32.3 ng/mL in 7 responders and was significantly higher than 29.5 ± 23.9 ng/mL (P < .01) for the 29 non-responders. CONCLUSIONS: These results suggest that a minimum effective plasma concentration of ATX is required to achieve sufficient clinical efficacy. We hypothesized a mechanism that results in the realization of a clinical effect when the plasma concentration exceeds a certain threshold in the potential response group, whereas will not improve even if the plasma concentration is increased in the unqualified non-responder group.

DOI： 10.1097/md.0000000000026552

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DOI： 10.1111/pcn.13199

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It is important to clarify how the breastfeeding method affects women's mental health, and how women's mental health affects the breastfeeding method in the early postpartum period when major depression and other psychiatric problems are most likely to occur. This study aimed to examine this bidirectional relationship in the early postpartum period. Participants were 2020 postpartum women who completed the Hospital Anxiety and Depression Scale (HADS) and Mother-to-Infant Bonding Scale (MIBS). We obtained data for participants' breastfeeding method for four weeks after childbirth. We performed a path analysis with factors including breastfeeding method (exclusive breastfeeding or non-exclusive breastfeeding), parity (primipara or multipara), the two HADS subscales (anxiety and depression), and the two MIBS subscales (lack of affection and anger and rejection). The path analysis showed that breastfeeding method did not significantly affect depression, anxiety, and maternal-infant bonding in the early postpartum period. Women with higher anxiety tended to use both formula-feeding and breastfeeding. Our study suggests that exclusive breastfeeding is not associated with maternal-fetal bonding in early postpartum, considering depression, anxiety, and parity.

DOI： 10.3390/nu13041184

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Background: Growth-associated protein 43 (GAP43), a synaptic protein involved in axonal growth and synaptic plasticity, is implicated in the pathophysiology of autism spectrum disorder (ASD) and schizophrenia. To examine the role of rare GAP43 variants in the genetic etiology of ASD and schizophrenia in a Japanese population, we performed resequencing and association analysis.Methods: First, we resequenced the GAP43 coding region in 295 ASD patients, 323 schizophrenia patients and 304 controls. Second, we genotyped rs561268447 in 273 ASD patients, 1,150 schizophrenia patients and 1,022 controls. Third, we performed an association analysis of rs561268447 in 568 ASD patients, 1,473 schizophrenia patients and 10,127 controls.Results: We identified a rare putatively damaging missense variant (rs561268447) in an ASD patient via resequencing. However, we did not detect the variant in 2,445 individuals via genotyping. The variant was not significantly associated with ASD or schizophrenia in the association analysis.Conclusion: This study does not provide evidence for the contribution of rare GAP43 variants to ASD or schizophrenia susceptibility in the Japanese population.

DOI： 10.1016/j.rasd.2021.101729

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BACKGROUND: Hormones of the hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA), and hypothalamic-pituitary-somatotropic (HPS) axes are potentially involved in major depressive disorder (MDD), but these hormones have not been simultaneously investigated in male patients with MDD. We investigated the association between male MDD symptoms and estradiol, testosterone, cortisol, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF1). METHODS: Serum estradiol, testosterone, cortisol, DHEAS, and IGF1 levels were measured in 54 male patients with MDD and 37 male controls and were compared with clinical factors. We investigated the associations between hormone levels and Hamilton Depression Rating Scale (HAM-D) scores. The correlations among hormones were also investigated. RESULTS: Patients had significantly lower estradiol levels than controls (22.4 ± 8.4 pg/mL vs. 26.1 ± 8.5 pg/mL, P = 0.040). Serum estradiol levels were negatively correlated with HAM-D scores (P = 0.000094) and positively correlated with Global Assessment of Functioning scores (P = 0.000299). IGF1 levels and the cortisol:DHEAS ratio were higher in patients than in controls (IGF1: 171.5 ± 61.8 ng/mL vs. 144.1 ± 39.2 ng/mL, P = 0.011; cortisol:DHEAS ratio: 0.07 ± 0.05 vs. 0.04 ± 0.02, P = 0.001). DHEAS levels were lower in patients than in controls (227.9 ± 108.4 μg/dL vs. 307.4 ± 131.2 μg/dL, P = 0.002). IGF1, cortisol:DHEAS ratio, and DHEAS were not significantly correlated with HAM-D scores. Cortisol and testosterone levels were not significantly different between patients and controls. Serum estradiol levels were positively correlated with DHEAS levels (P = 0.00062) in patients, but were not significantly correlated with DHEAS levels in controls. CONCLUSION: Estradiol may affect the pathogenesis and severity of patients with MDD in men, and other hormones, such as those in the HPA and HPS axes, may also be involved in male MDD. Additionally, a correlation between estradiol and DHEAS may affect the pathology of MDD in men.

DOI： 10.1186/s12888-021-03116-2

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞ポイント ◆COVID-19パンデミック下で医療従事者の約25%が不安や抑うつを有している.◆専門職による心理的介入だけでなく基本的なセルフケアの確保など現場の医療従事者が求める支援の実施が重要である.◆医療従事者は偏見や差別にさらされており,これらの克服など行政的な取り組みも必要である.

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Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Clinical Neuropsychopharmacology  

DOI： 10.5234/cnpt.12.1

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Language：Japanese   Publisher：(一社)日本小児精神神経学会  

【目的】自閉スペクトラム症の視線認知における脳内基盤解明を目指し、定型発達の視線認知活動を捉えることを目的とした。【対象と方法】定型発達3名を対象として視線認知課題中の脳活動を脳磁図(MEG)で記録した。課題では、研究対象者に「手がかり刺激が示す方向に従い、左右どちらかに呈示される標的刺激へ視線を移動する」よう教示した。手がかり刺激には、側方視した両眼の写真(Gaze条件)と矢印図形(Arrow条件)の2種類を用意した。脳磁図の解析は、刺激呈示から-100〜700msの区間を、2条件それぞれ約128回加算平均した。結果をSPM12によりMSP法を用いて分布電流源推定を行った。【結果】Gaze条件では、刺激呈示後160〜200msで顔および視線の動きに特有の反応であるM170がみられた。これらの活動は紡錘状回および上側頭溝付近にみられた。【結語】Gaze条件で「視線の動き」を認知する脳活動が観察されたため、本課題により視線認知における脳内活動を検出できる可能性が示唆された。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

Purpose: The Hospital Anxiety and Depression Scale (HADS) is a self-report questionnaire widely used to assess anxiety and depression. To the best of our knowledge, only four studies have examined the factor structure of the HADS for assessing pregnant women, with conflicting results. This study aimed to assess the factor structure and measurement invariance of the HADS for use with pregnant Japanese women. Participants and Methods: A total of 936 pregnant Japanese women completed the HADS questionnaire at three time points: the first and third trimester of pregnancy, and postpartum. We examined the factor structure of the HADS in Group 1 (n = 466) using exploratory factor analysis (EFA). We then compared the models identified in Group 1 with those from previous studies using confirmatory factor analysis (CFA) in Group 2 (n = 470). We performed multiple-group CFA for Group 2 to test the measurement invariance of the best-fit model across the three time points. Results: The EFA for the Group 1 data at the three time points revealed a two-factor model. In the CFA, the two-factor model from Group 1 showed the best fit with the data at the three time points. In the multiple-group CFA for Group 2, we confirmed the configural and metric invariance of the two-factor model across the three time points. Conclusion: Our findings provide evidence for a two-factor structure and weak measurement invariance of the HADS in pregnant Japanese women during the peripartum period.

DOI： 10.2147/NDT.S294918

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Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1038/s41398-020-01107-7

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Language：English   Publishing type：Research paper (scientific journal)  

Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

DOI： 10.1038/s41439-020-00125-7

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Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1186/s11689-020-09325-2

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Language：Japanese   Publisher：(株)三輪書店  

＜文献概要＞はじめに 米国精神医学会(American Psychiatric Association:APA)は,2013年5月に精神疾患の診断分類体系であるDiagnostic and Statistical of Mental Disorders(DSM)の第5版(DSM-5)を発表した.前回の改訂版(DSM-IV,1994年)以来,19年ぶりの改定となり,数多くの改訂がみられた.ここでは自閉スペクトラム症の新設,双極性障害の独立や物質使用障害の再編等,従来の診断カテゴリーから大幅な変更が施された部分を中心に概説する.

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Language：Japanese   Publisher：(一社)日本医学教育学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00050&link_issn=&doc_id=20200708060010&doc_link_id=10.11307%2Fmededjapan.51.3_231&url=https%3A%2F%2Fdoi.org%2F10.11307%2Fmededjapan.51.3_231&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Clinical Neuropsychopharmacology  

DOI： 10.5234/cnpt.11.23

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Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Clinical Neuropsychopharmacology  

DOI： 10.5234/cnpt.11.15

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Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1097/YPG.0000000000000250

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The ability to infer others' mental states is essential to social interactions. This ability, critically evaluated by testing whether one attributes false beliefs (FBs) to others, has been considered to be uniquely hominid and to accompany the activation of a distributed brain network. We challenge the taxon specificity of this ability and identify the causal brain locus by introducing an anticipatory-looking FB paradigm combined with chemogenetic neuronal manipulation in macaque monkeys. We find spontaneous gaze bias of macaques implicitly anticipating others' FB-driven actions. Silencing of the medial prefrontal neuronal activity with inhibitory designer receptor exclusively activated by designer drugs (DREADDs) specifically eliminates the implicit gaze bias while leaving the animals' visually guided and memory-guided tracking abilities intact. Thus, neuronal activity in the medial prefrontal cortex could have a causal role in FB-attribution-like behaviors in the primate lineage, emphasizing the importance of probing the neuronal mechanisms underlying theory of mind with relevant macaque animal models.

DOI： 10.1016/j.celrep.2020.03.013

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Objective: The objective was to reveal the relationship between dose and concentration of atomoxetine. Method: Fifty-five blood samples of 33 patients with ADHD were examined using high-performance liquid chromatography. Results: The plasma concentrations were 53.2 ± 67.0, 298.0 ± 390.5, and 639.3 ± 831.9 ng/mL at doses of 40 mg, 80 mg, and 120 mg, and the concentration/dose were 1.33 ± 1.67, 3.73 ± 4.88, and 5.33 ± 6.93 ng/mL/mg, respectively. Statistical analyses revealed a significant correlation between the concentration and the dose of atomoxetine (p = .004), and a trending toward significance in the difference in the concentration/dose in the three dosage groups (p = .064). The concentration/dose at 40 and 80 + 120 mg/day were 1.33 ± 1.67 and 4.22 ± 5.53 ng/mL/mg, the latter was significantly higher than the former (p = .006), which suggested non-linear pharmacokinetics. Conclusion: Clinicians should carefully titrate in high dose atomoxetine treatment.

DOI： 10.1177/1087054716661235

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/jcp.0000000000001158

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Language：English   Publishing type：Research paper (scientific journal)  

Purpose: Postpartum depression is a well-known risk factor, and postpartum anxiety and parity are potential risk factors, for mother-infant bonding disorder. However, few studies have focused on the relationships among these factors and mother-infant bonding. This cross-sectional study explored the associations between depression, anxiety and parity, and mother-infant bonding. Materials and Methods: Japanese mothers, both primiparas and multiparas, completed the Mother-to-Infant Bonding Scale (MIBS) and the Hospital Anxiety and Depression Scale (HADS) one month after childbirth. We performed a stepwise multiple regression analysis with the forward selection method to assess the effects of HADS anxiety and depression scores and parity as independent variables on mother-infant bonding as the dependent variable. Results: A total of 2379 Japanese mothers (1116 primiparas and 1263 multiparas) took part in the study. MIBS score (2.89 ± 2.68 vs 1.60 ± 2.11; p < 0.0001) was significantly higher in primiparas than in multiparas. HADS anxiety (6.55 ± 4.06 vs 4.63 ± 3.41; p < 0.0001) and depression (6.56 ± 3.43 vs 5.98 ± 3.20; p < 0.0001) scores were also significantly higher in primiparas than in multiparas. A stepwise multiple regression analysis with the forward selection method revealed that HADS depression and anxiety scores and parity were significantly associated with MIBS score (p = 0.003, 0.015 and 0.023). Conclusion: Depression, anxiety and primiparity were negatively associated with mother-infant bonding one month after childbirth.

DOI： 10.2147/NDT.S287036

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Language：English   Publishing type：Research paper (scientific journal)  

Background: Reliable and easy screening for metabolic syndrome (MetS) is important for patients with schizophrenia. The aim of this study was to assess the predictive utility of body mass index (BMI) for MetS among patients with schizophrenia in Japan. Methods: In total, 8468 patients (4705 males, 3763 females) with schizophrenia or schizoaffective disorders based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), or the International Classification of Diseases, tenth revision (ICD-10), were assessed for MetS using the criteria of the National Cholesterol Education Program Adult Treatment Panel III (ATP III-A). We applied a stratum-specific likelihood ratio (SSLR) analysis, which is independent of the prevalence of the target disease. Results: The mean (± standard deviation) age of these patients was 57.4 ± 13.5 years. The prevalence of MetS was 20.4%. Among males, the SSLRs predicting MetS were 0.03 (95% CI 0.02-0.06), 0.54 (95% CI 0.48-0.60), 2.77 (95% CI 2.44-3.14) and 8.75 (95% CI 7.40-10.36) for BMI <20 kg/m2, 20 kg/m2 ≤ BMI < 25 kg/m2, 25 kg/m2≤ BMI < 28 kg/m2, and 28 kg/m2≤BMI, respectively. For females, the SSLRs predicting MetS were 0.08 (95% CI 0.05-0.12), 0.73 (95% CI 0.66-0.82), 2.50 (95% CI 2.16-2.90) and 4.83 (95% CI 4.12-5.67) for the same BMI categories, respectively. Conclusion: The predictive utility of BMI is confirmed, and BMI has more predictive value in males than in females. Patients with a BMI of 28 kg/m2 or greater had a significantly higher SSLR than those with a BMI less than 28 kg/m2.

DOI： 10.2147/NDT.S269619

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A large earthquake can cause extreme stress and may adversely affect cognitive function in humans. We aimed to examine a possible association between psychological distress and incident dementia after the 2004 Niigata-Chuetsu earthquake in Japan. METHODS: This is a retrospective cohort study followed participants for 10-12 years. Subjects were 6,012 residents in 2005, 5,424 in 2006, and 5,687 in 2007 (age ≥40 years) living in Ojiya city who participated in the annual health check examinations after the 2004 Niigata-Chuetsu earthquake. Psychological distress was assessed using the Kessler Psychological Distress Scale (K10), and individuals with a K10 score ≥10 were considered to have psychological distress. Incident dementia cases were identified from a long-term care insurance database of the local government during the follow-up period. We evaluated hazard ratios (HRs) of psychological distress for incident dementia in each year, unadjusted and adjusted for covariates, including sex, age, occupation, BMI, and property damage of residential area. RESULTS: The average age of the subjects was 64.6 years in 2005, 64.6 in 2006, and 65.2 in 2007. Adjusted HRs were significantly higher (HR = 1.20-1.66) in the psychological distress group than in the reference group in each year. In particular, adjusted HR was high (HR = 2.89) in those with psychological distress in all three years (2005-2007). CONCLUSION: Psychological distress, especially persistent distress, is a risk factor for incident dementia in victims of large disasters.

DOI： 10.1016/j.jad.2019.08.041

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Language：English  

DOI： 10.1111/pcn.12920

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Language：English   Publishing type：Research paper (scientific journal)  

Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 μM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 μM clozapine and 30 μM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3-30 μM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.

DOI： 10.1038/s41398-019-0519-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background Insulin-like growth factor I (IGF-I) is a neurotrophic factor produced by the hypothalamic-pituitary-somatotropic axis and is considered a potential contributor to the pathology of major depressive disorder (MDD). Although it is known that the hypothalamic-pituitary-adrenal axis and cortisol are involved in the pathology of MDD, the association with dehydroepiandrosterone sulfate (DHEAS) remains unclear. The current study sought to clarify the relationship between these hormones and the pathology of MDD. Methods Subjects were 91 Japanese patients with a diagnosis of MDD. Serum IGF-I, cortisol, and DHEAS were measured. Samples were taken before breakfast after overnight fasting. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAM-D). Results Subjects included 59 men and 32 women with an average age of 44.1 +/- 13.1 years (mean +/- SD). The blood IGF-I level was 152.0 +/- 50.0 ng/mL, the cortisol level was 10.1 +/- 4.6, and the DHEAS level was 201.3 +/- 112.7 mu g/dL. The mean HAM-D score was 13.9 +/- 9.0. Serum IGF-I levels were not correlated with cortisol. Higher IGF-I, cortisol, and cortisol/DHEAS ratios were associated with higher HAM-D scores (adjusted R-2 = 0.240, P < 0.001), and higher IGF-I and cortisol were associated with higher melancholic or suicide subscores (adjusted R-2 = 0.200, P < 0.001; adjusted R-2 = 0.273, P < 0.001). Conclusions Our findings suggest that hormonal dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-somatotropic axes may be related to the symptom severity of MDD, melancholia, and suicide-related factors.

DOI： 10.1097/JCP.0000000000001071

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

DOI： 10.1093/schbul/sby140

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Direct-acting antivirals (DAAs) result in a highly sustained virological response rate and better patient tolerance. However, this therapeutic approach may, on rare occasions, give rise to psychiatric symptoms. We describe a case requiring discontinuation of DAA and ribavirin combination therapy due to psychiatric symptoms in a patient with congenital anxious personality traits. The information summarized here will be helpful to physicians treating chronic hepatitis C virus (HCV) infection in patients with underlying psychiatric problems. CASE PRESENTATION: A 57-year-old Japanese woman diagnosed with chronic HCV infection was prescribed DAA and ribavirin combination therapy. She had a history of mild innate anxiety and development of psychiatric symptoms due to interferon (IFN) therapy 8 years prior, which subsided with discontinuation of the therapy. Similar psychiatric symptoms such as enervation, palpitations, an episode of hyperventilation, and consciousness disturbances with myotonia were observed after the administration of the antiviral agents. No abnormal findings related to her symptoms were observed on laboratory or imaging results. Psychiatrists diagnosed the patient as having a somatization disorder induced by the antiviral agents on the basis of innate anxiety. After the discontinuation of therapy, her symptoms gradually improved. CONCLUSIONS: Although DAAs were not causative factors for psychiatric symptoms in phase 3 studies, a post-marketing study reported psychiatric symptoms such as depression in patients with underlying psychiatric problems. Our case suggests psychiatric symptoms might worsen after DAA and ribavirin administration in patients with underlying psychiatric disorders, and therefore, close monitoring is necessary for these patients, especially if they have a history of psychiatric symptoms after IFN.

DOI： 10.1186/s12876-019-1013-1

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Language：Japanese   Publisher：(公社)日本精神神経学会  

【背景】認知機能障害は統合失調症における最も重要な症状と考えられ,認知機能検査は患者の病態や予後を把握するため欠かせない検査であると考えられている.しかし,同検査の結果は,統合失調症の病態だけでなく,年齢や性別,罹病期間,抗精神病薬服薬量などの対象のもつさまざまな臨床的特徴に影響されていることが海外での先行研究で報告されているが,日本での研究はいまだ少ない.そこで本研究では,日本人統合失調症患者を対象に臨床的特徴が認知機能検査の結果に与える影響を検討した.【方法】2010年10月から2015年3月の間で新潟大学医歯学総合病院精神科に入院した統合失調症患者111名(男性41名,女性70名)のカルテから統合失調症認知機能簡易評価尺度日本語版(BACS日本語版)の各下位検査粗点と粗点合計およびcomposite scoreを調査する.同様に,対象者の年齢,性別,発症年齢,罹病期間,教育年数,抗精神病薬服薬量,抗コリン薬およびベンゾジアゼピン(BZD)系薬服薬の有無,簡易精神症状評価尺度(BPRS)得点の調査を行い,それらの関連性を検討するために重回帰分析を行った.なお,本研究は新潟大学医学部倫理委員会の承認を得ている.【結果】言語性記憶に罹病期間(R2=0.066, P=0.004)が,作動記憶に男性,教育年数,罹病期間(R2=0.178, P=2.49E-5)が,運動機能にBPRS得点と教育年数(R2=0.088, P=0.003)が,注意と情報処理速度にBZD系薬服薬,教育年数,年齢(R2=0.161, P=7.01E-5)が,遂行機能に男性,教育年数,年齢(R2=0.209, P=3.37E-6)が,粗点合計に教育年数,年齢,BZD系薬服薬(R2=0.183, P=1.80E-5)がそれぞれ寄与する要因として挙げられた.【結語】本研究はいまだ報告がない比較的急性期で入院中の日本人統合失調症患者を対象とし,BACS日本語版を用いた研究である.本研究の結果から,こうした一群においても日本人統合失調症患者の認知機能にはさまざまな臨床的特徴が影響していることが明らかとなった.(著者抄録)

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Language：Japanese   Publisher：全国精神科栄養士協議会  

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Other Link： http://search.jamas.or.jp/link/ui/2019259873

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: Whole-exome sequencing (WES) of multiplex families is a promising strategy for identifying causative variations for common diseases. To identify rare recessive risk variations for schizophrenia, we performed a WES study in a consanguineous family with affected siblings. We then performed follow-up sequencing of SPATA7 in schizophrenia-affected families. In addition, we performed a case-control study to investigate association between SPATA7 variations and schizophrenia. Patients and methods: WES was performed on two affected siblings and their unaffected parents, who were second cousins, of a multiplex schizophrenia family. Subsequently, we sequenced the coding region of SPATA7, a potential risk gene identified by the WES analysis, in 142 affected offspring from 137 families for whom parental DNA samples were available. We further tested rare recessive SPATA7 variations, identified by WES and sequencing, for associations with schizophrenia in 2,756 patients and 2,646 controls. Results: Our WES analysis identified rare compound heterozygous missense SPATA7 variations, p.Asp134Gly and p.Ile332Thr, in both affected siblings. Sequencing SPATA7 coding regions from 137 families identified no rare recessive variations in affected offspring. In the case-control study, we did not detect the rare compound heterozygous SPATA7 missense variations in patients or controls. Conclusion: Our data does not support the role of the rare compound heterozygous SPATA7 missense variations p.Asp134Gly and p.Ile332Thr in conferring a substantial risk of schizophrenia.

DOI： 10.2147/NDT.S218773

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Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1016/j.psychres.2018.10.062

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Language：Japanese   Publisher：(公社)日本精神神経学会  

抗精神病薬による薬物療法の進歩は,統合失調症患者の症状改善や社会復帰に多大な恩恵をもたらした.一方,一般人口と比較すると統合失調症患者の平均寿命は10年以上短いことが知られるようになり,肥満や糖脂質代謝異常といった,不規則な生活習慣や抗精神病薬の副作用によって生じる身体リスクが注目されるようになった.現在,わが国では精神科医療の地域移行を推進しているが,健康意識や健康管理が不十分なままでの「退院促進・地域移行」では,統合失調症患者の身体リスクがさらに高まり,寿命や健康寿命は短縮していく可能性が懸念される.このような背景から,日本精神科病院協会と日本臨床精神神経薬理学会は「抗精神病薬治療と身体リスクに関する合同プロジェクト」を立ち上げ,わが国の抗精神病薬治療に関連する身体リスクの実態調査と啓発活動に乗り出した.本稿では,同プロジェクトから得た知見を紹介し,若干の提言を述べたい.(著者抄録)

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞はじめに 本稿では,操作的診断(DSM-III)が登場した背景を振り返り,DSMの基本思想を再確認することで,診断基準に対する誤った直解主義を正す。さらに診断概念の多面性を整理した上で,今後の診断学の発展過程について考察する。

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DOI： 10.1111/eip.12472

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Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1016/j.celrep.2018.08.022

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Language：Japanese   Publisher：医歯薬出版(株)  

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

DOI： 10.1016/j.jpsychires.2018.05.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

BACKGROUND: Patients with schizophrenia have an increased prevalence of metabolic disturbances compared with the general population. However, the mechanisms underlying the metabolic side effects of antipsychotics are unknown. The aim of the present study was to compare the levels of high-density lipoprotein (HDL)-cholesterol in Japanese schizophrenia patients medicated with olanzapine, risperidone, or aripiprazole monotherapy. METHODS: This study was a post-hoc analysis of a nationwide survey, which included 433 Japanese outpatients with schizophrenia and 674 inpatients. A brief questionnaire was compiled that covered demographic data, systolic blood pressure, diastolic blood pressure, and HDL-cholesterol after reviewing the relevant literature and guidelines. To compare demographic and clinical characteristics, analysis of variance was performed for continuous variables and the chi-square test was performed for categorical variables. For comparisons of HDL-cholesterol levels among the three antipsychotic groups, analysis of covariance was carried out with age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference as confounding variables after stratification by body mass index (BMI) for each outpatient group and inpatient group. RESULTS: The mean age was 57.9 ± 14.0 years and the mean BMI was 23.4 ± 4.5 kg/m2. HDL-cholesterol levels when stratified by BMI differed significantly (p = 0.019) between the three antipsychotic groups after age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference in inpatients. A significant difference in HDL-cholesterol levels was only found in the overweight inpatient group, and no significant differences in HDL-cholesterol levels were found among the three antipsychotics for outpatients of all BMI stratifications or inpatients that were underweight or of normal weight. For post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group (p = 0.023). CONCLUSIONS: This study reveals a difference in HDL-cholesterol levels in overweight Japanese inpatients with schizophrenia resulting from the use of different antipsychotics. In the post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group. Further studies incorporating more detailed evaluations, including diet and physical activity, are needed to clarify the differences in HDL-cholesterol according to antipsychotic use.

DOI： 10.1186/s12888-018-1764-1

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AIMS: Although the relationship between body mass index and all-cause mortality is U-shaped, underweight has received comparatively less attention than obesity. There is only limited evidence to date regarding underweight among patients with schizophrenia. This is the first meta-analysis to address the prevalence of underweight in these patients. METHODS: We conducted database searches (PubMed, PsycINFO) to identify studies examining underweight in patients with schizophrenia. In total, 17 studies (18 groups) with 45,474 patients were included; data were extracted independently by two authors. A meta-analysis was performed to calculate the pooled prevalence of underweight in patients. RESULTS: The pooled prevalence of underweight was 6.2% (95% CI=4.5-8.6) for the 18 groups, which included 45,474 patients with schizophrenia. The heterogeneity was I2=98.9% (95% Cl=98.7-99.1%). Four studies with 4 groups, consisting of 30,014 individuals, focused on Japanese inpatients with schizophrenia. The pooled prevalence of underweight among inpatients in these 4 groups was 17.6% (95% CI=15.5-20.0). Fourteen studies were conducted with non-Japanese inpatients and included 14 groups of 15,460 patients with schizophrenia. The pooled prevalence of underweight in non-Japanese inpatients was 4.6% (95% CI=3.9-5.4). The proportion of underweight in the 18 groups significantly varied between Japanese inpatients and other patients. CONCLUSIONS: The results indicated that Japanese inpatients with schizophrenia have a high proportion of underweight. Future research should focus on evaluating interventions that target underweight.

DOI： 10.1016/j.schres.2017.10.017

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Language：Japanese   Publisher：(公社)日本精神科病院協会  

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Other Link： http://search.jamas.or.jp/link/ui/2019021846

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Numerous studies have suggested that an immune system imbalance plays an important role in schizophrenia. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine. It plays multiple roles in various biological processes, including inflammation and neurogenesis. Furthermore, several exhaustive serum proteomic profiling studies have identified MIF as a potential biomarker of schizophrenia. Here, we investigate MIF protein levels in serum and postmortem prefrontal cortex in patients with schizophrenia and controls. Moreover, we investigate the association of two functional polymorphisms in the MIF gene promoter region (MIF-794CATT5-8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) with schizophrenia. METHODS: We measured serum MIF levels with an enzyme-linked immunosorbent assay (ELISA) (51 patients vs. 86 controls) and postmortem brain MIF levels with a western blotting assay (18 patients vs. 22 controls). Subsequently, we genotyped the MIF-794CATT5-8 microsatellite with a fluorescence-based fragment assay and the MIF-173G/C SNP with a TaqMan SNP genotyping assay (1483 patients vs. 1454 controls). RESULTS: Serum MIF levels were significantly higher in patients with schizophrenia than in controls (p=0.00118), and were positively correlated with antipsychotic dose (Spearman's r=0.222, p=0.0402). In addition, an earlier age of onset was observed in patients with a high serum MIF level (≥40ng/mL) than those with a low serum MIF level (<40ng/mL) (p=0.0392). However, postmortem brain MIF levels did not differ between patients with schizophrenia and controls. The association study revealed that the CATT6-G haplotype was nominally significantly associated with schizophrenia (p=0.0338), and that the CATT6 allele and CATT6-G haplotype were significantly associated with female adolescent-onset schizophrenia (AsOS) (corrected p=0.0222 and p=0.0147, respectively). CONCLUSIONS: These results suggest that serum MIF level is a potential pharmacodynamic and/or monitoring marker of schizophrenia, and is related to a novel antipsychotic effect beyond dopamine antagonism. Furthermore, the MIF gene polymorphisms are associated with the risk for schizophrenia especially in adolescent females, and are potential stratification markers of schizophrenia. Further studies of MIF are warranted to elucidate the pathophysiology of schizophrenia and the effects of antipsychotics.

DOI： 10.1016/j.pnpbp.2018.01.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10 '9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (P best =5.8 × 10 '10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (P best =1.9 × 10 '9), TRANK1 (P best =2.1 × 10 '9) and ODZ4 (P best =3.3 × 10 '9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', P best ∼10 '29, R 2 ∼2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' P best ∼10 '13, R 2 ∼0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates∼0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.

DOI： 10.1038/mp.2016.259

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

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

DOI： 10.1016/j.jpsychires.2017.12.002

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

DOI： 10.1038/s41398-017-0061-y

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Language：English   Publishing type：Part of collection (book)   Publisher：Elsevier  

Significant variabilities exist in psychotropic disposition and response. Numerous polymorphisms in the genes coding for specific cytochrome P450 metabolizing enzymes and the ABCB1 transporter residing at the blood-brain barrier have been studied for their possible roles in individualized psychotropic drug therapy. Although molecular diagnostics are available for CYP2D6 and CYP2C19 genotyping, current data provide evidence for their use primarily in predicting adverse drug effects and possibly increasing compliance in subsets of populations. The involvement of the serotonergic system, especially the 5-HT2C receptor, provides convincing evidence of a genetic basis in predicting antipsychotic-induced weight gain. On the other hand, prediction of psychotropic drug effects based on polymorphisms in multiple-drug targets within the brain is limited by methodological and clinical problems, especially with the candidate-gene approach. Nevertheless, the lack of novel new drugs in psychiatry underscores the importance of refining current molecular approaches to provide insights into etiologies of mental disorders and their treatment.

DOI： 10.1016/B978-0-12-812626-4.00007-3

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It has long been known that antipsychotic drugs (ATP) causes tachycardia, however details such as the differences between ATP are not well known. In recent years, the relationship between the rise in resting heart rate (RHR) and the increased risk of death in the general population has been garnering attention. In this study, we examined the difference in action on RHR between olanzapine (OLZ) and aripiprazole (ARP). The changes in the RHR on switching from OLZ to ARP and on increasing from the starting OLZ dose to the final one were evaluated in 19 outpatients (Study 1) and in 29 outpatients with schizophrenia (Study 2), respectively. To analyze the RHR, electrocardiographic measurements were obtained. At the same day, the Brief Psychiatric Rating Scale (BPRS) was evaluated, and fasting blood samples were drawn after an overnight fast of at least 8 h to examine electrolytes. Both Study 1 and 2 were conducted with the approval of the Gene Ethics Committee of Niigata University Graduate School of Medical and Dental Sciences, and the patients were treated at the outpatient psychiatric clinic at Niigata University Medical and Dental Hospital. All patients had been diagnosed with schizophrenia based on the DSM-IV-TR. In the Study 1, OLZ of 14.6 ± 9.2mg (mean ± standard deviation) was switched to ARP of 20.8 ± 8.1mg. Significant decreases were observed in the mean RHR after the switch to ARP (73.7 ± 9.7 vs 65.8 ± 10.9 beats/min, p = 0.008). In the Study 2, the starting OLZ dose was 7.2 ± 3.2mg and the increasing OLZ dose was 18.3 ± 7.4mg. Significant increases were observed in the mean RHR after increasing OLZ (69.7 ± 14.0 vs 75.6 ± 14.3 beats/min, p = 0.004). In this study, it was shown that OLZ has a stronger RHR enhancing effect compared to ARP and its effects are dose-dependent. If the increase in RHR increases the mortality rate of patients with schizophrenia, it may be necessary to further investigate the differences between ATP in terms of the effect on RHR of second-generation antipsychotics with a strong anticholinergic action or phenothiazine antipsychotics.

DOI： 10.1371/journal.pone.0199922

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Language：English   Publisher：WILEY  

DOI： 10.1111/pcn.12564

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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

DOI： 10.1111/pcn.12564

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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

DOI： 10.1111/pcn.12526

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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

DOI： 10.1097/JCP.0000000000000724

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Language：Japanese   Publisher：(株)星和書店  

精神疾患に不眠は高頻度で認められ、その不眠が、精神疾患の再発・再燃のリスク因子になることや、直接、社会機能や認知機能の低下に関係することも知られている。また、身体的にも様々な影響があるとされ、とくにメタボリックシンドロームのリスクになることも報告されている。したがって、精神疾患に伴う不眠に適切に対応することが求められている。そのための精神科薬物治療の向上には、睡眠に関する研究のさらなる蓄積が必要である。実際の臨床では、(1)精神疾患そのものと関連する睡眠変化、(2)治療に用いられる向精神薬と関連する睡眠変化、この両者が複雑に絡み合った状態を観察していることになる。よって臨床研究においても、睡眠評価法として確立されている終夜睡眠ポリグラフィの利用に加え、診断、症状・副作用評価、用法・用量の設定、薬物血中濃度、併用薬など臨床精神薬理学の視点に立ったデータ収集と解析が重要である。(著者抄録)

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/mp.2016.88

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation.
Methods: Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas.
Results: In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients.
Implications: Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

DOI： 10.1097/JCP.0000000000000630

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Language：Japanese   Publisher：(公社)日本精神神経学会  

自閉スペクトラム症の多発罹患家系において,稀な変異が発症に重要な役割を果たすことが示唆されている.自閉スペクトラム症の稀なリスク変異を同定するため,われわれは4人の罹患者(同胞2人,母方いとこ2人)を有する多発罹患家系の全エクソームシークエンスおよび症例・対照サンプル(243対667)を用いたフォローアップ研究を実施した.多発罹患家系の4人(発端者,罹患同胞,非罹患同胞,保因者と推定される母)について全エクソームシークエンスを行ったところ,2つの稀な短縮型変異(RPS24遺伝子Q191X変異とCD300LF遺伝子P261fsX266変異)を同定した.これらの変異は,フォローアップ研究の910サンプルでは検出されなかった.本研究により,2つの稀な短縮型変異(RPS24遺伝子Q191X変異とCD300LF遺伝子P261fsX266変異)が自閉スペクトラム症の候補リスク変異であることが示唆された.(著者抄録)

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DOI： 10.1038/tp.2017.173

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background
Patients with schizophrenia have significantly shorter life expectancy than the general population, and a problem they commonly face is an unhealthy lifestyle, which can lead to obesity and metabolic syndrome. There is a very clear need to determine the prevalence of obesity, hypertension, hyperlipidemia, and diabetes mellitus which are components of metabolic syndrome in patients with schizophrenia, but there has been a paucity of large-scale studies examining this situation in Japan. The aim of our study was to address this need.
Setting & Participants
We conducted a large-scale investigation of the prevalence of obesity, hypertension, hyperlipidemia, and diabetes mellitus using a questionnaire in 520 outpatient facilities and 247 inpatient facilities of the Japan Psychiatric Hospitals Association between January 2012 and July 2013. There were 7,655 outpatients and 15,461 inpatients with schizophrenia.
Results
The outpatients had significantly higher prevalence of obesity, hypertension, hypertriglyceridemia, hyper-LDL cholesterolemia, and diabetes mellitus than the inpatients. The prevalence of hypo-HDL cholesterolemia was higher in inpatients than outpatients. Age-specific analysis showed the prevalence of obesity, hypertension, hypertriglyceridemia, hyper-LDL cholesterolemia, and diabetes mellitus among outpatients to be 2- to 3-fold higher than among inpatients. In individuals aged &gt;= 60 years, the prevalence of obesity and DM among outpatients was about 3-fold higher than among inpatients.
Conclusion
Japanese outpatients with schizophrenia were more likely to have physical risk such as obesity, hypertension, hyperlipidemia, and diabetes mellitus than inpatients. The physical risk to patients with schizophrenia may be affected by environmental parameters, such as type of care. The physical risk to Japanese patients with schizophrenia demands greater attention.

DOI： 10.1371/journal.pone.0166429

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

This study aimed to examine rural-urban differences in the prevalence of cognitive impairment in Japan.
We targeted 592 residents aged 65 years and older who did not use long-term care insurance services in one rural and two urban areas in Ojiya City, Japan. Of these, 537 (90.7 %) participated in the study. The revised Hasegawa's dementia scale (HDS-R) was used to assess cognitive function, and cognitive impairment was defined as a HDS-R score aecurrency sign20. Lifestyle information was obtained through interviews. The prevalence of cognitive impairment was compared according to the levels of predictor variables by odds ratios (ORs) calculated by a logistic regression analysis.
Mean age of participants was 75.7 years (SD 7.0). The prevalence of cognitive impairment was 20/239 (8.4 %) in the rural area and 6/298 (2.0 %) in the urban areas, for a total of 26/537 (4.8 %) overall. Men tended to have a higher prevalence of cognitive impairment (P = 0.0628), and age was associated with cognitive impairment (P for trend &lt; 0.0001). The rural area had a significantly higher prevalence of cognitive impairment (age- and sex-adjusted OR = 4.04, 95 % CI: 1.54-10.62) than urban areas. This difference was significant after adjusting for other lifestyle factors.
The prevalence of cognitive impairment was higher in the rural area relative to urban areas in Ojiya city. This regional difference suggests the existence of potentially modifiable factors other than lifestyle in relation to cognitive impairment.

DOI： 10.1007/s12199-016-0542-2

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Language：Japanese   Publisher：(株)南山堂  

＜Key Points＞抗精神病薬は致死的な不整脈(特にQT延長)を引き起こす可能性がある。QT間隔は薬剤以外にも、電解質異常、各種心疾患、遺伝子変異などのさまざまな因子が相加的・相乗的に影響しあうため、事前の予測が困難であり、心電図モニタリングが重要である。QTc間隔が500msecを超えた症例については、原因薬剤を中止し、循環器内科へ相談すべきである。これまで軽視されてきた第I度房室ブロックも放置すると生命予後に影響することがわかってきたため、QT以外の不整脈にも注意が必要である。(著者抄録)

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

DOI： 10.1038/srep33311

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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

DOI： 10.1002/ajmg.b.32444

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Language：Japanese   Publisher：(株)星和書店  

統合失調症の薬物療法では、最大限の効果と最小限の副作用を目指し、用量を設定することが重要である。しかし、臨床場面では有効性や安全性を考慮した至適用量の設定は難しいことが多い。また非定型抗精神病薬では副作用も薬剤ごとに特性が異なるためさらに至適用量の設定が困難になる。一方、抗精神病薬ではある程度の高用量で効果が頭打ちになることが知られており、用量と有効性の関係を考える上では、用量反応関係についての情報が役立つかもしれない。本稿では、用量反応性を踏まえ、主に非定型抗精神病薬に関しての用量と有効性に関して、初発エピソード、急性期におけるこれまでの知見や、難治性や治療抵抗性を対象とした高用量での検討について紹介し、安全性については副作用ごとに用量の調整について概説する。(著者抄録)

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Language：Japanese   Publisher：(株)星和書店  

「急性精神病」という診断は、精神科急性期医療においてよく用いられるもので、急性発症した精神病症状に対して暫定的に与えられる。精神病症状が短期で寛解に至ったものは、ICD-10では急性一過性精神病性障害、DSM-IV-TRでは短期精神病性障害に該当するが、寛解の判断が治療や予後に影響を与えるため、慎重な評価が必要となる。寛解の判断には、幻覚、妄想、解体などの精神病症状の評価だけではなく、認知機能や社会的機能が病前のレベルまで改善したかまで評価することも重要である。今回、我々は妄想、錯乱、情動不安定性を呈し、抗精神病薬による治療で1ヵ月以内に精神病症状は消失したものの、single photon emission computed tomographyでは脳血流異常が認められ、認知機能検査で認知機能低下が示唆され、約7ヵ月後に精神病症状を再発した症例を経験した。急性精神病の診断および治療における認知機能検査や脳機能画像の意味について考察を加えてここに報告する。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

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

DOI： 10.1016/j.schres.2016.01.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Progressive supranuclear palsy (PSP) is a four-repeat tauopathy with tau-positive, argyrophilic tuft-shaped astrocytes (TAs). We performed a pathological and clinical investigation in 40 consecutive autopsied Japanese patients with pathological diagnoses of PSP or PSP-like disease. Unequivocal TAs were present in 22 cases, all of which were confirmed to be PSP. Such TAs were hardly detected in the other 18 cases, which instead exhibited tau-positive, argyrophilic astrocytes, appearing as comparatively small clusters with central nuclei of irregularly shaped, coarse structures (equivocal TAs). Cluster analysis of the distribution pattern of tau-related pathology for these 18 cases identified two subgroups, pallido-nigro-luysian atrophy (PNLA) Type 1 (n=9) and Type 2 (n=9), the former being distinguished from the latter by the presence of tau-related lesions in the motor cortex, pontine nucleus and cerebellar dentate nucleus in addition to the severely affected PNL system. The duration from symptom onset until becoming wheelchair-bound was significantly longer in PNLAType 1. Immunoblotting of samples from the three disease conditions revealed band patterns of low-molecular-mass tau fragments at approximate to 35kDa. These findings shed further light on the wide pathological and clinical spectrum of four-repeat tauopathy, representing PSP in the broad sense rather than classical PSP.

DOI： 10.1111/bpa.12265

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Background
Olanzapine (OLZ) treatment is associated with a high risk of weight gain, and may cause abnormalities in glycolipid metabolism. Therefore, the underlying mechanism of OLZ-related weight gain is needed to clarify but not yet been adequately determined. In recent years, adipocytokines such as leptin, adiponectin, and tumor necrosis factor (TNF)-alpha, which play important roles in energy homeostasis, have been suggested as biomarkers of weight gain. Here, we determined if baseline plasma concentrations of leptin, adiponectin, and TNF-alpha predict weight gain following OLZ treatment.
Methods
We recruited 31 schizophrenia outpatients (12 men and 19 women, 28.8 +/- 10.2 years old) that were unmedicated or on another antipsychotic monotherapy medication. Baseline body mass index (BMI) and plasma levels of leptin, adiponectin, and TNF-alpha were obtained. All patients started or were switched to OLZ monotherapy for a maximum of 1 year. BMI was also obtained at the endpoint.
Results
Mean BMI change following OLZ treatment was 2.1 +/- 2.7 kg/m(2). BMI change from baseline to endpoint negatively-correlated with baseline leptin levels in female patients (r = 0.514, P = 0.024), but not male patients. Baseline adiponectin or TNF-alpha levels were not correlated with BMI change.
Conclusion
Baseline plasma leptin can have an effect on subsequent weight gain following OLZ treatment in female patients with schizophrenia.

DOI： 10.1371/journal.pone.0149518

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Dove Medical Press Ltd.  

Background: Metabolic syndrome is a growing concern among patients with schizophrenia because metabolic abnormalities are widely regarded as a major risk factor for cardiovascular disease and premature death. The current study assessed attitudes toward metabolic adverse events among patients with schizophrenia. Methods: A brief questionnaire was constructed to investigate patient recognition of the following broad areas: dietary habits, lifestyle, self-monitoring, knowledge, and medical practice. Between January 2012 and June 2013, questionnaires were sent to patients associated with 520 outpatient facilities and 247 inpatient facilities belonging to the Japan Psychiatric Hospital Association. All of the participants (n=22,072
inpatients =15,170, outpatients =6,902) were diagnosed with schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, or the International Classification of Diseases, tenth revision. Results: Approximately 55.0% (8,069/14,669) of inpatients and 44.8% of outpatients (2,978/6,649) reported that they did not exercise at all. Although 60.9% (4,116/6,760) of outpatients reported that they felt obese, only 35.6% (5,261/14,794) of inpatients felt obese. More than half of the inpatients (51.2%
7,514/14,690) and outpatients (60.8%
4,086/6,721) hoped to receive regular blood tests to prevent weight gain and diseases such as diabetes. Conclusion: Although more than half of patients hoped to prevent weight gain and diabetes, only a minority of patients were mindful of eating balanced meals and having physical exercise. Educational efforts and the promotion of the best pharmacotherapy and monitoring practices are needed for patients with schizophrenia.

DOI： 10.2147/NDT.S98711

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

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

DOI： 10.1016/j.psychres.2015.12.011

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Rare variations contribute substantially to autism spectrum disorder (ASD) liability. We recently performed whole-exome sequencing in two families with affected siblings and then carried out a follow-up study and identified ceroid-lipofuscinosis neuronal 8 (epilepsy, progressive with mental retardation) (CLN8) as a potential genetic risk factor for ASD. To further investigate the role of CLN8 in the genetic etiology of ASD, we performed resequencing and association analysis of CLN8 with ASD in a Japanese population. Resequencing the CLN8 coding region in 256 ASD patients identified five rare missense variations: g.1719291G&gt;A (R24H), rs201670636 (F39L), rs116605307 (R97H), rs143701028 (T108M) and rs138581191 (N152S). These variations were genotyped in 568 patients (including the resequenced 256 patients) and 1017 controls. However, no significant association between these variations and ASD was identified. This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population.

DOI： 10.1371/journal.pone.0144624

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Language：Japanese   Publisher：(公財)パブリックヘルスリサーチセンター  

DOI： 10.5058/stresskagakukenkyu.30.10

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Kokuseido Publishing Co. Ltd  

A patient with medication resistant schizophrenia underwent modified electroconvulsive therapy (12 sessions). Propofol was chosen as a hypnotic agent and the adjustment of its dose and stimulus intensity was attempted. However, despite using propofol of a dose minimally required for hypnosis, adequate seizures could not be induced even with the maximum stimulation. Assuming that propofol was preventing the induction of seizures, it was decided to reduce its dose and at the same time to combine it with remifentanil 100 μg starting from the fifth session. This allowed to reach the seizure adequacy during the next and the four subsequent sessions. Although from the tenth session on, adequate seizures could no longer be induced (possibly due to the development of resistance to propofol), the patient's symptoms showed improvement after completion of all 12 sessions.

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Language：Japanese   Publisher：(株)日本医事新報社  

＜point＞▼統合失調症患者は心血管疾患による死亡率が一般人口の約2倍であり、背景にはメタボリック症候群(MetS)の高い有病率があると思われる▼向精神薬の中でも、特に抗精神病薬はMetSの発症に少なからず関与している▼抗精神病薬の中でも、第2世代抗精神病薬、特にクロザピンやオランザピンにおいて体重増加、糖脂質代謝異常のリスクが高い▼向精神薬による治療を行う場合、定期的なモニタリング(バイタルサイン測定、体重測定、血液検査、心電図)は必須である(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background This study aimed to assess psychological distress (PD) in earthquake-stricken communities with regard to the extent of property damage for 3 years following the 2004 Niigata-Chuetsu earthquake in Japan.
Methods Subjects were participants of health check examinations in a community near the epicentre, and included 7097 residents (a parts per thousand yen18 years) in 2005, 6586 in 2006 and 6698 in 2007. Interviews assessed PD symptoms and lifestyles. The Kessler Psychological Distress Scale (K10) was used, with scores a parts per thousand yen20 considered as PD. The 137 subdistricts were divided into quartiles according to the proportion of half-completely destroyed houses at cut-offs of 18.9, 30.5 and 66.7%.
Results The PD prevalence was 17.0% in 2005, 13.2% in 2006 and 11.8% in 2007. In 2005, the more and most heavily damaged groups had significantly higher PD prevalence (OR = 1.5 and 1.4, respectively) than that of the least damaged group with a dose-dependent relationship (P = 0.0005). This association was weaker in 2006 (P = 0.0413) and in 2007 (P = 0.1816).
Conclusions Psychological distress prevalence was high in highly damaged areas, and the prevalence difference between areas with high versus low damage decreases with time. Extensive mental health care in communities with substantial damage should be expected to last 2 years after an earthquake.

DOI： 10.1093/pubmed/fdu052

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DOI： 10.1016/j.psychres.2015.07.016

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Two truncating variations (WDR90 V1125fs and EFCAB5 L1210fs), identified by whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder (ASD), were not detected in 257 ASD patients, 677 schizophrenia patients or 667 controls in a follow-up study. Thus, these variations were exclusively identified in the family, suggesting that rare truncating variations may have a role in the genetic etiology of ASD, at least in a subset of ASD patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2015.07.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

AimsRare heterozygous truncating variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare heterozygous truncating variations, we performed whole-exome sequencing (WES) in a multiplex ASD family with four affected individuals (two siblings and two maternal cousins), and a follow-up case-control study in a Japanese population.
MethodsWES was performed in four individuals (a proband, his affected and unaffected siblings, and their putative carrier mother) from the multiplex ASD family. Rare heterozygous truncating variations prioritized in WES were genotyped in 243 patients and 667 controls.
ResultsBy WES of the multiplex family, we prioritized two rare heterozygous truncating variations, RPS24Q191X and CD300LFP261fsX266. However, we did not identify these variations in patients or controls in the follow-up study.
ConclusionsOur findings suggest that two rare heterozygous truncating variations (RPS24Q191X and CD300LFP261fsX266) are risk candidates for ASD.

DOI： 10.1111/pcn.12274

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

DOI： 10.1016/j.genhosppsych.2015.03.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

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.

DOI： 10.1186/s13039-015-0144-5

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Language：Japanese   Publisher：(株)先端医学社  

統合失調症患者の平均余命は、一般人口にくらべて12〜15年短いと報告されている。統合失調症患者の自然死による死亡率は一般人口の約2倍であり、なかでも心血管疾患による死亡率が高く、男性で一般人口の2.3倍、女性では2.1倍にのぼる。また、統合失調症患者は一般人口にくらべてメタボリック症候群(MetS)の有病率が高いことが知られており、このことが統合失調症患者で心血管疾患による死亡率が高い原因の一つになっているものと思われる。統合失調症治療が薬物療法の発展とともに近年大きな進歩を遂げたことは事実であるが、このような背景を踏まえたうえで、今後は統合失調症患者の身体的なリスクにもより一層配慮した治療選択が望まれる。本稿では統合失調症患者におけるMetSの有病率、関連因子、原因、薬物療法におけるリスク、管理などにつき、当施設での研究を交えながら最近の知見を振り返る。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J03591&link_issn=&doc_id=20150730360002&doc_link_id=%2Fae6mopsb%2F2015%2F001503%2F003%2F0176-0182%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae6mopsb%2F2015%2F001503%2F003%2F0176-0182%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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DOI： 10.1002/ajmg.b.32303

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DOI： 10.1111/pcn.12233

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Objective: Recent studies suggest that the severity and drug response of depression and anxiety are correlated with childhood abuse. However, whether a history of child abuse can predict the severity and/or drug response of attention-deficit/hyperactivity disorder (ADHD) is unclear. Therefore, we conducted a retrospective study to assess the efficacy of atomoxetine in children with a history of child abuse.
Methods: We reviewed 41 cases of children treated with atomoxetine. Specifically, we compared dissociation associating symptoms (DAS) and other symptoms (OS) measured via the ADHD Rating Scale (ADHD-RS) in abused and nonabused children at baseline and at 8 weeks after atomoxetine administration.
Results: At baseline, abused children had higher total scores (38.7 +/- 9.3 vs. 30.5 +/- 9.4, p=0.011), and greater levels of hyperactivity/impulsivity (17.3 +/- 5.8 vs. 11.3 +/- 6.0, p=0.004) on the ADHD-RS than did nonabused children, whereas the inattention scores were similar between the two groups (21.4 +/- 4.8 vs. 19.2 +/- 4.6). Additionally, the total score and the two subscores decreased at week 8 for both groups. In the nonabused group, DAS (5.5 +/- 2.3 vs. 3.9 +/- 1.7, p&lt;0.001) and OS (25.0 +/- 8.1 vs. 17.4 +/- 6.7, p&lt;0.001) significantly decreased after atomoxetine treatment. However, DAS in the abused group did not change after atomoxetine treatment (5.9 +/- 2.3 vs. 5.1 +/- 1.8), whereas OS significantly decreased (32.8 +/- 7.6 vs. 25.7 +/- 7.2, p=0.002).
Conclusions: If DAS were caused by traumatic experiences in abused children, trauma treatment tools other than pharmacotherapy might be useful to treat DAS. These tools may include eye movement desensitization and reprocessing and trauma-focused cognitive behavioral therapy.

DOI： 10.1089/cap.2014.0119

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DOI： 10.1111/pcn.12236

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

AimsThe oxytocin receptor (OXTR) is implicated in the pathophysiology of autism spectrum disorder (ASD). A recent study found a rare non-synonymous OXTR gene variation, rs35062132 (R376G), associated with ASD in a Japanese population. In order to investigate the association between rare non-synonymous OXTR variations and ASD, we resequenced OXTR and performed association analysis with ASD in a Japanese population.
MethodsWe resequenced the OXTR coding region in 213 ASD patients. Rare non-synonymous OXTR variations detected by resequencing were genotyped in 213 patients and 667 controls.
ResultsWe detected three rare non-synonymous variations: rs35062132 (R376G/C), rs151257822 (G334D), and g.8809426G&gt;T (R150S). However, there was no significant association between these rare non-synonymous variations and ASD.
ConclusionsOur present study does not support the contribution of rare non-synonymous OXTR variations to ASD susceptibility in the Japanese population.

DOI： 10.1111/pcn.12205

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1-29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.

DOI： 10.1371/journal.pone.0119413

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Language：Japanese   Publisher：(株)星和書店  

統合失調症の突然死という表現型そのものを対象とした遺伝的研究はほとんどない。しかし、その突然死の大半は心筋梗塞によるものと報告されており、心血管疾患およびその危険因子である糖・脂質代謝異常や肥満を対象とした遺伝的研究は比較的多い。最近は、内科領域などの大規模GWASによって糖・脂質代謝異常、肥満などと関連する遺伝子領域が同定されている。これらの遺伝的要因に、抗精神病薬内服および統合失調症と関連するライフスタイルなどの環境要因が加わると、交互作用によって心血管疾患および突然死のリスクがさらに高まる可能性がある。また以前より、統合失調症と糖尿病の間に共通の遺伝的要因が存在することが示唆されているが、統合失調症および統合失調症で問題となる身体リスクの双方に関連する遺伝的要因を探るという研究手法も有望と考えられる。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Objectives To clarify the prevalence of underweight and overweight/obesity, and laboratory data for nutritional status in Japanese outpatients and inpatients with schizophrenia.
Design Cross-sectional study.
Setting A questionnaire conducted in inpatient and outpatient facilities in Japan.
Participants The population of adult patients with schizophrenia in Japan (N=23116).
Main outcome measures The prevalence of underweight and undernutrition in Japanese inpatients and outpatients with schizophrenia.
Results We conducted a large-scale investigation of the prevalence of underweight and undernutrition in 520 outpatient facilities and 247 inpatient facilities belonging to the Japan Psychiatric Hospitals Association between January 2012 and July 2013. There were 7655 outpatients and 15461 inpatients with schizophrenia. There was a significant difference in the distribution of three body mass index levels between outpatients and inpatients (p&lt;0.001). The proportion of underweight inpatients with schizophrenia was significantly higher than that among outpatients (p&lt;0.001). Age-specific analysis revealed that the proportion of underweight individuals aged 40years was higher in inpatients than in outpatients and in the general Japanese population. The proportion of individuals with hypocholesterolaemia was significantly higher in inpatients with schizophrenia than in outpatients (p&lt;0.001). There was a significant difference in the severity of underweight between outpatients and inpatients with schizophrenia; the proportion of severe underweight in inpatients was twofold higher than in outpatients.
Conclusions The prevalence of underweight and undernutrition in Japanese inpatients with schizophrenia was higher than in outpatients and the general population. Therefore, the physical risk of inpatients should be carefully considered in clinical practice.

DOI： 10.1136/bmjopen-2015-008720

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BACKGROUND: Cadherin13 (CDH13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule that plays a crucial role in morphogenesis and the maintenance of neuronal circuitry. CDH13 has been implicated in the susceptibility to a variety of psychiatric diseases. A recent genome-wide association study using Danish samples showed, for the first time, the involvement of a single nucleotide polymorphism (SNP) of CDH13 (intronic SNP rs8057927) in schizophrenia. Here, we investigated the association between other SNPs of CDH13 and schizophrenia and tried to replicate the association for the SNP of rs8057927, in the Japanese population. METHODS: Using TaqMan(®) SNP genotyping assays, five tag SNPs (rs12925602, rs7193788, rs736719, rs6565051, and rs7204454) in the promoter region of CDH13 were examined for their association with schizophrenia in two independent samples. The first sample comprised 665 patients and 760 controls, and the second sample comprised 677 patients and 667 controls. One tag SNP for rs8057927 was also examined for the association with schizophrenia in the first sample set. RESULTS: A GACAG haplotype of the five SNPs in the promoter region of CDH13 was significantly associated with schizophrenia in the first sample set (P=0.016 and corrected P=0.098). A combined analysis of the GACAG haplotype with the second sample set enhanced the significance (P=0.0026 and corrected P=0.021). We found no association between rs8057927 and schizophrenia in the first sample set. CONCLUSION: Our results suggest that CDH13 may contribute to the genetic risk of schizophrenia. Further replication on the association of CDH13 with schizophrenia and functional studies are required to confirm the current findings.

DOI： 10.2147/NDT.S84736

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Psychiatric Association  

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

DOI： 10.1176/appi.neuropsych.13120389

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Language：Japanese   Publisher：新潟大学災害・復興科学研究所  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

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

DOI： 10.1038/tpj.2014.6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

On 12 March 2011 an earthquake devastated the Matsunoyama and Matsudai districts of Tokamachi City, Niigata, Japan. These areas had high pre-existing suicide rates, especially among the elderly. We investigated whether mental health status became worse among the sufferers 5 months after the earthquake, and what kind of factors were implicated in any changes. A 15-item questionnaire that tapped earthquake-related variables and the Kessler 10 Psychological Distress Scale to measure psychological distress were distributed to 1923 residents aged over 40 years. The mean age (S.D.) of the total 1731 respondents (male, 805; female, 926) was 68.2 (13.1) years. Of these, we assessed K10 scores from 1346 respondents. The mean scores (S.D.) for K10 and K6 (six selected items from the K10) were 5.8 (6.3) and 3.4 (3.9), respectively. Among the respondents, 9.1% and 3.2% obtained a score of K10 &gt;= 15 and K6 &gt;= 13, respectively. These scores showed slightly higher psychological distress, especially among the elderly, in comparison with existing community-based data. Categorical regression analysis revealed significant and relatively strong effects of initial psychological impact, decrease in sleep hours, advanced age, and decrease in interpersonal relationships within the community on the 1(10 score. The last item suggests the importance of socio-environmental factors in post-disaster mental health. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2014.01.028

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Language：Japanese   Publisher：(株)星和書店  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

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

DOI： 10.1016/j.pnpbp.2014.03.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

We investigated the association between remission of depressive symptoms in fluvoxamine treatment and catechol-O-methyltransferase (COMT) gene. Sixteen SNPs in the COMT gene were investigated in 123 outpatients with major depression. Three single nucleotide polymorphisms located in the 5' region were associated with remission in fluvoxamine-treated outpatients with moderate to severe depression. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2014.04.030

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Language：Japanese   Publisher：(公財)臨床薬理研究振興財団  

GIPR遺伝子rs10423928多型別にオランザピン内服統合失調症のAA+AT群、TT群、健常対照のAA+AT群、TT群の4群間で唯一有意差があったのは、糖負荷後30分のインスリン値で、統合失調症のAA+AT群で他群より有意に高かった。未治療・他剤内服中の統合失調症患者をGIPR遺伝子rs10423928多型別にAA+AT群、TT群に分け、オランザピン開始・オランザピンへの切り替え後4週間のBMI変化量は、AA+AT群1.2、AT群0.5と有意差を認めた。抗精神病薬内服中の統合失調症群と健常対照群の比較では、ウエスト径が統合失調症群で、空腹時血糖値は健常対照群で有意に高値であった。GIP遺伝子-1920G/A多型で分けた統合失調症のAA群ではAG+GG群に比べBMI、ウエスト径が有意に高値であり、健常対照のAA群、AG+GG群間で有意差はなかった。オランザピン内服で認めたダンピング症候群、糖負荷時インクレチン過剰分泌がクエチアピンへ変更後に改善した1例を報告した。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

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

DOI： 10.1111/pcn.12136

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

ObjectiveAlthough several case reports suggested that donepezil hydrochloride can induce bradycardia or atrioventricular block, the details remain unclear. We implemented a study of the impact of donepezil hydrochloride administration on PR, RR, and QT intervals.
MethodsThe subjects were 18 patients who were diagnosed with either dementia or cognitive disorder (DSM-IV-TR) and were hospitalized between January 2011 and December 2012. After hospitalization, they were treated with donepezil hydrochloride. Clinical parameters and electrocardiograms before and after the administration of donepezil hydrochloride were retrieved from the patients' medical records.
ResultsAfter the administration of donepezil hydrochloride, the mean PR interval significantly increased from 177.330.9 to 186.8 +/- 38.4ms (p&lt;0.001). And the mean RR interval also significantly increased from 850.3 +/- 112.5 to 886.7 +/- 136.4ms (p=0.014). The mean difference in the PR interval before and after the administration of donepezil hydrochloride was 9.5 +/- 17.1 (range=-21.0-44.0) ms. The QT intervals were unaffected by the administration of donepezil hydrochloride.
ConclusionsCare should be taken when administering donepezil to patients with atrioventricular block, or patients taking other drugs that can prolong the PR interval. Copyright (c) 2014 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.2398

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Language：English   Publisher：MARY ANN LIEBERT, INC  

This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21(st) century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry-pharmacoepigenetics-that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a long way to cultivate transgenerational capacity and broader cognizance of the concept and practice of responsible innovation as an important criterion of 21(st) century omics science and personalized medicine. A new call is presently in place for the 2016 PRACP Werner Kalow prize. Nominations can be made in support of an exceptional individual interdisciplinary scholar, or alternatively, an entire research team, from any region in the world with a record of highly innovative contributions to global omics science and/or personalized medicine, in the spirit of responsible innovation. The application process is straightforward, requiring a signed, 1500-word nomination letter (by the applicant or sponsor) submitted not later than May 31, 2015. Wanderer, your footsteps are the road, and nothing more; wanderer, there is no road, the road is made by walking. By walking one makes the road, and upon glancing behind one sees the path that never will be trod again. Wanderer, there is no road - Only wakes upon the sea. Antonio Machado (1875-1939) "The real voyage of discovery consists not in seeking new landscapes but in having new eyes. " Marcel Proust (1871-1922)

DOI： 10.1089/omi.2014.0029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

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

DOI： 10.1016/j.pnpbp.2013.12.006

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Language：Japanese   Publisher：(株)星和書店  

抗精神病薬の登場以降、統合失調症に対する薬物治療は飛躍的に進歩した。第1世代抗精神病薬により陽性症状の改善効果が期待できるようになり、第2世代抗精神病薬では陽性症状に加え、陰性症状や認知機能の改善効果と錐体外路症状の軽減が期待できるようになった。しかし長期的な視点でとらえた場合の最大のベネフィットとは、やはり再発予防効果ではないだろうか。一方、近年では長期的な身体リスクも注目されるようになった。統合失調症患者ではメタボリックシンドローム発症のリスクが高まり、経過中に心血管疾患などを発症して平均余命が短縮すると考えられている。本稿では、統合失調症に対する薬物治療がもたらす長期的なベネフィットとしての再発予防効果について、また第2世代抗精神病薬を中心とした薬物治療が長期的にもたらす身体リスクとしてのMetSや心血管リスクについて述べ、その結果もたらされる死亡リスクに関して概説する。(著者抄録)

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Language：Japanese   Publisher：(株)全日本病院出版会  

耳鼻咽喉科領域の診療においても、うつ病を含む精神疾患を見落とさないことが重要である。身体症状が主訴であっても、うつ病、不安障害、身体表現性障害といった精神疾患を有する可能性がある。平素から患者の精神状態の評価を積極的に行うことが望ましく、特にうつ病については全患者にスクリーニングすることが求められている。本稿で紹介したK6/K10、M.I.N.I.、PHQ-9などを活用し、日常診療で遭遇する精神疾患の診断に役立てていただきたい。(著者抄録)

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DOI： 10.1016/j.psychres.2013.12.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN EPIDEMIOLOGICAL ASSOC  

Background: The 2004 Niigata-Chuetsu earthquake of Japan caused considerable damage. We assessed long-term changes in psychological distress among earthquake victims during the period 5 years after the earthquake.
Methods: The participants were people aged 18 years or older living in Yamakoshi, a community in Niigata Prefecture near the epicenter. A self-administered questionnaire survey was conducted annually for 5 consecutive years after the earthquake. Response rates were 1316/1841 (71.5%) in 2005, 667/1381 (48.3%) in 2006, 753/1451 (51.9%) in 2007, 541/1243 (43.5%) in 2008, and 814/1158 (70.3%) in 2009. The questionnaire asked about demographic characteristics, including sex, age, employment status, social network, and psychological status. Psychological distress was assessed using the 12-item General Health Questionnaire and was defined as a total score of 4 or higher.
Results: The overall prevalence of psychological distress decreased (P &lt; 0.0001) gradually from 2005 (51.0%) to 2008 (30.1%) but tended to increase from 2008 to 2009 (P = 0.1590). Subgroup analyses showed that prevalence did not decrease over the 5-year study period among participants with poor social contact (P = 0.0659). From 2008 to 2009 prevalence increased in women (+7.5%, P = 0.0403) and participants aged 65 years or older (+7.2%, P = 0.0400).
Conclusions: The prevalence of psychological distress in Yamakoshi people decreased steadily during the 4 years immediately after the earthquake but appeared to increase thereafter. The earthquake victims are still reestablishing their lives. Thus, continued attention should be focused on maintaining and further assessing their mental health.

DOI： 10.2188/jea.JE20130097

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DOI： 10.1016/j.ajp.2013.10.013

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

DOI： 10.1371/journal.pone.0086826

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

AimsIn Europe and North America, schizophrenia patients treated with antipsychotic agents have a higher prevalence of obesity and metabolic syndrome compared with healthy individuals. In Japan, the prevalence of overweight/obesity in the general population is considerably lower than that in Europe and North America. The purpose of this study was to investigate the prevalence of underweight and overweight/obesity as well as laboratory data in Japanese inpatients with schizophrenia.
MethodsThe subjects were 333 inpatients with schizophrenia and 191 age- and sex-matched healthy volunteers. Overweight/obesity was defined as body mass index (BMI) 25kg/m(2), standard weight was defined as BMI18.5 to &lt;25kg/m(2) and underweight was defined as BMI&lt;18.5kg/m(2).
ResultsA significant difference in the prevalence of the three BMI levels was observed between schizophrenia patients and controls (P&lt;0.001). The prevalence of underweight was significantly higher in schizophrenia patients than that in controls (P&lt;0.001). The prevalence of hypoproteinemia (P&lt;0.001) and of hypocholesterolemia (P&lt;0.001) were significantly higher in schizophrenia patients than in controls. In schizophrenia patients, the prevalence of hypotriglyceridemia was significantly higher in the underweight group than in the standard weight group (P=0.003) and in the overweight/obesity group (P&lt;0.001).
ConclusionsThe prevalence of underweight in Japanese inpatients with schizophrenia may be higher compared with that in the general population. Therefore, the physical health of inpatients should be more carefully taken into account in clinical practice.

DOI： 10.1111/pcn.12082

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DOI： 10.1111/pcn.12087

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DOI： 10.1016/j.schres.2013.10.036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

ObjectiveInterleukin-1 beta (IL-1) has been implicated in the pathophysiology of schizophrenia. To assess whether the IL1B gene confers increased susceptibility to schizophrenia, we conducted case-control and family-based studies and an updated meta-analysis.
MethodsWe tested the association between IL1B and schizophrenia in 1229 case-control and 112 trio samples using 12 markers, including common tagging single nucleotide variations (SNVs) and a rare non-synonymous variation detected by resequencing the coding regions. We also performed a meta-analysis of rs16944 using a total of 8724 case-control and 201 trio samples from 16 independent populations.
ResultsWe found no significant associations between any of the 12 SNVs examined and schizophrenia in either case-control or trio samples. Moreover, our meta-analysis results showed no significant association between the common SNV, rs16944, and schizophrenia.
ConclusionsThe present study does not support a role for IL1B in schizophrenia susceptibility. Copyright (c) 2013 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.2365

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Language：Japanese   Publisher：(株)星和書店  

新規の抗精神病薬や抗うつ薬が登場し、統合失調症やうつ病の薬物療法の選択肢は飛躍的に増えたため、副作用モニタリングの対象や方法も大きく変化してきている。副作用モニタリングは、(1)副作用による身体リスク、(2)副作用による治療中断、を減らすという重要な役割を持っている。「副作用による身体リスク」には、短期間で生命に危険が及ぶものと、長期にわたる経過の中で死亡率の増加につながるものがある。前者は従来から注目されており、モニタリングや対処法は比較的確立していると考えられる。一方で、「長期にわたる経過の中で死亡率の増加につながる副作用」に関しては、認知・注目度が低いというのが臨床現場の実状であり、その代表的なものとして、抗精神病薬による体重増加・肥満、糖・脂質代謝異常などの代謝性副作用が挙げられる。統合失調症患者の平均寿命が一般人口と比べて短いということの背景に、この代謝性副作用の存在が指摘されている。本稿では、当施設の研究結果を示しながら、抗精神病薬の代謝性副作用に対するモニタリングをどのように行っていくべきかを中心に概説する。(著者抄録)

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向精神薬に関連した循環器系有害事象として、起立性低血圧、致死性不整脈、心筋炎、糖脂質代謝障害による虚血性心疾患、静脈血栓塞栓症等があり、これらは致死的であることが多い。致死性不整脈は定期的な心電図検査によってある程度予測可能で、その発症を低下させることが可能かもしれない。他の有害事象は定期的なモニタリングによる早期発見は困難であるが、静脈血栓塞栓症であれば下肢の深部静脈血栓症、心筋炎であれば原因不明の心疾患や感冒様症状に合併した心機能異常を認めることが多く、循環器系有害事象を念頭に置き、これらの徴候に注意を払いつつ日々の診療を行うことが重要である。(著者抄録)

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DOI： 10.1016/j.schres.2013.08.028

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The side effects and interaction of memantine and donepezil hydrochloride when used concomitantly are currently unknown. We encountered a case of a 77-year-old female with Alzheimer's disease in which the concomitant use of memantine exacerbated the prolonged electrocardiogram PR interval which appeared while donepezil hydrochloride was being orally administered. In terms of the cardiac circulation system side effects caused by donepezil hydrochloride and memantine, bradycardia has been reported. However, clinicians should be also aware of PR prolongation associated with the concomitant use of donepezil and memantine. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.genhosppsych.2013.04.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919's association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.

DOI： 10.1371/journal.pone.0080696

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Language：Japanese   Publisher：(株)星和書店  

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DOI： 10.1111/pcn.12080

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Language：Japanese   Publisher：新潟大学災害・復興科学研究所  

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BACKGROUND: The prevalence of diabetes in patients with schizophrenia is 2- to 3-fold higher than in the general population. Glucose abnormalities were detected in 11.9% of Japanese schizophrenic patients in a recent cross-sectional study that included fasting glucose monitoring. However, detailed studies of glucose intolerance using the glucose tolerance test have been limited in Japanese patients with schizophrenia. We investigated the prevalence of abnormal glucose tolerance after glucose loading among Japanese inpatients with schizophrenia, with normal fasting glucose levels. METHOD: A total of 258 inpatients with schizophrenia participated in this study after giving their written informed consent. A 75-g oral glucose tolerance test was conducted in the morning after a 12-hour overnight fast. RESULTS: Among patients with normal fasting glucose, 81.3% had normal glucose tolerance, 17.3% had impaired glucose tolerance, and 1.3% were diagnosed with diabetes. CONCLUSIONS: This study showed that the frequency of impaired glucose tolerance in patients with schizophrenia with normal fasting glucose levels might be higher than in the general population. Careful monitoring and screening of patients with schizophrenia for abnormal glucose metabolism might therefore be necessary. Copyright © 2013 by Lippincott Williams &amp
Wilkins.

DOI： 10.1097/JCP.0b013e3182905775

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

The present study investigated the relationship between neural activity associated with gaze processing and autistic traits in typically developed subjects using magnetoencephalography. Autistic traits in 24 typically developed college students with normal intelligence were assessed using the Autism Spectrum Quotient (AQ). The Minimum Current Estimates method was applied to estimate the cortical sources of magnetic responses to gaze stimuli. These stimuli consisted of apparent motion of the eyes, displaying direct or averted gaze motion. Results revealed gaze-related brain activations in the 150-250 ms time window in the right posterior superior temporal sulcus (pSTS), and in the 150-450 ms time window in medial prefrontal regions. In addition, the mean amplitude in the 150-250 ms time window in the right pSTS region was modulated by gaze direction, and its activity in response to direct gaze stimuli correlated with AQ score. pSTS activation in response to direct gaze is thought to be related to higher-order social processes. Thus, these results suggest that brain activity linking eye contact and social signals is associated with autistic traits in a typical population. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2013.05.067

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Language：Japanese   Publisher：(株)星和書店  

統合失調症患者の生命予後は一般人口と比較して15年から30年短いと報告されており、抗精神病薬による心血管系、代謝系の有害事象が統合失調症患者の生命予後に影響を与えていると考えられているが、抗精神病薬を服用していなくても統合失調症患者では虚血性心疾患、脳卒中による死亡リスクが上昇することが示唆されている。静脈血栓塞栓症に関しては、現在服用中であることが発症、死亡リスクを上昇させているようである。抗精神病薬は用量依存的に致死性不整脈発症のリスクを上昇させていると考えられる。多剤併用は心血管疾患発症のリスクを上昇させ、死亡リスクも上昇させている可能性が高い。(著者抄録)

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Language：Japanese   Publisher：(株)星和書店  

第二世代抗精神病薬(以下SGAs)は、統合失調症患者のインスリン分泌に影響を与え耐糖能異常を惹起すると指摘されている。近年、SGAsにより低血糖を引き起こす可能性も指摘され、我々はquetiapine投与中に糖負荷後低血糖を生じ、perospironeやblonanserinへの置換で改善した症例を報告してきた。耐糖能異常の発症頻度には薬剤間差があり、clozapineやolanzapineに比しaripiprazoleはリスクが低いと報告されている。今回我々は、quetiapine投与中に生じた糖負荷後低血糖がaripiprazoleへの置換後改善したが、インスリン抵抗性の増大が持続した1例を経験したので報告する。低血糖症状は統合失調症の精神症状と区別しにくい。またインスリン抵抗性の増大は薬剤中止後も持続する可能性があり注意が必要である。(著者抄録)

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9-Hydroxyrisperidone (9-OH-RIS) is an active metabolite of the antipsychotic drug risperidone (RIS). The total active moiety level, in other words the sum of the RIS and 9-OH-RIS serum levels, may be important for estimating the clinical effects of RIS treatment. However, there have been no consistent results reported regarding the relationship between cytochrome P450 (CYP) 2D6 or adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) variant alleles and 9-OH-RIS or total active moiety plasma levels. Seventy-four Japanese patients treated with RIS were examined in the present study. Steady-state plasma RIS and 9-OH-RIS were measured. The CYP2D6*5, CYP2D6*10, ABCB1 3435C&gt
T, and ABCB1 2677G&gt
T/A genotypes were detected. Multiple regression analysis showed that the dose-corrected plasma RIS levels were significantly correlated with the number of CYP2D6 variant alleles and ABCB1 3435C&gt
T genotypes, whereas the 9-OH-RIS and total active moiety levels were significantly correlated with the ABCB1 3435C&gt
T genotypes and with age. On the other hand, the ABCB1 2677G&gt
T/A genotypes did not affect plasma RIS, 9-OH-RIS, or total active moiety levels. The ABCB1 3435C&gt
T genetic polymorphism may predict plasma 9-OH-RIS and total active moiety levels. Copyright © 2013 Lippincott Williams &amp
Wilkins.

DOI： 10.1097/JCP.0b013e31828ecd52

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives To search for schizophrenia susceptibility loci, we carried out a case-control study using 28601 microsatellite markers distributed across the entire genome. Materials and methods To control the highly multiple testing, we designed three sequential steps of screening using three independent sets of pooled samples, followed by the confirmatory step using an independent sample set (&gt;2200 case-control pairs). Results The first screening using pooled samples of 157 case-control pairs showed 2966 markers to be significantly associated with the disorder (P &lt; 0.05). After the second and the third screening steps using pooled samples of 150 pairs each, 374 markers remained significantly associated with the disorder. We individually genotyped all screening samples using a total of 1536 tag single nucleotide polymorphisms (SNPs) located in the vicinity of similar to 200 kb from the 59 positive microsatellite markers. Of the 167 SNPs that replicated the significance, we selected 31 SNPs on the basis of the levels of P values for the confirmatory association test using an independent-sample set. The best association signal was observed in rs13404754, located in the upstream region of SLC23A3. We genotyped six additional SNPs in the vicinity of rs13404754. Significant associations were observed in rs13404754, rs6436122, and rs1043160 in the cumulative samples (2617 cases and 2698 controls) (P = 0.005, 0.035, and 0.011, respectively). These SNPs are located in the linkage disequilibrium block of 20 kb in size containing SLC23A3, CNPPD1, and FAM134A genes. Conclusion Genome-wide association study using microsatellite markers suggested SLC23A3, CNPPD1, and FAM134A genes as candidates for schizophrenia susceptibility in the Japanese population. Psychiatr Genet 23: 117-123 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Psychiatric Genetics 2013, 23:117-123

DOI： 10.1097/YPG.0b013e32835fe4f1

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DOI： 10.1016/j.psychres.2012.11.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objective We examined sex differences in the effect of olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), or quetiapine (QTP) on mean corrected QT (QTc) intervals among 222 patients with schizophrenia. Methods Subjects were patients with schizophrenia who were treated with either OLZ (n=69), RIS (n=60), ARP (n=62), or QTP (n=31). Electrocardiographic measurements were conducted, and the QT interval was corrected using Bazett's correction formula. Results The mean QTc interval of the QTP group was significantly longer than that of the RIS group (p=0.002) or ARP group (p=0.029). The mean QTc interval of the OLZ group was also significantly longer than that of the RIS group (p=0.006). In female participants, the difference in the mean QTc interval among the four second-generation antipsychotic (SGA) groups was statistically significant (p=0.002), whereas in male patients, there was no significant difference in the mean QTc interval among the four SGA groups. Post hoc analyses showed that sex differences in QTc interval were observed only in OLZ treatment group (p=0.007). Conclusion To our knowledge, this is the first study to demonstrate sex differences in the effect of four SGAs on the QTc interval. Copyright (c) 2013 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.2309

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MicroRNA may play a role in the pathophysiology of schizophrenia. A recent meta-analysis of genome-wide association studies indicated a significant association between schizophrenia and a common intronic variation in MIR137HG (microRNA 137 host gene) encoding the primary microRNA-137. To explore additional risk variations for schizophrenia, we resequenced MIR137 and performed an association analysis in 1321 Japanese individuals. By resequencing, we detected four sequence variations in the 5' and 3' flanking regions. There were no significant associations between these variations and schizophrenia. Our resequencing and association analysis of MIR137 failed to find additional risk variations for schizophrenia. © 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.

DOI： 10.1111/pcn.12047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Although second-generation antipsychotics (SGAs) are characterized by fewer prolactin (PRL)-related side effects compared with first-generation antipsychotics, the detailed effects of SGAs on the plasma PRL levels still remain unclear. We examined the differences in plasma PRL levels among 268 patients treated for schizophrenia with olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), quetiapine (QTP), or perospirone (PER). The participants had received antipsychotic monotherapy with stable doses of OLZ, RIS, ARP, QTP, or PER for &gt;= 3 weeks, and fasting blood samples were drawn to examine plasma PRL levels. The differences in median plasma PRL levels in all (P&lt;0.001), male (P&lt;0.001) and female patients (P&lt;0.001) among the five SGA groups were statistically significant. A stepwise multiple regression analysis showed that ARP treatment was found to contribute to lower plasma PRL level, while female sex, RIS, OLZ and chlorpromazine equivalent dose were found to contribute to a higher plasma PRL level. The median value of plasma PRL level in the RIS group was twice as much compared with that in the OLZ group, although this was not statistically significant. In this study, OLZ had a considerable effect on plasma PRL level, similar to RIS, while PER did not affect plasma PRL levels, similar to QTP. Further studies are needed to clarify the differences in plasma PRL levels among SGAs. (C) 2013 Elsevier B. V. All rights reserved.

DOI： 10.1016/j.schres.2012.12.027

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Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： http://search.jamas.or.jp/link/ui/2013155597

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Selective serotonin reuptake inhibitors (SSRIs) are associated with an increased risk of bleeding, and the inhibition of serotonin transporters by SSRIs is thought to be responsible for this side effect [1]. Here, we report that the platelet count returned to normal after discontinuation of paroxetine in a patient with idiopathic thrombocytopenic purpura. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.genhosppsych.2012.06.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objectives There have so far been few papers studying the metabolic syndrome (MetS) prevalence rate in Japanese patients with schizophrenia. We studied the MetS prevalence rate in Japanese controls and inpatients with schizophrenia and compared the prediction factors for the occurrence of MetS. Methods The subjects were 319 inpatients with schizophrenia and 154 controls. The predictive utilities of body mass index (BMI) and the individual components of MetS for MetS diagnosis were evaluated. Results The prevalence of MetS did not differ between schizophrenia and control subjects. Subjects with schizophrenia showed higher prevalences of the MetS criteria for high-density lipoprotein cholesterol (HDL) (p&lt;0.001) and waist circumference (WC) (p&lt;0.001). In subjects with schizophrenia, the predictive power was found to be highest for HDL, followed by WC, BMI, triglyceride, diastolic blood pressure (BP), systolic BP and fasting plasma glucose. However, in control subjects, the predictive power was found to be highest for triglyceride, followed by WC, systolic BP, BMI, HDL, diastolic BP and fasting plasma glucose. HDL was the component most predictive of MetS in subjects with schizophrenia treated with antipsychotics. Conclusion Because, in normal clinical practice, it is difficult to obtain temporal measurements for all of the MetS criteria, measurement of HDL may be useful for predicting the MetS. Copyright (c) 2013 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.2295

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Language：Japanese   Publisher：(株)星和書店  

本稿では、atomoxetine(ATX)の薬理とおとなの注意欠如・多動性障害(ADHD)への効果を概観した。ATXは前頭皮質でノルアドレナリントランスポーターを阻害し、シナプス間ドパミン濃度を上昇させることでその薬理作用をもたらすと考えられている。ATXは成人ADHD患者の中核症状にも有効であり、副作用は今のところ少ないと考えられているが、その有効性は小児ADHDに対するものよりも小さい可能性がある。また成人ADHD患者には小児期よりも多彩な二次障害や併存症が存在すると言われており、それらに関する効果を検討した研究も進められている。ADHDに併存する情緒不安定性や不安関連症状、喫煙ADHD患者が禁煙する場合の離脱症状や喫煙衝動、ADHD患者の自動車運転能力などについてはATXは有効である可能性があるが、今後さらなるエビデンスの蓄積が必要である。またATXの成人ADHD患者への長期投与効果については十分に分かっていない部分もあり、確実な診断の上で慎重に投与されるべきである。(著者抄録)

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DOI： 10.1038/tpj.2011.36

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Language：English  

DOI： 10.1111/pcn.12012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Brain-derived neurotrophic factor (BDNF) has been suggested to play a role in the pathophysiology of schizophrenia. The C270T polymorphism (rs56164415) in the BDNF 5-non-coding region has been extensively investigated for an association with schizophrenia, but with conflicting results. An updated meta-analysis was therefore performed of 13 casecontrol association studies (3505 patients and 3992 controls). An association was found between the T allele and schizophrenia. The association was significant in the East Asian population, but not in the Caucasian population. It is suggested that the BDNF C270T polymorphism contributes to schizophrenia susceptibility, especially in East Asian subjects.

DOI： 10.1111/pcn.12018

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Objective: In Japan, the prevalence of overweight/obesity in the general population is considerably lower and the mean duration of hospitalization of patients with schizophrenia is much longer than those in Europe and North America. The aim of this study was to investigate whether these differences in ethnics or healthcare systems influence the nutritional status of patients with schizophrenia. Methods: Body mass index (BMI) and blood biochemistry tests were determined at hospitalization and at discharge for 171 Japanese patients who were hospitalized for the treatment of acute phase schizophrenia. Results: For 56 patients who were overweight/obese at hospitalization, BMI (p &lt
0.001), fasting plasma glucose (p = 0.039), and low-density lipoprotein (p = 0.027) were significantly lower at discharge than at hospitalization. BMI at hospitalization, duration of hospitalization, and age were associated with a decrease in BMI during hospitalization. Among the 115 patients who were not overweight/obese at hospitalization, there were no changes in BMI and blood biochemistry tests between hospitalization and discharge. Conclusions: Compared with inpatients, outpatients with schizophrenia may be more likely to be overweight/obese in Japan. © 2013, Baywood Publishing Co., Inc.

DOI： 10.2190/PM.45.3.e

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Background: Cell adhesion molecules (CAMs) play pivotal role in the development of the central nervous system (CNS) and have also been reported to play role in the pathophysiology of schizophrenia. Missense mutations in the CAMs genes might alter the binding of their ligands, increasing the vulnerability to develop schizophrenia.
Methods: We selected 15 missense mutations in the CAMs genes of the CNS reported in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and examined the association between these mutations and schizophrenia in 278 patients and 284 control subjects (first batch). We also genotyped the positive single nucleotide polymorphisms (SNPs) in 567 patients and 710 control subjects (second batch) and in 635 patients and 639 control subjects (replication samples).
Results: Genotypic and allelic distributions of rs2298033 in the ITGA8 gene between the schizophrenia and control groups were significantly different in the first batch (p = 0.005 and 0.007, respectively). Gender-based analysis revealed that the allelic and genotypic distributions of rs2298033 in the ITGA8 were significantly different between the schizophrenia and control groups among females in both batches (p = 0.010, 0.011 and 0.0086, 0.010, respectively) but not among males. Combine analysis of rs2298033 with the replication samples revealed a more significant differences (p = 0.0032; 0.0035 in the overall subjects and p = 0.0024; 0.0025 in the female subjects, respectively). The significant differences for rs2802808 of the NFASC gene were only observed in the female subgroup of the first batch.
Conclusion: These results suggest that the ITGA8 gene might have gender-specific roles in the development of schizophrenia. Further replication and functional studies are required to confirm these findings. (c) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2012.11.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC OCCUPATIONAL HEALTH  

Personality and Resilience Associated with Perceived Fatigue of Local Government Employees Responding to Disasters: Hideaki KITAMURA, et al. Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences-Objectives: According to some newspapers, concerns are growing over the health of local government employees in the Great East Japan Earthquake disaster areas. Concerns were consistently present after the Hanshin-Awaji and Niigata-Chuetsu earthquakes but not studied analytically. Methods: Municipal employees responding to the disasters after an earthquake and floods answered a questionnaire about the degrees of workload, fatigue, psychological distress, resilience and personality traits. Results: Two-thirds of the employees suffered fatigue and psychological distress, which were significantly correlated with workload but inversely correlated with emotional stability personality traits and psychological resilience. Conclusions: Together with substantial workload, individual differences in emotional stability and to lesser degree in resilience were found to have an impact on perceived fatigue. These individual factors should be considered as potential mediators of distresses among local government employees responding to disasters. (J Occup Health 2013; 55: 1-5)

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Objectives There are few reports regarding quetiapine (QTP)-related QT prolongation. We examined the change in QT interval after switching from aripiprazole (ARP), olanzapine (OLZ), or risperidone (RIS) to QTP. Methods Twenty subjects treated with ARP, OLZ, or RIS were enrolled in the study. Following baseline assessments, which included QT interval and electrolytes, these three drugs were switched to QTP for each subject. The same parameters were evaluated following a switch to QTP. Results All 20 patients who had been treated with ARP, OLZ, or RIS were successfully switched to QTP. Significant increases were observed in the total mean corrected QT (QTc) interval after switching (p = 0.014). The coefficient of variation for the extent of change in QTc interval was 1.66. The mean QTc with ARP treatment was significantly increased after QTP treatment (p = 0.004). Conclusions Quetiapine might have a greater effect on QTc interval than other second-generation antipsychotics. However, because there was a considerable variability in the extent of QTc prolongation after switch to QTP, further studies are required to clarify the effect of QTP on QTc interval. Copyright © 2012 John Wiley &amp
Sons, Ltd.

DOI： 10.1002/hup.2277

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DOI： 10.1038/mp.2012.74

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background: Individuals with autistic spectrum disorder (ASD) demonstrate an impaired ability to infer the mental states of others from their gaze. Thus, investigating the relationship between ASD and eye gaze processing is crucial for understanding the neural basis of social impairments seen in individuals with ASD. In addition, characteristics of ASD are observed in more comprehensive visual perception tasks. These visual characteristics of ASD have been well-explained in terms of the atypical relationship between high- and low-level gaze processing in ASD. Method: We studied neural activity during gaze processing in individuals with ASD using magnetoencephalography, with a focus on the relationship between high- and low-level gaze processing both temporally and spatially. Minimum Current Estimate analysis was applied to perform source analysis of magnetic responses to gaze stimuli. Results: The source analysis showed that later activity in the primary visual area (V1) was affected by gaze direction only in the ASD group. Conversely, the right posterior superior temporal sulcus, which is a brain region that processes gaze as a social signal, in the typically developed group showed a tendency toward greater activation during direct compared with averted gaze processing. Conclusion: These results suggest that later activity in V1 relating to gaze processing is altered or possibly enhanced in high-functioning individuals with ASD, which may underpin the social cognitive impairments in these individuals. (C) 2013 S. Karger AG, Basel

DOI： 10.1159/000354866

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Language：English   Publishing type：Part of collection (book)   Publisher：Elsevier Inc.  

Significant variabilities exist in psychotropic disposition and response. Numerous polymorphisms in the genes coding for specific cytochrome P-450 metabolizing enzymes and the ABCB1 transporter residing at the blood-brain barrier have been studied for their possible roles in individualized psychotropic drug therapy. Although molecular diagnostics are available for CYP2D6 and CYP2C19 genotyping, current data provide evidence for their use primarily in predicting adverse drug effects and possibly increasing compliance in subsets of populations. The involvement of the serotonergic system, especially the 5-HT2C receptor, provides convincing evidence of a genetic basis in predicting antipsychotic-induced weight gain. On the other hand, prediction of psychotropic drug effects based on polymorphisms in multiple drug targets within the brain is limited by methodological and clinical problems, especially with the candidate gene approach. Nevertheless, the lack of novel new drugs in psychiatry underscores the importance of refining current molecular approaches to provide insights into etiologies of mental disorders and their treatment. © 2013 Copyright © 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/B978-0-12-391918-2.00006-8

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People with schizophrenia have higher rates of medical illness and mortality than the general population. Cardiovascular disease is a major contributor to premature death in patients with schizophrenia. There has been an increase literature discussing the high prevalence of dyslipidemia, which is one of risk factors for cardiovascular disease, induced by second generation antipsychotic agents. Depression is associated with increased risks of diabetes, hypertension, cardiovascular disease. However, those may not be secondary to the use of antidepressant agents. In order to reduce the risk of cardiovascular disease in patients with schizophrenia receiving antipsychotic agents, obtaining fasting lipid measurements at regular intervals is needed. Further investigations are needed to evaluate the effects of antidepressive agents on lipid profiles. © 2012 Springer Science+Business Media New York.

DOI： 10.1007/s11883-012-0292-6

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Language：English   Publisher：American Psychiatric Publishing Inc.  

DOI： 10.1176/appi.neuropsych.12100243

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Several studies have shown increased rates of hyperglycemia and diabetes in schizophrenic patients treated with olanzapine. However, the underlying mechanism is poorly understood. Glucose-dependent insulinotropic polypeptide (GIP) is known to affect insulin secretion by pancreatic beta cells. Recently, a meta-analysis study reported an association between a GIP receptor (GIPR) gene polymorphism (rs10423928) and insulin secretion measured by an oral glucose tolerance test (OGTT). We assessed the influence of this GIPR gene polymorphism on glucose metabolism in 60 schizophrenic patients treated with olanzapine and 103 healthy controls. The GIPR gene polymorphism was determined using TaqMan methods. We performed repeated-measures analysis of variance (ANOVA) and one-way ANOVA for the glucose and insulin levels during OGTTs in four groups divided by the GIPR gene polymorphism and cohort (schizophrenia or control). We found significant effects of the GIPR gene and cohort on the insulin levels at 30 min. Our findings suggest that schizophrenic patients with the A allele of GIPR rs10423928 are at risk of developing hyperinsulinemia when treated with antipsychotics.
The Pharmacogenomics Journal (2012) 12, 507-512; doi:10.1038/tpj.2011.28; published online 12 July 2011

DOI： 10.1038/tpj.2011.28

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The development of impaired glucose tolerance induced by antipsychotics (APs) is of concern as a serious adverse effect of psychiatric drug therapy. However, the mechanism by which APs cause dysfunction of the glucose-insulin response is not fully understood. Recent studies have shown that patients treated with APs for schizophrenia were more likely to exhibit impaired glucose tolerance after a glucose load compared with healthy control subjects, even if fasting glucose levels were within the reference range. To explain these findings, we hypothesized that insulin secretion is increased in schizophrenic patients treated with AP, even those normal fasting glucose (NFG) levels. Therefore, oral glucose tolerance tests were conducted in 159 Japanese inpatients with AP-treated schizophrenia and in 90 healthy subjects without schizophrenia. Plasma glucose and serum insulin concentrations were measured before (0 minute) and at 30, 60, 90, and 120 minutes after the oral glucose load. Although insulin levels at 0 minute were similar in both groups of subjects, insulin levels were significantly higher in the patients treated with AP at all times after the glucose load than in the healthy subjects. In analyses of NFG subjects, insulin levels were significantly higher in the patients treated with AP compared with the healthy subjects at all times after glucose loading. Overall, we found that insulin secretion in response to a glucose load was significantly higher in the patients treated with AP, irrespective of NFG. These results suggest that APs affect the glucose-insulin response, which may lead to subclinical insulin resistance before the onset of overt glucose intolerance.

DOI： 10.1097/JCP.0b013e3182742ea4

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1819.2012.02396.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Panic disorder (PD) is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Due to the lack of power in previous association studies, genes that are truly associated with PD might not be detected. In this study, we conducted a genome-wide association study (GWAS) in two independent data sets using the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. We obtained imputed genotypes for each GWAS and performed a meta-analysis of two GWAS data sets (718 cases and 1717 controls). For follow-up, 12 single-nucleotide polymorphisms (SNPs) were tested in 329 cases and 861 controls. Gene ontology enrichment and candidate gene analyses were conducted using the GWAS or meta-analysis results. We also applied the polygenic score analysis to our two GWAS samples to test the hypothesis of polygenic components contributing to PD. Although genome-wide significant SNPs were not detected in either of the GWAS nor the meta-analysis, suggestive associations were observed in several loci such as BDKRB2 (P = 1.3 x 10(-5), odds ratio = 1.31). Among previous candidate genes, supportive evidence for association of NPY5R with PD was obtained (gene-wise corrected P = 6.4 x 10(-4)). Polygenic scores calculated from weakly associated SNPs (P&lt;0.3 and 0.4) in the discovery sample were significantly associated with PD status in the target sample in both directions (sample I to sample II and vice versa) (P&lt;0.05). Our findings suggest that large sets of common variants of small effects collectively account for risk of PD.

DOI： 10.1038/tp.2012.89

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Language：English   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.schres.2012.06.043

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Language：Japanese   Publisher：(株)星和書店  

急性期治療のため入院した統合失調症患者160名の内、入院時body mass index(BMI)が25kg/m2以上の患者53名(33.1%)について、入院時と退院時のBMIおよび血液・生化学検査値を調査した。平均在院日数は114.4±90.0日であった。入院時に比較し、退院時ではBMI(p&lt;0.001)、空腹時血糖(p=0.039)が有意に減少した。53名中17名(32.1%)が退院時に標準体重となり、入院時と退院時で肥満、過体重、標準体重の割合が有意に異なっていた(p&lt;0.001)。入院から退院までのBMI変化量と入院期間は、負の相関を示した(r=0.597、p&lt;0.001)。本研究では、外来で過体重/肥満であった統合失調症患者が精神科病棟に入院することで、過体重/肥満が改善に向かうことが示された。これは、外来時の偏った食生活が入院によって是正されたことによると考えられる。外来治療中の統合失調症患者の方が入院患者に比べて過体重/肥満の割合が多い可能性が示唆され、外来では患者の食生活および身体的健康により配慮すべきかもしれない。(著者抄録)

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1819.2012.02388.x

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Language：Japanese   Publisher：新潟大学災害・復興科学研究所  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Objective: Antipsychotic-treated schizophrenia patients are susceptible to dyslipidemia. However, the results of previous studies of North American and UK populations including various races have been contradictory with regard to which lipid measure was the most affected in patients with schizophrenia taking antipsychotic agents. The aim of this study was to investigate the effect of schizophrenia patients receiving antipsychotic agents on each lipid measure in a Japanese population.
Methods: The samples included 136 control individuals and 157 patients with schizophrenia treated with antipsychotic agents. Age, gender distribution and body mass index (BMI) of the controls were matched with the patients.
Results: The high-density lipoprotein cholesterol (HDL-cholesterol) levels were significantly lower in patients than in the control subjects (P&lt;.001). However, there were no significant differences in either the low-density lipoprotein cholesterol (LDL-cholesterol) or triglyceride levels between the patient and control groups. We performed a multiple linear regression analysis, and schizophrenia receiving antipsychotics was an independent predictor of decreased HDL-cholesterol. An increased BMI, male gender and cigarette smoking were also major predictors of a decreased HDL-cholesterol level (r(2)=0.42, P&lt;.001).
Conclusion: At least in Japanese with schizophrenia receiving antipsychotic agents, the HDL-cholesterol levels should be closely monitored in all patients, even those who are not obese or do not smoke, to decrease their risk of cardiovascular disease. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.genhosppsych.2012.04.002

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Language：Japanese   Publisher：(株)アークメディア  

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Other Link： http://search.jamas.or.jp/link/ui/2012367326

Language：Japanese   Publisher：(株)アークメディア  

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Other Link： http://search.jamas.or.jp/link/ui/2012367330

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

We surveyed 3078 sufferers in Tsunan (Niigata), an intermediate and mountainous area of Japan, after the 2011 Northern Nagano Prefecture Earthquake. More subjects reported fear of the earthquake or related anxiety symptoms and insomnia in Tsunan than in the control group. Female sex and older age were found to be risk factors for poor psychological outcome. Those with risk factors should be carefully followed up.

DOI： 10.1111/j.1440-1819.2012.02366.x

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DOI： 10.1016/j.pscychresns.2011.12.008

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Language：Japanese   Publisher：(株)星和書店  

臨床に従事する精神科医師として、合理的な薬物治療を実践するための根拠や理論を理解することは重要である。多くの精神疾患の正確な病態はいまだ不明であり、数多くの病態仮説が提唱されている。統合失調症に関しては、現在でも最も有力な仮説であるドパミン仮説に基づいて多くの抗精神病薬が開発されてきたが、十分な利益を受けられない患者が存在する。ドパミン仮説を超えた新規の作用機序をもつ統合失調症治療薬の開発が進められているが、今のところ成功には至っていない。ゲノム多様性に関する研究により統合失調症の遺伝要因が明らかにされつつあり、その発症機序が解明されれば、根治療法の開発につながる可能性がある。(著者抄録)

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Language：Japanese   Publisher：(一社)日本社会精神医学会  

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Language：Japanese   Publisher：(株)星和書店  

本稿では、本邦での注意欠如・多動性障害(ADHD)の臨床で活用しうる薬理学的知見をまとめた。治療薬として認可を受けているmethylphenidate(MPH)およびatomoxetine(ATX)については多くのエビデンスがあり、その薬理学的プロファイルから、早期の効果発現が望まれる場合にはMPHが、1日中持続する効果が望まれる場合にはATXが第一選択と考えられる。チックの併存がある場合にはATXが優先される。両者の薬効の違いには薬理学的作用点の違いが関連していると考えられるが、まだ不明な点も多い。適応外使用となるがADHD治療に活用できる薬剤として、clonidineなどのα2受容体作動薬や、imipramine、nortriptylineなどの三環系抗うつ薬などがあり、臨床薬理学的エビデンスからADHD中核症状に有効となり得る。またイコサペントエン酸などのオメガ3脂肪酸も新しい治療として注目されている。Risperidoneなどの抗精神病薬は知的障害を持つ例や衝動性・攻撃性の強い例で中核症状以外の部分で有効となる可能性がある。(著者抄録)

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Language：English   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.psychres.2012.02.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

What is known and Objective: Aripiprazole has a low risk of extrapyramidal symptoms. Switching to aripiprazole has been reported to improve tardive dyskinesia caused by other medications. The authors report a case and review previous reports of dystonia and dyskinesia associated with aripiprazole. Case summary: We present a case of a 22-year-old man with schizophrenia who experienced dyskinesia and dystonia associated with aripiprazole. Switching from olanzapine to aripiprazole resulted in worsening dyskinesia and new onset of dystonia. The patients dyskinesia and dystonia improved after switching from aripiprazole to quetiapine therapy. What is new and Conclusion: There were several previous case reports on dyskinesia and dystonia associated with aripiprazole medication. The risk factors for tardive dyskinesia include older age and female sex. However, our case was a male patient who was younger compared with the previous cases and so should have been less at risk for dyskinesia in comparison with the previous cases. The effects of aripiprazole can include tardive movement disorders. Dyskinesia, dystonia and psychotic symptoms were improved with relatively small dose of quetiapine in this case. Whether some second-generation antipsychotics are more effective than others in the treatment of tardive dyskinesia remains unclear.

DOI： 10.1111/j.1365-2710.2011.01290.x

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DOI： 10.1111/j.1440-1819.2012.02338x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective: The underlying mechanism for second-generation antipsychotic (SGA)-related glucose-lipid metabolic dysfunction is not fully understood. Recent studies have suggested a possible impact of SGAs on endocrine regulation, especially on adipocytokines. We examined the effect of each SGA on various adipocytokines in normal fasting glucose (NFG) subjects.
Method: The study population comprised 113 Japanese inpatients with schizophrenia who were treated with olanzapine, risperidone, or quetiapine, and 123 healthy control (CONT) volunteers. All of the subjects were diagnosed with NFG. Plasma concentration of adiponectin, leptin, tumor necrosis factor alpha, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were compared between the SGA and CONT groups.
Results: Second-generation antipsychotic subjects had significantly higher leptin levels in comparison to the CONT subjects. The plasma concentration of adiponectin, total cholesterol, and high-density lipoprotein cholesterol in the SGA subjects were significantly lower than those in the CONT subjects. There were no significant differences in tumor necrosis factor alpha, triglyceride, and low-density lipoprotein cholesterol levels between the 2 groups. In a stepwise multiple regression analysis, olanzapine was found to be a factor that contributed to decreased adiponectin levels, And the CONT subjects were detected to be a factor associated with lower leptin levels.
Conclusions: The present study indicates the possibility that the administration of SGAs may affect adipocytokines in the NFG stage, excluding the impaired fasting glucose group, which is in the transition stage into diabetes mellitus.

DOI： 10.1097/JCP.0b013e3182524393

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Language：Japanese   Publisher：(株)星和書店  

本稿では、現在本邦で注意欠如・多動性障害(ADHD)の治療薬として使用できるmethylphenidate(MPH)およびatomoxetine(ATX)に関する知見を中心に、将来的に治療の最適化に役立つ可能性のある薬理遺伝学的研究をまとめた。これまでに多くのADHDの薬理遺伝学的研究が行われ、ドパミン・トランスポーター遺伝子、ノルアドレナリン・トランスポーター遺伝子、D4、D5受容体遺伝子などがMPH治療反応性に関わっており、ATXについてドパミン・トランスポーター遺伝子およびD4受容体遺伝子の多型が治療反応性に関与していると報告されている。MPHの代謝にはカルボキシルエステラーゼ1が関与しており、この遺伝子の変異によりMPHの代謝が阻害される可能性がある。これらの研究の結果は必ずしも一致したものではないが、ADHDの薬理遺伝学的研究による知見が積み重なることで、次代のオーダーメイド医療に資することが期待される。(著者抄録)

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Language：English   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.schres.2012.01.034

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DOI： 10.1016/j.psychres.2011.11.005

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Language：Japanese   Publisher：(株)星和書店  

自閉症スペクトラム、特に精神遅滞を伴わない高機能群では、乳幼児期に適切な診断や支援を受けることなく成人し、社会に出てから様々なストレス因に反応し二次的に抑うつや不安を呈する事例が多々見られる。ストレス関連障害とは、外的なストレスに起因して日常生活や職業・学業的機能に著しい支障をきたす疾患群であり、適応障害や心的外傷後ストレス障害などのトラウマ関連障害を含む。自閉症スペクトラムは、生物学的にストレス脆弱性を有しており、生来の社会性の障害によりソーシャルスキルが著しく低く、また否定的な自動思考を認めやすいことから、ストレスに反応して適応障害をきたしやすい。心的外傷後ストレス障害などのトラウマ関連障害についての報告は少ないが、わが国ではタイムスリップ現象として自閉症スペクトラム症例の独特の記憶想起が報告されている。本稿ではストレス関連障害を呈した自閉症スペクトラム症例を提示し、ストレスやトラウマを契機に不適応に至る背景についての考察を行いたい。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

We conducted a detailed association analysis between the tryptophan hydroxylase 2 gene and autism spectrum disorders in a Japanese population using 19 markers, including tagging single nucleotide polymorphisms and a novel missense variation, p.R225Q identified through exon resequencing. However, we failed to obtain supportive evidence for an association. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2011.09.001

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1819.2012.02321.x

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Objectives The 2004 Niigata-Chuetsu earthquake of Japan caused a great deal of damage, and people living in the affected region are still struggling to reconstruct their lives. The aim of this study was to determine factors associated with psychological distress in people living in a town at the epicenter 3 years after the earthquake. Methods We conducted a cross-sectional study from June 2007 to January 2008. Participants included 225 individuals living in Kawaguchi (age ≥20 years) who reported psychological symptoms. Information on family structure, employment status, alcohol use, social network, and extent of house damage was elicited by public health nurses conducting structured interviews. Levels of psychological distress were assessed with the Kessler Psychological Distress Scale (K10), with a K10 score ≥25 defined as psychological distress. Results The mean age of participants was 66.1 ± 12.9 years. The prevalence of psychological distress varied among different employment classes, being 5/73 (6.8%) for participants with paid employment, 12/50 (24.0%) for fulltime housewives, and 11/101 (10.9%) for those who were unemployed (χ 2 = 8.42, P = 0.015). It also varied between participants who had lost contact with people in the community and those who had no change in social contact [9/20 (45.0%) vs. 19/189 (10.1%), respectively
χ 2 = 19.04, P&lt
0.001]. Multiple logistic regression analysis showed that age [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.91-0.98], poor or loss of contact with people in the community (OR 6.97, 95% CI 1.85-26.2), and lack of employment (full-time housewives or unemployed individuals) (OR 6.74, 95% CI 1.62-28.0) were associated with psychological distress. Conclusions People who lose their social network are at a very high risk for post-earthquake psychological distress and require appropriate care. © The Japanese Society for Hygiene 2011.

DOI： 10.1007/s12199-011-0225-y

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1819.2011.02310.x

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1819.2011.02316.x

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Language：Japanese   Publisher：(公財)先進医薬研究振興財団  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Most antipsychotic agents can cause QT prolongation, which causes torsades de pointes. The QT interval in healthy subjects is longer during nighttime than during daytime. The QT interval of patients treated with antipsychotics may be prolonged during nighttime, and the effects of antipsychotics on the QT interval may differ between antipsychotics. This study investigated the circadian dynamics of the QT interval in patients treated with antipsychotics and healthy controls, using a 24-hour Holter electrocardiogram in a clinical setting. Sixty-six patients with a diagnosis of schizophrenia that were treated with risperidone or olanzapine and 40 healthy volunteers were enrolled. The QT intervals were corrected using the Fridericia formula (QTcF = QT / RR1/3). Mean +/- SD nighttime QTcFs were 411.6 +/- 29.0, 395.9 +/- 21.2, and 387.8 +/- 19.0 milliseconds (ms) in the risperidone, olanzapine, and control groups, respectively. The mean daytime QTcFs were 397.7 +/- 23.4, 392.4 +/- 18.9, and 382.6 +/- 17.3 ms, respectively. The mean nighttime QTcF of the risperidone group was significantly longer than that of the olanzapine and control groups, although there was no significant difference in the mean daytime QTcF between the risperidone and olanzapine groups. The current study used 24-hour Holter electrocardiograms to reveal significantly longer QT intervals in the risperidone group especially during nighttime. In clinical practices, evaluations of the QT interval have been conducted over short periods in the daytime, but it is believed that such methods may not be able to fully elucidate the effects of antipsychotics on the QT interval.

DOI： 10.1097/JCP.0b013e31823f6f21

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Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P &lt; 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (a

DOI： 10.1002/ajmg.b.31249

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objective A dose-dependent increase in risk of sudden cardiac death for the antipsychotic drug risperidone was reported. However, few reports have so far addressed QT prolongation associated with the use of risperidone or its major active metabolite, which is also used as a separate antipsychotic drug, paliperidone. Methods The present study evaluated associations between risperidone metabolism and QT interval in 61 psychiatric patients who had been receiving risperidone for &gt;= 4 weeks at an average dosage of 4.7 mg/day. Plasma risperidone and paliperidone levels were measured and electrocardiographic measurements were also obtained. Results There was no correlation between risperidone dosage and QTc or plasma risperidone levels and QTc. However, there was a significant positive correlation between plasma paliperidone levels and QTc (r = 0.361; p = 0.004). There was no correlation between age and dose-corrected plasma risperidone levels or between age and QTc. There was a significant positive correlation between age and dose-corrected plasma paliperidone levels (r = 0.290; p = 0.023). Conclusion Clinically, paliperidone is considered to play a more important role in QT prolongation than risperidone. Copyright c 2011 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.1258

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objective The sum of the serum levels of risperidone (RIS) and 9-hydroxyrisperidone (9-OH-RIS), which is the active moiety serum level, could be important for estimating the clinical effects of RIS. However, there have been no consistent results reported about the relationship between cytochrome P450 (CYP) 2D6*10 allele and plasma 9-OH-RIS or active moiety levels. We investigated the effect of the number of CYP2D6*10 alleles on steady-state plasma RIS, 9-OH-RIS, and active moiety levels in Japanese patients. Methods Steady-state plasma RIS, 9-OH-RIS, and active moiety levels were measured in 64 patients treated with an average dosage of 4.6 mg/day. Results The number of CYP2D6* 10 alleles significantly affected dose-corrected plasma RIS levels (p = 0.001), and the median concentrations in ng/ml/mg were 0.94 (0 allele) vs. 1.73 (1 allele) vs. 3.05 (2 alleles). The number of CYP2D6* 10 alleles did not affect plasma 9-OH-RIS or active moiety levels. Conclusion The present study shows that the number of CYP2D6* 10 alleles affected plasma RIS levels but not plasma 9-OH-RIS and plasma active moiety levels. Because the plasma active moiety levels can influence antipsychotic effects or side effects, the genetic screening of the CYP2D6* 10 allele for RIS in Asian populations may not be clinically important. Copyright (C) 2012 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.1260

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Language：Japanese   Publisher：(株)医学書院  

DOI： 10.11477/mf.1405102080

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Other Link： http://search.jamas.or.jp/link/ui/2012132981

Publishing type：Research paper (scientific journal)   Publisher：Genetics and Molecular Research  

DOI： 10.4238/2012.april.27.13

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Language：English   Publisher：FUNPEC-EDITORA  

DOI： 10.4238/2012.April.27.13

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Language：Japanese   Publisher：Japanese Society of Clinical Pharmacology and Therapeutics  

Physical health problems, specifically glucose/lipid metabolism and cardiovascular comorbidity, in schizophrenic patients have become a major focus in both clinical care and research in recent years. The association of schizophrenia with metabolic and other cardiovascular disease risk factors is a complex interplay between environmental (including lifestyle, diet and substance use), genetic and illness-related (such as specific symptoms) factors, as well as the effects of treatment. Both past and more recent studies have confirmed the high rate of premature mortality due to cardiovascular disease in people with schizophrenia. Moreover, antipsychotic medication per se may induce cardiovascular and metabolic abnormalities (such as obesity, hyperglycemia, dyslipidemia and the metabolic syndrome) that are associated with increased risks of type 2 diabetes mellitus and cardiovascular disease. Controversy remains about the contribution of individual antipsychotic drugs to this increased risk and whether they cause sudden cardiac death through prolongation of the corrected QT interval. The need for screening, monitoring and prevention of metabolic and other cardiovascular disease risk factors has been acknowledged in the psychiatric literature. However, the evaluation of screening practices by clinicians has consistently shown that they are suboptimal. In our facilities, we monitor the physical risks induced by novel antipsychotics by performing comprehensive examination for metabolic syndrome-related side effects and QT interval abnormality, and continue to follow the health of patients with schizophrenia. In this report, we introduce the results of research in our facilities, which is based on evidence reported in overseas countries, and attempt to show the preventive measures for each physical risk associated with novel antipsychotics.

DOI： 10.3999/jscpt.43.151

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing &gt;2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 x 10(-6)), PDE4A (P = 1.4 x 10(-6)), and PLAT (P = 1 x 10(-3)), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 x 10(-12)) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population. (C) 2011 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.31233

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Language：Japanese   Publisher：(株)星和書店  

抗精神病薬の効果に関する薬剤間の差はいまだ明らかとは言えないが、抗精神病薬の副作用は薬剤間で明らかに異なることが知られ、抗精神病薬の選択は副作用の違いを考慮して行われている。第二世代抗精神病薬の広まりにより錐体外路症状などの副作用は減少傾向にあるが、肥満や糖・脂質代謝異常、心電図のQT延長、高プロラクチン血症といった副作用への注目が高まっている。本稿では、これらの抗精神病薬の副作用に関する知見について当施設における研究結果を交え概説し、より副作用の少ない抗精神病薬治療を行うための助けとしたい。(著者抄録)

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Language：Japanese   Publisher：(一社)日本小児精神神経学会  

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Language：Japanese   Publisher：(株)アークメディア  

60歳時に不眠・不安が出現し、書字困難、筋強剛、ふらつきも認める61歳女性症例について検討した。神経内科への通院では軽快せず、精神疾患が疑われた。精神科入院時には抑うつや不安は認められず、主体は急速進行性の認知症であった。MRI拡散強調画像(DWI)で大脳皮質に高信号を、脳波では全般性徐派を認め、この時点でクロイツフェルト・ヤコブ病(CJD)を疑った。発症13ヵ月後、無言・無動・全身性ミオクローヌス、脳波上の周期性同期性放電(PSD)が出現し、孤発性CJDと診断した。後方視的に、DWIで明らかな認知障害が出現する以前(発症5ヵ月時点)から大脳皮質に高信号を認めた。DWIや脳波は初期のCJDを疑う所見として有用であると思われた。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J01552&link_issn=&doc_id=20111012180004&doc_link_id=%2Fao1clphd%2F2011%2F004010%2F005%2F1279-1286%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fao1clphd%2F2011%2F004010%2F005%2F1279-1286%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)先端医学社  

これまでの画像研究の蓄積で、自閉症スペクトラム(ASD)者の下前頭回、眼窩前頭皮質、前帯状皮質、上側頭溝、扁桃体、紡錘状回、島、後頭頂葉、補足運動野、大脳基底核、小脳、視床などの構造、機能が定型発達者とくらべて異なることが明らかとなってきている。またASDの臨床症状(社会性、コミュニケーション、こだわり、こころの理論、模倣、表情認知の障害)と関連する脳領域も解明されてきており、脳形態・機能画像や遺伝子多型などを組み合わせることにより、ASDの診断や重症度を予測する生物学的診断マーカーを同定することが今後の課題であるといえる。(著者抄録)

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Language：Japanese   Publisher：(株)星和書店  

統合失調症における薬物療法に関連した循環器系副作用として、頻脈、徐脈、起立性低血圧、心室細動に至る致死性不整脈、心筋炎、静脈血栓塞栓症等が知られている。これら循環器系副作用は、統合失調症患者の生命予後に大きな影響を与えていると考えられる。また、第一世代抗精神病薬のみならず第二世代抗精神病薬も同様に循環器系副作用の危険因子であると報告されている。こうした副作用の発現を予防するため、各薬剤のプロフィールを考慮に入れ、また、患者個人の危険因子を検討した上での薬剤選択、用量設定が必要である。患者個人に危険因子が存在する場合には、標準12誘導心電図はもとより、必要に応じて、ホルター心電図、心エコー、下肢静脈エコーの施行や、心電図モニタによる監視が推奨される。(著者抄録)

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/JCP.0b013e318221e80d

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objectives There have been few reports regarding olanzapine (OLZ)-related QT prolongation and hyperprolactinemia. This study evaluated the dose-dependent effect of OLZ on QT interval and plasma prolactin (PRL) level in a single sample of patients with schizophrenia.
Methods Twenty-six subjects treated with varying starting doses of OLZ were enrolled in the study. Following baseline assessments, which included completion of the Brief Psychiatric Rating Scale (BPRS), measurements of Body Mass Index (BMI), QT interval, electrolytes, fasting plasma glucose, PRL, hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), and low density lipoprotein (LDL), the dose of OLZ was increased for each subject. The same parameters were evaluated following the increased dose treatment.
Results A significant decrease was observed in BPRS score (p=0.01) following treatment with an increased dose of OLZ. Significant increases were observed in BMI (p=0.032), QTc (p=0.031), and plasma PRL level (p=0.028). The mean values of electrolytes, fasting plasma glucose, HbA1c, TC, TG, HDL and LDL treatment were unchanged by the switch to increased-dose OLZ treatment.
Conclusion We have demonstrated the dose-dependent effect of OLZ on the QT interval and the plasma PRL level of patients with schizophrenia. Copyright (C) 2011 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.1218

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Language：Japanese   Publisher：(株)エムイー振興協会  

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Other Link： http://search.jamas.or.jp/link/ui/2011324919

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

The CYP2D6 enzyme is a capacity-limited high-affinity drug elimination pathway that metabolizes numerous psychiatric medicines. The capacity-limited nature of this enzyme suggests that drug dose may serve as an important factor that influence genotype-phenotype associations. However, dose dependency of CYP2D6 genotype contributions to drug elimination, and its interaction with environmental factors (e. g., smoking) did not receive adequate attention in translational study designs. Fluvoxamine is a selective serotonin reuptake inhibitor antidepressant. Fluvoxamine concentration is one of the factors previously linked to clinical remission in moderate to severe depression. We investigated the joint effect of smoking (an inducer of CYP1A2) and CYP2D6 genotype on interindividual variability in fluvoxamine steady-state concentration. Fluvoxamine concentration was measured in 87 patients treated with 50, 100, 150 or 200 mg/d. While CYP2D6 genotype significantly influenced fluvoxamine concentration in all four dose groups (p &lt; 0.05), the percentage variance explained (R(2)) by CYP2D6 decreased as the dose of fluvoxamine increased. Smoking status (nonsmokers vs. smoking 20 or more cigarettes/d) significantly affected fluvoxamine concentration in the 50 mg/d group only (p = 0.005). Together, CYP2D6 genotype and smoking status explained 23% of the variance in fluvoxamine concentration but only at the low 50 mg/d dose group. These findings contribute to evidence-based and personalized choice of fluvoxamine dose using smoking status and CYP2D6 genetic variation. Additionally, these data lend evidence for drug dose as an important variable in translational pharmacogenetic study design and pharmaceutical phenotype associations with capacity-limited drug metabolism pathways such as CYP2D6.

DOI： 10.1177/0269881110370504

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Language：Japanese   Publisher：(株)先端医学社  

マイクロRNA(miRNA)とは蛋白質をコードしない小分子RNAであり、標的となるmRNAに結合してその翻訳を制御し、神経発達やシナプス機能に重要な役割を果たしている。死後脳研究、遺伝子関連研究、動物モデル研究からこれまでに得られた知見をまとめると、miRNA関連遺伝子のまれな変異により成熟miRNAの発現変化や標的mRNAの翻訳異常が引き起こされる結果として、最終的には統合失調症の発症に至る可能性がある。統合失調症の病態におけるmiRNA機能異常の分子機構が解明され、将来的にはmiRNAを標的とした画期的な抗精神病薬の開発につながることが期待される。(著者抄録)

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Language：Japanese   Publisher：(株)星和書店  

注意欠如・多動性障害(ADHD)は、不注意、多動、衝動性の主症状が幼児期より顕在化する発達障害の一群である。ADHDの治療では、欧米では古くよりmethylphenidate(MPH)やamphetamineなどの中枢刺激薬を中心とした薬物療法が行われてきており、現在我が国でも、中枢刺激薬のMPH徐放剤(コンサータ)と非中枢刺激薬である選択的ノルアドレナリン再取り込み阻害薬atomoxetine(ストラテラ)の2剤が、ADHDに保険適応のある治療薬として使用可能である。これまでに発表されている欧米における最新のADHD薬物治療ガイドラインでは、いずれも中枢刺激薬が薬物治療の第一選択薬として位置づけられているのに対し、我が国のガイドラインでは、薬物療法は心理社会的介入などを含めた包括的治療の選択肢の1つとして位置づけられており、さらに中枢刺激薬のMPH徐放剤と非中枢刺激薬のatomoxetineが第一選択薬として同格に位置づけられていることが特色となっている。最近のメタ解析では、中枢刺激薬とatomoxetineのADHDに対する効果は同等であると報告されており、欧米のガイドラインもこのようなエビデンスを受けて、今後改訂されていくことが予想される。我が国独自のガイドラインを作成・改訂して行くにあたり、日本人のADHDを対象とした臨床研究が圧倒的に不足しており、今後、我が国における臨床経験とエビデンスを積み重ねていくことが急務の課題である。(著者抄録)

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統合失調症治療において、初回エピソード顕在化以前の前駆期からの治療介入を推奨する意見もあるが、この前駆期を前方視的に診断しようと作成された発症危険精神状態(at risk mental state)という診断基準も偽陽性率が高く、感情鈍麻や意欲低下などの陰性症状を主体に経過する単純型統合失調症のような病態についてはほぼ診断不可能であるという問題がある。一方、統合失調症の発病前より進行性に脳の構造および機能的変化が出現するという報告があり、こうした脳画像所見は前駆期および単純型統合失調症の生物学的マーカーとなる可能性がある。我々は、陰性症状と社会機能低下に加えて弱い精神病様症状を呈し、単純型統合失調症および発症危険精神状態と診断された24歳女性に対してaripiprazoleを投与したところ、陰性症状に加えて、認知機能および局所脳血流低下が改善した症例を経験したので報告する。(著者抄録)

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Language：Japanese   Publisher：(有)科学評論社  

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Other Link： http://search.jamas.or.jp/link/ui/2011279306

Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/mp.2010.37

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

DOI： 10.1016/j.pnpbp.2010.10.024

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Background: Japan is located in an area prone to natural disasters, and major earthquakes have occurred recently in rural areas where the proportion of elderly adults is high. Although elderly persons are vulnerable members of communities at a time of disaster, the prevalence of mental disorders among this population has yet to be reported in Japan. This study aimed to determine the prevalence of mental disorders and suicidal thoughts among community-dwelling elderly persons 3 years after an earthquake and to identify risk factors associated with their quality of life (QOL).
Methods: Face-to-face interviews were conducted with 496 community-dwelling persons aged 65 years or older in areas of Japan where 2 major earthquakes had occurred during a 3-year period. The main outcome was diagnosis of a mental disorder or suicidality.
Results: During the 3-year period after the earthquake, 1.6% of men and 5.5% of women had received a diagnosis of major depression. There were no cases of posttraumatic stress disorder. Women were more likely than men to report suicidality (7.8% vs 3.8%, P = 0.075).
Conclusions: The prevalence of mental disorders was lower than that reported in previous studies. Despite the low prevalence of mental disorders, the percentage of community-dwelling elderly persons with subclinical mental health symptoms was high. The results indicate that appropriate public health and medical interventions are warranted after a natural disaster.

DOI： 10.2188/jea.JE20100093

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Bentham Science Publishers B.V.  

DOI： 10.2174/187569211794728841

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1819.2011.02210.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

We measured the thalamic volumes of 38 subjects with autism spectrum disorders (ASD), including autism, Asperger&apos;s disorder, and pervasive developmental disorder not otherwise specified, and 16 matched healthy controls. Thalamic volume in all ASD subgroups was significantly smaller compared with volume in the control subjects. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.pscychresns.2010.07.001

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Language：English   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.schres.2010.08.001

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Language：Japanese   Publisher：(株)アークメディア  

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Other Link： http://search.jamas.or.jp/link/ui/2011162745

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objective We examined whether discontinuation and the responses to fluvoxamine (FLV) administration could predict the subsequent discontinuation and the responses to paroxetine (PRX) in patients with depression.
Methods The subjects comprised 106 outpatients who were diagnosed with depression, and clinical evaluation was conducted every 2 weeks. Patients who discontinued FLV because of side effects or did not achieve remission with 200 mg/day of FLV, the drug was switched to PRX. The maximum dose of PRX was 40 mg/day.
Results Among 10 patients who discontinued FLV, PRX was also discontinued in one patient. Of 33 patients without remission on FLV, PRX was discontinued because of side effects in two patients. There was no statistical difference in the discontinuation rates between the two groups. Four of 10 patients who discontinued FLV achieved remission, while nine of 33 patients without remission with FLV achieved remission with PRX. The remission rate was not significantly different between the two groups.
Conclusion Discontinuation and the responses related to FLV could not serve as a predictor for the subsequent discontinuation and the responses related to PRX. Copyright (C) 2010 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.1147

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Background. Risperidone (RIS) has the highest propensity to elevate plasma prolactin (PRL) levels. While the active metabolite 9-hydroxy-rispendone (9-OH-RIS) plays a predominant role in the efficacy and side effects of RIS, the mechanistic details are still poorly understood The present study evaluated the gender differences in the relationship between plasma levels of RIS or 9-OH-RIS and PRL
Methods Twenty-one male and 19 female subjects treated with RIS were enrolled in the present series All patients had been receiving RIS for at least 4 weeks at an average dosage of 47 mg/day Plasma RIS, 9-OH-RIS and PRL levels were measured
Results. In the male patients, there was no correlation between the RIS dosage and plasma PRL levels. between plasma RIS levels and PRL levels, or between the plasma 9-OH-RIS levels and PRL levels In the female patients, there was a significant positive correlation between the plasma 9-OH-RIS levels and PRL levels (rs = 0 456, p =0 049) There was a trend toward a significant positive correlation between the RIS dosage and plasma PRL levels There was no correlation between the plasma RIS levels and PRL levels
Conclusion. 9-OH-RIS is considered to play a more important role in PRL elevation than RIS, and a gender difference exists in the effect of 9-OH-RIS on PRL level. (C) 2010 Elsevier Inc. All rights reserved

DOI： 10.1016/j.pnpbp.2010.07.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Many gene variants are involved in the susceptibility to schizophrenia and some of them are expected to be associated with other human characters. Recently reported meta-analysis of genetic associations revealed nucleotide variants in synaptic vesicular transport/Golgi apparatus genes with schizophrenia. In this study, we selected the dymeclin gene (DYM) as a candidate gene for schizophrenia. The DYM gene encodes dymeclin that has been identified to be associated with the Golgi apparatus and with transitional vesicles of the reticulum-Golgi interface. A three-step case-control study of total of 2105 Japanese cases of schizophrenia and 2087 Japanese control subjects was carried out for tag single-nucleotide polymorphisms (SNPs) in the DYM gene and an association between an SNP, rs833497, and schizophrenia was identified (allelic P-2 x 10(-5), in the total sample). DYM is the causal gene for Dyggve-Melchior-Clausen syndrome and this study shows the second neuropsychiatric disorder in which the DYM gene is involved. The present data support the involvement of Golgi function and vesicular transport in the presynapse in schizophrenia. Journal of Human Genetics (2010) 55, 631-634; doi:10.1038/jhg.2010.72; published online 17 June 2010

DOI： 10.1038/jhg.2010.72

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Language：Japanese   Publisher：(株)医学書院  

日本の国際的診断方式の使用状況を調査する目的でアンケート調査を実施し,327名の精神科医から回答を得た。回答者を基準派(診断に操作的診断基準を重視する群)と記述派(診断に記述的診断方法を重視する群)に分け,その比較を中心に解析した。基準派の中でも説明・告知には記述的診断方法を用いるものが17.7%,記述派の中でも明確な診断基準による診断を治療上有用と答えたものが45.3%おり,また代表的な4つの精神疾患の診断確定法では,記述派は疾患により多様な診断方法を用いるなど,両派にはともに目的別に両診断を使い分ける群が存在した。双方の長所と短所を十分に把握したうえで,互いの短所を相補う形で用いられることが望ましいと考えられた。(著者抄録)

DOI： 10.11477/mf.1405101697

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J00749&link_issn=&doc_id=20100907240007&doc_link_id=10.11477%2Fmf.1405101697&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1405101697&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

We investigated whether the promoter region of the serotonin transporter gene (5-HTTLPR) polymorphism influenced neurochemical metabolism in 26 individuals with autism spectrum disorder. Individuals with the S/S genotype of the 5-HTTLPR polymorphism showed significantly lower levels of N-acetylaspartate/creatine in the right medial prefrontal cortex compared with those with the S/L genotype. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.pscychresns.2010.04.015

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DOI： 10.1016/j.pnpbp.2010.04.006

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Background: Perospirone was developed in Japan and is used for the treatment of schizophrenia and related illnesses. The authors investigated the relationship between the dosage of perospirone and the plasma levels of perospirone and its active metabolite, ID15036, and also evaluated the impact of the plasma concentrations of perospirone and ID15036 on the plasma prolactin level to examine whether perospirone or ID15036 affected the dopamine D(2) blockade, in psychiatric patients treated with perospirone.
Methods: The subjects consisted of 21 adults treated with perospirone (4-60 mg/day). The plasma perospirone and ID15036 levels were measured in 21 patients and serum prolactin levels were investigated in 10 male patients with schizophrenia.
Results: The plasma ID15036 level was higher than the plasma perospirone, and a positive correlation was observed between the dosage of perospirone and the ID15036 levels (p = 0.032). The 10 male patients showed a positive correlation between the plasma perospirone levels and plasma prolactin levels (r = 0.688, p = 0.028) and between the plasma ID15036 levels and prolactin levels (r = 0.775, p = 0.009).
Conclusion: The plasma levels of ID15036 may have a greater impact on the dopamine D(2) blockade than perospirone in patients treated with perospirone. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2010.03.027

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DOI： 10.1016/j.pnpbp.2010.04.008

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER WIEN  

Neuregulin-1 (NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1 beta 1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients (n = 40) and healthy volunteers (n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 +/- A 0.40 ng/mL, similar to 213 +/- A 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic influence of antipsychotic medications, there was no significant effect of chronic haloperidol treatment on serum Ig-NRG1 immunoreactivity in monkeys. These findings suggest that serum NRG1 levels are decreased in patients with chronic schizophrenia and influenced by their SNP8NRG243177 alleles.

DOI： 10.1007/s00702-010-0418-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background: Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia than in those of controls. Methods: Gene expression was screened by Illumina Human-6 Expression BeadChip arrays and confirmed by real-time reverse transcription-polymerase chain reaction assays and Western blot analysis. Results: Expression of GNB1L was lower in patients with schizophrenia than in control subjects in both Australian (10 schizophrenia cases and 10 controls) and Japanese (43 schizophrenia cases and 11 controls) brain samples. TBX1 could not be evaluated due to its low expression levels. Expression levels of the other genes were not significantly lower in patients with schizophrenia than in control subjects. Association analysis of tag single-nucleotide polymorphisms in the GNB1L gene region did not confirm excess homozygosity in 1918 Japanese schizophrenia cases and 1909 Japanese controls. Haloperidol treatment for 50 weeks increased Gnb1l gene expression in prefrontal cortex of mice. Conclusions: Taken together with the impaired prepulse inhibition observed in heterozygous Gnb1l knockout mice reported by the previous study, the present findings support assertions that GNB1L is one of the genes in the 22q11DS region responsible for increasing the risk of schizophrenia.

DOI： 10.1093/schbul/sbn160

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Gene expression profiling with microarray technology suggests that peripheral blood cells might be a surrogate for postmortem brain tissue in studies of schizophrenia. The development of an accessible peripheral biomarker would substantially help in the diagnosis of this disease. We used a bioinformatics approach to examine whether the gene expression signature in whole blood contains enough information to make a specific diagnosis of schizophrenia. Unpaired t-tests of gene expression datasets from 52 antipsychotics-free schizophrenia patients and 49 normal controls identified 792 differentially expressed probes. Functional profiling with DAVID revealed that eleven of these genes were previously reported to be associated with schizophrenia, and 73 of them were expressed in the brain tissue. We analyzed the datasets with one of the supervised classifiers, artificial neural networks (ANNs). The samples were subdivided into training and testing sets. Quality filtering and stepwise forward selection identified 14 probes as predictors of the diagnosis. ANNs were then trained with the selected probes as the input and the training set for known diagnosis as the output. The constructed model achieved 91.2% diagnostic accuracy in the training set and 87.9% accuracy in the hold-out testing set. On the other hand, hierarchical clustering, a standard but unsupervised classifier, failed to separate patients and controls. These results suggest analysis of a blood-based gene expression signature with the supervised classifier, ANNs, might be a diagnostic tool for schizophrenia. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2009.12.024

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The pathogenesis of schizophrenia has yet to be fully characterized. Gene-environment interactions have been found to play a crucial role in the vulnerability to this disease. Among various environmental factors, inflammatory immune processes have been most clearly implicated in the etiology and pathology of schizophrenia. Cytokines, regulators of immune/inflammatory reactions and brain development, emerge as part of a common pathway of genetic and environmental components of schizophrenia. Maternal infection, obstetric complications, neonatal hypoxia and brain injury all recruit cytokines to mediate inflammatory processes. Abnormal expression levels of specific cytokines such as epidermal growth factor, interleukins (IL) and neuregulin-1 are found both in the brain and peripheral blood of patients with schizophrenia. Accordingly, cytokines have been proposed to transmit peripheral immune/inflammatory signals to immature brain tissue through the developing blood-brain barrier, perturbing structural and phenotypic development of the brain. This cytokine hypothesis of schizophrenia is also supported by modeling experiments in animals. Animals treated with specific cytokines of epi

DOI： 10.1111/j.1440-1819.2010.02094.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The adenylate cyclase-activating polypeptide 1 (ADCYAP1) gene encodes a neuropeptide with neurotransmission activity, which is known as the pituitary adenylate cyclase-activating polypeptide. Associations of two polymorphisms, rs1893154 and rs2856966 (Asp54Gly), in the ADCYAP1 gene with schizophrenia were reported earlier by a Japanese case-control study. In this study, we tried to confirm the association in 2027 Japanese patients with schizophrenia and 2058 controls. The power to detect an association was more than 0.9. However, we did not detect allelic associations of rs1893154 with schizophrenia (P=0.36). Although rs2856966 was nominally significant (P=0.045), the association was in the opposite direction from that reported earlier. Combined data and meta-analysis of the two studies comprising nearly 6000 Japanese case-control patients did not show significant associations (P=0.53-0.86). It is concluded that single-nucleotide polymorphisms, including Asp54Gly, of the ADCYAP1 gene are unlikely to play a sizeable role in the genetic susceptibility to schizophrenia. Psychiatr Genet 20:123-125 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI： 10.1097/YPG.0b013e32833a1f52

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Language：Japanese   Publisher：(株)星和書店  

うつ病治療において、最初のSSRIを副作用で中断した場合、次の治療を別のSSRIで安全に行えるかについては不明である。本研究では、fluvoxamine(FLV)を副作用で中断した症例をparoxetine(PRX)へ置換し、同一個体において忍容性の違いを検討した。対象は大うつ病性障害と診断された外来患者94例。初診後FLVで治療開始し、経過中にFLVを副作用で中断した症例をPRXへ置換し、副作用による中断の有無を検討した。94例中、FLVを副作用で中断したものは10例(10.6%)であり、そのうち7例が消化器系症状で中断していた。この10例のうち、PRXも副作用で中断したものは1例(10%)であり、FLVとPRXの副作用中断の割合に統計学的有意差を認めなかった(p=1.000)。よって、うつ病治療においてFLVを副作用で中断した場合でも、PRXへの切り替え治療は安全に行える可能性が示唆された。(著者抄録)

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Language：Japanese   Publisher：(公財)臨床薬理研究振興財団  

抗うつ薬に関する薬物動態学的因子および薬理力学的因子を包括的に検討し、個々の症例に合わせた個別化抗うつ薬治療を実現するための科学的根拠を確立した。SSRIであるフルボキサミンの血中濃度に影響を与える因子、フルボキサミン血中濃度とうつ病の寛解との関係、フルボキサミン治療によるうつ病の寛解とCOMT遺伝子多型との関係について検討した。フルボキサミン用量が増加するにつれてCYP2D6遺伝子型がフルボキサミン血中濃度に与える影響が小さくなった。一日のフルボキサミン内服用量が低いほどCYP2D6遺伝子型および喫煙がフルボキサミン血中濃度に強い影響を持つことが示唆された。P2プロモーター領域rs2075507のT(A)アリルとうつ病の寛解との間に強い関連を認めた。高いCOMT活性、すなわち低ドパミン状態の方がフルボキサミン治療で寛解しやすかった。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background: Neural endocannabinoid function appears to be involved in schizophrenia. Two endocannabinoid receptors, CB1 and CB2, are found in the brain and elsewhere in the body. We investigated roles of CB2 in schizophrenia.
Materials and Methods: An association study was performed between tag single nucleotide polymorphisms (SNPs) in the CNR2 gene encoding the CB2 receptor and schizophrenia in two independent case-control populations. Allelic differences of associated SNPs were analyzed in human postmortem brain tissues and in cultured cells. Prepulse inhibition and locomotor activity in C57BL/6JJmsSlc mice with CB2 receptor antagonist AM630 administration was examined.
Results: The analysis in the first population revealed nominally significant associations between schizophrenia and two SNPs, and the associations were replicated in the second population. The R63 allele of rs2501432 (R63Q) (p = .001), the C allele of rs12744386 (p = .005) and the haplotype of the R63-C allele (p = 5 X 10(-6)) were significantly increased among 1920 patients with schizophrenia compared with 1920 control subjects in the combined population. A significantly lower response to CB2 ligands in cultured CHO cells transfected with the R63 allele compared with those with Q63, and significantly lower CB2 receptor mRNA and protein levels found in human brain with the CC and CT genotypes of rs12744386 compared with 11 genotype were observed. AM630 exacerbated MK-801- or methamphetamine-induced disturbance of prepulse inhibition and hyperactivity in C57BL/6JJmsSlc mice.
Conclusions: These findings indicate an increased risk of schizophrenia for people with low CB2 receptor function.

DOI： 10.1016/j.biopsych.2009.09.024

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Several genome-wide linkage studies have suggested linkage between markers on the long arm of chromosome 22 and schizophrenia. It has also been reported that 22q11.2 deletions increase the risk of schizophrenia. Therefore, 22q is a candidate region for schizophrenia. To search for genetic susceptibility loci for schizophrenia on 22q, we conducted a three-stage case-control association study in Japanese individuals. In the first stage, we examined 13 microsatellite markers on 22q in 766 individuals (340 patients with schizophrenia and 426 control individuals) and found a potential association of AFM262VH5 (D22S283) with schizophrenia. In the second stage, we performed fine mapping of the myosin heavy chain 9, non-muscle (MYH9) gene, where AFM262VH5 is located, using 25 tagging single nucleotide polymorphisms (SNPs). We obtained potential associations between three SNPs in MYH9 and schizophrenia in 1193 individuals (595 patients and 598 controls), which included the individuals analyzed in the first stage. In the third stage, however, we could not replicate these associations in 4694 independent individuals (2288 patients and 2406 controls). Our results suggest that MYH9 does not confer increased susceptibility to schizophrenia in the Japanese population, although we could not exclude possible contributions of other genes on 22q to the pathogenesis of schizophrenia. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2010.01.023

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Language：Japanese   Publisher：(株)永井書店  

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Other Link： http://search.jamas.or.jp/link/ui/2010195561

Language：Japanese   Publishing type：Research paper (scientific journal)  

When predicting the effects of medication for psychiatric diseases and their side effects based on genetic information, there are many things to consider besides just genetic information, including the index to be evaluated. We have shown before that it is important to simultaneously analyze both pharmacokinetic factors such as the blood concentration and pharmacodynamic factors such as the site of drug action, when searching for genetic information that can be used to predict the treatment effects of fluvoxamine for depression and its side effects. For example, we have shown that there exists a specific concentration that can be used to predict remission in the treatment of depression with fluvoxamine (Fukui et al, 2008)
however, it is considered that without a sufficient examination of such factors besides genetic information, it is difficult to predict the effects using just genetic information. On the other hand, the situation is more complex with medication for schizophrenia. Although it appears that consensus has been obtained in that the goal of medication for depression is remission, the goal of medication for schizophrenia is not clear and it cannot be said that prediction studies on the effects have been sufficiently conducted using genetic information. Therefore, at our facility, focusing on metabolic anomalies due to antipsychotics, QT prolongation, and hyperprolactinemia, which have become issues in recent years, a prediction study on side effects was conducted. Because such side effects can be quantified, in comparison with the effects study, it is advantageously simple to examine the relationship with genetic information. However, in the course of this study, we discovered that there was a gender difference in terms of glycolipid metabolic anomalies, that antipsychotics particularly extended the QT interval during nighttime, and that prolactine following the administration of antipsychotics temporally increased before declining again a few weeks later. We believe that when examining the relationship between side effects and genetic information, the genetic information may not be sufficiently utilized unless the analysis is performed after obtaining a better understanding of the characteristics of such side effects.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Calcineurin (CN) is a calcium/calmodulin-dependent serine/threonine protein phosphatase and regulates neuronal structure, neurotransmission and activity-dependent gene expression. Several studies have indicated that CN signaling is likely to be involved in the pathogenesis of schizophrenia. The gene encoding CN-binding protein 1 (CABIN1) is located on 22q11.23, one of the common susceptibility loci for schizophrenia. Therefore, CABIN1 is a promising functional and positional candidate gene for schizophrenia. To assess whether CABIN1 is implicated in vulnerability to schizophrenia, we conducted a case-control association study between CABIN1 and schizophrenia. The results showed no evidence of an association between CABIN1 and schizophrenia using 11 tagging single nucleotide polymorphisms in 1193 Japanese subjects. Our results suggest that CABIN1 may not confer increased susceptibility for schizophrenia in the Japanese population. Journal of Human Genetics (2010) 55, 179-181; doi: 10.1038/jhg.2009.136; published online 15 January 2010

DOI： 10.1038/jhg.2009.136

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Language：Japanese   Publisher：(株)メディカルレビュー社  

以前より統合失調症患者では心血管疾患による死亡率が高いことが知られていたが、近年の研究により、統合失調症患者では一般人口と比較してメタボリックシンドロームの頻度が高いことが報告されてきた。したがって、統合失調症患者においてメタボリックシンドロームの管理を厳密に行うことにより、心血管疾患による死亡率を減少させることが可能になると考えられる。近年、未服薬の統合失調症患者でメタボリックシンドロームの背後にあるインスリン抵抗性が高いことや、インスリン感受性を増加させるサイトカインであるアディポネクチンが統合失調症患者で低値であること、インスリン感受性の低下を引き起こすサイトカインであるTNF-αが統合失調症患者で高値を示すことなどが報告されている。統合失調症患者でメタボリックシンドロームの頻度が高い原因としては、第2世代抗精神病薬による影響、統合失調症患者における視床下部-下垂体-副腎系の調節障害、統合失調症と糖尿病に共通した遺伝学的背景、統合失調症患者に特有の食習慣、運動習慣などが挙げられている。本稿では、統合失調症とメタボリックシンドロームとの関係と、統合失調症患者におけるメタボリックシンドロームの管理について概説する。(著者抄録)

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Language：Japanese   Publisher：(株)星和書店  

レビー小体型認知症(dementia with Lewy bodies:DLB)は、認知機能の動揺、繰り返す幻視、特発性のパーキンソニズムを中核的特徴とする変性疾患である。DLBではアセチルコリンエステラーゼ阻害薬であるdonepezil(DPZ)の有効性が示唆されており、適応外ではあるが比較的広く用いられている。しかし臨床現場においてDPZの副作用としてパーキンソニズムは消化器症状ほど十分には認識されていない。今回われわれは、パーキンソニズムがDPZ中止により一旦は軽減したものの再投与により悪化したDLBの1例を経験した。DPZがコリン神経伝達を増強することで黒質線条体経路におけるドパミン神経伝達の減弱が生じ、パーキンソニズムが悪化したと推察される。DLBに対してDPZを投与する際には、パーキンソニズムを惹起あるいは悪化させる可能性に留意して注意深く観察することが必要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The dopamine D3 receptor (DRD3) has been suggested to be involved in the pathophysiology of schizophrenia. DRD3 has been tested for an association with schizophrenia, but with conflicting results. A recent meta-analysis suggested that the haplotype T-T-T-G for the SNPs rs7631540-rs1486012-rs2134655-rs963468 may confer protection against schizophrenia. However, almost all previous studies of the association between DRD3 and schizophrenia have been performed using a relatively small sample size and a limited number of markers. To assess whether DRD3 is implicated in vulnerability to schizophrenia, we conducted case-control association studies and performed an updated meta-analysis. In the first population (595 patients and 598 controls), we examined 16 genotyped single nucleotide polymorphisms (SNPs), including tagging SNPs selected from the HapMap database and SNPs detected through resequencing, as well as 58 imputed SNPs that are not directly genotyped. To confirm the results obtained, we genotyped the SNPs rs7631540-rs1486012-rs2134655-rs963468 in a second, independent population (2126 patients and 2228 controls). We also performed an updated meta-analysis of the haplotype, combining the results obtained in five populations, with a total sample size of 7551. No supportive evidence was obtained for an association between DRD3 and schizophrenia in our Japanese subjects. Our updated meta-analysis also failed to confirm the existence of a protective haplotype. To draw a definitive conclusion, further studies using larger samples and sufficient markets should be carried out in various ethnic populations. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2009.10.016

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PubMed

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Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： http://search.jamas.or.jp/link/ui/2011002481

Language：English   Publisher：The Japanese Society of Clinical Neuropsychopharmacology  

Purpose: The purpose of this study is to compare the steady-state plasma levels of HAL between Japanese, Koreans and Swedes who were treated with HAL monotherapy per os. <br>Method: The steady-state plasma levels of haloperidol (HAL) in 75 Japanese, 120 Korean, and 50 Swedish psychiatric patients treated orally with HAL were compared. <br>Results: Significantly higher doses of HAL were used in the Koreans (mean dose = 21 mg/day) than in the Japanese (15 mg/day) or Swedes (9 mg/day) (one-way analysis of variance (ANOVA) (p<0.0001), Bonferroni's post test (p<0.001)). The mean concentration/daily dose ratio (C/D ratio) of HAL was 2.2 times higher in Korean patients (2.78 nmol/L/mg/day) and 1.5 times higher in Japanese patients (1.88 nmol/L/mg/day) than that in Swedish patients (1.24 nmol/L/mg/day). A significant difference in the C/D ratio was observed among the 3 ethnic groups (one-way ANOVA; p<0.0001). <br>Discussion: The higher C/D ratio of HAL in Asians might be partly due to the higher frequency of the <i>CYP2D6^*10</i> allele in Asians; however, interethnic differences in the activity of other enzymes, such as CYP3A4, might have caused the differences in the present study, especially at the higher doses of HAL.

DOI： 10.5234/cnpt.1.24

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Other Link： http://search.jamas.or.jp/link/ui/2012047010

Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1819.2010.02112.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL