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

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

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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Language：Japanese   Publisher：新潟周産母子研究会  

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

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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Other Link： https://www.nature.com/articles/s41598-022-22017-2

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

DOI： 10.1111/pcn.13494

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

DOI： 10.1002/pcn5.36

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

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

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

DOI： 10.1002/pcn5.28

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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

DOI： 10.1002/pcn5.24

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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

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

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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Other Link： https://link.springer.com/article/10.1186/s12877-021-02418-0/fulltext.html

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

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

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

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

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

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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Language：English  

DOI： 10.1111/pcn.13199

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

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

DOI： 10.5234/cnpt.12.1

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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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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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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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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：(公社)日本精神神経学会  

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

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

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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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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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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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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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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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DOI： 10.1111/pcn.12920

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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

Web of Science

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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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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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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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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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DOI： 10.1111/eip.12472

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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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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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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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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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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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DOI： 10.1111/pcn.12564

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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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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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DOI： 10.1038/mp.2016.88

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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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DOI： 10.1038/tp.2017.173

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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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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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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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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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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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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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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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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   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：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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Language：English   Publisher：ELSEVIER SCIENCE INC  

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：English   Publisher：WILEY-BLACKWELL  

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：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：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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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：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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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：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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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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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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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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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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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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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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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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DOI： 10.1111/pcn.12080

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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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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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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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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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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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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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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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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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DOI： 10.1038/tpj.2011.36

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DOI： 10.1111/pcn.12012

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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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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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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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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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DOI： 10.1176/appi.neuropsych.12100243

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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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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.

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DOI： 10.1111/j.1440-1819.2012.02396.x

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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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DOI： 10.1016/j.schres.2012.06.043

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DOI： 10.1111/j.1440-1819.2012.02388.x

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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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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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DOI： 10.1016/j.psychres.2012.02.025

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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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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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DOI： 10.1016/j.schres.2012.01.034

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DOI： 10.1016/j.psychres.2011.11.005

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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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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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DOI： 10.1111/j.1440-1819.2011.02310.x

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DOI： 10.1111/j.1440-1819.2011.02316.x

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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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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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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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DOI： 10.4238/2012.april.27.13

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DOI： 10.4238/2012.April.27.13

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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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DOI： 10.1097/JCP.0b013e318221e80d

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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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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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DOI： 10.1038/mp.2010.37

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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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DOI： 10.2174/187569211794728841

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DOI： 10.1111/j.1440-1819.2011.02210.x

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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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DOI： 10.1016/j.schres.2010.08.001

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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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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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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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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.

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DOI： 10.1016/j.pnpbp.2010.04.006

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

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   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：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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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  

Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P&lt;0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P &lt; 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary. (C) 2009 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.30941

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

Background: The present study was designed to find a good alternative to the voxel-based specific region analysis of Alzheimer's disease (VSRAD) on magnetic resonance images, which has high accuracy for discriminating between very early Alzheimer's disease (AD) patients and healthy controls. Because magnetic resonance imaging is not necessarily available in ordinary psychiatric hospitals in Japan, this type of study is of clinical significance.
Methods: In 30 psychiatric inpatients with a variety of diagnoses, the mean area of the inferior horn (Area), the mean width of the medial temporal lobe (Width), and their ratio (Area/Width) were measured on computed tomography (CT) section that was parallel to the orbitomeatus line. These three indices of medial temporal atrophy were compared separately with Z-scores from VSRAD, which indicate the degree to which the mean values deviate from control. Specifically, higher Z-scores indicate a smaller volume of the medical temporal lobe.
Results: The mean (+/-SD) of the CT indices Area, Width, and Area/Width were 39.6 +/- 22.1 mm(2), 10.3 +/- 3.01 mm, and 4.65 +/- 4.03, respectively. The mean (+/-SD) of the Z-scores from VSRAD was 1.47 +/- 0.76. The CT indices were all significantly correlated with the Z-scores while controlling for age (Area, r = 0.38, d.f. = 27, P = 0.04; Width, r = -0.45, d.f. = 27, P = 0.01; Area/Width, r = 0.57, d.f. = 27, P = 0.001). Of the three CT indices, Area/Width had the largest area under the curve (AUC) in receiver operating characteristic (ROC) curve analysis regarding Z-scores &gt;= 1.0 as the gold standard for the detection of subtle medial temporal atrophy.
Conclusion: Although we cannot conclude that Area/Width from CT scans is a perfect alternative to Z-scores from VSRAD &gt;= 1.0 because of its lower sensitivity, it was found that we can expect Z-scores &gt;= 1.0 at an Area/Width ratio &gt;= 4.0. Further research with a larger sample size and prospective design is required to confirm the usefulness of our CT method in the evaluation of medial temporal atrophy in psychiatric patients.

DOI： 10.1111/j.1479-8301.2009.00281.x

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

Peptidylarginine deiminases (PADIs), five isoforms of which have been identified, catalyze the conversion of arginine residues to citrulline residues in proteins. Recent studies have revealed that abnormal activation of PADI2, the gene for which is expressed throughout the nervous system, is likely to be related to the pathogenesis of neuropsychiatric diseases with neurodegenerative processes, such as Alzheimer&apos;s disease and multiple sclerosis. Such a progressive neurodegenerative process could be involved in the etiology and/or course of schizophrenia, and PADI2 may be a candidate gene for schizophrenia. To assess whether PADI2 has a role in vulnerability to schizophrenia, we conducted a two-stage case-control association study in Japanese individuals. In a screening population of 534 patients and 559 control individuals, we examined eight single-nucleotide polymorphisms (SNPs) including four haplotype tag SNPs and four coding SNPs in PADI2. There was a potential association of a synonymous SNP in exon 7 with schizophrenia. However, we could not replicate this association in a confirmatory population of 2126 patients and 2228 control individuals. The results of this study suggest that PADI2 does not contribute to genetic susceptibility to schizophrenia. Journal of Human Genetics (2009) 54, 430-432; doi: 10.1038/jhg.2009.52; published online 29 May 2009

DOI： 10.1038/jhg.2009.52

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

Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.

DOI： 10.1093/hmg/ddp166

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DOI： 10.1136/bmj.a1792

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Language：English   Publisher：MARY ANN LIEBERT, INC  

Applications of omics technologies in the postgenomics era swiftly expanded from rare monogenic disorders to multifactorial common complex diseases, pharmacogenomics, and personalized medicine. Already, there are signposts indicative of further omics technology investment in nutritional sciences (nutrigenomics), environmental health/ecology (ecogenomics), and agriculture (agrigenomics). Genotype-phenotype association studies are a centerpiece of translational research in omics science. Yet scientific and ethical standards and ways to assess and communicate risk information obtained from association studies have been neglected to date. This is a significant gap because association studies decisively influence which genetic loci become genetic tests in the clinic or products in the genetic test marketplace. A growing challenge concerns the interpretation of large overlap typically observed in distribution of quantitative traits in a genetic association study with a polygenic/multifactorial phenotype. To remedy the shortage of risk assessment and communication tools for association studies, this paper presents the concept of edge effect. That is, the shift in population edges of a multifactorial quantitative phenotype is a more sensitive measure (than population averages) to gauge the population level impact and by extension, policy significance of an omics marker. Empirical application of the edge effect concept is illustrated using an original analysis of warfarin pharmacogenomics and the VKORC1 genetic variation in a Brazilian population sample. These edge effect analyses are examined in relation to regulatory guidance development for association studies. We explain that omics science transcends the conventional laboratory bench space and includes a highly heterogeneous cast of stakeholders in society who have a plurality of interests that are often in conflict. Hence, communication of risk information in diagnostic medicine also demands attention to processes involved in production of knowledge and human values embedded in scientific practice, for example, why, how, by whom, and to what ends association studies are conducted, and standards are developed (or not). To ensure sustainability of omics innovations and forecast their trajectory, we need interventions to bridge the gap between omics laboratory and society. Appreciation of scholarship in history of omics science is one remedy to responsibly learn from the past to ensure a sustainable future in omics fields, both emerging (nutrigenomics, ecogenomics), and those that are more established (pharmacogenomics). Another measure to build public trust and sustainability of omics fields could be legislative initiatives to create a multidisciplinary oversight body, at arm's length from conflict of interests, to carry out independent, impartial, and transparent innovation analyses and prospective technology assessment.

DOI： 10.1089/omi.2009.0011

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

There is strong evidence for a negative association between schizophrenia and rheumatoid arthritis ( RA). However, the mechanism for this association is unknown. We hypothesize that these two diseases share susceptibility genes. Recently, extensive studies have identified some RA susceptibility genes, including NFKBIL1, SLC22A4, RUNX1, FCRL3 and PADI4, in the Japanese population. To assess whether polymorphisms in these RA susceptibility genes are implicated in vulnerability to schizophrenia, we conducted a two-stage case-control association study in Japanese subjects. In a screening population of 534 patients and 559 control subjects, we examined eight polymorphisms in RA susceptibility genes and found a potential association of padi4_94 in PADI4 with schizophrenia. However, we could not replicate this association in a confirmatory population of 2126 patients and 2228 control subjects. The results of this study suggest that these polymorphisms in RA susceptibility genes do not contribute to genetic susceptibility to schizophrenia.

DOI： 10.1038/jhg.2008.4

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

DOI： 10.2174/1875692110907030146

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Language：English   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

DOI： 10.1111/j.1440-1819.2008.01914.x

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DOI： 10.1111/j.1440-1819.2009.02023.x

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

Several studies have reported that the cytochrome P450 (CYP) 2D6 plays all important role ill the fluvoxamine metabolism. However, some other studies have reported that the CYP2D6 genotype has no major impact on the fluvoxamine concentration. This Study investigated the close-dependent effect of CYP2D6-variant alleles oil the steady-state fluvoxamine concentration. There were 23 patients whose plasma concentrations Of fluvoxamine were measured at 4 doses (50, 100, 150, and 200 mg/d). The differences in the plasma fluvoxamine concentration were analyzed between 2 genotype groups divided by the number of CYP2D6-variant alleles (with 0 and 1 or 2 variant alleles). The results demonstrated the nonlinear kinetics Of fluvoxamine metabolism, and the degree of nonlinear kinetics decreased as the dose was increased. Significant differences in fluvoxamine concentration were observed between the subjects with 0 variant alleles and the Subjects with 1 or 2 variant alleles (P = 0.044) when they were treated by 50 mg of fluvoxamine. There were no significant differences in the plasma concentration of fluvoxamine at 100, 150, and 200 mg/d. The present study suggests that the effect of the CYP2D6 genotype oil fluvoxamine metabolism is greater at lower closes of fluvoxamine.

DOI： 10.1097/FTD.0b013e31818d73b3

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

Aim: This study was undertaken 5 months after the 2004 Niigata-Chuetsu earthquake in Japan to assess factors that impacted on psychological distress and its recovery.
Methods: Three thousand and twenty-six adult victims who lived in temporary shelter and in seriously damaged areas were evaluated by questionnaire. The questionnaire queried subject profile, degree of house damage, health status, and psychological distress using a 5-point scale before, immediately and 5 months after the earthquake.
Results: Immediately after the earthquake, 59.3% of the subjects had psychological distress. At 5 months after the earthquake, however, this percentage decreased to 21.8%. The psychological distress immediately after the earthquake was significantly serious in victims who: (i) were female; (ii) felt stronger fear of the earthquake and the aftershocks; (iii) lived at home or office after the earthquake; and (iv) were injured due to the earthquake or suffered from sickness after the earthquake. In contrast, the factors impairing psychological recovery 5 months after the earthquake were as follows: (i) being with unfamiliar member(s) during the night after the earthquake; (ii) serious house damage; (iii) living in temporary shelter or at a relative&apos;s home after the earthquake; and (iv) physical illness after the earthquake.
Conclusion: Despite differences between disasters, these results were consistent with those in some previous studies and may be useful for long-term mental care support.

DOI： 10.1111/j.1440-1819.2008.01842.x

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/YPG.0b013e328306c7dc

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DR DIETRICH STEINKOPFF VERLAG  

Interleukin 2 (IL-2) and IL-4 are pleiotropic cytokines regulating Th1/Th2 balance and have a regulatory activity in brain function. Thus these cytokines have been implicated in the pathophysiology of schizophrenia. The latest studies provided controversial results regarding the genetic associations of these cytokines. The functional polymorphisms, IL2-330T/G and IL4-590C/T, were associated with schizophrenia in a German population, although contradictory findings were also reported in a Korean population. To ascertain whether IL2 and IL4 contribute to vulnerability to schizophrenia, we conducted a moderate-scale case-control (536 patients and 510 controls) association study for seven polymorphisms in Japanese subjects. There were no significant associations of these genes with schizophrenia using either single marker or haplotype analyses. The present study suggests that IL2 and IL4 do not contribute to vulnerability to schizophrenia in the Japanese population.

DOI： 10.1007/s00406-008-0813-z

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Language：English   Publisher：FUTURE MEDICINE LTD  

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DOI： 10.2217/14622416.9.7.819

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

Therapeutic drug monitoring studies of selective serotonin reuptake inhibitor (SSRI) antidepressants thus far failed to identify a clear concentration-response relationship in major depression. Majority of the previous studies defined clinical response as 50% or greater reduction from baseline in depression rating scale scores. Because many patients who meet these criteria still present symptoms associated with functional impairment, there is a need to consider "remission" as an alternative end point in concentration-response analyses of SSRIs. The present 12-week prospective study investigated the relationship between fluvoxamine (an SSRI) plasma concentration and remission in outpatients with depression. We used a flexible dose titration study designed to mimic clinical practice within the therapeutic dose range of fluvoxamine (25-200 mg/d). Receiver operating characteristics (ROC) curve was computed to determine the optimal fluvoxamine plasma concentration for remission using 269 concentration data obtained from 80 patients. Analysis of the ROC curve from the entire study sample did not reveal a fluvoxamine concentration significantly predicting remission. By contrast, ROC analysis specifically in patients with moderate to severe depression (N = 51; baseline 17-item Hamilton Rating Scale for Depression score &gt;= 20) found a fluvoxamine concentration of 61.4 ng/mL as a significant predictor of remission. In conclusion, therapeutic drug monitoring may be useful for rational titration and individualization of fluvoxamine dose and predicting remission in patients with moderate to severe depression, who may presumably display lesser placebo component in pharmacodynamic response.

DOI： 10.1097/JCP.0b013e3181730850

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

Chromosome 1p13 is linked with schizophrenia in Japanese families, and one of the candidate genes in this region is the netrinG1 (NTNG1) gene at 1p13.3. Associations of 56 tag single-nucleotide polymorphisms (SNPs) with schizophrenia were explored by transmission disequilibrium analysis in 160 Japanese trios and by case-control analysis in 2174 Japanese cases and 2054 Japanese controls. An association between SNP rs628117 and schizophrenia was identified by case-control comparison (nominal allelic p = 0.0009; corrected p = 0.006). The associated polymorphism is located in intron 9 and in the haplotype block encompassing the alternatively spliced exons of the gene. Allelic association of a different SNP in the same haplotype block in Japanese families was previously reported. These findings support that the NTNG1 gene is associated with schizophrenia in the Japanese. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2008.02.053

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DOI： 10.1111/j.1440-1819.2008.01762.x

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

Systematic linkage disequilibrium (LD) mapping of 8p12-21 in the Icelandic population identified neuregulin 1 (NRG1) as a pdrne candidate gene for schizophrenia. However, results of replication studies have been inconsistent, and no large sample analyses have been reported. Therefore, we designed this study with the aim of assessing this putative association between schizophrenia and NRG1 (especially HAP(ICE) region and exon region) using a gene-based association approach in the Japanese population.
This study was a two-stage association analysis with a different panel of samples, in which the significant association found in the first-set screening samples (1126 cases and 1022 controls) was further assessed in the confirmation samples (1262 cases and 1172 controls, and 166 trio samples). In the first-set scan, 60 SNPs (49 tagging SNPs from HapMap database, four SNPs from other papers, and seven SNPs detected in the mutation scan) were examined.
One haplotype showed a significant association in the first-set screening samples (Global P-value= 0.0244, uncorrected). However, we could not replicate this association in the following independent confirmation samples. Moreover, we could not find sufficient evidence for association of the haplotype identified as being significant in the first-set samples by imputing ungenotyped SNPs from HapMap database.
These results indicate that the positionally and functionally attractive regions of NRG1 are unlikely to contribute to susceptibility to schizophrenia in the Japanese population. Moreover, the nature of our results support that two-stage analysis with large sample size is appropriate to examine the susceptibility genes for common diseases. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2008.01.010

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

Introduction: Glutamate dysfunction has been implicated in the pathophysiology of schizophrenia. The metabotropic glutamate receptors (rnGluRs) are G-protein-coupled receptors. GRM7, the gene that encodes mGluR7, is expressed in many regions of the human central nervous system. The GRM7 gene is located on human chromosome 3p26, which has been suggested by linkage analysis to contain a susceptibility locus for schizophrenia.
Methods: We screened for mutations in all exons, exori/intron junctions, and promoter regions of the GRM7 gene in Japanese patients with schizophrenia and evaluated associations between the detected polymorphisms and schizophrenia. We examined the influence of one polymorphism associated with schizophrenia on the expression of GRM7 by dual-luciferase assay in transfected cells.
Results: Twenty-five polymorphisms/mutations were detected in GRM7. Case-control analysis revealed a potential association of a synonymous polymorphism (371 T/C, rs3749380) in exon 1 with schizophrenia in our case-control study of 2293 Japanese patients with schizophrenia and 2382 Japanese control subjects (allelic p=0.009). Dual-luciferase assay revealed suppression of transcription activity by exon 1 containing this polymorphism and a statistically significant difference in the promoter activity between the T and C alleles.
Conclusions: Our results support the possible association of a GRM7 gene polymorphism with genetic susceptibility to schizophrenia. (C) 2008 Elsevier B.V All rights reserved.

DOI： 10.1016/j.schres.2008.01.027

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

The GRM3 gene, which encodes a metabotropic glutamate receptor, is an important candidate gene for susceptibility to schizophrenia. Two single nucleotide polymorphisms (SNPs), rs1468412 and rs2299225 in intron 3, were reported to be associated with schizophrenia in Japanese and Chinese populations, respectively. Haplotypes with these SNPs were also reported to be associated with schizophrenia. In the present study, we attempted to replicate these single marker and haplotype associations in a case-control study of 1,916 Japanese patients with schizophrenia and 1,915 Japanese control subjects. In addition to these two SNPs, we genotyped rs274622 in the promoter region of GRM3. In the present study, none of these polymorphisms were associated with schizophrenia (rs274622, allelic P = 0.68; rs1468412, allelic P = 0.74; rs2299225, allelic P = 0.20). Haplotypes constructed with these SNPs also were not associated with schizophrenia (P = 0.18-0.84). Meta-analysis of five case-control studies of more than 3,000 patients with schizophrenia and more than 3,000 control subjects did not support the associations of rs1468412 and rs2299225 with schizophrenia. Our data indicate that SNPs previously reported to be associated with schizophrenia do not contribute to genetic susceptibility to schizophrenia. (C) 2007 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.30610

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS AS  

Objective. To revise the psychopharmacology algorithms for the treatment of mood disorders published in 1999 in Japan. Methods. The algorithms were established based on clinical psychopharmacological evidence, the results of a questionnaire survey sent to 200 Japanese psychiatrists, and the consensus of all the research members. Results. Six categorized algorithms have been developed, i.e. mild or moderate major depression, severe non-psychotic major depression, psychotic depression, mania, bipolar depression, and rapid cycling mood disorder. Conclusion. The revised algorithms will be helpful for the treatment of mood disorders in Japan.

DOI： 10.1080/13651500701330791

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

DOI： 10.2217/14622416.9.7.819

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

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

Background: Although several previous studies have been conducted, the neural basis of autism spectrum disorder (ASD) is poorly understood. The objective of the present study was to determine whether individuals with ASD have altered brainchemical metabolites and whether such alterations are related to their autistic symptoms.
Methods: N-acetylaspartate (NAA)/creatine (Cr) and choline/Cr ratios in the right medial temporal lobe (MTL), medial prefrontal cortex, and cerebellar vermis were measured in 38 individuals with ASD (mean age = 12.9years), including 12 with autism, 15 with Asperger's Disorder, and 11 with pervasive developmental disorder not otherwise specified (PDD-NOS), and 16 matched healthy control subjects (mean age = 11.5 years) with proton magnetic resonance spectroscopy. Autistic symptoms were assessed by the Childhood Autistic Rating Scale-Tokyo Version.
Results: There was a significant group difference for NAA/Cr ratio in the right MTL between the autism, Asperger's Disorder, PDD-NOS, and control groups (p &lt;.001), and the autism group had a significantly lower NAA/Cr ratio compared with the PDD-NCS (p &lt;.001) and control (p &lt;.001) groups. In the ASD group, there was a significant negative correlation between NAA/Cr ratio in the right MTL and their Childhood Autistic Rating Scale-Tokyo Version total scores (r = -.44, p =.01) and subscales of emotional response (r = -.38, p =.02) and listening response (r = -.54, p =.00 1).
Conclusions: The results of the present study suggest that subjects with ASD have abnormalities of neural integrity in the amygdalahippocampus region that are related to their severity and social impairments.

DOI： 10.1016/j.biopsych.2007.05.015

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

Serotonin (5-hydroxytryptamine [5-HT]) may be implicated in both the pathophysiology of schizophrenia and in mediating atypical antipsychotic drug effects. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme involved in the synthesis of 5-HT. Some genetic variants of the TPHI gene have been tested for their associations with schizophrenia, but with conflicting results. To assess whether TPHI is implicated in vulnerability to schizophrenia, we conducted a case-control association study (409 patients and 440 controls) for six single nucleotide polymorphisms in Japanese subjects and performed an updated meta-analysis. There were no significant associations between the polymorphisms or haplotypes of TPHI and schizophrenia in our Japanese subjects. Our updated meta-analysis, which included six population-based case-control studies, suggests the possible involvement of the TPHI 218A allele in susceptibility to schizophrenia. To draw any conclusion, however, further studies using larger sample sizes should be carried out in various ethnic populations. (C) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2007.08.002

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

Background Evidence suggests that, as a group, patients with schizophrenia have intellectual deficits that may precede the manifestation of psychotic symptoms; however, how successfully intelligence tests are able to discriminate schizophrenia from other psychotic disorders has yet to be investigated in detail.
Methods Using Wechsler Adult Intelligence Scale - Revised (WAIS-R) data for 55 inpatients with schizophrenia and 28 inpatients with non-schizophrenic psychotic disorders (NSPD) (schizophreniform disorder, brief psychotic disorder, delusional disorder, psychotic disorder due to a general medical condition, and psychotic disorders not otherwise specified), intelligence performance was compared between schizophrenia and NSPD and among different subtypes of schizophrenia.
Results There were no significant differences in intelligence quotient (IQ), verbal IQ (VIQ) and performance IQ (PIQ) discrepancy, and subtest scores of WAIS-R between the patients with schizophrenia and those with NSPD. These diagnostic groups were not discriminated well by any WAIS-R variables. Schizophrenia patients with prominent negative symptoms, on the other hand, had a significantly larger IQ discrepancy (VIQ &gt; PIQ) than those without prominent negative symptoms and NSPD patients. Intelligence performance in schizophrenia did not differ with respect to diagnostic subtypes and longitudinal courses.
Conclusions The current study failed to show diagnostic usefulness of WAIS-R in discriminating schizophrenia and other psychoses. A diagnosis of schizophrenia does not significantly impact intellectual deficits in psychotic disorders.

DOI： 10.1111/j.1365-2788.2007.00964.x

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Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/sj.mp.4002019

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

We analyzed a large multiplex schizophrenia pedigree collected in mid-eastern Japan using 322 microsatellite markers distributed throughout the whole autosome. Under an autosomaldominant inheritance model, the highest pairwise LOD score (LOD = 1.69) was found at 4q (D4S2431: theta= 0.0), and LOD scores at two other loci 3q (ATA34GO6) and 8q (D8S1128) were 1.62 and 1.46, respectively. In multipoint analysis, LOD scores of the regions on 4q and 3q remained at a similar level; however, the LOD score of the region on 8q apparently decreased. Additional dense map analysis revealed haplotypes on 4q and 3q regions shared by affected individuals. On chromosome 4q, the haplotype spanning about 8 centiMorgans (cM) was shared by four of six genotyped individuals with schizophrenia and one affected individual whose haplotype was estimated. On 3q, the haplotype spanning about 20 cM was shared by five genotyped individuals with schizophrenia. We obtained two candidate regions of major susceptibility loci for schizophrenia on chromosomes 3q and 4q. (c) 2007 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.30488

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

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotrophic cytokine and exerts neuroprotective and neurodegenerative effects in brain, Several studies have indicated that TNF-alpha is likely related to the pathogenesis of schizophrenia. Recent genetic investigations have revealed that a TNF-alpha gene promoter polymorphism (-G308A) is associated with schizophrenia, although negative findings have also been reported. To assess whether the TNF-alpha gene promoter variants including -G308A could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (265 cases and 424 controls) and the transmission disequilibrium test (TDT) analysis (83 trios) for four polymorphisms (-G238A, -G308A, -C857T and -T1031C) in Japanese subjects. In a case-control analysis, there was no significant association between the promoter polymorphisms or haplotypes in the TNF-alpha gene and schizophrenia. In the TDT analysis, we also did not observe transmission distortion. Our results suggest that the above four polymorphisms in the promoter region of the TNF-alpha gene appear not to confer increased susceptibility for schizophrenia in a Japanese population. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2006.03.009

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Language：English   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.schres.2007.05.032

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

Interleukin-1 (IL1) is an inflammatory cytokine and exerts neurodegenerative effects in the brain. Several studies have indicated that IL1 is likely to be involved in the pathogenesis of schizophrenia. Recent genetic studies have revealed that the IL1 gene complex (IL,1 alpha, IL1, beta and IL1 receptor antagonist) was associated with schizophrenia, although contradictory findings have also been reported. To assess whether the IL1 gene complex was implicated in vulnerability to schizophrenia, the authors conducted a case-control association study (416 patients with schizophrenia and 440 control subjects) for nine polymorphisms in Japanese subjects. The authors found no association between the IL1 gene complex polymorphisms and schizophrenia using either single-marker or haplotype analyses. The results of the present study suggest that the IL1 gene complex does not play a major role in conferring susceptibility to schizophrenia in the Japanese population.

DOI： 10.1111/j.1440-1819.2007.01671.x

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

The authors examined the diagnosis before the onset of schizophrenia and retrospectively evaluated the presence/absence of early prodromal symptoms (EPS) and their types (such as depressive symptoms, anxiety symptoms, and obsessive-compulsive [OC] symptoms) and the period from the onset of these symptoms to that of schizophrenia in 219 inpatients with schizophrenia diagnosed according to the DSM-IV(-TR). A diagnosis was made before the onset of schizophrenia in 53 patients (24.2%). The diagnoses were mood disorder in 39 patients, anxiety disorder in seven, obsessive-compulsive disorder (OCD) in three, adjustment disorder in two, and eating disorder in two. EPS were present in 65 (29.7%) of all patients, slightly more frequent in female patients (male : female = 1:1.41). In the group with EPS, depressive symptoms (61.5%) were most frequently observed, followed by anxiety symptoms (23.1%) and OC symptoms (9.2%). The age at onset for each type of symptom was significantly lower for OC symptoms (14.5 +/- 2.4 years) than for the other symptoms (approx. 20 years). The mean period from the onset of each symptom to that of schizophrenia was the shortest for depressive symptoms (2.7 +/- 3.1 years) and the longest (&gt; 4 years) for OC symptoms. These results as well as previous studies in Western countries showed that more non-specific and general symptoms are frequently present for some years before the onset of schizophrenia. With consideration of this point, efforts toward early detection of schizophrenia are important.

DOI： 10.1111/j.1440-1819.2007.01685.x

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

Background: Factor structure of the 12-item General Health Questionnaire (GHQ- 12) was studied by a survey of subjects who had experienced the 2004 Niigata-Chuetsu earthquake (6.8 on the Richter scale) in Japan.
Methods: Psychological distress was measured at two years after the earthquake by using GHQ-12 in 2,107 subjects (99.0% response rate) who suffered the earthquake. GHQ-12 was scored by binary, chronic and Likert scoring method. Confirmatory factor analysis was used to reveal the factor structure of GHQ-12. Categorical regression analysis was performed to evaluate the relationships between various background factors and GHQ-12 scores.
Results: Confirmatory factor analysis revealed that the model consisting of the two factors and using chronic method gave the best goodness-of-fit among the various models for factor structure. Recovery in the scale for the factor 'social dysfunction' was remarkably impaired compared with that of the factor 'dysphoria'. Categorical regression analysis revealed that various factors, including advanced age, were associated with psychological distress. Advanced age affected the impaired recovery of factor 'social dysfunction' score as well as total GHQ score.
Conclusion: The two-factor structure of GHQ-12 was conserved between the survey at five month and that at two years after the earthquake. Impaired recovery in the ability to cope with daily problems in the subjects who had experienced the earthquake was remarkable even at two years after the earthquake.

DOI： 10.1186/1471-2458-7-175

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Language：English   Publisher：AMER PSYCHIATRIC PUBLISHING, INC  

DOI： 10.1176/ps.2007.58.7.1013

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

Catechol-O-methyltransferase (COMT) is one of the enzymes that degrade catecholamine neurotransmitters including dopamine. The COMT gene is located on 22q11.2, a common susceptibility locus for schizophrenia. Therefore, COMT is a strong functional and positional candidate gene for schizophrenia. A common functional polymorphism (rs4680, Val 158Met) has been extensively tested for an association with schizophrenia, but with conflicting results. Recent studies indicate that if COMT is implicated in susceptibility to schizophrenia, this cannot be wholly accounted for by the Va1158Met polymorphism. To assess this view, the authors conducted a case-control association study (399 patients with schizophrenia and 440 control subjects) for five functional polyrnorphisms (rs2075507, rs737865, rs6267, rs4680 and rs165599) in Japanese subjects. There were no significant associations found between the polyrnorphisms or haplotypes of COMT and schizophrenia. The present study shows that these five functional COMT polymorphisms do not play a major role in conferring susceptibility to schizophrenia in Japanese. (C) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2007.03.015

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The protein interacting with C-kinase 1 (PICK1) has been implicated in the susceptibility to schizophrenia. PICK I interacts with enzymes and receptors that play roles in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two studies reported associations between schizophrenia and two PICK1 gene polymorphisms, rs3952 in Chinese and Japanese populations and rs2076369 in a Japanese population. We attempted to confirm these associations in a case-control study of 1765 Japanese patients with schizophrenia and 1851 Japanese control subjects. Neither polymorphism was associated with schizophrenia (rs3952, p = 0.755; rs2076369, p = 0.997). A haplotype block with these polymorphisms spanning the 5' region of the PICK1 gene showed high linkage disequilibrium in the Japanese population (D' = 0.98, r(2) = 0.34); however, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and polymorphisms of the PICK1 gene identified thus far are unlikely to contribute to genetic susceptibility to schizophrenia in the Japanese population. (c) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2007.02.008

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

A total of 283 patients with somatoform disorder (SFD) seen in a psychiatry clinic were surveyed and their diagnostic subtypes, demographic features, and comorbidities, analyzed. The results indicate that: (i) SFD comprises 5.8% of first-visit outpatients; (ii) undifferentiated SFD (USFD) and SFD not otherwise specified (SFD-NOS) account for the majority of patients; (iii) there are 1.7-fold more women than men; (iv) age of onset is lower in patients with somatization disorder or body dysmorphic disorder and higher in patients with hypochondriasis or pain disorder; (v) the mean number of years of education was 11.2 years; and (vi) comorbid illness were seen in 24.8% of patients, and included mood disorder, anxiety disorder, and personality disorder, as well as borderline intellectual functioning and mental retardation. The data indicate that the majority of patients with SFD are given a diagnosis of residual category, such as USFD or SFD-NOS, and that the age of onset varies depending on the diagnostic subtype. SFD was more frequently seen in women, associated with comorbidities.

DOI： 10.1111/j.1440-1819.2007.01664.x

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

Fasciculation and elongation of protein zeta-1 (FEZ1) is a binding partner of Disrupted-In-Schizophrenia 1 (DISC1). Because the DISC1 gene is shown to be a causative gene for psychosis in a Scottish family, the FEZ1 gene may well have importance in mental disease. A previous association study that analyzed polymorphisms of the FEZ1 gene in Japanese patients with schizophrenia and control subjects found significant association of the Asp123Glu polymorphism with schizophrenia. In the present study, we examined two polymorphic markers, rs559668 and rs597570 (Asp123Glu), in the FEZ1 gene to confirm the association in 1920 Japanese patients with schizophrenia and 1920 control subjects. The power to detect an association was more than 0.98. However, we did not detect genotypic associations of either of these two single nucleotide polymorphisms with schizophrenia (p = 1 and 0.79, respectively). We concluded that the missense mutation Asp123Glu of the FEZ1 gene is unlikely to play a substantial role in the genetic susceptibility to schizophrenia. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2007.02.055

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

There is cumulative evidence that neuregulin I (NRG1) is a susceptibility gene for schizophrenia. Postmortem studies on brains from schizophrenia patients have revealed changes in the mRNA expression levels of v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), one of the NRG1 receptor genes. These observations suggest that NRG1-ERBB signaling is involved in the pathogenesis of schizophrenia. To assess whether the ERBB3 gene could be implicated in vulnerability to schizophrenia, we conducted a case-control (399 patients and 438 controls) association study in Japanese subjects. There were no significant association between the polymorphisms or haplotypes of ERBB3 and schizophrenia. The present study shows that ERBB3 does not play a major role in conferring susceptibility to schizophrenia in the Japanese population. (c) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2007.01.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：B C DECKER INC  

Objective: To compare long-term survival rates and causes of death in community-dwelling elderly with and without depression using the International Research Diagnostic Criteria administered by a psychiatrist.
Method: From 1985 to 2000, we prospectively examined Japanese persons (N = 920) aged 65 years or older. Cases with depression (n = 158) and a control sample without depression (N = 762) were evaluated. The main outcome variables were survival rates and causes of mortality.
Results: By 2000, 61% of the subjects with depression had died. By contrast, 48% had died in the control group at the completion of the 15-year follow-up. Using age-adjusted Kaplan-Meier survival analysis, we found a hazard ratio (HR) of 1.49 (95% confidence interval [Cl] 1.16-1.89) for mortality in the depressed group compared with controls (p=.0009). Importantly, in female subjects with depression, the HR was 1.55 (95% Cl 1.16-2.07; p =.002). In males with depression, by contrast, the HR (1.34) was not significant (95% Cl 0.84-2.13; p =.19). Significantly more subjects died of cerebrovascular disorders, malignant tumors, respiratory disorders, or suicide after the onset of depression compared with controls (p &lt; .05).
Conclusions: Depression appears to be associated with a significant increase in the risk of mortality among elderly Japanese subjects, particularly in females. The elderly with a diagnosis of depression may be at an elevated risk of mortality owing to cerebrovascular disorder, malignant tumors, respiratory disorders, or suicide. These prospective data provide a new quantitative insight on gender differences and the long-term public health significance of depression among the community-dwelling elderly.

DOI： 10.2310/6650.2007.06040

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

DOI： 10.2310/6650.2007.06042

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