Updated on 2023/01/26

写真a

 
SOMEYA Toshiyuki
 
Organization
Academic Assembly Institute of Medicine and Dentistry IGAKU KEIRETU Professor
Graduate School of Medical and Dental Sciences Professor
Faculty of Medicine School of Medicine Professor
Title
Professor
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Degree

  • 医学博士 ( 1990.9   滋賀医科大学 )

Research Areas

  • Life Science / Psychiatry

Research History (researchmap)

  • Niigata University   Faculty of Medicine

    2018.2

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  • Niigata University

    2018.2

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  • Niigata University Graduate School of Medical and Dental Sciences   Professor

    2001.4

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  • Niigata University   Faculty of Medicine School of Medicine   Professor

    1998.1

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  • Niigata University   Faculty of Medicine   Professor

    1998.1 - 2001.3

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Research History

  • Niigata University   Faculty of Medicine

    2018.2

  • Niigata University   Faculty of Medicine

    2014.2 - 2018.1

  • Niigata University   Research Institute for Natural Hazards and Disaster Recovery

    2011.4 - 2014.3

  • Niigata University   Graduate School of Medical and Dental Sciences   Professor

    2001.4

  • Niigata University   Faculty of Medicine School of Medicine   Professor

    1998.1

  • Niigata University   Professor

    1998.1 - 2001.3

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Papers

  • Serum cortisol and insulin-like growth factor 1 levels in major depressive disorder and schizophrenia. International journal

    Hiroshi Arinami, Yuichiro Watanabe, Yutaro Suzuki, Misuzu Tajiri, Nobuto Tsuneyama, Toshiyuki Someya

    Scientific reports   13 ( 1 )   1148 - 1148   2023.1

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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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  • Factor structure of the parental bonding instrument for pregnant Japanese women

    Naoki Fukui, Yuichiro Watanabe, Koyo Hashijiri, Takaharu Motegi, Maki Ogawa, Jun Egawa, Takayuki Enomoto, Toshiyuki Someya

    Scientific Reports   12 ( 1 )   2022.11

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

    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

  • Clinical manifestations of schizophrenia in four patients with variants in voltage-gated calcium channel-encoding genes: a case series. International journal

    Tzuyao Lo, Itaru Kushima, Branko Aleksic, Akira Yoshimi, Toshiyuki Someya, Yuichiro Watanabe, Norio Ozaki

    Psychiatry and clinical neurosciences   2022.10

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    DOI: 10.1111/pcn.13494

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  • COVID-19パンデミックにおける教育実践 遠隔同期型の多職種連携教育における学修効果の解析

    河内 泉, 中島 寛音, 中嶋 大和, 青木 亜美, Olga Razvina, 福井 直樹, 齋藤 昭彦, 土田 正則, 佐藤 昇, 染矢 俊幸

    医学教育   53 ( Suppl. )   158 - 158   2022.7

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

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  • Elevation of EGR1/zif268, a Neural Activity Marker, in the Auditory Cortex of Patients with Schizophrenia and its Animal Model

    Yuriko Iwakura, Ryoka Kawahara-Miki, Satoshi Kida, Hidekazu Sotoyama, Ramil Gabdulkhaev, Hitoshi Takahashi, Yasuto Kunii, Mizuki Hino, Atsuko Nagaoka, Ryuta Izumi, Risa Shishido, Toshiyuki Someya, Hirooki Yabe, Akiyoshi Kakita, Hiroyuki Nawa

    Neurochemical Research   2022.4

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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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    Other Link: https://link.springer.com/article/10.1007/s11064-022-03599-9/fulltext.html

  • Novel missense SETD1A variants in Japanese patients with schizophrenia: Resequencing and association analysis. International journal

    Ryo Morikawa, Yuichiro Watanabe, Hirofumi Igeta, Reza K Arta, Masashi Ikeda, Satoshi Okazaki, Satoshi Hoya, Takeo Saito, Ikuo Otsuka, Jun Egawa, Takaki Tanifuji, Nakao Iwata, Toshiyuki Someya

    Psychiatry research   310   114481 - 114481   2022.4

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

    DOI: 10.1016/j.psychres.2022.114481

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  • Theory of mind tested by implicit false belief: a simple and full‐fledged mental state attribution

    Isao Hasegawa, Jun Egawa, Keisuke Kawasaki, Taketsugu Hayashi, Ryota Akikawa, Toshiyuki Someya, Isao Hasegawa

    The FEBS Journal   2022.1

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

    DOI: 10.1111/febs.16322

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  • Polymorphisms in the hypoxia inducible factor binding site of the macrophage migration inhibitory factor gene promoter in schizophrenia. International journal

    Satoshi Okazaki, Shuken Boku, Yuichiro Watanabe, Ikuo Otsuka, Tadasu Horai, Ryo Morikawa, Atsushi Kimura, Naofumi Shimmyo, Takaki Tanifuji, Toshiyuki Someya, Akitoyo Hishimoto

    PloS one   17 ( 3 )   e0265738   2022

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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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  • Association Between the Number of Remaining Teeth and Body Mass Index in Japanese Inpatients with Schizophrenia. International journal

    Masataka Otake, Shin Ono, Yuichiro Watanabe, Koichiro Kumagai, Koji Matsuzawa, Hiroyuki Kasahara, Masaya Ootake, Takuro Sugai, Toshiyuki Someya

    Neuropsychiatric disease and treatment   18   2591 - 2597   2022

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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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  • Short daytime napping reduces the risk of cognitive decline in community-dwelling older adults: a 5-year longitudinal study

    Kaori Kitamura, Yumi Watanabe, Kazutoshi Nakamura, Chikako Takano, Naomi Hayashi, Hisami Sato, Toshiyuki Someya

    BMC Geriatrics   21 ( 1 )   2021.12

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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

  • Influence of Atomoxetine on Relationship Between ADHD Symptoms and Prefrontal Cortex Activity During Task Execution in Adult Patients International journal

    Atsunori Sugimoto, Yutaro Suzuki, Kiyohiro Yoshinaga, Naoki Orime, Taketsugu Hayashi, Jun Egawa, Shin Ono, Takuro Sugai, Toshiyuki Someya

    Frontiers in Human Neuroscience   15   755025 - 755025   2021.11

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    <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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  • Identification of Bonding Difficulties in the Peripartum Period Using the Mother-to-Infant Bonding Scale-Japanese Version and Its Tentative Cutoff Points International journal

    Koyo Hashijiri, Yuichiro Watanabe, Naoki Fukui, Takaharu Motegi, Maki Ogawa, Jun Egawa, Takayuki Enomoto, Toshiyuki Someya

    Neuropsychiatric Disease and Treatment   Volume 17   3407 - 3413   2021.11

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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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  • 向精神薬の整理により行動・心理症状と運動症状が改善したハンチントン病による認知症の1例

    宮下 真子, 渡部 雄一郎, 本郷 祥子, 小池 直人, 佐治 越爾, 深石 翔, 三上 剛明, 小野寺 理, 染矢 俊幸

    新潟医学会雑誌   135 ( 9 )   209 - 209   2021.9

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  • レム睡眠行動障害とてんかんの鑑別を要した1例

    森川 亮, 大竹 将貴, 三上 剛明, 須貝 拓朗, 小出 眞悟, 上村 昌寛, 小野寺 理, 染矢 俊幸

    新潟医学会雑誌   135 ( 8 )   178 - 179   2021.8

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  • Perceived parenting before adolescence and parity have direct and indirect effects via depression and anxiety on maternal-infant bonding in the perinatal period. International journal

    Naoki Fukui, Takaharu Motegi, Yuichiro Watanabe, Koyo Hashijiri, Ryusuke Tsuboya, Maki Ogawa, Takuro Sugai, Jun Egawa, Takayuki Enomoto, Toshiyuki Someya

    Psychiatry and clinical neurosciences   75 ( 10 )   312 - 317   2021.7

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

    DOI: 10.1111/pcn.13289

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  • The lowest effective plasma concentration of atomoxetine in pediatric patients with attention deficit/hyperactivity disorder International journal

    Atsunori Sugimoto, Yutaro Suzuki, Naoki Orime, Taketsugu Hayashi, Kiyohiro Yoshinaga, Jun Egawa, Shin Ono, Takuro Sugai, Yoshimasa Inoue, Toshiyuki Someya

    Medicine   100 ( 27 )   e26552 - e26552   2021.7

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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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  • Withdrawal from long-term use of caffeinated drinks can cause schizophrenia-like symptoms: A case report. International journal

    Keigo Onda, Takayuki Yukawa, Masashi Sakaue, Ryusuke Tsuboya, Emiko Inoue, Toshiyuki Someya

    Psychiatry and clinical neurosciences   75 ( 5 )   181 - 182   2021.5

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    DOI: 10.1111/pcn.13199

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  • Exclusive Breastfeeding Is Not Associated with Maternal-Infant Bonding in Early Postpartum, Considering Depression, Anxiety, and Parity. International journal

    Naoki Fukui, Takaharu Motegi, Yuichiro Watanabe, Koyo Hashijiri, Ryusuke Tsuboya, Maki Ogawa, Takuro Sugai, Jun Egawa, Takayuki Enomoto, Toshiyuki Someya

    Nutrients   13 ( 4 )   2021.4

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

    DOI: 10.3390/nu13041184

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  • Resequencing and association analysis of GAP43 with autism spectrum disorder and schizophrenia in a Japanese population

    Reza K. Arta, Yuichiro Watanabe, Emiko Inoue, Yoshihiro Nawa, Ryo Morikawa, Jun Egawa, Itaru Kushima, Hirofumi Igeta, Satoshi Hoya, Atsunori Sugimoto, Andi J. Tanra, Norio Ozaki, Toshiyuki Someya

    RESEARCH IN AUTISM SPECTRUM DISORDERS   82   2021.4

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    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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  • Role of insulin-like growth factor 1, sex and corticosteroid hormones in male major depressive disorder. International journal

    Hiroshi Arinami, Yutaro Suzuki, Misuzu Tajiri, Nobuto Tsuneyama, Toshiyuki Someya

    BMC psychiatry   21 ( 1 )   157 - 157   2021.3

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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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  • A case of hyperprolactinemia and delusion of pregnancy during clozapine treatment

    Keigo Onda, Takayuki Yukawa, Emiko Inoue, Ryusuke Tsuboya, Masashi Sakaue, Toshiyuki Someya

    Clinical Neuropsychopharmacology and Therapeutics   12 ( 0 )   1 - 4   2021.1

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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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  • Factor Structure and Measurement Invariance of the Hospital Anxiety and Depression Scale Across the Peripartum Period Among Pregnant Japanese Women. International journal

    Maki Ogawa, Yuichiro Watanabe, Takaharu Motegi, Naoki Fukui, Koyo Hashijiri, Ryusuke Tsuboya, Takuro Sugai, Jun Egawa, Rie Araki, Kazufumi Haino, Masayuki Yamaguchi, Koji Nishijima, Takayuki Enomoto, Toshiyuki Someya

    Neuropsychiatric disease and treatment   17   221 - 227   2021

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    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.

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  • Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder. International journal

    Hidekazu Kato, Itaru Kushima, Daisuke Mori, Akira Yoshimi, Branko Aleksic, Yoshihiro Nawa, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Hiroki Kimura, Yuko Arioka, Keita Tsujimura, Mako Morikawa, Takashi Okada, Toshiya Inada, Masahiro Nakatochi, Keiko Shinjo, Yutaka Kondo, Kozo Kaibuchi, Yasuko Funabiki, Ryo Kimura, Toshimitsu Suzuki, Kazuhiro Yamakawa, Masashi Ikeda, Nakao Iwata, Tsutomu Takahashi, Michio Suzuki, Yuko Okahisa, Manabu Takaki, Jun Egawa, Toshiyuki Someya, Norio Ozaki

    Translational psychiatry   10 ( 1 )   421 - 421   2020.12

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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.

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  • Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility. Reviewed International journal

    Yoshihiro Nawa, Hiroki Kimura, Daisuke Mori, Hidekazu Kato, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Itaru Kushima, Branko Aleksic, Yuko Arioka, Mako Morikawa, Takashi Okada, Toshiya Inada, Kozo Kaibuchi, Masashi Ikeda, Nakao Iwata, Michio Suzuki, Yuko Okahisa, Jun Egawa, Toshiyuki Someya, Fumichika Nishimura, Tsukasa Sasaki, Norio Ozaki

    Human genome variation   7 ( 1 )   37 - 37   2020.11

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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.

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  • Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia. Reviewed International journal

    Kanako Ishizuka, Tomoyuki Yoshida, Takeshi Kawabata, Ayako Imai, Hisashi Mori, Hiroki Kimura, Toshiya Inada, Yuko Okahisa, Jun Egawa, Masahide Usami, Itaru Kushima, Mako Morikawa, Takashi Okada, Masashi Ikeda, Aleksic Branko, Daisuke Mori, Toshiyuki Someya, Nakao Iwata, Norio Ozaki

    Journal of neurodevelopmental disorders   12 ( 1 )   25 - 25   2020.9

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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.

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  • The relationship between schizophrenia patients' attitudes towards physical health and the prevalence of metabolic syndrome

    Takuro Sugai, Yutaro Suzuki, Manabu Yamazaki, Norio Sugawara, Norio Yasui-Furukori, Kazutaka Shimoda, Takao Mori, Yuji Ozeki, Yuichiro Watanabe, Hiroshi Matsuda, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    Clinical Neuropsychopharmacology and Therapeutics   11 ( 0 )   23 - 34   2020.5

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    DOI: 10.5234/cnpt.11.23

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  • Association of selected antipsychotics on the triglyceride levels in patients with schizophrenia in inpatient and outpatient settings Reviewed

    Shin Ono, Takuro Sugai, Yutaro Suzuki, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Yuji Ozeki, Hiroshi Matsuda, Norio Sugawara, Norio Yasui-Furukori, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    Clinical Neuropsychopharmacology and Therapeutics   11 ( 0 )   15 - 22   2020.4

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    DOI: 10.5234/cnpt.11.15

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  • Whole-exome sequencing in a family with a monozygotic twin pair concordant for schizophrenia and a follow-up case-control study of identified de-novo variants. Reviewed International journal

    Satoshi Hoya, Yuichiro Watanabe, Ayako Nunokawa, Ikuo Otsuka, Masako Shibuya, Hirofumi Igeta, Akitoyo Hishimoto, Toshiyuki Someya

    Psychiatric genetics   30 ( 2 )   60 - 63   2020.4

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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.

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  • Macaques Exhibit Implicit Gaze Bias Anticipating Others' False-Belief-Driven Actions via Medial Prefrontal Cortex. Reviewed International journal

    Taketsugu Hayashi, Ryota Akikawa, Keisuke Kawasaki, Jun Egawa, Takafumi Minamimoto, Kazuto Kobayashi, Shigeki Kato, Yukiko Hori, Yuji Nagai, Atsuhiko Iijima, Toshiyuki Someya, Isao Hasegawa

    Cell reports   30 ( 13 )   4433 - 4444   2020.3

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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.

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  • Non-Linear Pharmacokinetics of Atomoxetine in Adult Japanese Patients With ADHD. International journal

    Atsunori Sugimoto, Yutaro Suzuki, Naoki Orime, Taketsugu Hayashi, Jun Egawa, Takuro Sugai, Yoshimasa Inoue, Toshiyuki Someya

    Journal of attention disorders   24 ( 3 )   490 - 493   2020.2

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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.

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  • Lower Prolactin Levels in Patients Treated With Aripiprazole Regardless of Antipsychotic Monopharmacy or Polypharmacy

    Takuro Sugai, Yutaro Suzuki, Manabu Yamazaki, Norio Sugawara, Norio Yasui-Furukori, Kazutaka Shimoda, Takao Mori, Yuji Ozeki, Hiroshi Matsuda, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    Journal of Clinical Psychopharmacology   40 ( 1 )   14 - 17   2020.1

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  • Depression, Anxiety and Primiparity are Negatively Associated with Mother-Infant Bonding in Japanese Mothers. International journal

    Takaharu Motegi, Yuichiro Watanabe, Naoki Fukui, Maki Ogawa, Koyo Hashijiri, Ryusuke Tsuboya, Takuro Sugai, Jun Egawa, Rie Araki, Kazufumi Haino, Masayuki Yamaguchi, Koji Nishijima, Takayuki Enomoto, Toshiyuki Someya

    Neuropsychiatric disease and treatment   16   3117 - 3122   2020

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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.

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  • Predictive Utility of Body Mass Index for Metabolic Syndrome Among Patients with Schizophrenia in Japan. International journal

    Norio Sugawara, Norio Yasui-Furukori, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Takuro Sugai, Hiroshi Matsuda, Yutaro Suzuki, Yuji Ozeki, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    Neuropsychiatric disease and treatment   16   2229 - 2236   2020

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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.

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  • Psychological distress as a risk factor for dementia after the 2004 Niigata-Chuetsu earthquake in Japan. Reviewed International journal

    Kazutoshi Nakamura, Yumi Watanabe, Kaori Kitamura, Keiko Kabasawa, Toshiyuki Someya

    Journal of affective disorders   259   121 - 127   2019.12

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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.

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  • Identifying the factor structure of the Mother-to-Infant Bonding Scale for post-partum women and examining its consistency during pregnancy. Reviewed International journal

    Takaharu Motegi, Naoki Fukui, Koyo Hashijiri, Ryusuke Tsuboya, Takuro Sugai, Jun Egawa, Setsuko Mitome, Rie Araki, Kazufumi Haino, Masayuki Yamaguchi, Koichi Takakuwa, Takayuki Enomoto, Toshiyuki Someya

    Psychiatry and clinical neurosciences   73 ( 10 )   661 - 662   2019.10

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  • Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases. Reviewed International journal

    Yutaro Kobayashi, Yuriko Iwakura, Hidekazu Sotoyama, Eiko Kitayama, Nobuyuki Takei, Toshiyuki Someya, Hiroyuki Nawa

    Translational psychiatry   9 ( 1 )   181 - 181   2019.8

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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.

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  • Hormonal Dynamics Effect of Serum Insulin-Like Growth Factor I and Cortisol/Dehydroepiandrosterone Sulfate Ratio on Symptom Severity of Major Depressive Disorder. Reviewed

    Tajiri M, Suzuki Y, Tsuneyama N, Arinami H, Someya T

    Journal of clinical psychopharmacology   39 ( 4 )   367 - 371   2019.7

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    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.

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  • Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect. Reviewed International journal

    Masashi Ikeda, Atsushi Takahashi, Yoichiro Kamatani, Yukihide Momozawa, Takeo Saito, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Takaya Sakusabe, Yoshimi Iwayama, Tomoko Toyota, Tomoyasu Wakuda, Mitsuru Kikuchi, Nobuhisa Kanahara, Hidenaga Yamamori, Yuka Yasuda, Yuichiro Watanabe, Satoshi Hoya, Branko Aleksic, Itaru Kushima, Heii Arai, Manabu Takaki, Kotaro Hattori, Hiroshi Kunugi, Yuko Okahisa, Tohru Ohnuma, Norio Ozaki, Toshiyuki Someya, Ryota Hashimoto, Takeo Yoshikawa, Michiaki Kubo, Nakao Iwata

    Schizophrenia bulletin   45 ( 4 )   824 - 834   2019.6

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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.

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  • A case report of psychiatric symptoms following direct-acting antiviral and ribavirin combination therapy for chronic hepatitis C in a patient with innate anxiety. Reviewed International journal

    Akira Sakamaki, Kenya Kamimura, Naoki Fukui, Haruka Watanabe, Norihiro Sakai, Kentaro Tominaga, Kenichi Mizuno, Masaaki Takamura, Hirokazu Kawai, Takuro Sugai, Satoshi Yamagiwa, Toshiyuki Someya, Shuji Terai

    BMC gastroenterology   19 ( 1 )   85 - 85   2019.6

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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.

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  • Rare compound heterozygous missense SPATA7 variations and risk of schizophrenia; whole-exome sequencing in a consanguineous family with affected siblings, follow-up sequencing and a case-control study. Reviewed International journal

    Hirofumi Igeta, Yuichiro Watanabe, Ryo Morikawa, Masashi Ikeda, Ikuo Otsuka, Satoshi Hoya, Masataka Koizumi, Jun Egawa, Akitoyo Hishimoto, Nakao Iwata, Toshiyuki Someya

    Neuropsychiatric disease and treatment   15   2353 - 2363   2019

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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.

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  • Pathological alterations of chondroitin sulfate moiety in postmortem hippocampus of patients with schizophrenia. Reviewed International journal

    Takayuki Yukawa, Yuriko Iwakura, Nobuyuki Takei, Mami Saito, Yuichiro Watanabe, Kazuhiko Toyooka, Michihiro Igarashi, Kazuhiro Niizato, Kenichi Oshima, Yasuto Kunii, Hirooki Yabe, Junya Matsumoto, Akira Wada, Mizuki Hino, Shuji Iritani, Shin-Ichi Niwa, Ryoko Takeuchi, Hitoshi Takahashi, Akiyoshi Kakita, Toshiyuki Someya, Hiroyuki Nawa

    Psychiatry research   270   940 - 946   2018.12

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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.

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  • Updated meta-analysis of CMYA5 rs3828611 and rs4704591 with schizophrenia in Asian populations. Reviewed

    Hoya S, Watanabe Y, Shibuya M, Someya T

    Early intervention in psychiatry   12 ( 5 )   938 - 941   2018.10

  • Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. Reviewed International journal

    Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo Ogawa, Emiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu-Ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, Norio Ozaki

    Cell reports   24 ( 11 )   2838 - 2856   2018.9

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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.

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  • Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population. Reviewed International journal

    Yuan Zhang, Akitoyo Hishimoto, Ikuo Otsuka, Yuichiro Watanabe, Shusuke Numata, Hidenaga Yamamori, Shuken Boku, Tadasu Horai, Toshiyuki Someya, Tetsuro Ohmori, Ryota Hashimoto, Ichiro Sora

    Journal of psychiatric research   103   161 - 166   2018.8

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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.

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  • High-density lipoprotein-cholesterol and antipsychotic medication in overweight inpatients with schizophrenia: post-hoc analysis of a Japanese nationwide survey. Reviewed International journal

    Shin Ono, Takuro Sugai, Yutaro Suzuki, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Yuji Ozeki, Hiroshi Matsuda, Norio Sugawara, Norio Yasui-Furukori, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    BMC psychiatry   18 ( 1 )   180 - 180   2018.6

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    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.

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  • Prevalence of underweight in patients with schizophrenia: A meta-analysis. Reviewed International journal

    Norio Sugawara, Kazushi Maruo, Takuro Sugai, Yutaro Suzuki, Yuji Ozeki, Kazutaka Shimoda, Toshiyuki Someya, Norio Yasui-Furukori

    Schizophrenia research   195   67 - 73   2018.5

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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.

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  • Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia. Reviewed International journal

    Satoshi Okazaki, Akitoyo Hishimoto, Ikuo Otsuka, Yuichiro Watanabe, Shusuke Numata, Shuken Boku, Naofumi Shimmyo, Makoto Kinoshita, Emiko Inoue, Tetsuro Ohmori, Toshiyuki Someya, Ichiro Sora

    Progress in neuro-psychopharmacology & biological psychiatry   83   33 - 41   2018.4

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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.

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  • A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder Reviewed

    M. Ikeda, A. Takahashi, Y. Kamatani, Y. Okahisa, H. Kunugi, N. Mori, T. Sasaki, T. Ohmori, Y. Okamoto, H. Kawasaki, S. Shimodera, T. Kato, H. Yoneda, R. Yoshimura, M. Iyo, K. Matsuda, M. Akiyama, K. Ashikawa, K. Kashiwase, K. Tokunaga, K. Kondo, T. Saito, A. Shimasaki, K. Kawase, T. Kitajima, K. Matsuo, M. Itokawa, T. Someya, T. Inada, R. Hashimoto, T. Inoue, K. Akiyama, H. Tanii, H. Arai, S. Kanba, N. Ozaki, I. Kusumi, T. Yoshikawa, M. Kubo, N. Iwata, Advanced Collaborative Study of Mood Disorder (COSMO) team

    Molecular Psychiatry   23 ( 3 )   639 - 647   2018.3

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    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.

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  • Effects of nutritional education on weight change and metabolic abnormalities among patients with schizophrenia in Japan: A randomized controlled trial. Reviewed International journal

    Norio Sugawara, Toyoaki Sagae, Norio Yasui-Furukori, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Takuro Sugai, Hiroshi Matsuda, Yutaro Suzuki, Yuji Ozeki, Kurefu Okamoto, Toshiyuki Someya

    Journal of psychiatric research   97   77 - 83   2018.2

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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.

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  • Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. Reviewed International journal

    Yanjie Yu, Yingni Lin, Yuto Takasaki, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Kanako Ishizuka, Miho Toyama, Itaru Kushima, Daisuke Mori, Yuko Arioka, Yota Uno, Tomoko Shiino, Yukako Nakamura, Takashi Okada, Mako Morikawa, Masashi Ikeda, Nakao Iwata, Yuko Okahisa, Manabu Takaki, Shinji Sakamoto, Toshiyuki Someya, Jun Egawa, Masahide Usami, Masaki Kodaira, Akira Yoshimi, Tomoko Oya-Ito, Branko Aleksic, Kinji Ohno, Norio Ozaki

    Translational psychiatry   8 ( 1 )   12 - 12   2018.1

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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.

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  • Effects of olanzapine on resting heart rate in Japanese patients with schizophrenia. Reviewed International journal

    Misuzu Tajiri, Yutaro Suzuki, Takuro Sugai, Nobuto Tsuneyama, Toshiyuki Someya

    PloS one   13 ( 7 )   e0199922   2018

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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.

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  • Two cases of musical hallucination successfully treated with quetiapine Reviewed

    Hideaki Kitamura, Mami Saito, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   71 ( 11 )   789 - 789   2017.11

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  • Rare PDCD11 variations are not associated with risk of schizophrenia in Japan Reviewed

    Satoshi Hoya, Yuichiro Watanabe, Akitoyo Hishimoto, Ayako Nunokawa, Naoshi Kaneko, Tatsuyuki Muratake, Naofumi Shinmyo, Ikuo Otsuka, Shujiro Okuda, Emiko Inoue, Hirofumi Igeta, Masako Shibuya, Jun Egawa, Naoki Orime, Ichiro Sora, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   71 ( 11 )   780 - 788   2017.11

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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.

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  • Rare FBXO18 variations and risk of schizophrenia: Whole-exome sequencing in two parent-affected offspring trios followed by resequencing and case-control studies Reviewed

    Satoshi Hoya, Yuichiro Watanabe, Akitoyo Hishimoto, Ayako Nunokawa, Emiko Inoue, Hirofumi Igeta, Ikuo Otsuka, Masako Shibuya, Jun Egawa, Ichiro Sora, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   71 ( 8 )   562 - 568   2017.8

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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.

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  • Effect of GWAS-Identified Genetic Variants on Maximum QT Interval in Patients With Schizophrenia Receiving Antipsychotic Agents: A 24-Hour Holter ECG Study Reviewed

    Junzo Watanabe, Naoki Fukui, Yutaro Suzuki, Takuro Sugai, Shin Ono, Nobuto Tsuneyama, Mami Saito, Misuzu Tajiri, Toshiyuki Someya

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   37 ( 4 )   452 - 455   2017.8

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    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.

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  • High-resolution copy number variation analysis of schizophrenia in Japan

    I Kushima, B Aleksic, M Nakatochi, T Shimamura, T Shiino, A Yoshimi, H Kimura, Y Takasaki, C Wang, J Xing, K Ishizuka, T Oya-Ito, Y Nakamura, Y Arioka, T Maeda, M Yamamoto, M Yoshida, H Noma, S Hamada, M Morikawa, Y Uno, T Okada, T Iidaka, S Iritani, T Yamamoto, M Miyashita, A Kobori, M Arai, M Itokawa, M -C Cheng, Y -A Chuang, C -H Chen, M Suzuki, T Takahashi, R Hashimoto, H Yamamori, Y Yasuda, Y Watanabe, A Nunokawa, T Someya, M Ikeda, T Toyota, T Yoshikawa, S Numata, T Ohmori, S Kunimoto, D Mori, N Iwata, N Ozaki

    Molecular Psychiatry   22 ( 3 )   430 - 440   2017.3

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  • Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder Reviewed

    Yutaro Suzuki, Misuzu Tajiri, Atsunori Sugimoto, Naoki Orime, Taketsugu Hayashi, Jun Egawa, Takuro Sugai, Yoshimasa Inoue, Toshiyuki Someya

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   37 ( 1 )   27 - 31   2017.2

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    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.

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  • Survey on the management of physical risks induced by psychotropic agents in Japan. Reviewed

    Orime N, Suzuki Y, Someya T

    Clin Neuropsychopharmacol Ther   8   42 - 46   2017

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  • Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders. Reviewed

    Ishizuka K, Fujita Y, Kawabata T, Kimura H, Iwayama Y, Inada T, Okahisa Y, Egawa J, Usami M, Kushima I, Uno Y, Okada T, Ikeda M, Aleksic B, Mori D, Someya T, Yoshikawa T, Iwata N, Nakamura H, Yamashita T, Ozaki N

    Transl Psychiatry   7 ( 8 )   e1184 - e1184   2017

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    DOI: 10.1038/tp.2017.173

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  • High Prevalence of Obesity, Hypertension, Hyperlipidemia, and Diabetes Mellitus in Japanese Outpatients with Schizophrenia: A Nationwide Survey Reviewed

    Takuro Sugai, Yutaro Suzuki, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Yuji Ozeki, Hiroshi Matsuda, Norio Sugawara, Norio Yasui-Furukori, Yoshitake Minami, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    PLOS ONE   11 ( 11 )   e0166429   2016.11

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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.

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  • Rural-urban differences in the prevalence of cognitive impairment in independent community-dwelling elderly residents of Ojiya city, Niigata Prefecture, Japan Reviewed

    Kazutoshi Nakamura, Kaori Kitamura, Yumi Watanabe, Hiroko Shinoda, Hisami Sato, Toshiyuki Someya

    ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE   21 ( 6 )   422 - 429   2016.11

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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.

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  • Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. Reviewed International journal

    Yuto Takasaki, Takayoshi Koide, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Itaru Kushima, Kanako Ishizuka, Daisuke Mori, Mariko Sekiguchi, Masashi Ikeda, Miki Aizawa, Naoko Tsurumaru, Yoshimi Iwayama, Akira Yoshimi, Yuko Arioka, Mami Yoshida, Hiromi Noma, Tomoko Oya-Ito, Yukako Nakamura, Shohko Kunimoto, Branko Aleksic, Yota Uno, Takashi Okada, Hiroshi Ujike, Jun Egawa, Hitoshi Kuwabara, Toshiyuki Someya, Takeo Yoshikawa, Nakao Iwata, Norio Ozaki

    Scientific reports   6   33311 - 33311   2016.9

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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.

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  • Rare UNC13B variations and risk of schizophrenia: Whole-exome sequencing in a multiplex family and follow-up resequencing and a case-control study Reviewed

    Jun Egawa, Satoshi Hoya, Yuichiro Watanabe, Ayako Nunokawa, Masako Shibuya, Masashi Ikeda, Emiko Inoue, Shujiro Okuda, Kenji Kondo, Takeo Saito, Naoshi Kaneko, Tatsuyuki Muratake, Hirofumi Igeta, Nakao Iwata, Toshiyuki Someya

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   171 ( 6 )   797 - 805   2016.9

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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.

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  • Difference in prevalence of metabolic syndrome between Japanese outpatients and inpatients with schizophrenia: A nationwide survey Reviewed

    Takuro Sugai, Yutaro Suzuki, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Yuji Ozeki, Hiroshi Matsuda, Norio Sugawara, Norio Yasui-Furukori, Yoshitake Minami, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   171 ( 1-3 )   68 - 73   2016.3

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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.

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  • Pathological and Clinical Spectrum of Progressive Supranuclear Palsy: With Special Reference to Astrocytic Tau Pathology Reviewed

    Yuichi Yokoyama, Yasuko Toyoshima, Atsushi Shiga, Mari Tada, Hideaki Kitamura, Kazuko Hasegawa, Osamu Onodera, Takeshi Ikeuchi, Toshiyuki Someya, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    BRAIN PATHOLOGY   26 ( 2 )   155 - 166   2016.3

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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.

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  • Effect of Serum Leptin on Weight Gain Induced by Olanzapine in Female Patients with Schizophrenia Reviewed

    Nobuto Tsuneyama, Yutaro Suzuki, Kazushi Sawamura, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Mami Saito, Toshiyuki Someya

    PLOS ONE   11 ( 3 )   e0149518   2016.3

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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.

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  • Attitudes toward metabolic adverse events among patients with schizophrenia in Japan Reviewed

    Norio Sugawara, Norio Yasui-Furukori, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Takuro Sugai, Hiroshi Matsuda, Yutaro Suzuki, Yoshitake Minami, Yuji Ozeki, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    Neuropsychiatric Disease and Treatment   12   427 - 436   2016.2

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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.

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  • Rare truncating variations and risk of schizophrenia: Whole-exome sequencing in three families with affected siblings and a three-stage follow-up study in a Japanese population Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Masako Shibuya, Masashi Ikeda, Akitoyo Hishimoto, Kenji Kondo, Jun Egawa, Naoshi Kaneko, Tatsuyuki Muratake, Takeo Saito, Satoshi Okazaki, Ayu Shimasaki, Hirofumi Igeta, Emiko Inoue, Satoshi Hoya, Takuro Sugai, Ichiro Sora, Nakao Iwata, Toshiyuki Someya

    PSYCHIATRY RESEARCH   235   13 - 18   2016.1

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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.

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  • Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population Reviewed

    Emiko Inoue, Yuichiro Watanabe, Jingrui Xing, Itaru Kushima, Jun Egawa, Shujiro Okuda, Satoshi Hoya, Takashi Okada, Yota Uno, Kanako Ishizuka, Atsunori Sugimoto, Hirofumi Igeta, Ayako Nunokawa, Toshiro Sugiyama, Norio Ozaki, Toshiyuki Someya

    PLOS ONE   10 ( 12 )   e0144624   2015.12

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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.

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  • The effectiveness of combining remifentanil with propofol to achieve seizure adequacy in a patient undergoing modified electroconvulsive therapy Reviewed

    Tatsunori Watanabe, Kiyohiro Yoshinaga, Yutaro Suzuki, Toshiyuki Someya, Hiroshi Baba

    Japanese Journal of Anesthesiology   64 ( 10 )   1072 - 1075   2015.10

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    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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  • Property damage and long-term psychological distress after the 2004 Niigata-Chuetsu earthquake in Ojiya, Japan: a community-based study Reviewed

    Kazutoshi Nakamura, Kaori Kitamura, Yoshiharu Kim, Toshiyuki Someya

    JOURNAL OF PUBLIC HEALTH   37 ( 3 )   398 - 405   2015.9

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    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.

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  • Association analysis of the HLA-DRB1*01 and HLA-DRB1*04 with schizophrenia by tag SNP genotyping in the Japanese population Reviewed

    Woraphat Ratta-Apha, Shuken Boku, Kentaro Mouri, Satoshi Okazaki, Ikuo Otsuka, Ichiro Sora, Akitoyo Hishimoto, Yuichiro Watanabe, Ayako Nunokawa, Toshiyuki Someya, Osamu Shirakawa

    PSYCHIATRY RESEARCH   229 ( 1-2 )   627 - 628   2015.9

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  • Whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder and a follow-up study Reviewed

    Jun Egawa, Yuichiro Watanabe, Atsunori Sugimoto, Ayako Nunokawa, Masako Shibuya, Hirofumi Igeta, Emiko Inoue, Satoshi Hoya, Naoki Orime, Taketsugu Hayashi, Toshiro Sugiyama, Toshiyuki Someya

    PSYCHIATRY RESEARCH   229 ( 1-2 )   599 - 601   2015.9

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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.

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  • Rare heterozygous truncating variations and risk of autism spectrum disorder: Whole-exome sequencing of a multiplex family and follow-up study in a Japanese population Reviewed

    Emiko Inoue, Yuichiro Watanabe, Jun Egawa, Atsunori Sugimoto, Ayako Nunokawa, Masako Shibuya, Hirofumi Igeta, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   69 ( 8 )   472 - 476   2015.8

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    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.

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  • Improvement of dumping syndrome and oversecretion of glucose-dependent insulinotropic polypeptide following a switch from olanzapine to quetiapine in a patient with schizophrenia Reviewed

    Aiko Watanabe, Naoki Fukui, Yutaro Suzuki, Takaharu Motegi, Hirofumi Igeta, Nobuto Tsuneyama, Toshiyuki Someya

    GENERAL HOSPITAL PSYCHIATRY   37 ( 4 )   372.e5 - 6   2015.7

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

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  • Assessment of copy number variations in the brain genome of schizophrenia patients Reviewed

    Miwako Sakai, Yuichiro Watanabe, Toshiyuki Someya, Kazuaki Araki, Masako Shibuya, Kazuhiro Niizato, Kenichi Oshima, Yasuto Kunii, Hirooki Yabe, Junya Matsumoto, Akira Wada, Mizuki Hino, Takeshi Hashimoto, Akitoyo Hishimoto, Noboru Kitamura, Shuji Iritani, Osamu Shirakawa, Kiyoshi Maeda, Akinori Miyashita, Shin-ichi Niwa, Hitoshi Takahashi, Akiyoshi Kakita, Ryozo Kuwano, Hiroyuki Nawa

    MOLECULAR CYTOGENETICS   8   46   2015.7

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    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.

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  • DRD2 Ser311Cys Polymorphism and Risk of Schizophrenia Reviewed

    Yuichiro Watanabe, Masako Shibuya, Toshiyuki Someya

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   168 ( 3 )   224 - 228   2015.4

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  • Developmental prosopagnosia referred to outpatient psychiatric service Reviewed

    Hideaki Kitamura, Jun Egawa, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   69 ( 4 )   238 - 239   2015.4

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  • Efficacy of Atomoxetine for Symptoms of Attention-Deficit/Hyperactivity Disorder in Children with a History of Child Abuse Reviewed

    Atsunori Sugimoto, Yutaro Suzuki, Taro Endo, Keita Matsumoto, Toshiro Sugiyama, Toshiyuki Someya

    JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY   25 ( 3 )   269 - 271   2015.4

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    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.

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  • QT prolongation associated with memantine in Alzheimer's disease Reviewed

    Hiromi Takehara, Yutaro Suzuki, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   69 ( 4 )   239 - 240   2015.4

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  • Resequencing and association analysis of OXTR with autism spectrum disorder in a Japanese population Reviewed

    Jun Egawa, Yuichiro Watanabe, Masako Shibuya, Taro Endo, Atsunori Sugimoto, Hirofumi Igeta, Ayako Nunokawa, Emiko Inoue, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   69 ( 3 )   131 - 135   2015.3

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    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.

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  • Novel Rare Missense Variations and Risk of Autism Spectrum Disorder: Whole-Exome Sequencing in Two Families with Affected Siblings and a Two-Stage Follow-Up Study in a Japanese Population Reviewed

    Jun Egawa, Yuichiro Watanabe, Chenyao Wang, Emiko Inoue, Atsunori Sugimoto, Toshiro Sugiyama, Hirofumi Igeta, Ayako Nunokawa, Masako Shibuya, Itaru Kushima, Naoki Orime, Taketsugu Hayashi, Takashi Okada, Yota Uno, Norio Ozaki, Toshiyuki Someya

    PLOS ONE   10 ( 3 )   2015.3

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    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.

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  • High prevalence of underweight and undernutrition in Japanese inpatients with schizophrenia: a nationwide survey Reviewed

    Takuro Sugai, Yutaro Suzuki, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Yuji Ozeki, Hiroshi Matsuda, Norio Sugawara, Norio Yasui-Furukori, Yoshitake Minami, Kurefu Okamoto, Toyoaki Sagae, Toshiyuki Someya

    BMJ OPEN   5 ( 12 )   e008720   2015

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    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.

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  • Association analysis of the Cadherin13 gene with schizophrenia in the Japanese population. Reviewed International journal

    Ikuo Otsuka, Yuichiro Watanabe, Akitoyo Hishimoto, Shuken Boku, Kentaro Mouri, Kyoichi Shiroiwa, Satoshi Okazaki, Ayako Nunokawa, Osamu Shirakawa, Toshiyuki Someya, Ichiro Sora

    Neuropsychiatric disease and treatment   11   1381 - 93   2015

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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.

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  • GIPR gene polymorphism and weight gain in patients with schizophrenia treated with olanzapine Reviewed

    Shin Ono, Yutaro Suzuki, Naoki Fukui, Kazushi Sawamura, Takuro Sugai, Junzo Watanabe, Nobuto Tsuneyama, Toshiyuki Someya

    Journal of Neuropsychiatry and Clinical Neurosciences   27 ( 2 )   162 - 164   2015

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    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.

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  • Effect of risperidone metabolism and P-glycoprotein gene polymorphism on QT interval in patients with schizophrenia Reviewed

    Y. Suzuki, N. Tsuneyama, N. Fukui, T. Sugai, J. Watanabe, S. Ono, M. Saito, Y. Inoue, T. Someya

    PHARMACOGENOMICS JOURNAL   14 ( 5 )   452 - 456   2014.10

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    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.

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  • Psychological distress in an earthquake-devastated area with pre-existing high rate of suicide Reviewed

    Akira Tachibana, Hideaki Kitamura, Masanobu Shindo, Hiroko Honma, Toshiyuki Someya

    PSYCHIATRY RESEARCH   219 ( 2 )   336 - 340   2014.10

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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.

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  • Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism Reviewed

    Yasuto Kunii, Itaru Miura, Junya Matsumoto, Mizuki Hino, Akira Wada, Shin-ichi Niwa, Hiroyuki Nawa, Miwako Sakai, Toshiyuki Someya, Hitoshi Takahashi, Akiyoshi Kakita, Hirooki Yabe

    Progress in Neuro-Psychopharmacology and Biological Psychiatry   53   123 - 128   2014.8

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    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.

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  • Promoter variation in the catechol-O-methyltransferase gene is associated with remission of symptoms during fluvoxamine treatment for major depression Reviewed

    Naoki Fukui, Yutaro Suzuki, Takuro Sugai, Junzo Watanabe, Shin Ono, Nobuto Tsuneyama, Toshiyuki Someya

    PSYCHIATRY RESEARCH   218 ( 3 )   353 - 355   2014.8

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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.

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  • Changes in PR and QTc intervals after switching from olanzapine to risperidone in patients with stable schizophrenia Reviewed

    Yutaro Suzuki, Takuro Sugai, Shin Ono, Kazushi Sawamura, Naoki Fukui, Junzo Watanabe, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   68 ( 5 )   353 - 356   2014.5

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    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.

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  • Cardiovascular pharmacodynamics of donepezil hydrochloride on the PR and QT intervals in patients with dementia Reviewed

    Hirofumi Igeta, Yutaro Suzuki, Misuzu Tajiri, Toshiyuki Someya

    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL   29 ( 3 )   292 - 294   2014.5

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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.

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  • Bernard Lerer: Recipient of the 2014 Inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine (Pacific Rim Association for Clinical Pharmacogenetics) Reviewed

    Vural Ozdemir, Laszlo Endrenyi, Sukru Aynacioglu, Nicola Luigi Bragazzi, Collet Dandara, Edward S. Dove, Lynnette R. Ferguson, Christy Jo Geraci, Ernst Hafen, Belgin Eroglu Kesim, Eugene Kolker, Edmund J. D. Lee, Adrian LLerena, Muradiye Nacak, Kazutaka Shimoda, Toshiyuki Someya, Sanjeeva Srivastava, Brian Tomlinson, Effy Vayena, Louise Warnich, Umit Yasar

    OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY   18 ( 4 )   211 - 221   2014.4

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    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)

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  • Association analysis of putative cis-acting polymorphisms of interleukin-19 gene with schizophrenia Reviewed

    Satoshi Okazaki, Yuichiro Watanabe, Akitoyo Hishimoto, Toru Sasada, Kentaro Mouri, Kyoichi Shiroiwa, Noriomi Eguchi, Woraphat Ratta-Apha, Ikuo Otsuka, Ayako Nunokawa, Naoshi Kaneko, Masako Shibuya, Toshiyuki Someya, Osamu Shirakawa, Ichiro Sora

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   50   151 - 156   2014.4

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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.

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  • A rare MIR138-2 gene variation is associated with schizophrenia in a Japanese population Reviewed

    Yuichiro Watanabe, Masako Shibuya, Ayako Nunokawa, Naoshi Kaneko, Hirofumi Igeta, Jun Egawa, Toshiyuki Someya, Akitoyo Hishimoto, Kentaro Mouri, Ichiro Sora

    PSYCHIATRY RESEARCH   215 ( 3 )   801 - 802   2014.3

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  • Psychological Recovery 5 Years After the 2004 Niigata-Chuetsu Earthquake in Yamakoshi, Japan Reviewed

    Kazutoshi Nakamura, Kaori Kitamura, Toshiyuki Someya

    JOURNAL OF EPIDEMIOLOGY   24 ( 2 )   125 - 131   2014.3

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    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.

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  • The cardiomyopathy-associated 5 (CMYA5) gene and risk of schizophrenia: Meta-analysis of rs3828611 and rs4704591 in East Asian populations Reviewed

    Yuichiro Watanabe, Masako Shibuya, Toshiyuki Someya

    Asian Journal of Psychiatry   7 ( 1 )   95 - 96   2014.2

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  • Psychiatrists' Attitudes toward Metabolic Adverse Events in Patients with Schizophrenia Reviewed

    Norio Sugawara, Norio Yasui-Furukori, Manabu Yamazaki, Kazutaka Shimoda, Takao Mori, Takuro Sugai, Yutaro Suzuki, Toshiyuki Someya

    PLOS ONE   9 ( 1 )   e86826   2014.1

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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.

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  • High prevalence of underweight and undernutrition in Japanese inpatients with schizophrenia Reviewed

    Yutaro Suzuki, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   68 ( 1 )   78 - 82   2014.1

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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.

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  • Possible association between the oxytocin receptor gene and N-acetylaspartate of the right medial temporal lobe in autism spectrum disorders Reviewed

    Jun Egawa, Yuichiro Watanabe, Taro Endo, Hideaki Kitamura, Toshiyuki Someya

    Psychiatry and Clinical Neurosciences   68 ( 1 )   83   2014.1

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  • Effects of olanzapine on the PR and QT intervals in patients with schizophrenia Reviewed

    Yutaro Suzuki, Shin Ono, Nobuto Tsuneyama, Kazushi Sawamura, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   152 ( 1 )   313 - 314   2014.1

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  • Interleukin 1 beta gene and risk of schizophrenia: detailed case-control and family-based studies and an updated meta-analysis Reviewed

    Masako Shibuya, Yuichiro Watanabe, Ayako Nunokawa, Jun Egawa, Naoshi Kaneko, Hirofumi Igeta, Toshiyuki Someya

    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL   29 ( 1 )   31 - 37   2014.1

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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.

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  • Brain stem volume reduction revealed by voxel-based morphometry in a patient with REM sleep behavior disorder and synucleinopathy.

    Kitamura H, Otake M, Inoue E, Someya T

    Journal of Sleep Medicine and Disorders   1 ( 2 )   1010   2014

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  • Replication in a Japanese population that a MIR30E gene variation is associated with schizophrenia. Reviewed International journal

    Yuichiro Watanabe, Yoshimi Iijima, Jun Egawa, Ayako Nunokawa, Naoshi Kaneko, Tadao Arinami, Hiroshi Ujike, Toshiya Inada, Nakao Iwata, Hiroshi Kunugi, Masanari Itokawa, Tsukasa Sasaki, Norio Ozaki, Ryota Hashimoto, Masako Shibuya, Hirofumi Igeta, Toshiyuki Someya

    Schizophrenia research   150 ( 2-3 )   596 - 597   2013.11

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  • Deterioration in donepezil-induced PR prolongation after a coadministration of memantine in a patient with Alzheimer's disease Reviewed

    Hirofumi Igeta, Yutaro Suzuki, Takaharu Motegi, Aiko Sasaki, Yuichi Yokoyama, Toshiyuki Someya

    GENERAL HOSPITAL PSYCHIATRY   35 ( 6 )   680.e9 - 10   2013.11

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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.

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  • An Evaluation of Association between a Novel Hippocampal Biology Related SNP (rs7294919) and Schizophrenia Reviewed

    Jiewei Liu, Shusuke Numata, Masashi Ikeda, Yuichiro Watanabe, Xue-bin Zheng, Xiongjian Luo, Makoto Kinoshita, Ayako Nunokawa, Toshiyuki Someya, Tetsuro Ohmori, Jin-xin Bei, Siow-Ann Chong, Jimmy Lee, Zhiqiang Li, Jianjun Liu, Nakao Iwata, Yongyong Shi, Ming Li, Bing Su

    PLOS ONE   8 ( 11 )   e80696   2013.11

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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.

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  • Association of rs2129575 in the tryptophan hydroxylase 2 gene with clinical phenotypes of autism spectrum disorders Reviewed

    Jun Egawa, Yuichiro Watanabe, Taro Endo, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   67 ( 6 )   457 - 458   2013.9

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  • The prevalence of glucose intolerance in japanese schizophrenic patients with a normal fasting glucose level Reviewed

    Shin Ono, Yutaro Suzuki, Naoki Fukui, Takuro Sugai, Junzo Watanabe, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    Journal of Clinical Psychopharmacology   33 ( 4 )   525 - 527   2013.8

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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.

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  • Neural activity in the posterior superior temporal region during eye contact perception correlates with autistic traits Reviewed

    Naoya Hasegawa, Hideaki Kitamura, Hiroatsu Murakami, Shigeki Kameyama, Mutsuo Sasagawa, Jun Egawa, Taro Endo, Toshiyuki Someya

    NEUROSCIENCE LETTERS   549   45 - 50   2013.8

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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.

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  • Impact of the ABCB1 gene polymorphism on plasma 9-hydroxyrisperidone and active moiety levels in japanese patients with schizophrenia Reviewed

    Yutaro Suzuki, Nobuto Tsuneyama, Naoki Fukui, Takuro Sugai, Junzo Watanabe, Shin Ono, Mami Saito, Toshiyuki Someya

    Journal of Clinical Psychopharmacology   33 ( 3 )   411 - 414   2013.6

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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.

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  • Genome-wide association study of schizophrenia using microsatellite markers in the Japanese population Reviewed

    Hiroki Shibata, Ken Yamamoto, Zhu Sun, Akira Oka, Hidetoshi Inoko, Tadao Arinami, Toshiya Inada, Hiroshi Ujike, Masanari Itokawa, Mamoru Tochigi, Yuichiro Watanabe, Toshiyuki Someya, Hiroshi Kunugi, Tatsuyo Suzuki, Nakao Iwata, Norio Ozaki, Yasuyuki Fukumaki

    PSYCHIATRIC GENETICS   23 ( 3 )   117 - 123   2013.6

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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

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  • Association between OXTR and clinical phenotypes of autism spectrum disorders Reviewed

    Jun Egawa, Yuichiro Watanabe, Taro Endo, Ryu Tamura, Toshiyuki Someya, Yuichiro Watanabe, Naio Masuzawa

    PSYCHIATRY RESEARCH   208 ( 1 )   99 - 100   2013.6

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  • Sex differences in the effect of four second-generation antipsychotics on QTc interval in patients with schizophrenia Reviewed

    Yutaro Suzuki, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL   28 ( 3 )   215 - 219   2013.5

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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.

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  • Resequencing and association analysis of MIR137 with schizophrenia in a Japanese population Reviewed

    Jun Egawa, Ayako Nunokawa, Masako Shibuya, Yuichiro Watanabe, Naoshi Kaneko, Hirofumi Igeta, Toshiyuki Someya

    Psychiatry and Clinical Neurosciences   67 ( 4 )   277 - 279   2013.5

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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.

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  • Differences in plasma prolactin levels in patients with schizophrenia treated on monotherapy with five second-generation antipsychotics Reviewed

    Yutaro Suzuki, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   145 ( 1-3 )   116 - 119   2013.4

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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.

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  • [Predictors of adverse effects induced by antipsychotics]. Reviewed

    Fukui N, Someya T

    Nihon rinsho. Japanese journal of clinical medicine   71 ( 4 )   641 - 647   2013.4

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  • Prolongation of idiopathic thrombocytopenic purpura associated with paroxetine administration Reviewed

    Shin Ono, Yutaro Suzuki, Toshiyuki Someya

    GENERAL HOSPITAL PSYCHIATRY   35 ( 2 )   213.e13 - 5   2013.3

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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.

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  • Low prevalence of metabolic syndrome and its prediction in Japanese inpatients with schizophrenia Reviewed

    Yutaro Suzuki, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL   28 ( 2 )   188 - 191   2013.3

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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.

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  • DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia. Reviewed

    Tanaka S, Syu A, Ishiguro H, Inada T, Horiuchi Y, Ishikawa M, Koga M, Noguchi E, Ozaki N, Someya T, Kakita A, Takahashi H, Nawa H, Arinami T

    The pharmacogenomics journal   13 ( 1 )   27 - 34   2013.2

  • Association of the BDNFC270T polymorphism with schizophrenia: Updated meta-analysis Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   67 ( 2 )   123 - 125   2013.2

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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.

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  • Manic symptoms associated with pregabalin in a patient with conversion disorder Reviewed

    Takayuki Yukawa, Yutaro Suzuki, Naoki Fukui, Masataka Otake, Takuro Sugai, Toshiyuki Someya

    Psychiatry and Clinical Neurosciences   67 ( 2 )   129 - 130   2013.2

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  • Effects of hospitalization in a psychiatric ward on the body weight of Japanese patients with schizophrenia Reviewed

    Yutaro Suzuki, Takeaki Mikami, Misuzu Tajiri, Takuro Kunizuka, Hiroko Abe, Toshiyuki Someya

    International Journal of Psychiatry in Medicine   45 ( 3 )   261 - 268   2013.1

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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.

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  • A missense mutation in the ITGA8 gene, a cell adhesion molecule gene, is associated with schizophrenia in Japanese female patients Reviewed

    Irwan Supriyanto, Yuichiro Watanabe, Kentaro Mouri, Kyoichi Shiroiwa, Woraphat Ratta-Apha, Masakuni Yoshida, Genki Tamiya, Toru Sasada, Noriomi Eguchi, Kenji Okazaki, Osamu Shirakawa, Toshiyuki Someya, Akitoyo Hishimoto

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   40   347 - 352   2013.1

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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.

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  • Personality and Resilience Associated with Perceived Fatigue of Local Government Employees Responding to Disasters Reviewed

    Hideaki Kitamura, Masanobu Shindo, Akira Tachibana, Hiroko Honma, Toshiyuki Someya

    JOURNAL OF OCCUPATIONAL HEALTH   55 ( 1 )   1 - 5   2013.1

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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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  • Changes in QT interval after switching to quetiapine in Japanese patients with schizophrenia Reviewed

    Yutaro Suzuki, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    Human Psychopharmacology   28 ( 1 )   94 - 96   2013.1

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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.

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  • Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population (letter). Reviewed

    Ikeda M, Aleksic B, Yamada K, Iwayama-Shigeno Y, Matsuo K, Numata S, Watanabe Y, Ohnuma T, Kaneko T, Fukuo Y, Okochi T, Toyota T, Hattori E, Shimodera S, Itakura M, Nunokawa A, Shibata N, Tanaka H, Yoneda H, Arai H, Someya T, Ohmori T, Yoshikawa T, Ozaki N, Iwata N

    Mol Psychiatry   18 ( 6 )   636 - 638   2013

  • Altered Activity of the Primary Visual Area during Gaze Processing in Individuals with High-Functioning Autistic Spectrum Disorder: A Magnetoencephalography Study Reviewed

    Naoya Hasegawa, Hideaki Kitamura, Hiroatsu Murakami, Shigeki Kameyama, Mutsuo Sasagawa, Jun Egawa, Ryu Tamura, Taro Endo, Toshiyuki Someya

    NEUROPSYCHOBIOLOGY   68 ( 3 )   181 - 188   2013

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    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

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  • Pharmacogenomics in Psychiatric Disorders Reviewed

    Y.W. Francis Lam, Naoki Fukui, Takuro Sugai, Junzo Watanabe, Yuichiro Watanabe, Yutato Suzuki, Toshiyuki Someya

    Pharmacogenomics   191 - 223   2013

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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.

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  • Lipid effects of psychiatric medications Reviewed

    Junzo Watanabe, Yutaro Suzuki, Toshiyuki Someya

    Current Atherosclerosis Reports   15 ( 1 )   292   2013

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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.

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  • Late-onset delirium after an overdose of acetaminophen in a case of benzodiazepine dependence Reviewed

    Yutaro Suzuki, Keita Shinada, Naoki Orime, Toshiyuki Someya

    Journal of Neuropsychiatry and Clinical Neurosciences   25 ( 4 )   E28 - E29   2013

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  • Association between the GIPR gene and the insulin level after glucose loading in schizophrenia patients treated with olanzapine Reviewed

    S. Ono, Y. Suzuki, N. Fukui, T. Sugai, J. Watanabe, N. Tsuneyama, T. Someya

    PHARMACOGENOMICS JOURNAL   12 ( 6 )   507 - 512   2012.12

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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

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  • Excessive Insulin Secretion in Japanese Schizophrenic Patients Treated With Antipsychotics Despite Normal Fasting Glucose Levels Reviewed

    Takuro Sugai, Yutaro Suzuki, Naoki Fukui, Junzo Watanabe, Shin Ono, Nobuto Tsuneyama, Toshiyuki Someya

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   32 ( 6 )   750 - 755   2012.12

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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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  • Oxytocin receptor (OXTR) gene and risk of schizophrenia: Case-control and family-based analyses and meta-analysis in a Japanese population Reviewed

    Yuichiro Watanabe, Naoshi Kaneko, Ayako Nunokawa, Masako Shibuya, Jun Egawa, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   66 ( 7 )   622 - 622   2012.12

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  • Meta-analysis of genome-wide association studies for panic disorder in the Japanese population Reviewed

    T. Otowa, Y. Kawamura, N. Nishida, N. Sugaya, A. Koike, E. Yoshida, K. Inoue, S. Yasuda, Y. Nishimura, X. Liu, Y. Konishi, F. Nishimura, T. Shimada, H. Kuwabara, M. Tochigi, C. Kakiuchi, T. Umekage, T. Miyagawa, A. Miyashita, E. Shimizu, J. Akiyoshi, T. Someya, T. Kato, T. Yoshikawa, R. Kuwano, K. Kasai, N. Kato, H. Kaiya, K. Tokunaga, Y. Okazaki, H. Tanii, T. Sasaki

    TRANSLATIONAL PSYCHIATRY   2   e186   2012.11

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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.

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  • Supportive evidence for the association between the Gln2Pro polymorphism in the SIGMAR1 gene and schizophrenia in the Japanese population: A case-control study and an updated meta-analysis Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Naoshi Kaneko, Masako Shibuya, Jun Egawa, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   141 ( 2-3 )   279 - 280   2012.11

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  • Quetiapine-induced insulin resistance after switching from blonanserin despite a loss in both bodyweight and waist circumference Reviewed

    Yutaro Suzuki, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   66 ( 6 )   534 - 535   2012.10

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  • The lipid profiles in Japanese patients with schizophrenia treated with antipsychotic agents Reviewed

    Junzo Watanabe, Yutaro Suzuki, Takuro Sugai, Naoki Fukui, Shin Ono, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    GENERAL HOSPITAL PSYCHIATRY   34 ( 5 )   525 - 528   2012.9

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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.

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  • Early psychological distress among sufferers after the 2011 Northern Nagano Prefecture Earthquake Reviewed

    Masanobu Shindo, Hideaki Kitamura, Akira Tachibana, Hiroko Honma, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   66 ( 5 )   454 - 456   2012.8

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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.

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  • Decreased leftward bias of prefrontal activity in autism spectrum disorder revealed by functional near-infrared spectroscopy. Reviewed

    Tamura R, Kitamura H, Endo T, Abe R, Someya T

    Psychiatry research   203 ( 2-3 )   237 - 240   2012.8

  • Influence of the 5-HTR1A C-1019G polymorphism on clinical phenotypes of autism spectrum disorders Reviewed

    Jun Egawa, Taro Endo, Ryu Tamura, Naio Masuzawa, Naoki Fukui, Takuro Sugai, Toshiyuki Someya

    PSYCHIATRY RESEARCH   198 ( 2 )   336 - 337   2012.7

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  • Improvement of tardive dyskinesia and dystonia associated with aripiprazole following a switch to quetiapine: case report and review of the literature Reviewed

    S. Ono, Y. Suzuki, M. Shindo, T. Endo, N. Fukui, T. Sugai, T. Someya

    JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS   37 ( 3 )   370 - 372   2012.6

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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.

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  • Improvement in quetiapine-induced hypoglycemia following a switch to blonanserin Reviewed

    Yutaro Suzuki, Nobuto Tsuneyama, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Mami Saito, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   66 ( 4 )   370 - 371   2012.6

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  • Dysregulation of Adipocytokines Related to Second-Generation Antipsychotics in Normal Fasting Glucose Patients With Schizophrenia Reviewed

    Takuro Sugai, Yutaro Suzuki, Naoki Fukui, Shin Ono, Junzo Watanabe, Nobuto Tsuneyama, Toshiyuki Someya

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   32 ( 3 )   390 - 393   2012.6

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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.

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  • A two-stage case-control association study between the tryptophan hydroxylase 2 (TPH2) gene and schizophrenia in a Japanese population Reviewed

    Yuichiro Watanabe, Jun Egawa, Yoshimi Iijima, Ayako Nunokawa, Naoshi Kaneko, Masako Shibuya, Tadao Arinami, Hiroshi Ujike, Toshiya Inada, Nakao Iwata, Mamoru Tochigi, Hiroshi Kunugi, Masanari Itokawa, Norio Ozaki, Ryota Hashimoto, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   137 ( 1-3 )   264 - 266   2012.5

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  • Exploration of a possible association between the tryptophan hydroxylase 2 (TPH2) gene and panic symptoms induced by carbon dioxide in healthy individuals Reviewed

    Ryo Abe, Yuichiro Watanabe, Akira Tachibana, Ayako Nunokawa, Masanobu Shindo, Naoya Hasegawa, Toshiyuki Someya

    PSYCHIATRY RESEARCH   197 ( 3 )   358 - 359   2012.5

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  • A detailed association analysis between the tryptophan hydroxylase 2 (TPH2) gene and autism spectrum disorders in a Japanese population Reviewed

    Jun Egawa, Yuichiro Watanabe, Ayako Nunokawa, Taro Endo, Naoshi Kaneko, Ryu Tamura, Toshiro Sugiyama, Toshiyuki Someya

    PSYCHIATRY RESEARCH   196 ( 2-3 )   320 - 322   2012.4

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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.

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  • Improvement in QTc prolongation induced by zotepine following a switch to perospirone Reviewed

    Yutaro Suzuki, Junzo Watanabe, Takuro Sugai, Naoki Fukui, Shin Ono, Nobuto Tsuneyama, Mami Saito, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   66 ( 3 )   244 - 244   2012.4

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  • Social network disruption as a major factor associated with psychological distress 3 years after the 2004 Niigata-Chuetsu earthquake in Japan Reviewed

    Mari Oyama, Kazutoshi Nakamura, Yuko Suda, Toshiyuki Someya

    Environmental Health and Preventive Medicine   17 ( 2 )   118 - 123   2012.3

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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.

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  • Delirium associated with duloxetine in a depressed patient with Alzheimer's dementia Reviewed

    Yutaro Suzuki, Mami Saito, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   66 ( 2 )   166 - 166   2012.3

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  • Six-year complete remission in a patient with disorganized schizophrenia during maintenance electroconvulsive therapy without antipsychotic medication Reviewed

    Hideaki Kitamura, Takuro Sugai, Naoki Orime, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   66 ( 2 )   164 - 165   2012.3

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  • Increased Risk of Antipsychotic-Related QT Prolongation During Nighttime A 24-Hour Holter Electrocardiogram Recording Study Reviewed

    Junzo Watanabe, Yutaro Suzuki, Naoki Fukui, Shin Ono, Takuro Sugai, Nobuto Tsuneyama, Toshiyuki Someya

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   32 ( 1 )   18 - 22   2012.2

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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.

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  • Association of SNPs linked to increased expression of SLC1A1 with schizophrenia. Reviewed

    Horiuchi Yasue, Iida Syuhei, Koga Minori, Ishiguro Hiroki, Iijima Yoshimi, Inada Toshiya, Watanabe Yuichiro, Someya Toshiyuki, Ujike Hiroshi, Iwata Nakao, Ozaki Norio, Kunugi Hiroshi, Tochigi Mamoru, Itokawa Masanari, Arai Makoto, Niizato Kazuhiro, Iritani Shuji, Kakita Akiyoshi, Takahashi Hitoshi, Nawa Hiroyuki, Arinami Tadao

    Am J Med Genet B Neuropsychiatr Genet   159B ( 1 )   30 - 37   2012.1

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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

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  • Effect of the cytochrome P450 2D6*10 allele on risperidone metabolism in Japanese psychiatric patients Reviewed

    Yutaro Suzuki, Naoki Fukui, Nobuto Tsuneyama, Junzo Watanabe, Shin Ono, Takuro Sugai, Mami Saito, Yoshimasa Inoue, Toshiyuki Someya

    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL   27 ( 1 )   43 - 46   2012.1

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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.

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  • QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone Reviewed

    Yutaro Suzuki, Naoki Fukui, Junzo Watanabe, Shin Ono, Takuro Sugai, Nobuto Tsuneyama, Mami Saito, Yoshimasa Inoue, Toshiyuki Someya

    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL   27 ( 1 )   39 - 42   2012.1

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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.

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  • Case-control study and meta-analysis of Ser311Cys polymorphism in the DRD2 gene demonstrate lack of association with risk for schizophrenia in the Japanese population

    Y. Watanabe, A. Nunokawa, N. Kaneko, M. Shibuya, J. Egawa, N. Fukui, T. Someya

    Genetics and Molecular Research   11 ( 2 )   1142 - 1145   2012

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  • Case-control study and meta-analysis of Ser311Cys polymorphism in the DRD2 gene demonstrate lack of association with risk for schizophrenia in the Japanese population

    Y. Watanabe, A. Nunokawa, N. Kaneko, M. Shibuya, J. Egawa, N. Fukui, T. Someya

    GENETICS AND MOLECULAR RESEARCH   11 ( 2 )   1142 - 1145   2012

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  • Positive Association of Phencyclidine-Responsive Genes, PDE4A and PLAT, With Schizophrenia Reviewed

    Xiangdong Deng, Hiromi Takaki, Lixiang Wang, Tosihide Kuroki, Tatsuo Nakahara, Kijiro Hashimoto, Hideaki Ninomiya, Tadao Arinami, Toshiya Inada, Hiroshi Ujike, Masanari Itokawa, Mamoru Tochigi, Yuichiro Watanabe, Toshiyuki Someya, Hiroshi Kunugi, Nakao Iwata, Norio Ozaki, Hiroki Shibata, Yasuyuki Fukumaki

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   156B ( 7 )   850 - 858   2011.12

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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.

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  • Changes in the Metabolic Parameters and QTc Interval After Switching From Olanzapine to Aripiprazole in Japanese Patients With Stable Schizophrenia Reviewed

    Yuatro Suzuki, Takuro Sugai, Shin Ono, Kazushi Sawamura, Naoki Fukui, Junzo Watanabe, Nobuto Tsuneyama, Toshiyuki Someya

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   31 ( 4 )   526 - 528   2011.8

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  • Dose-dependent effects of olanzapine on QT intervals and plasma prolactin levels in Japanese patients with stable schizophrenia Reviewed

    Yutaro Suzuki, Shin Ono, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Nobuto Tsuneyama, Kazushi Sawamura, Toshiyuki Someya

    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL   26 ( 6 )   440 - 443   2011.8

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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.

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  • CYP2D6 genotype and smoking influence fluvoxamine steady-state concentration in Japanese psychiatric patients: lessons for genotype-phenotype association study design in translational pharmacogenetics Reviewed

    Yutaro Suzuki, Takuro Sugai, Naoki Fukui, Junzo Watanabe, Shin Ono, Yoshimasa Inoue, Vural Ozdemir, Toshiyuki Someya

    JOURNAL OF PSYCHOPHARMACOLOGY   25 ( 7 )   908 - 914   2011.7

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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.

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  • Exploring functional polymorphisms in the dopamine receptor D2 gene using prolactin concentration in healthy subjects

    N. Fukui, Y. Suzuki, T. Sugai, J. Watanabe, S. Ono, N. Tsuneyama, T. Someya

    MOLECULAR PSYCHIATRY   16 ( 4 )   356 - 358   2011.4

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  • Dose-dependent increase in the QTc interval in aripiprazole treatment after risperidone Reviewed

    Yutaro Suzuki, Shin Ono, Naoki Fukui, Takuro Sugai, Junzo Watanabe, Nobuto Tsuneyama, Toshiyuki Someya

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   35 ( 2 )   643 - 644   2011.3

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  • Prevalence of Mental Disorders and Suicidal Thoughts Among Community-Dwelling Elderly Adults 3 Years After the Niigata-Chuetsu Earthquake Reviewed

    Yuriko Suzuki, Atsuro Tsutsumi, Maiko Fukasawa, Hiroko Honma, Toshiyuki Someya, Yoshiharu Kim

    JOURNAL OF EPIDEMIOLOGY   21 ( 2 )   144 - 150   2011.3

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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.

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  • Asia-Pacific Health 2020 and Genomics without Borders: Co-production of Knowledge by Science and Society Partnership for Global Personalized Medicine Reviewed

    Vural Ozdemir, David H. Muljono, Tikki Pang, Lynnette R. Ferguson, Aresha Manamperi, Sofia Samper, Toshiyuki Someya, Anne Marie Tassé, Shih-Jen Tsai, Hong-Hao Zhou, Edmund J.D. Lee

    Current Pharmacogenomics and Personalized Medicine   9 ( 1 )   1 - 5   2011

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  • Reduced thalamus volume in non-right-handed male patients with autism spectrum disorders Reviewed

    Jun Egawa, Yuichiro Watanabe, Hideaki Kitamura, Taro Endo, Ryu Tamura, Naoya Hasegawa, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   65 ( 4 )   395 - 395   2011

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  • Reduced thalamic volume observed across different subgroups of autism spectrum disorders Reviewed

    Ryu Tamura, Hideaki Kitamura, Taro Endo, Naoya Hasegawa, Toshiyuki Someya

    PSYCHIATRY RESEARCH-NEUROIMAGING   184 ( 3 )   186 - 188   2010.12

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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.

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  • A case-control study and meta-analysis of association between a common copy number variation of the glutathione S-transferase mu I (GSTM1) gene and schizophrenia Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Naoshi Kaneko, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   124 ( 1-3 )   236 - 237   2010.12

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  • Differences in clinical effect and tolerance between fluvoxamine and paroxetine: A switching study in patients with depression Reviewed

    Yutaro Suzuki, Nobuto Tsuneyama, Naoki Fukui, Takuro Sugai, Junzo Watanabe, Shin Ono, Toshiyuki Someya

    HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL   25 ( 7-8 )   525 - 529   2010.11

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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.

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  • Gender differences in the relationship between the risperidone metabolism and the plasma prolactin levels in psychiatric patients Reviewed

    Yutaro Suzuki, Naoki Fukui, Junzo Watanabe, Shin Ono, Takuro Sugai, Nobuto Tsuneyama, Yoshimasa Inoue, Toshiyuki Someya

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   34 ( 7 )   1266 - 1268   2010.10

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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

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  • An association study between the dymeclin gene and schizophrenia in the Japanese population Reviewed

    Saori Yazaki, Minori Koga, Hiroki Ishiguro, Toshiya Inada, Hiroshi Ujike, Masanari Itokawa, Takeshi Otowa, Yuichiro Watanabe, Toshiyuki Someya, Nakao Iwata, Hiroshi Kunugi, Norio Ozaki, Tadao Arinami

    JOURNAL OF HUMAN GENETICS   55 ( 9 )   631 - 634   2010.9

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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

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  • 5-HTTLPR polymorphism influences prefrontal neurochemical metabolites in autism spectrum disorder Reviewed

    Taro Endo, Hideaki Kitamura, Ryu Tamura, Jun Egawa, Takuro Sugai, Naoki Fukui, Yutaro Suzuki, Toshiyuki Someya

    PSYCHIATRY RESEARCH-NEUROIMAGING   183 ( 2 )   170 - 173   2010.8

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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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  • Increase in the risk of chlorpromazine-induced QT prolongation during nighttime: Is a short-period ECG during daytime sufficient? Reviewed

    Yutaro Suzuki, Junzo Watanabe, Shin Ono, Naoki Fukui, Takuro Sugai, Nobuto Tsuneyama, Toshiyuki Someya

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   34 ( 6 )   1122 - 1123   2010.8

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  • The wide variability of perospirone metabolism and the effect of perospirone on prolactin in psychiatric patients Reviewed

    Yutaro Suzuki, Kazushi Sawamura, Shin Ono, Naoki Fukui, Takuro Sugai, Junzo Watanabe, Nobuto Tsuneyama, Yoshimasa Inoue, Toshiyuki Someya

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   34 ( 6 )   830 - 833   2010.8

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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.

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  • Aripiprazole monotherapy in a patient with major depressive disorder Reviewed

    Yuichi Yokoyama, Hideaki Kitamura, Toshiyuki Someya

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   34 ( 6 )   1124 - 1125   2010.8

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  • [Psychiatric disorders]. Reviewed

    Watanabe Y, Someya T

    Nihon rinsho. Japanese journal of clinical medicine   68 Suppl 8   402 - 405   2010.8

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  • Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism Reviewed

    M. Shibuya, E. Komi, R. Wang, T. Kato, Y. Watanabe, M. Sakai, M. Ozaki, T. Someya, H. Nawa

    JOURNAL OF NEURAL TRANSMISSION   117 ( 7 )   887 - 895   2010.7

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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.

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  • Supportive Evidence for Reduced Expression of GNB1L in Schizophrenia Reviewed

    Hiroki Ishiguro, Minori Koga, Yasue Horiuchi, Emiko Noguchi, Miyuki Morikawa, Yoshimi Suzuki, Makoto Arai, Kazuhiro Niizato, Shyuji Iritani, Masanari Itokawa, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Hiroshi Kunugi, Tsukasa Sasaki, Makoto Takahashi, Yuichiro Watanabe, Toshiyuki Someya, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Tadao Arinami

    SCHIZOPHRENIA BULLETIN   36 ( 4 )   756 - 765   2010.7

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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.

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  • Diagnostic classification of schizophrenia by neural network analysis of blood-based gene expression signatures Reviewed

    Makoto Takahashi, Hiroshi Hayashi, Yuichiro Watanabe, Kazushi Sawamura, Naoki Fukui, Junzo Watanabe, Tsuyoshi Kitajima, Yoshio Yamanouchi, Nakao Iwata, Katsuyoshi Mizukami, Takafumi Hori, Kazutaka Shimoda, Hiroshi Ujike, Norio Ozaki, Kentarou Iijima, Kazuo Takemura, Hideyuki Aoshima, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   119 ( 1-3 )   210 - 218   2010.6

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    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.

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  • Cytokine hypothesis of schizophrenia pathogenesis: evidence from human studies and animal models. Reviewed

    Watanabe Yuichiro, Someya Toshiyuki, Nawa Hiroyuki

    Psychiatry Clin Neurosci   64 ( 3 )   217 - 230   2010.6

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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

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  • Replication study of association between ADCYAP1 gene polymorphisms and schizophrenia Reviewed

    Minori Koga, Hiroki Ishiguro, Yasue Horiuchi, Toshiya Inada, Hiroshi Ujike, Masanari Itokawa, Takeshi Otowa, Yuichiro Watanabe, Toshiyuki Someya, Tadao Arinami

    PSYCHIATRIC GENETICS   20 ( 3 )   123 - 125   2010.6

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    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.

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  • Brain Cannabinoid CB2 Receptor in Schizophrenia Reviewed

    Hiroki Ishiguro, Yasue Horiuchi, Maya Ishikawa, Minori Koga, Keiko Imai, Yoshimi Suzuki, Miyuki Morikawa, Toshiya Inada, Yuichiro Watanabe, Makoto Takahashi, Toshiyuki Someya, Hiroshi Ujike, Nakao Iwata, Norio Ozaki, Emmanuel S. Onaivi, Hiroshi Kunugi, Tsukasa Sasaki, Masanari Itokawa, Makoto Arai, Kazuhiro Niizato, Shyuji Iritani, Izumi Naka, Jun Ohashi, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Tadao Arinami

    BIOLOGICAL PSYCHIATRY   67 ( 10 )   974 - 982   2010.5

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    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.

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  • Failure to find an association between myosin heavy chain 9, non-muscle (MYH9) and schizophrenia: A three-stage case-control association study Reviewed

    Hideki Amagane, Yuichiro Watanabe, Naoshi Kaneko, Ayako Nunokawa, Tatsuyuki Muratake, Hiroki Ishiguro, Tadao Arinami, Hiroshi Ujike, Toshiya Inada, Nakao Iwata, Hiroshi Kunugi, Tsukasa Sasaki, Ryota Hashimoto, Masanari Itokawa, Norio Ozaki, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   118 ( 1-3 )   106 - 112   2010.5

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

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  • Customized pharmacotherapies in schizophrenia Reviewed

    Yutaro Suzuki, Naoki Fukui, Junzo Watanabe, Shin Ono, Takuro Sugai, Nobuto Tsuneyama, Toshiyuki Someya

    Japanese Journal of Neuropsychopharmacology   30 ( 2 )   77 - 81   2010.4

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    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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  • A case-control association analysis of CABIN1 with schizophrenia in a Japanese population Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Naoshi Kaneko, Toshiyuki Someya

    JOURNAL OF HUMAN GENETICS   55 ( 3 )   179 - 181   2010.3

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    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

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  • The dopamine D3 receptor (DRD3) gene and risk of schizophrenia: Case-control studies and an updated meta-analysis Reviewed

    Ayako Nunokawa, Yuichiro Watanabe, Naoshi Kaneko, Takuro Sugai, Saori Yazaki, Tadao Arinami, Hiroshi Ujike, Toshiya Inada, Nakao Iwata, Hiroshi Kunugi, Tsukasa Sasaki, Masanari Itokawa, Norio Ozaki, Ryota Hashimoto, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   116 ( 1 )   61 - 67   2010.1

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    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.

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  • A comparison of haloperidol plasma levels among Japanese, Korean and Swedish psychiatric patients. Reviewed

    Morita S, Roh HK, Shimoda K, Someya T, Shibasaki M, Hirokane G, Svensson JO, Bertilsson L

    Clin Neuropsychopharm Ther   1   24 - 31   2010

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    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<sup>*</sup>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.

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  • Significant interaction of manic episodes with the clinical course of obsessive-compulsive disorder Reviewed

    Yohei Takasu, Hideaki Kitamura, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   64 ( 4 )   443 - 444   2010

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  • Preliminary Genome-Wide Association Study of Bipolar Disorder in the Japanese Population Reviewed

    Eiji Hattori, Tomoko Toyota, Yuichi Ishitsuka, Yoshimi Iwayama, Kazuo Yamada, Hiroshi Ujike, Yukitaka Morita, Masafumi Kodama, Kenji Nakata, Yoshio Minabe, Kazuhiko Nakamura, Yasuhide Iwata, Nori Takei, Norio Mori, Hiroshi Naitoh, Yoshio Yamanouchi, Nakao Iwata, Norio Ozaki, Tadafumi Kato, Toru Nishikawa, Atsushi Kashiwa, Mika Suzuki, Kunihiko Shioe, Manabu Shinohara, Masami Hirano, Shinichiro Nanko, Akihisa Akahane, Mikako Ueno, Naoshi Kaneko, Yuichiro Watanabe, Toshiyuki Someya, Kenji Hashimoto, Masaomi Iyo, Masanari Itokawa, Makoto Arai, Masahiro Nankai, Toshiya Inada, Sumiko Yoshida, Hiroshi Kunugi, Michiko Nakamura, Yoshimi Iijima, Yuji Okazaki, Teruhiko Higuchi, Takeo Yoshikawa

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   150B ( 8 )   1110 - 1117   2009.12

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    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.

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  • Comparison of voxel-based specific region analysis of Alzheimer's disease and simple computed tomography evaluation of medial temporal atrophy in psychiatric patients Reviewed

    Yuichi Yokoyama, Hideaki Kitamura, Toshiyuki Someya

    PSYCHOGERIATRICS   9 ( 3 )   127 - 131   2009.9

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    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.

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  • A two-stage case-control association study of PADI2 with schizophrenia Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Naoshi Kaneko, Tadao Arinami, Hiroshi Ujike, Toshiya Inada, Nakao Iwata, Hiroshi Kunugi, Masanari Itokawa, Takeshi Otowa, Norio Ozaki, Toshiyuki Someya

    JOURNAL OF HUMAN GENETICS   54 ( 7 )   430 - 432   2009.7

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    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

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  • Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia Reviewed

    Minori Koga, Hiroki Ishiguro, Saori Yazaki, Yasue Horiuchi, Makoto Arai, Kazuhiro Niizato, Shuji Iritani, Masanari Itokawa, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Hiroshi Kunugi, Tsukasa Sasaki, Makoto Takahashi, Yuichiro Watanabe, Toshiyuki Someya, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Christian Muchardt, Moshe Yaniv, Tadao Arinami

    HUMAN MOLECULAR GENETICS   18 ( 13 )   2483 - 2494   2009.7

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    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.

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  • Hypoglycaemia induced by second generation antipsychotic agents in schizophrenic non-diabetic patients. Reviewed

    Suzuki Y, Watanabe J, Fukui N, Ozdemir V, Someya T

    BMJ (Clinical research ed.)   338   a1792   2009.5

  • Risk Assessment and Communication Tools for Genotype Associations with Multifactorial Phenotypes: The Concept of "Edge Effect" and Cultivating an Ethical Bridge between Omics Innovations and Society Reviewed

    Vural Ozdemir, Guilherme Suarez-Kurtz, Raphaelle Stenne, Andrew A. Somogyi, Toshiyuki Someya, S. Oguz Kayaalp, Eugene Kolker

    OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY   13 ( 1 )   43 - 61   2009.2

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    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.

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  • Two-stage case-control association study of polymorphisms in rheumatoid arthritis susceptibility genes with schizophrenia Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Naoshi Kaneko, Tatsuyuki Muratake, Tadao Arinami, Hiroshi Ujike, Toshiya Inada, Nakao Iwata, Hiroshi Kunugi, Masanari Itokawa, Takeshi Otowa, Norio Ozaki, Toshiyuki Someya

    JOURNAL OF HUMAN GENETICS   54 ( 1 )   62 - 65   2009.1

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    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.

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  • A transdisciplinary forum for study of individual and population variability in response to health interventions and personalized medicine Reviewed

    V. Ozdemir, T. Someya

    Current Pharmacogenomics and Personalized Medicine   7 ( 3 )   146 - 148   2009

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  • Post-traumatic symptoms among the children and adolescents 2 years after the 2004 Niigata-Chuetsu earthquake in Japan Reviewed

    Taro Endo, Toshiki Shioiri, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   63 ( 2 )   253 - 253   2009

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  • A case of wrist fracture during modified electroconvulsive therapy Reviewed

    Uebaba S, Kitamura H, Someya T

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   63 ( 6 )   772   2009

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  • Dose-Dependent Effect of the CYP2D6 Genotype on the Steady-state Fluvoxamine Concentration Reviewed

    Junzo Watanabe, Yutaro Suzuki, Naoki Fukui, Takuro Sugai, Shin Ono, Yoshimasa Inoue, Toshiyuki Someya

    THERAPEUTIC DRUG MONITORING   30 ( 6 )   705 - 708   2008.12

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    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.

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  • Factors impacting on psychological distress and recovery after the 2004 Niigata-Chuetsu earthquake, Japan: Community-based study Reviewed

    Hideki Kuwabara, Toshiki Shioiri, Shin-Ichi Toyabe, Tsuyoshi Kawamura, Masataka Koizumi, Miki Ito-Sawamura, Kouhei Akazawa, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   62 ( 5 )   503 - 507   2008.10

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    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.

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  • Replication study for associations between polymorphisms in the CLDN5 and DGCR2 genes in the 22q11 deletion syndrome region and schizophrenia Reviewed

    Hiroki Ishiguro, Keiko Imai, Minori Koga, Yasue Horiuchi, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Masanari Itokawa, Hiroshi Kunugi, Tsukasa Sasaki, Yuichiro Watanabe, Toshiyuki Someya, Tadao Arinami

    PSYCHIATRIC GENETICS   18 ( 5 )   255 - 256   2008.10

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  • Association study of interleukin 2 (IL2) and IL4 with schizophrenia in a Japanese population Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Masako Shibuya, Naoshi Kaneko, Hiroyuki Nawa, Toshiyuki Someya

    EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE   258 ( 7 )   422 - 427   2008.10

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    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.

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  • Concentration-response. relationship for fluvoxamine using remission as an endpoint - A receiver operating characteristics curve analysis in major depression Reviewed

    Yutaro Suzuki, Naoki Fukui, Kazushi Sawamura, Takuro Sugai, Junzo Watanabe, Shin Ono, Yoshimasa Inoue, Vural Ozdemir, Toshiyuki Someya

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   28 ( 3 )   325 - 328   2008.6

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    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.

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  • Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations Reviewed

    T. Ohtsuki, Y. Horiuchi, M. Koga, H. Ishiguro, T. Inada, N. Iwata, N. Ozaki, H. Ujike, Y. Watanabe, T. Someya, T. Arinami

    NEUROSCIENCE LETTERS   435 ( 3 )   194 - 197   2008.4

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    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.

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  • Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample Reviewed

    Masashi Ikeda, Nagahide Takahashi, Shinichi Saito, Branko Aleksic, Yuichiro Watanabe, Ayako Nunokawa, Yoshio Yamanouchi, Tsuyoshi Kitajima, Yoko Kinoshita, Taro Kishi, Kunihiro Kawashima, Ryota Hashimoto, Hiroshi Ujike, Toshiya Inada, Toshiyuki Someya, Masatoshi Takeda, Norio Ozaki, Nakao Iwata

    SCHIZOPHRENIA RESEARCH   101 ( 1-3 )   1 - 8   2008.4

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    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.

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  • A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia Reviewed

    Tsuyuka Ohtsuki, Minori Koga, Hiroki Ishiguro, Yasue Horiuchi, Makoto Arai, Kazuhiro Niizato, Masanari Itokawa, Toshiya Inada, Nakao Iwata, Shyuji Iritani, Norio Ozaki, Hiroshi Kunugi, Hiroshi Ujike, Yuichiro Watanabe, Toshiyuki Someya, Tadao Arinami

    SCHIZOPHRENIA RESEARCH   101 ( 1-3 )   9 - 16   2008.4

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    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.

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  • Replication study and meta-analysis of the genetic association of GRM3 gene polymorphisms with schizophrenia in a large Japanese case-control population Reviewed

    Talal Albalushi, Yasue Horiuchi, Hiroki Ishiguro, Minori Koga, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Yuichiro Watanabe, Toshiyuki Someya, Tadao Arinami

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   147B ( 3 )   392 - 396   2008.4

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    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.

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  • Large-scale case-control study of a functional polymorphism in the glutamate receptor, metabotropic 3 gene in patients with schizophrenia Reviewed

    Ayako Nunokawa, Yuichiro Watanabe, Hideaki Kitamura, Naoshi Kaneko, Tadao Arinami, Hiroshi Ujike, Toshiya Inada, Nakao Iwata, Hiroshi Kunugi, Masanari Itokawa, Norio Ozaki, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   62 ( 2 )   239 - 240   2008.4

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    DOI: 10.1111/j.1440-1819.2008.01762.x

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  • Revised psychopharmacological algorithms for the treatment of mood disorders in Japan Reviewed

    Nobutaka Motohashi, Kunihiko Shioe, Jun Nakamura, Akihiko Ohshima, Kazuo Yamada, Hiroki Ozawa, Toshiyuki Someya, Ysuke Uchitomi, Teruhiko Higuchi

    INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE   12 ( 1 )   11 - 18   2008.3

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    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.

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  • A survey of the personalized medicine landscape Reviewed

    Ozdemir V, Dube MP, Tardif JC, de Denus S, Phillips M, Stenne R, Shimoda K, Someya T, Godard B

    Pharmacogenomics   9 ( 7 )   819 - 823   2008

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  • [Cerebral dysfunction and biochemical metabolic anomalies of the brain in pervasive developmental disorders]. Reviewed

    Endo T, Shioiri T, Someya T

    Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica   110 ( 10 )   887 - 892   2008

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  • Altered chemical metabolites in the Amygdala-Hippocampus region contribute to autistic symptoms of autism spectrum disorders Reviewed

    Taro Endo, Toshiki Shioiri, Hideaki Kitamura, Teruo Kimura, Sumio Endo, Naio Masuzawa, Toshiyuki Someya

    BIOLOGICAL PSYCHIATRY   62 ( 9 )   1030 - 1037   2007.11

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    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.

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  • The tryptophan hydroxylase 1 (TPH1) gene and risk of schizophrenia: A moderate-scale case-control study and meta-analysis Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Naoshi Kaneko, Toshiyuki Someya

    NEUROSCIENCE RESEARCH   59 ( 3 )   322 - 326   2007.11

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    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.

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  • Does operational diagnosis of schizophrenia significantly impact intellectual deficits in psychotic disorders? Reviewed

    H. Kitamura, T. Shioiri, M. Itoh, Y. Sato, K. Shichiri, T. Someya

    JOURNAL OF INTELLECTUAL DISABILITY RESEARCH   51   812 - 820   2007.10

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    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.

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  • Support for association of the PPP3CC gene with schizophrenia Reviewed

    Y. Horiuchi, H. Ishiguro, M. Koga, T. Inada, N. Iwata, N. Ozaki, H. Ujike, T. Muratake, T. Someya, T. Arinami

    MOLECULAR PSYCHIATRY   12 ( 10 )   891 - 893   2007.10

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  • Autosomal linkage analysis of a Japanese single multiplex schizophrenia pedigree reveals two candidate loci on chromosomes 4q and 3q Reviewed

    Naoshi Kaneko, Tatsuyuki Muratake, Hideki Kuwabara, Takanori Kurosaki, Mitsuru Takei, Tsuyuka Ohtsuki, Tadao Arinami, Shoji Tsuji, Toshiyuki Someya

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   144B ( 6 )   735 - 742   2007.9

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    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.

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  • No association between the tumor necrosis factor-alpha gene promoter polymorphisms and schizophrenia in a Japanese population Reviewed

    Yuichiro Watanabe, Tatsuyuki Muratake, Naoshi Kaneko, Naoki Fukui, Yasushi Nara, Toshiyuki Someya

    PSYCHIATRY RESEARCH   153 ( 1 )   1 - 6   2007.9

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    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.

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  • Meta-analysis of case-control association studies between the C270T polymorphism of the brain-derived neurotrophic factor gene and schizophrenia Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Naoshi Kaneko, Toshiyuki Someya

    SCHIZOPHRENIA RESEARCH   95 ( 1-3 )   250 - 252   2007.9

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    DOI: 10.1016/j.schres.2007.05.032

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  • Lack of association between the interleukin-1 gene complex and schizophrenia in a Japanese population Reviewed

    Yuichiro Watanabe, Ayako Nunokawa, Naoshi Kaneko, Tatsuyuki Muratake, Masataka Koizumi, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   61 ( 4 )   364 - 369   2007.8

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    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.

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  • Early prodromal symptoms and diagnoses before first psychotic episode in 219 inpatients with schizophrenia Reviewed

    Toshiki Shioiri, Keita Shinada, Hideki Kuwabara, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   61 ( 4 )   348 - 354   2007.8

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    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.

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  • Factor structure of the General Health Questionnaire (GHQ-12) in subjects who had suffered from the 2004 Niigata-Chuetsu earthquake in Japan: a community-based study Reviewed

    Shin-ichi Toyabe, Toshiki Shioiri, Kuriko Kobayashi, Hideki Kuwabara, Masataka Koizumi, Taro Endo, Miki Ito, Hiroko Honma, Noboru Fukushima, Toshiyuki Someya, Kouhei Akazawa

    BMC PUBLIC HEALTH   7   175   2007.7

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    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.

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  • Suicide in Japan Reviewed

    Ryo Abe, Toshiki Shioiri, Toshiyuki Someya

    PSYCHIATRIC SERVICES   58 ( 7 )   1013 - 1013   2007.7

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  • No associations exist between five functional polymorphisms in the catechol-O-methyltransferase gene and schizophrenia in a Japanese population Reviewed

    Ayako Nunokawa, Yulchiro Watanabe, Tatsuyuki Muratake, Naoshi Kaneko, Masataka Koizumi, Toshiyuki Someya

    NEUROSCIENCE RESEARCH   58 ( 3 )   291 - 296   2007.7

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    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.

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  • PICK1 is not a susceptibility gene for schizophrenia in a Japanese population: Association study in a large case-control population Reviewed

    H. Ishiguro, M. Koga, Y. Horiuchi, T. Inada, N. Iwata, N. Ozaki, H. Ujike, T. Muratake, T. Someya, T. Arinami

    NEUROSCIENCE RESEARCH   58 ( 2 )   145 - 148   2007.6

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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.

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  • Diagnostic classification and demographic features in 283 patients with somatoform disorder Reviewed

    Hideki Kuwabara, Michito Otsuka, Masanobu Shindo, Shin Ono, Toshiki Shioiri, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   61 ( 3 )   283 - 289   2007.6

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    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.

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  • Failure to confirm the association between the FEZ1 gene and schizophrenia in a Japanese population Reviewed

    Minori Koga, Hiroki Ishiguro, Yasue Horiuchi, Talal Albalushi, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Tatsuyuki Muratake, Toshiyuki Someya, Tadao Arinami

    NEUROSCIENCE LETTERS   417 ( 3 )   326 - 329   2007.5

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    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.

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  • No association between the ERBB3 gene and schizophrenia in a Japanese population Reviewed

    Yuichiro Watanabe, Naoki Fukui, Ayako Nunokawa, Tatsuyuki Muratake, Naoshi Kaneko, Hideaki Kitamura, Toshiyuki Someya

    NEUROSCIENCE RESEARCH   57 ( 4 )   574 - 578   2007.4

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    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.

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  • Asymmetry in scientific method and limits to Cross-Disciplinary dialogue: Toward a shared language and science policy in pharmacogenomics and human disease genetics Reviewed

    Vural Ozdemir, Bryn Williams-Jones, Janice E. Graham, Sheldon H. Preskorn, Dimitrios Gripeos, Stephen J. Glatt, Robert H. Friis, Christopher Reist, Sandor Szabo, James B. Lohr, Toshiyuki Someya

    JOURNAL OF INVESTIGATIVE MEDICINE   55 ( 3 )   130 - 141   2007.4

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  • Dose-dependent effects of the 3435 C &gt; T genotype of ABCB1 gene on the steady-state plasma concentration of fluvoxamine in psychiatric patients Reviewed

    Naoki Fukui, Yutaro Suzuki, Kazushi Sawamura, Takuro Sugai, Junzo Watanabe, Yoshimasa Inoue, Toshiyuki Someya

    THERAPEUTIC DRUG MONITORING   29 ( 2 )   185 - 189   2007.4

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    This study investigated effects of the 3435 C &gt; T genotype of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1, MDR1) gene on the steady-state plasma concentration of fluvoxamine (FLV).
    Methods: Sixty-two psychiatric patients were treated with different doses (50, 100, 150, and 200 mg/d) of FLV. Blood samples were collected after at least 2 weeks of treatment with the same daily dose to obtain steady-state concentrations of FLV, and 3435 C &gt; T genotype was determined by polymerase chain reaction.
    Results: FLV concentration-to-dose ratio was significantly different among 3435 C &gt; T genotype groups at the 200 mg/d dose (P = 0.019). A post-hoc analysis revealed that FLV concentration-to-dose ratio was significantly higher in the TT genotype group as compared with the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.861 vs 0.434, P = 0,026). FLV concentration-to-dose ratio was significantly higher in the CT + TT genotype group than the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.618 vs 0.434, P = 0.031). At 50, 100, and 150 mg/d dose, FLV concentration-to-dose ratios were not significantly different among 3435 C &gt; T genotype groups. At 50, 100, and 150 mg/d dose, no significant differences were found in FLV concentration-to-dose ratios between the CT + TT genotype group and CC genotype group.
    Conclusions: This study suggests that pharmacokinetics of FLV depend on ABCB1 gene polymorphism only at the 200 mg/d dose.

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  • Survival rate and causes of mortality in the elderly with depression: A 15-year prospective study of a Japanese community sample, the Matsunoyama-Niigata Suicide Prevention Project Reviewed

    Tsuyoshi Kawamura, Toshiki Shioiri, Kuniaki Takahashi, Vural Ozdemir, Toshiyuki Someya

    JOURNAL OF INVESTIGATIVE MEDICINE   55 ( 3 )   106 - 114   2007.4

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    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.

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  • Synergistic association of mitochondrial uncoupling protein (UCP) genes with schizophrenia Reviewed

    Katsuhito Yasuno, Satoshi Ando, Shinnosuke Misumi, Satoshi Makino, Jerzy K. Kulski, Tatsuyuki Muratake, Naoshi Kaneko, Hideki Amagane, Toshiyuki Someya, Hidetoshi Inoko, Hidemichi Suga, Kousuke Kanemoto, Gen Tamiya

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   144B ( 2 )   250 - 253   2007.3

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    Many studies suggest that mitochondrial dysfunction is involved in the pathophysiology of schizophrenia. We performed a case-control study using tag SNPs in the mitochondrial uncoupling protein genes, UCP2, UCP4, and BMCP1/UCP5, to investigate their association with schizophrenia. These neuronal UCPs are expressed in various brain tissues and may exert a neuroprotective effect against increased oxidative stress. We found modest associations between schizophrenia and the four tag SNPs, rs660339 (odds ratio (OR) = 1.330; P = 0.0043) and rs649446 (OR = 0.739; P = 0.0069) in UCP2, and rs10807344 (OR = 0.622; P = 0.0029) and rs2270450 (OR = 0.704; P = 0.0043) in UCP4, all of which were statistically significant even after correcting for multiple comparisons. Moreover, we found a statistically significant synergistic interaction between UCP2 and UCP4 by using the multifactor dimensionality reduction (MDR) method. The synergistic interaction was also confirmed by the logistic regression analysis, where the maximal OR was obtained when the risk alleles at rs660339 and rs10807344 were simultaneously homozygous. Individuals possessing homozygous risk alleles at these two loci have a 7.6-fold risk of developing schizophrenia compared with those of minimal OR. Our findings suggest that UCP2 and UCP4 have a modest but important involvement in the genetic etiology of schizophrenia. This is the first report of the association between schizophrenia and neuronal UCPs. (c) 2006 Wiley-Liss, Inc.

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  • Parental mental health affects behavioral changes in children following a devastating disaster: a community survey after the 2004 Niigata-Chuetsu earthquake Reviewed

    Taro Endo, Toshiki Shioiri, Toshiyuki Someya, Shinichi Toyabe, Kohei Akazawa

    GENERAL HOSPITAL PSYCHIATRY   29 ( 2 )   175 - 176   2007.3

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  • Mapping translational research in personalized therapeutics: from molecular markers to health policy Reviewed

    Vural Ozdemir, Bryn Williams-Jones, Dan M. Cooper, Toshiyuki Someya, Beatrice Godard

    PHARMACOGENOMICS   8 ( 2 )   177 - 185   2007.2

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    Translational research is frequently used in the bioscience literature to refer to the translation of basic science into practical applications at the point of patient care. With the introduction of theragnostics, a new medical subspecialty that fuses therapeutics and diagnostic medicine with the goal of providing individualized pharmacotherapy, we suggest that the focus of translational research is shifting. We identify two bottlenecks or gaps in translational research for theragnostics: GAP1 translation from basic science to first-in-human proof-of-concept; and GAP2 translation from clinical proof-of-concept to development of evidence-based personalized treatment guidelines. GAP1 translational research in theragnostics is usually performed in traditional craft-based studies with small sample sizes and led by independent academic or industry researchers. In contrast, GAP2 translational investigations typically rely on large research consortiums and population-based biobanks that couple biomarker information with longitudinal 'real-life' observational data on a broad range of pharmacological phenotypes. Despite an abundance of research on the use of biobanks in disease gene discovery, there has been little conceptual work on whether and to what extent population biobanks can be utilized for translating genomics discoveries to practical treatment guidelines for theragnostic tests.

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  • RGS4 is not a susceptibility gene for schizophrenia in Japanese: Association study in a large case-control population Reviewed

    H. Ishiguro, Y. Horiuchi, M. Koga, T. Inada, N. Iwata, N. Ozaki, H. Ujike, T. Muratake, T. Someya, T. Arinami

    SCHIZOPHRENIA RESEARCH   89 ( 1-3 )   161 - 164   2007.1

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    The regulator of the G-protein signaling 4 (RGS4) has been implicated in the susceptibility to schizophrenia. RGS4 interacts with ErbB3 that acts as receptors for neuregulin 1 and these proteins may play a role in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two meta-analysis studies provided different interpretations for the genetic association between RGS4 and schizophrenia. We attempted to confirm this association in a case-control study of 1918 Japanese patients with schizophrenia and 1909 Japanese control subjects. Four widely studied single nucleotide polymorphisms (SNPs) were genotyped, and none showed association with schizophrenia. SNP 1 (rs10917670), p = 0.92; SNP 4 (rs951436), p=0.9 1; SNP 7 (rs951439), p = 0.27; and SNP 18 (rs2661319), p=0.43. A haplotype block constructed by these SNPs spans the 5' flanking region to the 5' mid-region of the RGS4 gene. Previous meta-analysis showed that both two major haplotypes of this block were risk haplotypes. The two common haplotypes were observed in the Japanese population. However, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and SNPs of the RGS4 gene identified thus far are unlikely to contribute to the genetic susceptibility to schizophrenia in the Japanese population. (c) 2006 Elsevier B.V. All rights reserved.

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  • Countertransference to psychiatric patients in a clinical setting: Development of the Feeling Checklist-Japanese version Reviewed

    Fujika Katsuki, Masahiro Goto, Hirohumi Takagi, Vurnal Ozdemir, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   60 ( 6 )   727 - 735   2006.12

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    Countertransference is an important dimension of the therapeutic alliance between care providers and patients. The Feeling Checklist (FC) is a self-report questionnaire for the assessment of countertransference by hospital staff toward patients. The FC was translated from English into Japanese and its factor structure, reliability, and validity in the Japanese version (FC-J) were examined. A total of 281 Japanese psychiatric nurses were tested with the FC-J. All nurses were primarily involved in provision of psychiatric care. Principal-component factor analysis with varimax rotation was performed to identify the potential components of the FC-J. In a factor analysis of the FC-J, seven factors were extracted. The five subscales that were determined and labeled included Reject, Distance, Helpfulness, Closeness, and Involvement, which collectively accounted for 56.0% of the variance. Cronbach's alpha, a measure of internal consistency, for individual subscales was 0.833 for Reject, 0.763 for Distance, 0.768 for Helpfulness, 0.617 for Closeness, and 0.663 for Involvement. Notably, there was a significant correlation between the FC-J and the Nurse Attitude Scale (P &lt; 0.0001). Moreover, one-way ANOVA was performed with each FC-J subscale to examine differences among psychiatric diagnoses in the study sample. A significant difference was found for Involvement (P &lt; 0.001), with the total score on Involvement being the highest in the personality disorder group. These results are considered to verify the reliability and validity of the FC-J as a scale to measure countertransference among Japanese care providers. The use of this scale allows individual care providers to recognize and be cognizant of their own countertransference objectively and thereby contributes to improve the relationship between patients and care providers.

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  • Gender differences in prolactin elevation induced by olanzapine in Japanese drug-naive schizophrenic patients Reviewed

    Kazushi Sawamura, Yutaro Suzuki, Naoki Fukul, Takuro Sugai, Toshiyuki Someya

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   30 ( 8 )   1511 - 1514   2006.12

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    We investigated the effect of gender on plasma prolactin levels in 20 Japanese drug-naive schizophrenic patients [10 male, 10 female, aged 25.4 +/- 10.3 (mean +/- S.D.), range 12-46 years] treated with olanzapine. Plasma prolactin levels were measured at baseline, and weeks 3 and 8 after starting titration of olanzapine. Comparisons of plasma prolactin levels between baseline and week 3, and between baseline and week 8 were made by repeated analysis of variance (ANOVA) and paired t-test. Two-way ANOVA showed a significant difference in olanzapine-induced prolactin changes between male and female patients (P=0.037). In male patients (n = 10), the plasma concentration of prolactin at week 3 was significantly higher than at baseline (P=0.016), but there was no significant difference between the plasma concentration of prolactin at week 8 and at baseline or week 3 (P =0.191). In female patients (n = 10), there was a significant change of prolactin between baseline and week 3 (P=0.005), and between baseline and week 8 (P=0.047). Our results indicate the possibility of gender differences in prolactin elevation induced by olanzapine in Japanese drug-naive schizophrenic patients. These gender-based findings may be helpful for clinicians when deciding the frequency of follow-up visits once a patient starts olanzapine therapy. (c) 2006 Published by Elsevier Inc.

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  • Could endogenous substrates of drug-metabolizing enzymes influence constitutive physiology and drug target responsiveness? Reviewed

    Vural Ozdemir, Arzu Gunes, Maija-Liisa Dahl, M. Gabriella Scordo, Bryn Williams-Jones, Toshiyuki Someya

    PHARMACOGENOMICS   7 ( 8 )   1199 - 1210   2006.12

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    Integration of genomic data from pharmacokinetic pathways and drug targets is an emerging trend in bioinformatics, but is there a clear separation of pharmacokinetic pathways and drug targets? Should we also consider the potential interactions of endogenous substrates of drug-metabolizing enzymes with receptors and other molecular drug targets as we combine pharmacogenomic datasets? We discuss these overarching questions through a specific pharmacogenomic case study of the cytochrome P450 (CYP)2D6, serotonin and dopamine triad. Importantly, CYP2D6 may contribute to the regeneration of serotonin from 5-methoxytryptamine by virtue of its catalytic function as a 5-methoxyindolethylamine O-demethylase. Furthermore, serotonergic neurons provide a regulatory feedback on dopaminergic neurotransmission. Hence, we hypothesize that independent of its role as a pharmacokinetic gene, CYP2D6 may nuance the regulation of serotonergic and dopaminergic neurophysiology. Additionally, we reflect upon the contribution of hyperspecialization in biomedicine to the present disconnect between research on pharmacokinetics and drug targets, and the potential for remedying this important gap through informed dialogue among clinical pharmacologists, human geneticists, bioethicists and applied social scientists.

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  • Sustained brain-derived neurotrophic factor up-regulation and sensorimotor gating abnormality induced by postnatal exposure to phencyclidine: comparison with adult treatment Reviewed

    Makoto Takahashi, Akiyoshi Kakita, Takashi Futamura, Yuichiro Watanabe, Makoto Mizuno, Kenji Sakimura, Eero Castren, Toshitaka Nabeshima, Toshiyuki Someya, Hiroyuki Nawa

    JOURNAL OF NEUROCHEMISTRY   99 ( 3 )   770 - 780   2006.11

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    Brain-derived neurotrophic factor (BDNF) is involved in synaptic development and plasticity, and alterations in BDNF expression or signaling are implicated in drug addiction and psychiatric diseases, such as depression and schizophrenia. In this study, we administered phencyclidine to postnatal and adult rats with different time schedules, and determined the correlations between BDNF expression and the behavioral effects. Both single and repeated phencyclidine injections into adult rats induced BDNF up-regulation in the corticolimbic system and a decrease in prepulse inhibition, both of which were transient. In contrast, subchronic postnatal administration increased BDNF protein and mRNA levels in the hippocampus and entorhinal cortex, which were sustained until 8 weeks of age. In parallel, the postnatal rats treated with phencyclidine developed a persistent decrease in prepulse inhibition at the adult stage. The chronic BDNF increase appeared to contribute to the prepulse inhibition abnormality, as subchronic BDNF infusion into the hippocampus of normal rats mimicked the prepulse inhibition deficits. This study suggests that phencyclidine exposure during brain development induces sustained BDNF up-regulation in the limbic system with a biological link to sensorimotor gating deficits.

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  • Association study of a functional promoter polymorphism of the X-box binding protein 1 gene in Japanese patients with schizophrenia Reviewed

    Yuichiro Watanabe, Naoki Fukui, Tatsuyuki Muratake, Hideki Amagane, Naoshi Kaneko, Ayako Nunokawa, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   60 ( 5 )   633 - 635   2006.10

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    The functional promoter polymorphism -116C/G of the X-box binding protein 1 (XBP1) gene was found to be associated with schizophrenia in Han Chinese and Japanese subjects, although contradictive negative findings were also reported in European populations. To confirm this association in a Japanese population, the authors conducted a case-control association study. There was no significant difference in both genotype and allele frequencies between the patients and control subjects, suggesting that the XBP1 -116C/G polymorphism might not confer increased susceptibility for schizophrenia in a Japanese population. However, further studies using a larger sample with detailed clinical data should be performed in several populations.

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  • Lack of a relationship between the pupillary light reflex response and state/trait anxiety in remitted patients with panic disorder Reviewed

    Toshiki Shioiri, Hideki Kuwabara, Ryo Abe, Atsuhiko Iijima, Maki Kojima-Maruyama, Hideaki Kitamura, Takehiko Bando, Toshiyuki Someya

    JOURNAL OF AFFECTIVE DISORDERS   95 ( 1-3 )   159 - 164   2006.10

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    Objective: Recently, some studies have indicated that pupillary function only correlates with state/trait anxiety in healthy subjects. In the present study, we examined whether or not there were relationships between the PLR functions and state/trait anxiety in remitted (the absence of panic attack (PA) symptoms for at least 6 months) PD patients compared to normal control (NC) subjects.
    Methods: Before and after audiovisual stimulation (AS) that induced mental stress through exposure to video images of high stress experiences, such as driving motor vehicles, the pupillary light reflex (PLR) was measured with an infrared pupillometer in 30 remitted PD patients and 30 age- and gender-matched NC subjects. In order to examine the relationships between the 8 PLR parameters (initial pupillary diameter in darkness, pupillary diameter at maximum constriction, constriction ratio, latency of the reflex, time to reach maximum constriction and time constant of redilation) and state/trait anxiety, we used the State-Trait Anxiety Inventory (STAI) and stepwise multiple regression analysis.
    Results: There was no significant group difference in the STAI-T score and STAI-S scores before and after AS. We confirmed the significant relationships between pupillary function and state/trait anxiety in NC subjects, but not in PD patients.
    Conclusions: These findings suggest that in contrast to NCs, even remitted PD patients may have dysfunctional PLR regulation with mental loading, such as AS. Moreover, it is possible that the abnormalities of ANS exist extensively in PD, since almost all panic symptoms, including PA, are involved in cardiovascular symptoms, but not pupillary ones. (c) 2006 Elsevier B.V. All rights reserved.

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  • The effect of 5-hydroxytryptamine 3A and 3B receptor genes on nausea induced by paroxetine Reviewed

    T. Sugai, Y. Suzuki, K. Sawamura, N. Fukui, Y. Inoue, T. Someya

    PHARMACOGENOMICS JOURNAL   6 ( 5 )   351 - 356   2006.9

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    We investigated the effect of 5-hydroxytryptamine 3A and 3B receptor (HTR3A and HTR3B) gene polymorphisms on nausea induced by paroxetine in Japanese psychiatric patients. Blood samples were collected from 78 individuals after at least 2 weeks treatment with the same daily dose of paroxetine. The patients visited every 2 weeks and the paroxetine dose was changed in response to their clinical symptoms. Nausea was assessed at each visit. The Tyr129Ser polymorphism of the HTR3B gene had a significant effect on the incidence of nausea (P = 0.038). Logistic regression analysis also showed that patients with the Tyr/Tyr genotype had a 3.95-fold (P = 0.048) higher risk of developing nausea than patients with the Ser allele. HTR3A gene polymorphisms and the CYP2D6 gene polymorphisms had no significant effect on the incidence of nausea. The mean score of nausea severity was corrected by the Bonferroni test. HTR3B gene polymorphisms are significant predictors of paroxetine-induced nausea.

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  • Impaired psychological recovery in the elderly after the Niigata-Chuetsu Earthquake in Japan: a population-based study Reviewed

    Shin-ichi Toyabe, Toshiki Shioiri, Hideki Kuwabara, Taroh Endoh, Naohito Tanabe, Toshiyuki Someya, Kouhei Akazawa

    BMC PUBLIC HEALTH   6   230   2006.9

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    Background: An earthquake measuring 6.8 on the Richter scale struck the Niigata-Chuetsu region of Japan at 5.56 P. M. on the 23rd of October, 2004. The earthquake was followed by sustained occurrence of numerous aftershocks, which delayed reconstruction of community lifelines. Even one year after the earthquake, 9,160 people were living in temporary housing. Such a devastating earthquake and life after the earthquake in an unfamiliar environment should cause psychological distress, especially among the elderly.
    Methods: Psychological distress was measured using the 12-item General Health Questionnaire (GHQ-12) in 2,083 subjects (69% response rate) who were living in transient housing five months after the earthquake. GHQ-12 was scored using the original method, Likert scoring and corrected method. The subjects were asked to assess their psychological status before the earthquake, their psychological status at the most stressful time after the earthquake and their psychological status at five months after the earthquake. Exploratory and confirmatory factor analysis was used to reveal the factor structure of GHQ12. Multiple regression analysis was performed to analyze the relationship between various background factors and GHQ-12 score and its subscale.
    Results: GHQ-12 scores were significantly elevated at the most stressful time and they were significantly high even at five months after the earthquake. Factor analysis revealed that a model consisting of two factors ( social dysfunction and dysphoria) using corrected GHQ scoring showed a high level of goodness-of-fit. Multiple regression analysis revealed that age of subjects affected GHQ-12 scores. GHQ-12 score as well as its factor 'social dysfunction' scale were increased with increasing age of subjects at five months after the earthquake.
    Conclusion: Impaired psychological recovery was observed even at five months after the Niigata-Chuetsu Earthquake in the elderly. The elderly were more affected by matters relating to coping with daily problems.

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  • Differences in characteristics between suicide victims who left notes or not Reviewed

    Hideki Kuwabara, Toshiki Shioiri, Akiyoshi Nishimura, Ryo Abe, Hideyuki Nushida, Yasuhiro Ueno, Kohel Akazawa, Toshiyuki Someya

    JOURNAL OF AFFECTIVE DISORDERS   94 ( 1-3 )   145 - 149   2006.8

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    Background: Suicide notes (SN) are one of markers of the severity of a suicide attempt and are said to provide a valuable insight into the thinking of suicide victims before the fatal act [Shah, A., De, T., 1998. Suicide and the elderly. Int. J. Psychiat. Clin Pract. 2, 3-18]. To examine whether suicide victims who wrote notes (note writers: NW) differ from those who did not, we investigated the characteristics of a sample of more than 5000 Japanese suicides using multiple logistic regression analysis.
    Methods: For all suicide victims (5161 cases), we examined the following information: gender, age, suicide method, reason for suicide, marital status, residential status, history of psychiatric disorders, previous suicidal behavior, physical disease, and content of suicide notes.
    Results: Mean incidence of NW was 30.1% (male: 29.7%, female: 30.8%). NW in Japan had the following characteristics; higher proportion in female and living alone, suicide by more lethal methods such as carbon monoxide, hanging or sharp instruments. On the other hand, non-NW had tendencies to commit suicide for reasons of physical illness and psychiatric disorder, and/or history of previous psychiatric disorders.
    Limitations: This study is observational and discusses only completed, not attempted, suicide. Medical and psychiatric comorbidity are judged only by the history of diagnosis and the information about the problems in relationships is based not on valid criteria for inclusion.
    Conclusions: Although these findings show ethnic differences, it is possible that SN may be considered an indicator of a serious suicide attempt. Further studies of SN are needed to confirm this. (c) 2006 Elsevier B.V. All rights reserved.

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  • Clinical features and treatment outcome in Japanese patients with social anxiety disorder: Chart review study Reviewed

    Masanobu Shindo, Toshiki Shioiri, Hidki Kuwabara, Maki Maruyama, Ryu Tamura, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   60 ( 4 )   410 - 416   2006.8

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    The lifetime prevalence of social anxiety disorder (SAD) is high at 3-13%, but there have been only limited reports investigating the clinical features of this disorder in a large number of Japanese patients. The authors have conducted a retrospective, chart review study of 52 patients with SAD and obtained the following results. (i) The proportion of SAD in first visit outpatients at the Department of Psychiatry, Niigata University Medical and Dental Hospital, Niigata, Japan, was 1.04%. The male : female ratio was 1:0.73, so male patients appeared to be more common in the sample. (ii) With regard to subtype, generalized type (73% of the patients) was more common than non-generalized type (27%). (iii) The mean age of onset was 18.6 +/- 7.8 years, and there was a trend towards onset of disease at a younger age in the generalized type compared to the non-generalized type. (iv) The most common chief complaint was anxiety and tension in front of others (40.4%). (v) Pharmacotherapy resulted in improvement in 63.5% of the patients. Treatment by fluvoxamine and alprazolam resulted in high response rates of more than 70%.

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  • Routine use of operational diagnostic criteria affects the pharmacotherapy of dysthymia: National questionnaire survey of experienced psychiatrists in Japan Reviewed

    Taro Endo, Toshiki Shioiri, Hideaki Kitamura, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   60 ( 4 )   521 - 523   2006.8

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    The purpose of the present paper was to evaluate, with the use of a questionnaire, how Japanese psychiatrists diagnose and treat a typical adult dysthymia case. Clinicians who routinely use operational diagnostic criteria (ODC) had more correct diagnoses than those who did not. Approximately 70% of psychiatrists who routinely use ODC chose selective serotonin re-uptake inhibitors (SSRI) as the first choice of treatment, while of those psychiatrists who do not use these criteria, only half prescribed SSRI. This difference was statistically significant (P = 0.01). The results of the present study suggest that psychiatrists who are familiar with ODC tend to treat dysthymia according to evidence-based pharmacotherapy.

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  • Attention-deficit/hyperactivity disorder and dissociative disorder among abused children Reviewed

    Taro Endo, Toshiro Sugiyama, Toshiyuki Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   60 ( 4 )   434 - 438   2006.8

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    The aim of this study was to investigate the psychiatric problems and characteristics among children of child abuse (CA). Specifically, the authors investigated whether attention-deficit/hyperactivity disorder (ADHD) symptoms were exhibited before or after CA. A total of 39 abused child inpatients who were treated at Aichi Children's Health and Medical Center, Aichi, Japan, (mean age, 10.7 +/- 2.6; mean IQ scores, 84.1 +/- 19.3) were included in the study. The most frequent diagnosis was dissociative disorder in 59% of abused subjects. ADHD was diagnosed in 18% of abused subjects, and 71% of ADHD children had comorbid dissociative disorder. A total of 67% of all CA subjects fulfilled the ADHD criteria A according to DSM-IV-TR, however, only 27% of those fulfilled the criteria before CA. The subjects of dissociative disorder fulfilled ADHD criteria A more frequently than those of non-dissociative disorder (P = 0.013), and this result led to an increase in the frequency of the apparent ADHD. The rate of ADHD-suspected parents in the subjects who fulfilled ADHD criteria A after CA was significantly lower than those who fulfilled it before CA (P = 0.005). While it is difficult to distinguish ADHD from dissociative disorder, abused children may have increased apparent ADHD due to dissociative disorder. Further studies should be conducted in order to explore the distinct biological differences between ADHD before CA and the subjects who fulfilled ADHD criteria A after CA.

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  • Parietal white matter abnormalities in obsessive-compulsive disorder: A magnetic resonance spectroscopy study at 3-Tesla Reviewed

    H. Kitamura, T. Shioiri, T. Kimura, M. Ohkubo, T. Nakada, T. Someya

    Acta Psychiatrica Scandinavica   114 ( 2 )   101 - 108   2006.8

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    Objective: To identify a neurochemical basis for the hypothesis that an aberrant cortico-subcortical circuit underlies obsessive-compulsive disorder (OCD). The white matter was also investigated because of recent research which suggests the altered connectivity of axons. Method: Using 3-Tesla magnetic resonance spectroscopy, the relative concentrations of N-acetylaspartate (NAA) and choline-containing compounds (Cho) to creatine/phosphocreatine (Cr) were measured in the anterior cingulate, basal ganglia, thalamus, frontal and parietal white matter of 12 OCD patients, and 32 control subjects. Results: The mean concentration of Cho/Cr was significantly higher in the patients than in the controls, but only in the parietal white matter, while no significant group differences in NAA/Cr were observed in any of the brain regions. Parietal Cho/Cr correlated positively with the severity of OCD symptoms. Conclusion: This finding provides indirect evidence for the parietal white matter involvement in OCD, thus suggesting a change in the phospholipids of myelinated axons and/or glia cells. Copyright © 2006 The Authors.

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  • No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population Reviewed

    Y Watanabe, T Muratake, N Kaneko, A Nunokawa, T Someya

    SCHIZOPHRENIA RESEARCH   84 ( 1 )   29 - 35   2006.5

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    Brain-derived neurotrophic factor (BDNF) plays important roles in the survival, maintenance and growth of neurons. Several studies have indicated that BDNF is likely to be related to the pathogenesis of schizophrenia. Recent genetic analyses have revealed that BDNF gene polymorphisms are associated with schizophrenia, although contradictory negative findings have also been reported. To assess whether three BDNF gene polymorphisms (rs988748, C132T and rs6265) could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (349 patients and 423 controls) in Japanese subjects. We found no association between these BDNF gene polymorphisms and schizophrenia using both single-marker and haplotype analyses. The results of the present study suggest that these three BDNF gene polymorphisms do not play major roles in conferring susceptibility to schizophrenia in a Japanese population. However, further studies assessing the associations between these BDNF gene polymorphisms and schizophrenia should be performed in several other ethnic populations. (c) 2006 Elsevier B.V. All rights reserved.

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  • Polymorphisms in the 5-hydroxytryptamine 2A receptor and cytochromeP4502D6 genes synergistically predict fluvoxamine-induced side effects in Japanese depressed patients Reviewed

    Y Suzuki, K Sawamura, T Someya

    NEUROPSYCHOPHARMACOLOGY   31 ( 4 )   825 - 831   2006.4

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    5-Hydroxytryptamine (5-HT) receptors are thought to be associated with the gastrointestinal side effects induced by selective serotonin reuptake inhibitors. CytochromeP450 (CYP) 2D6 may also be associated with the side effects induced by fluvoxamine, since the plasma fluvoxamine concentration depends on a CYP2D6 gene polymorphism. This study investigated whether 5-HT receptor and CYP2D6 gene polymorphisms could predict the occurrence of the side effects. The effects of 5-HT receptor and CYP2D6 gene polymorphisms on the incidence of gastrointestinal side effects induced by fluvoxamine were investigated in 100 depressed outpatients who gave written consent to participate in the study. The patients visited every 2 weeks until the week 12 end point and the fluvoxamine dose was changed in response to their clinical symptoms. All side effects, including the gastrointestinal side effects, were assessed at each visit. Polymerase chain reaction was used to determine A-1438G of the 5-HT2A receptor, C195T and Pro16Ser of the 5-HT3A receptor, Tyr129Ser of the 5-HT3B receptor, and the * 5 and * 10 alleles of CYP2D6. Both the A-1438G polymorphism of the 5-HT2A receptor gene and the CYP2D6 gene polymorphism had significant effects on the incidence of gastrointestinal side effects. Cox regression was used to analyze the combination effect of the two polymorphisms on the gastrointestinal side effects. Cox regression analysis showed that lower metabolizers (LMs) of CYP2D6 with the G/G genotype of the 5-HT2A A-1438G polymorphism had a 4.242-fold ( P = 0.009) and LMs with the A/G genotype had a 4.147-fold ( P = 0.004) higher risk of developing gastrointestinal side effects than normal metabolizers with the A/A genotype. The 5-HT3A and 3B gene polymorphisms had no significant effects on the incidence of gastrointestinal side effects. 5-HT2A receptor and CYP2D6 gene polymorphisms had a synergistic effect for the prediction of fluvoxamine-induced gastrointestinal side effects.

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  • Supportive evidence for neuregulin 1 as a susceptibility gene for schizophrenia in a Japanese population Reviewed

    N Fukui, T Muratake, N Kaneko, H Amagane, T Someya

    NEUROSCIENCE LETTERS   396 ( 2 )   117 - 120   2006.3

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    Schizophrenia is a complex genetic disorder and affects approximately 1% of the population worldwide. Recently, Stefansson et al. identified neuregulin 1 (NRG1) on 8p12 as a susceptibility gene for schizophrenia in the Icelandic population. It was reported that the at-risk haplotype ("HapICE") constructed from five SNPs and two microsatellite markers was found to be over-represented in patients with schizophrenia compared to controls. Since then several independent studies have supported the association of NRG1 with schizophrenia. We performed a case-control association study using the four SNPs in a Japanese sample. We genotyped three SNPs (SNP8NRG221533, SNP8NRG241930, and SNP8NRG243177) from Stefansson et al. and one SNP (rs1081062) located in intron 1 of NRG1. There were no significant differences in allele frequencies for each SNP between cases and controls, however, homozygotes of minor alleles in SNP8NRG241930, SNP8NRG243177, and rs1081062 were associated with an increased risk of schizophrenia (P = 0.025, OR = 4.14; P = 0.041, OR = 1.43; and P = 0.0023, OR = 3.06, respectively). Furthermore, the haplotype constructed from four SNPs shows a significant association with schizophrenia (permutation P = 0.026). Our data support the hypothesis that NRG1 gene is a susceptibility gene for schizophrenia. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

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  • Mania after vascular dementia in a patient with bipolar II disorder Reviewed

    Y Watanabe, T Shioiri, H Kuwabara, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   60 ( 1 )   117 - 118   2006.2

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  • [Molecular pharmacogenetic study on antipsychotic-drug therapy responders with depression or schizophrenia]. Reviewed

    Suzuki Y, Sawamura H, Someya T

    Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica   108 ( 6 )   633 - 641   2006

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  • Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility loci on chromosomes 1p, 14q, and 20p Reviewed

    T Arinami, T Arinami, T Ohtsuki, H Ishiguro, H Ujike, Y Tanaka, Y Morita, M Mineta, M Takeichi, S Yamada, A Imamura, K Ohara, H Shibuya, K Ohara, Y Suzuki, T Muratake, N Kaneko, T Someya, T Inada, T Yoshikawa, T Toyota, K Yamada, T Kojima, S Takahashi, O Osamu, T Shinkai, M Nakamura, H Fukuzako, T Hashiguchi, S Niwa, T Ueno, H Tachikawa, T Hori, T Asada, S Nanko, H Kunugi, R Hashimoto, N Ozaki, N Iwata, M Harano, H Arai, T Ohnuma, Kusumi, I, T Koyama, H Yoneda, Y Fukumaki, H Shibata, S Kaneko, H Higuchi, N Yasui-Furukori, Y Numachi, M Itokawa, Y Okazaki

    AMERICAN JOURNAL OF HUMAN GENETICS   77 ( 6 )   937 - 944   2005.12

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    The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD = 3.39) and suggestive evidence of linkage to 14q11.2 (LOD = 2.87), 14q11.2- q13.2 (LOD = 2.33), and 20p12.1-p11.2 (LOD = 2.33). Although linkage to these regions has received little x attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study-which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent-indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

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  • A study of emotional attitude of psychiatric nurses: Reliability and validity of the Nurse Attitude Scale Reviewed

    Fujika Katsuki, Masahiro Goto, Toshiyuki Someya

    INTERNATIONAL JOURNAL OF MENTAL HEALTH NURSING   14 ( 4 )   265 - 270   2005.12

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    In psychiatric nursing, the exchange of feelings among nurses and patients is vital. However, expressed emotion (EE) studies that have been performed in family studies of schizophrenia indicate that a high EE score can predict the relapse of schizophrenic patients. In the case of long-term inpatients at a psychiatric hospital in Japan, the emotional attitude of nurses towards patients is anticipated to have some effect on the course of the illness. In the present study, we revised part of the phrasing of the Japanese version of the Family Attitude Scale, and renamed it the Nurse Attitude Scale (NAS). We tested 189 nurses with this scale, and examined reliability and validity. In a factor analysis of the NAS, three factors were extracted, which we termed criticism, hostility, and positive remarks. These factors are the same as items for assessment on the Camberwell Family Interview, a method of EE assessment. Cronbach's a for individual subscales was 0.848 for criticism, 0.845 for hostility, and 0.685 for positive remarks. With regard to test-retest reliability, there were significant correlations with values of 0.65 for criticism, 0.77 for hostility, and 0.44 for positive remarks. In addition, there was a significant correlation between the NAS and Pines' Burnout scores. These facts, thus suggested that the NAS represents an approximation of the EE of psychiatric nurses. In addition, these findings indicated that the state of burnout in psychiatric nurses resulted in a critical attitude towards patients.

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  • [Genetic testing and gene-based testing for mental disorders]. Reviewed

    Muratake T, Someya T

    Nihon rinsho. Japanese journal of clinical medicine   63 Suppl 12   254 - 257   2005.12

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  • A candidate pathway strategy for integration of pharmacogenomic components of variability in antipsychotic treatment outcomes: A focus on aripiprazole

    Christopher Reist, Lawrence J. Albers, Stephen R. Marder, Bryn Williams-Jones, Joseph C. Wu, Steven Mee, Kazutaka Shimoda, Toshiyuki Someya, Vural Ozdemir

    Current Pharmacogenomics   3 ( 4 )   305 - 317   2005.12

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    Aripiprazole is the first atypical antipsychotic introduced to medical practice with partial dopamine-serotonin agonist properties. Other new molecular entities such as bifeprunox, a partial agonist at the dopamine D2 and serotonin 5-HT1A receptors, are currently being evaluated in early stage drug development as potential antipsychotic agents. As a partial agonist, whether aripiprazole displays an agonist effect or attenuates dopaminergic neurotransmission may depend on regional variations in endogenous dopamine tone. Hence, aripiprazole offers a therapeutic advantage to differentially modulate dopaminergic activity in brain regions in a graded fashion. This mechanism of action is intriguing when considered in the context of the dopamine hypothesis of schizophrenia whereby positive symptoms (e.g. hallucinations and delusions) are associated with increased mesolimbic dopaminergic activity while reduced activity in mesocortical dopaminergic pathways underlies negative symptoms (e.g. avolition and anhedonia) and cognitive deficits. Despite its therapeutic promise, antipsychotic response to aripiprazole is highly variable, and some patients do not respond at all to drug therapy. Treatment-emergent adverse events associated with aripiprazole include insomnia, anxiety, akathisia or worsening of psychosis in some patients. These observations suggest that the underlying mechanism of action of aripiprazole in psychotic disorders is more complex than what would be anticipated solely by simple partial agonist effects at the dopamine D2 receptor. For example, while aripiprazole attenuates dopaminergic hyperactivity it does not increase locomotor activity in reserpinized (hypodopaminergic) rats, which is not fully consistent with a partial agonist mode of action. Aripiprazole can induce a diverse range of effects at dopamine D2 receptors (agonism, antagonism, partial agonism) depending on the cellular milieu defined by promiscuous interactions with a host of signaling partners and variability in local G protein complement and concentration. This diversity provides an opportunity to illustrate the importance of integrating data on genetic variation in pharmacokinetic pathways and molecular targets for antipsychotics including biogenic amine receptors and their downstream signaling partners. Theragnostics, a new subspecialty of molecular medicine formed by combination of therapeutics with diagnostics, offers the potential to synthesize different types of biomarkers (DNA and protein-based) in the context of antipsychotic treatment outcomes. Because the dopamine receptor genetic variation is extensively reviewed elsewhere, we discuss the pharmacogenomic significance of variability in genes encoding for the 5-HT1A (HTR1A) and 5-HT2A (HTR2A) receptors and CYP2D6- and CYP3A4-mediated aripiprazole metabolism. As the field moves toward predictive genetic testing for newer antipsychotics, we emphasize the need for collaboration among pharmacogeneticists, bioethicists and specialists in science and technology studies. ©2005 Bentham Science Publishers Ltd.

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  • Dysfunctional baroreflex regulation of sympathetic nerve activity in remitted patients with panic disorder - A new methodological approach Reviewed

    T Shioiri, M Kojima-Maruyama, T Hosoki, H Kitamura, A Tanaka, M Yoshizawa, T Bando, T Someya

    EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE   255 ( 5 )   293 - 298   2005.10

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    Background Many researchers have studied the abnormalities of autonomic nervous system (ANS) such as decreased heart rate variability, which is a risk factor for sudden cardiac death, in patients with panic disorder (PD). However, no consistent abnormality has been uncovered to date. One of the reasons for this controversy may be due to the fact that most of these conventional studies have analyzed each physiological variable independent of other indices. We examined the ANS in PD patients using a new method which can more directly investigate the function of the baroreflex by examining the relation between the blood pressure (BP) and heart rate (HR). Methods During rest and audiovisual stimulation (AS) as mental stress such as being exposed to video imaginary of experiences such as driving motor vehicles, cardiovascular parameters, HR and BP were consecutively measured in 13 remitted PD patients and twenty aged and gender-matched normal controls (NC). In this study, to assess the cardiovascular ANS function (baroreflex) in PD we used the power spectrum analysis as usual and the mean of lag time (tau) between the Mayer wave components, which was closely related to sympathetic nerve activity of vasomotor, of HR and BP variability as a new trial. Results The PD patients and NC did not differ with regard to the power spectrum analysis of the heart rate. We found that t in the PD group was significantly shorter than that in the NC both before and after AS, especially before. Conclusions These findings suggest that remitted PD patients may have a dysfunctional baroreflex regulation of sympathetic nerve activity.

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  • Linkage disequilibrium in aquaporin 4 gene and association study with schizophrenia Reviewed

    T Muratake, N Fukui, N Kaneko, H Amagane, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   59 ( 5 )   595 - 598   2005.10

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    Aquaporin 4 (AQP4) has an important role in water homeostasis of human brain and a dysfunction of AQP4 could induce pathological conditions in neuronal activity. Several genome scan studies for schizophrenia found a suggestive linkage on 18q, where human AQP4 (18q11.2-12.1) is located nearby. A case-control study was performed which comprised 261 schizophrenia subjects and 278 controls from the Japanese population with four SNP markers. We found strong linkage disequilibrium (LD) and an LD block in the AQP4 gene but found no association between AQP4 and schizophrenia, both single SNP and haplotype analyses. The present study shows that AQP4 is not directly associated with schizophrenia in these Japanese patients.

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  • Diffusion tensor analysis in chronic schizophrenia - A preliminary study on a high-field (3.0T) system Reviewed

    H Kitamura, H Matsuzawa, T Shioiri, T Someya, IL Kwee, T Nakada

    EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE   255 ( 5 )   313 - 318   2005.10

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    The objective of this study was to delineate further the nature of diffusion anisotropy abnormalities in frontal white matter previously observed in schizophrenic patients using a high-field magnetic resonance imaging (MRI) system. Six schizophrenia patients and six healthy control subjects were examined using a highfield MRI (3.0T) system. In order to confirm previously reported abnormalities in anisotropy, data were first analyzed to determine fractional anisotropy (FA), a frequently utilized general index of anisotropy. Subsequently, the identical data set was subjected to lambda chart analysis (LCA), a newly developed algorithm for diffusion tensor analysis (DTA) that more effectively provides eigenvalue information. Frontal white matter FA was found to be significantly reduced in schizophrenic patients compared to control subjects, confirming previously reported findings. LCA revealed that the decline in FA was due to a disproportionate increase in small eigenvalue components, and not due to a decline in principal eigenvalue components.

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  • Incidence of note-leaving remains constant despite increasing suicide rates Reviewed

    T Shioiri, A Nishimura, K Akazawa, R Abe, H Nushida, Y Ueno, M Kojika-Maruyama, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   59 ( 2 )   226 - 228   2005.4

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    Suicide notes (SN) are potentially valuable sources of information about the psychological states of the suicidal person. It was hypothesized that there was a significant relation between suicide rate and note-leaving rate and that the incidence of note-leaving was increased during prolonged economic recession. During 21 years (1981-2001) in Kobe, of a total of 18 558 violent deaths, 5161 were due to suicide (27.8%), with 3417 male cases (66.2%) and 1754 female cases (33.8%). For each year the annual suicide rates and note-leaving rates were calculated, and this represents the percentage of committed suicides in which SN were left, among all suicide victims. In spite of the prolonged economic slump, the note-leaving rate remained almost constant (23.4-36.2%). Pearson's correlation coefficient showed no significant correlation between suicide rate and note-leaving rates (r = 0.27, P = 0.23). The finding that the incidence of note-leaving remains constant despite increasing suicide rates may suggest that the reasons for suicide do not affect note-leaving. There are cross-cultural, ethnic, and racial variations in suicidal behaviors. Although this finding may be specific in Japan, further studies of SN are needed to help clarify the suicidal states of mind.

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  • No association of EGF polymorphism with schizophrenia in a Japanese population Reviewed

    Y Watanabe, N Fukui, T Muratake, N Kaneko, T Someya

    NEUROREPORT   16 ( 4 )   403 - 405   2005.3

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    Epidermal growth factor (EGF) signal regulates the development of dopaminergic neurons and monoamine metabolism. It is suggested that EGF protein levels are decreased in the brain and blood of patients with schizophrenia. A recent study has reported that a polymorphism in EGF gene (rs4444903) is associated with schizophrenia in Finnish men. To confirm this association for another population in larger samples, we conducted a case-control association study on a Japanese population (337 cases and 421 controls). No significant difference was observed in both the allelic and genotype distribution between cases and controls in women, men and total samples. Our results suggest that the polymorphism in EGF gene might not confer increased susceptibility for schizophrenia in a Japanese population. (c) 2005 Lippincott Williams E Wilkins.

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  • Effects of concomitant fluvoxamine on the plasma concentration of etizolam in Japanese psychiatric patients - Wide interindividual variation in the drug interaction Reviewed

    Y Suzuki, Y Kawashima, T Shioiri, T Someya

    THERAPEUTIC DRUG MONITORING   26 ( 6 )   638 - 642   2004.12

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    Administration of fluvoxamine with concomitant benzodiazepines is common in clinical situations. This study investigated the effects of the coadministration of fluvoxamine on plasma concentrations of etizolam and evaluated the effects of various fluvoxamine doses on drug interactions with etizolam. Subjects were 18 Japanese outpatients concomitantly treated with fluvoxamine before or after monotherapy with etizolam. Plasma concentrations of etizolam were measured using a column-switching high-performance liquid chromatographic method with ultraviolet detection. In 17 subjects treated concomitantly with fluvoxamine at 25 mg or 50 mg, the ranges of plasma concentrations of etizolam corrected for the dose increased from 2.0-13.3 (mean 6.3 +/- 3.6, n = 17) in monotherapy to 2.7-18.2 (mean 9.6 +/- 5.1, n = 17) ng/mL/mg in concomitant doses. Wide variations were observed in the drug interactions; however, coadministration with fluvoxamine produced significant changes in the plasma concentrations of etizolam (P &lt; 0.0001) with a median of 42.9% (range 0.0 to 235.0%). Although the sleepiness of the subjects was evaluated using the Stanford Sleepiness Scale, no changes in sleepiness were found between the etizolam-monotherapy and the fluvoxamine-concomitant states. Of the 12 subjects treated concomitantly with fluvoxamine at 25 mg, 2 subjects received fluvoxamine at a dose increased up to 150 mg, and another received fluvoxamine at a dose increased up to 200 mg. They showed an increase in the plasma concentrations of etizolam in a fluvoxamine dose-dependant manner; more particularly, the increased dose of fluvoxamine (150 mg and 200 mg) resulted in about a twofold variation in plasma concentrations of etizolam.

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  • Momentary changes in the cardiovascular autonomic system during mental loading in patients with panic disorder: a new physiological index "rho(max)" Reviewed

    T Shioiri, M Kojima, T Hosoki, H Kitamura, A Tanaka, T Bando, T Someya

    JOURNAL OF AFFECTIVE DISORDERS   82 ( 3 )   395 - 401   2004.11

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    Background: Although panic disorder (PD) is suggestive of autonomic nervous system dysfunction, especially in the cardiovascular autonomic system (CAS), the results in many previous studies are still controversial. Using a new physiological index which could well reflect emotional reaction to visual stimuli (Yoshizawa, M., Sugita, N., Tanaka, A., Abe, K., Yambe, T., Nitta, S., 2001. Quantiatative Physioligical Evaluation of Three Dimensional Images. The Seventh International Conference on Virtual Systems and Multumedia, 25-27.), we studied momentary changes in the CAS in patients with PD during audiovisual stimulation (AS) as mental loading. Methods: During AS, exposed to a video of imaginary experiences such as driving a motor vehicle or diving into the sea, blood pressure (BP) and heart rate (HR) were measured in 12 remitted patients with PD and 19 age- and sex-matched normal controls (NC). We used the maximum cross-correlation coefficient (rho(max)) from the BP to the HR, whose frequency components were limited to around 0.1 Hz. Results: The p(max) was an available index which could detect the momentary changes in the CAS during AS in both groups. The two-way ANOVA disclosed significant group and time effects on the rho(max). The momentary response to emotional stimuli in the PD patients was slower than that in the NC subjects. Limitations: Antidepressants have a potential impact on the autonomic variables in this study. Conclusions: These findings suggest that there may be a dysfunction of the CAS in remitted PD patients and that the dysfunction may be one of the trait markers of PD. To confirm these findings, however, further studies with a large sample size are required. (C) 2004 Elsevier B.V. All rights reserved.

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  • Effects of dosage and CYP2D6-mutated allele on plasma concentration of paroxetine Reviewed

    K Sawamura, Y Suzuki, T Someya

    EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY   60 ( 8 )   553 - 557   2004.10

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    Objective: We investigated the effect of dosages of paroxetine and cytochrome P450 (CYP) 2D6 genotypes on the plasma concentration of paroxetine in Japanese patients being treated with paroxetine.
    Methods: Blood samples were collected from 73 individuals after at least 2-week of the same daily dose of paroxetine. The plasma paroxetine concentration was measured using HPLC, and the CYP2D6 genotypes were identified by PCR. Genotype groups were compared by one-way analysis of variance at different paroxetine doses.
    Results: The mean plasma paroxetine concentrations at daily doses of 10, 20, 30, and 40 ng/ml were 6.67.4, 34.926.8, 74.837.2, and 130.596.8 ng/m, respectively, showing a disproportionate and nonlinear increase in plasma drug levels of paroxetine upon increasing doses. Plasma paroxetine concentrations in patients with CYP2D6*10 alleles were significantly higher than those without *10 allele at 10 mg/day (7.36.11 vs. 2.993.52 ng/ml), but there was no significant difference between *1/*1, *1/*10 and *10/*10 genotypes at the higher doses. Similarly, patients with CYP2D6*5 alleles showed higher plasma paroxetine concentrations than those without *5 allele, although differences in the plasma paroxetine concentration did not reach statistical significance level because of the small number of subjects with *5 alleles.
    Conclusions: Our results indicate the possibility of saturation in paroxetine metabolism with an increase in paroxetine dose, and that CYP2D6*10 allele(s) have significant impact on plasma paroxetine concentration at low doses in Japanese population.

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  • Forecasting the number of inpatients with schizophrenia Reviewed

    T Someya, Y Suzuki, PC Sham, SW Tang

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   58 ( 5 )   573 - 578   2004.10

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    There has been much discussion in Japan regarding the reduction of psychiatric beds. For effective healthcare planning, reliable forecasting is important. The purpose of this study was to predict the number of future schizophrenic inpatients using quantitative methodology. Data was obtained from a survey of schizophrenic inpatients conducted annually at the end of March by the Niigata Prefecture from 1974 to 2003. The numbers of schizophrenic inpatients in different age groups over a long period of time were used in a precise time-series analysis to establish trends. Then these past trends were used to forecast inpatient numbers for future years. The pattern of ascents and declines of each inpatient group stratified by age appeared to be duplicated by the next older age group 10 years later. The numbers of inpatients with schizophrenia in 2013 and 2023 are projected to be 78.5% and 56.7% of the number of patients in 2003, respectively. By 2033, the number is forecast to decline to 41.0% of the number in 2003. This study forecasts that inpatients with schizophrenia will decrease substantially over the next several decades. Policy should be designed to reflect this trend.

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  • Genetic and expression analyses of FZD3 in schizophrenia Reviewed

    M Ide, T Muratake, K Yamada, Y Iwayama-Shigeno, K Iwamoto, H Takao, T Toyota, N Kaneko, Y Minabe, K Nakamura, T Kato, N Mori, T Asada, T Someya, T Yoshikawa

    BIOLOGICAL PSYCHIATRY   56 ( 6 )   462 - 465   2004.9

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    Background- Wnt signaling plays important roles in neurodevelopmental processes. Frizzled is a receptor of Wnt protein, and the Frizzled 3 (FZD3) gene was recently reported to be associated with schizophrenia. Our study attempted to confirm associations between FZD3 and schizophrenia in Japanese family and cased control samples.
    Methods. Genetic associations were evaluated using family-based transmission tests (212 families, 643 subjects) and case-control analysis (540 schizophrenia patients, 540 control sample). Six single nucleotide polymorphisms (SNTs) on the FZD3 locus were genotyped, and levels of FZD3 mRNA expression in postmortem brains were examined.
    Results. Neither family- nor population-based studies supported associations between FZD3 and schizophrenia. FZD3 expression was unaltered in schizophrenic brains.
    Conclusions. Although two prior studies have reported associations using limited numbers ofSNPs on FZD3, our intensive studyfailed to support any major contribution of FZD3 to schizophrenia susceptibility.

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  • Pupillary light reflex in panic disorder - A trial using audiovisual stimulation Reviewed

    M Kojima, T Shioiri, T Hosoki, H Kitamura, T Bando, T Someya

    EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE   254 ( 4 )   242 - 244   2004.8

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    Background Although many previous studies reported abnormalities of autonomic function in patients with panic disorder (PD), almost all targets in those studies primarily focused on cardiovascular autonomic functions. In the present study, we determined whether PD patients exhibited abnormalities in the pupillary autonomic nervous system (ANS). Methods Before and after audiovisual stimulation (AS), which induced mental stress through exposure to video images of high stress experiences, such as driving motor vehicles, the pupillary light reflex (PLR) was measured by infrared pupillometer in 13 remitted PD patients and twenty age- and gender-matched normal controls (NC). Results Before and after AS, there were no significant differences in initial pupillary diameters in dark conditions (D1), pupillary diameters at maximum constriction (D2) or constriction ratios (CR: (D1-D2)/D1) between PD and NC subjects. However, the CR ratio (CR before/CR after) was significantly higher in the PD group than in the NC. Conclusions These findings suggest that even remitted PD patients may have a dysfunctional PLR regulation with experimental stressors such as AS.

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  • The Japanese version of the Depressive Experiences Questionnaire: Its reliability and validity for lifetime depression in a working population Reviewed

    H Kuwabara, K Sakado, M Sakado, T Sato, T Someya

    COMPREHENSIVE PSYCHIATRY   45 ( 4 )   311 - 315   2004.7

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    We have developed a Japanese version of the Depressive Experiences Questionnaire (DEQ), devised by Blatt et al., for assessing depression-prone personality and examined the questionnaire's reliability (test-retest reliability and internal consistency) and validity. To examine the questionnaire's validity, we evaluated its factorial validity and discriminant power for depression (i.e., construct validity). To test the construct validity of the DEQ with and without depression proneness, the scores on the DEQ subscales were compared between subjects with and without a lifetime history of major depressive disorder (MDD). The Inventory to Diagnose Depression, Lifetime version (IDDL), was used to identify lifetime depression. The reliability tests showed that the Japanese version has reliability almost similar to that of the original version. While the self-criticism has good reliability, the dependency appears to have only modest reliability. In the comparisons between subjects with and without lifetime histories of major depression, the former had significantly higher scores on the self-criticism dimension of the DEQ than did the latter, suggesting that the Japanese version of the DEQ, especially the self-criticism, may have the ability to distinguish individuals with lifetime depression from normal controls. We conclude that the DEQ is an acceptable instrument for assessing the depression-prone personality. (C) 2004 Elsevier Inc. All rights reserved.

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  • Establishment of new cloned enzyme donor immunoassays (CEDIA((R))) for haloperidol and bromperidol Reviewed

    N Yasui-Furukori, M Saito, H Furukori, Y Inoue, T Someya, S Kaneko, T Tateishi

    THERAPEUTIC DRUG MONITORING   26 ( 3 )   336 - 341   2004.6

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    The authors have developed and verified the precision and accuracy of new automated cloned enzyme donor immunoassays (CEDIA(R)) for baloperidol and bromperidol, and cross-validations have been performed with conventional semiautomated EIA kits (MARKIT(R)-M) and high-performance liquid chromatographic (HPLC) methods. The CEDIA(R) method provides a quick (about 10 minutes) assay for haloperidol or bromperidol, requiring no serum/plasma pretreatment or predilution. The CEDIA(R) haloperidol/bromperidol assay showed little or no cross reactivity with either their metabolites or many drugs commonly coprescribed. MARKIT(R)-M revealed considerable cross reactivity values proportional to the spiked amounts of reduced metabolites. Precision, accuracy, recovery, and linearity testing for the CEDIA(R) assay were all sufficient for clinical use. Significant linear correlations were found between CEDIA(R) and HPLC in measuring haloperidol (CEDIA(R) = 1.06 x HPLC + 0.869; n = 44, rs = 0.913, P &lt; 0.001) and bromperidol (CEDIA(R) = 1.06 x HPLC + 0.606; n = 56, rs = 0.914, P &lt; 0.001) concentrations. This study has, therefore, demonstrated that the CEDIA(R) assay has a quick run time with high precision and accuracy, and this method is a useful tool for the TDM of haloperidol or bromperidol.

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  • Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5 Reviewed

    H. Ohtake, T. Shimohata, K. Terajima, T. Kimura, R. Jo, R. Kaseda, O. Iizuka, M. Takano, Y. Akaiwa, H. Goto, H. Kobayashi, T. Sugai, T. Muratake, T. Hosoki, T. Shioiri, K. Okamoto, O. Onodera, K. Tanaka, T. Someya, T. Nakada, S. Tsuji

    Neurology   62 ( 9 )   1601 - 1603   2004.5

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    We report of a woman aged 52 years born to consanguineous parents and seeking treatment for progressive dementia and delusion. Neurologic examination revealed dementia and emotional instability, indifference, and confabulation. There was also mild spasticity of the bilateral lower limbs. MRI revealed diffuse white matter hyperintensity on T2-weighted images accompanied by hypointense areas on fluid-attenuated inversion recovery images. A homozygous missense mutation was identified in EIF2B5.

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  • Economic slump and suicide method: Preliminary study in Kobe Reviewed

    R Abe, T Shioiri, A Nishimura, H Nushida, Y Ueno, M Kojima, H Kitamura, K Akazawa, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   58 ( 2 )   213 - 216   2004.4

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    During the recent half decade, Japan's suicide rate at approximately 25 deaths per 100 000 people has been one of the highest rates in the world. From the perspective of suicide prevention by restricting access to suicidal means, the aim of the present study was to examine what kind of suicidal method increased during prolonged economic slump. During 21 years (1981-2001), for all suicide victims (5161 cases) the gender, age, and suicide methods were investigated. The yearly full unemployment rate was also used as a representative socioeconomic factor during the same periods in Japan using government statistics, and the relationship between methods of suicide and full unemployment rate was investigated. Pearson's correlation suggested that there was a significant correlation only for hanging rate (r=0.736, P&lt;0.001), but not for the percentages of other methods of suicide. This finding that unemployed persons may have a susceptibility towards certain suicide methods could help in the prevention of suicides. Mental health in Japan should be given more attention, especially for the working population, and social programs offering help should be considered widely.

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  • Transmission disequilibrium test and haplotype analysis of the NOTCH4 gene in Japanese patients with schizophrenia Reviewed

    N Kaneko, T Muratake, H Amagane, M Sakurai, T Tanaka, S Tsuji, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   58 ( 2 )   199 - 205   2004.4

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    A recent study reported that the NOTCH4 gene was highly associated with schizophrenia in the British population. To confirm this association for another population, a case-control study was conducted and a transmission disequilibrium test (TDT) analysis was performed on a group of Japanese subjects (235 pairs of schizophrenia patients and controls, and 78 trios consisting of probands and their parents) using two single nucleotide polymorphisms and three microsatellite markers for the NOTCH4 gene. Haplotype analysis was also studied in case-control and family based data sets. In all markers except for (CTG)n (P=0.012, before correction for multiple testing), no differences were found in the case-control study. The TDT analysis also revealed only a weak transmission disequilibrium in (TTAT)n (genotype-wise P=0.012). The finding of the present study could not support the original findings that the NOTCH4 gene itself is associated with susceptibility to schizophrenia.

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  • Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats Reviewed

    Y Watanabe, S Hashimoto, A Kakita, H Takahashi, J Ko, M Mizuno, T Someya, PH Patterson, H Nawa

    NEUROSCIENCE RESEARCH   48 ( 3 )   345 - 353   2004.3

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    Cytokines have been implicated in the etiology or pathology of various psychiatric diseases of developmental origin such as autism and schizophrenia. Leukemia inhibitory factor (LIF) is induced by a variety of brain insults and known to have many influences on mature and immature nervous system. Here, we assessed the neurobehavioral and pathological consequences of peripheral administration of LIF in newborn rats. Subcutaneous LIF injection induced STAT3 phosphorylation in many brain regions and increased glial fibrillary acidic protein (GFAP) immunoreactivity in the neocortex, suggesting that LIF had direct effects in the central nervous system. The LIF-treated rats displayed decreased motor activity during juvenile stages, and developed abnormal prepulse inhibition in the acoustic startle test during and after adolescence. They displayed normal learning ability in active avoidance test, however. Brain neuronal structures and startle responses were grossly normal, except for the cortical astrogliosis during neonatal LIF administration. These results indicate that LIF induction in the periphery of the infant has a significant, but discrete impact on neurobehavioral development. (C) 2003 Elsevier Ireland Ltd and The Japan Neuroscience Society. All rights reserved.

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  • The effects of a 5-hydroxytryptamine 1A receptor gene polymorphism on the clinical response to fluvoxamine in depressed patients Reviewed

    Y Suzuki, K Sawamura, T Someya

    PHARMACOGENOMICS JOURNAL   4 ( 4 )   283 - 286   2004

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    We investigated the effects of a 5-hydroxytryptamine (5-HT) 1A receptor gene polymorphism on the clinical response to fluvoxamine (FLV) in 65 depressed outpatients who gave written consent to participate in the study. Patients visited every 2 weeks after the first examination until the week 12 end point and were evaluated by the 17-item Hamilton Rating Scale for Depression (HAM-D-17) at each visit. FLV dose was changed in response to their clinical symptoms. The Gly272Asp polymorphism of the 5-HT1A receptor gene was identified by a PCR method. The subjects with the Asp allele had a significantly higher % reduction in the HAM-D-17 score than those with the Gly/Gly genotype at week 2 (P = 0.009), week 6 (P = 0.036), and week 12 (P = 0.031). There was a significant difference in the genotype distribution between the responders and nonresponders. These results suggest that the Gly272Asp polymorphism of the 5-HT1A receptor gene may predict the response to FLV.

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  • A psychometrically derived impulsive trait related to a polymorphism in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in a Japanese nonclinical population: Assessment by the Barratt Impulsiveness Scale (BIS) Reviewed

    K Sakado, M Sakado, T Muratake, C Mundt, T Someya

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   121B ( 1 )   71 - 75   2003.8

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    Although a number of studies have shown that human impulsive traits are associated with indices of central serotonin function, few researchers have investigated the relationship between a polymorphism in the serotonin transporter gene-linked region (5-HTTLPR) and a psychometrically derived impulsive trait. We determined the 5-HTTLPR polymorphism in 123 employed Japanese male adults using the polymerase chain reaction. The distribution of allelic frequency was determined and also investigated the relationship of the 5-HTTLPR polymorphism to a impulsive trait as measured by the Barratt Impulsiveness Scale, 11th version (BIS-11). The distribution of allelic frequency was found to be almost identical to that previously reported in Japanese (the frequency for the long (L)/L, L/short (S), and S/S genotypes was: 3,28, and 68%, respectively). In a comparison between the genotype groups, the S/S genotype group significantly higher scored for the total BIS-11 and the subscale attentional impulsiveness than the L/S + L/L genotype group. These findings suggest that individuals with a homozygous S-allele may be more impulsive than those with the other genotype. (C) 2003 Wiley-Liss, Inc.

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  • Effect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population Reviewed

    T Someya, K Shimoda, Y Suzuki, S Sato, Y Kawashima, G Hirokane, S Morita, A Yokono, S Takahashi

    NEUROPSYCHOPHARMACOLOGY   28 ( 8 )   1501 - 1505   2003.8

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    We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.1470.69 ng/ml/mg) and RHAL (1.1071.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL = 0.68 +/- 0.31 ng/ml/mg, RHAL = 0.2870.37 ng/ml/mg), those with one CYP2D6*10 (HAL = 0.70 +/- 0.23 ng/ml/mg, RHAL = 0.31 +/- 0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL = 0.69 +/- 0.14 ng/ml/mg, RHAL = 0.40 +/- 0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (&lt;10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43 +/- 0.23 ng/ml/mg, 0.34 +/- 0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18 +/- 0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.

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  • A decrease in interleukin-1 receptor antagonist expression in the prefrontal cortex of schizophrenic patients Reviewed

    K Toyooka, Y Watanabe, S Iritani, E Shimizu, M Iyo, R Nakamura, K Asama, T Makifuchi, A Kakita, H Takahashi, T Someya, H Nawa

    NEUROSCIENCE RESEARCH   46 ( 3 )   299 - 307   2003.7

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    Interleukin-1 (IL-1) mediates psychological stress responses by regulating monoamine metabolism and secretion of corticotropin-releasing factor, and is therefore, implicated in various psychiatric diseases. To evaluate the contribution of IL-1 signaling to the brain pathology of schizophrenia, we measured protein and/or mRNA levels for IL-1beta and endogenous IL-1 receptor antagonist (IL-1RA) in the postmortem brain tissues of prefrontal and parietal cortex, putamen, and hypothalamus. Both protein and mRNA levels of IL-1RA were specifically decreased in the prefrontal cortex of schizophrenic patients, whereas IL-1beta levels were not significantly altered in all the regions examined. The IL-1RA decrease was not correlated with the dose of antipsychotics given to patients. There was no influence of this illness on protein levels for IL-1 receptor type I in the prefrontal cortex, either. In contrast, IL-1RA serum levels were increased in schizophrenic patients, especially in drug-free patients, as reported previously. These findings suggest that chronic schizophrenia down-regulates IL-1RA production the prefrontal cortex, irrespective of its impact on the periphery. IL-1RA reduction might reflect an immunopathologic trait of the prefrontal region in schizophrenic patients. (C) 2003 Elsevier Science Ireland Ltd and Japan Neuroscience Society. All rights reserved.

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  • Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles Reviewed

    Y Suzuki, T Shioiri, T Muratake, Y Kawashima, S Sato, M Hagiwara, Y Inoue, K Shimoda, T Someya

    EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY   58 ( 12 )   829 - 833   2003.4

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    Objectives: Administration of fluvoxamine (FLV) with concomitant benzodiazepines is common in clinical situations. We studied the effects of the coadministration of FLV on plasma concentrations of alprazolam (ALP). We also studied the effects of CYP2C19(*)2 or CYP2C19(*)3 on these drug interactions.
    Methods: The subjects were 23 Japanese outpatients all concomitantly treated with FLV either before or after monotherapy with ALP. We measured the plasma concentrations of ALP and FLV using a column-switching, high-performance liquid chromatographic method with ultraviolet detection. The CYP2C19(*)2 or CYP2C19(*)3 alleles were identified using a polymerase chain reaction analysis.
    Results: Coadministration with FLV produced significant, on average 58%, increases in the plasma concentrations of ALP (P &lt; 0.001). There were, however, wide variations in the interactive effects of the coadministration of FLV on the plasma concentrations of ALP. While there were some subjects who had greater increases in plasma ALP concentrations, more than 100%, in response to the coadministration of FLV among the subjects with no mutated or one mutated allele, there are no subjects who had increases in plasma ALP concentrations of more than 50% among the subjects with two mutated alleles. The differences of these variances among the three genotype groups reached a level of significance (P &lt; 0.05).
    Conclusion: Coadministration of FLV significantly increased the plasma concentrations of ALP compared with ALP monotherapy. Wide variations were observed in the drug interactions, with the CYP2C19 genotype possibly being related to these interactions.

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  • [Contribution of neurotrophic factors and cytokines to schizophrenia]. Reviewed

    Nawa H, Futamura T, Mizuno M, Takahashi M, Toyooka K, Someya T

    Nihon rinsho. Japanese journal of clinical medicine   61 ( 3 )   521 - 528   2003.3

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  • Initial genome-wide scan for linkage with schizophrenia in the Japanese Schizophrenia Sib-pair Linkage Group (JSSLG) families. Reviewed

    Japanese Schizophrenia Sib-Pair Linkage Group, Arinami T, Ishiguro H, Minowa Y, Otsuki T, Tsujita T, Imamura A, Yoshikawa T, Toyota T, Yamada K, Shimizu H, Yoshitsugu K, Shibata H, Fujii Y, Fukumaki Y, Tashiro N, Inada T, Iijima Y, Kitao Y, Furuno T, Someya T, Muratake T, Kaneko N, Tsuji S, Mineta M, Takeichi M, Ujike H, Takehisa Y, Tanaka Y, Nakata K, Kitajima T, Nishiyama T, Yamanouchi Y, Iwata N, Ozaki N, Ohara K, Shibuya H, Ohara K, Suzuki Y, Ohmori O, Shinkai T, Hori H, Nakamura J, Kojima T, Takahashi S, Tanabe E, Yara K, Nanko S, Yoneda H, Koh J, Sakai J, Inada Y, Kusumi I, Kameda K, Koyama T, Fukuzako H, Hashiguchi T, Tanabe K, Okazaki Y

    Am J Med Genet   120B ( 1 )   22 - 28   2003

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  • Relationships between Plasma β-Amyloid Peptide 1–42 and Atherosclerotic Risk Factors in Community-Based Older Populations

    Yoshinori Fujiwara, Makoto Takahashi, Masaharu Tanaka, Tanji Hoshi, Toshiyuki Someya, Shoji Shinkai

    Gerontology   49 ( 6 )   374 - 379   2003

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  • Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of patients with chronic schizophrenia Reviewed

    K Toyooka, S Iritani, T Makifuchi, O Shirakawa, N Kitamura, K Maeda, R Nakamura, K Niizato, M Watanabe, A Kakita, H Takahashi, T Someya, H Nawa

    JOURNAL OF NEUROCHEMISTRY   83 ( 4 )   797 - 806   2002.11

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    Many postsynaptic density proteins carrying postsynaptic density-95/discs large/zone occludens-1 (PDZ) domain(s) interact with glutamate receptors to control receptor dynamics and synaptic plasticity. Here we examined the expression of PDZ proteins, synapse-associated protein (SAP) 97, postsynaptic density (PSD)-95, chapsyn-110, GRIP1 and SAP102, in post-mortem brains of schizophrenic patients and control subjects, and evaluated their contribution to schizophrenic pathology. Among these PDZ proteins, SAP97 exhibited the most marked change: SAP97 protein levels were decreased to less than half that of the control levels specifically in the prefrontal cortex of schizophrenic patients. In parallel, its binding partner, GluR1, similarly decreased in the same brain region. The correlation between SAP97 and GluR1 levels in control subjects was, however, altered in schizophrenic patients. SAP102 levels were also significantly reduced in the hippocampus of schizophrenic patients, but this reduction was correlated with sample storage time and post-mortem interval. There were no changes in the levels of the other PDZ proteins in any of the regions examined. In addition, neuroleptic treatment failed to mimic the SAP97 change. These findings suggest that a phenotypic loss of SAP97 is associated with the postsynaptic impairment in prefrontal excitatory circuits of schizophrenic patients.

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  • Blink rate variability in patients with panic disorder: New trial using audiovisual stimulation Reviewed

    M Kojima, T Shioiri, T Hosoki, M Sakai, T Bando, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   56 ( 5 )   545 - 549   2002.10

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    Several lines of evidence have implicated central dopaminergic pathways in the modulation of spontaneous blink rate (BR). Furthermore, previous studies have indicated a relationship between spontaneous BR and anxiety and/or depression. However, to our knowledge, there is no report on the examination of BR in a group of patients with panic disorder (PD). During the conditions of rest and with audiovisual stimulation, exposed to a video of imaginary experiences, such as driving a motor vehicle or diving into the sea, BR was examined in 11 male patients with PD and compared with the BR of 16 age-matched normal controls. The BR was significantly higher in PD patients relative to normal controls under both conditions. In particular, the PD group had a higher BR score during the sea scene as relaxation compared with the normal controls. In conclusion, although the sample size was small the present preliminary study, these findings suggest that BR may have potential for application in the assessment of anxiety state, which is consistent with previous studies.

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  • Impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients Reviewed

    K Shimoda, T Someya, A Yokono, S Morita, G Hirokane, S Takahashi, M Okawa

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   22 ( 4 )   371 - 378   2002.8

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    We investigated the effect of the CYP2C19 and CYP2D6 genotypes on the metabolism of amitriptyline (AT) in Japanese psychiatric patients. Steady-state concentrations of AT and its metabolites (nortriptyline [NT], trans-10-hydroxy-nortriptyline [EHNT], cis-10-hydroxy-nortriptyline [ZHNT], trans-10-hydroxy-amitriptyline [EHAT], and cis-10-hydroxy-amitriptyline [ZHAT]) in 50 patients were determined by high-performance liquid chromatography. Significantly higher plasma concentrations of AT corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 were observed (no mutated alleles vs. two mutated alleles: 36.0 +/- 18.2 vs. 64.0 +/- 25.2 ng/mL/mg/kg, p = 0.025). A significantly higher AT/NT ratio was seen in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 (no mutated alleles vs. two mutated alleles: 1.27 +/- 0.59 vs. 3.40 +/- 1.02, p = 0.001). A trend for higher NT/EHNT ratio in the subjects with two mutated alleles of CYP2D6 than in those with no mutated alleles of CYP2D6 was observed (no mutated alleles vs. two mutated alleles: 0.73 +/- 0.39 vs. 1.31 +/- 0.81, p = 0.068). A trend for higher plasma concentrations of total hydroxylated metabolites of AT (EHAT + ZHAT) corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 was found (no mutated alleles vs. two mutated alleles: 9.5 +/- 5.8 vs. 17.8 +/- 8.9, p = 0.051). Therefore, the genotype of CYP2C19 is one of the important determinants of the plasma concentrations of AT and the capacity to desmethylate AT. Mother compound AT is shunted via hydroxylation pathways from AT to EHAT and ZHAT in the subjects with homozygotes of mutated alleles of CYP2C19 in order to compensate for the decreased capacity to desmethylate AT.

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  • Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients Reviewed

    K Toyooka, K Asama, Y Watanabe, T Muratake, M Takahashi, T Someya, H Nawa

    PSYCHIATRY RESEARCH   110 ( 3 )   249 - 257   2002.7

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    Neurotrophic factors regulate neuronal development as well as synaptic plasticity, and their impairment is often implicated as a cause of schizophrenia. Among various neurotrophic molecules, brain-derived neurotrophic factor (BDNF) levels have been found to be increased in the corticolimbic regions of patients' brains. In the present study, we assessed peripheral BDNF levels in whole blood as well as in the serum of two independent groups of schizophrenic patients (n = 34 in each group) and healthy volunteers (n = 35 and n = 27, respectively). BDNF protein levels in fresh serum and blood of the patients and volunteers were measured using a two-site enzyme immunoassay and correlated with the number and decay of platelets. In addition to the studies of patients and volunteers, neuroleptic effects on BDNF levels were assessed by administering haloperidol to adult rats for 2 weeks or 5 months. The major findings were as follows: BDNF levels were significantly reduced in the serum of schizophrenic patients (P &lt; 0.005, Mann-Whitney U-test) but not in their whole blood. Antipsychotic dose did not correlate with serum BDNF levels. Moreover, chronic administration of haloperidol failed to decrease serum BDNF levels in adult rats. Abnormal levels of BDNF are evident not only in the brain of schizophrenic patients, but also in their peripheral blood. The BDNF reduction in serum but not in whole blood suggests a potential deficit in neurotrophic factor release in patients with schizophrenia. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

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  • Evaluation of dextromethorphan N-demethylation activity as a biomarker for cytochrome P450 3A activity in man Reviewed

    Y Kawashima, M Hagiwara, Y Inoue, T Someya

    PHARMACOLOGY & TOXICOLOGY   90 ( 2 )   82 - 88   2002.2

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    The present study evaluates the usefulness of dextromethorphan N-demethylation activity indices to reflect cytochrome P450 (CYP) 3A activity in man. Indices of dextromethorphan N-demethylation activity were categorized as N-1=3-methoxymorphinan/dextromethorphan, N-2=3-hydroxymorphinan/dextrorphan, N-3=(3-methoxymorphinan + 3-hydroxymorphinan)/(dextromethorphan + dextrorphan). Two mg of midazolam were administered orally to 22 Japanese mate volunteers. and midazolam clearance determined. Thirty mg of dextromethorphan were also orally administered to these volunteers and N-1, N-2 and N-3 indices determined by 12 hr urine collection. Results showed N-2 and N-3 were highly correlated (r&gt;0.99, P&lt;0.001), and significantly correlated to oral midazolam clearance (r = 0.45, P&lt;0.05), suggesting that N-2 and N-3 are more suitable than N-1 when using dextromethorphan as an index of individual CYP3A activity.

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  • Lack of impact of CYP1A2 genetic polymorphism (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position -2964 in the 5 '-flanking region of CYP1A2) on the plasma concentration of haloperidol in smoking male Japanese with schizophrenia Reviewed

    K Shimoda, T Someya, S Morita, G Hirokane, A Yokono, S Takahashi, M Okawa

    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY   26 ( 2 )   261 - 265   2002.2

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    The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of haloperidol (HAL) in 40 male smokers with schizophrenia was investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position - 2964 in the 5 ' -flanking region of CYP1A2 were identified by polymerase chain-reaction-restricted fragment length polymorphism method. Regarding C/A polymorphism in intron I at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A (n = 2/1), A/C (n = 14) and C/C (n = 5) genotypes (one-way analysis of variance: 63.1 +/- 18.5, 47.8 +/- 12.5 and 50.8 +/- 15.1 ng/ml/mg/kg, respectively, F(2,37) = 2.556, P = .09). Regarding G/A polymorphism at position -2964 in the 5 ' -flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G (n = 24) and G/A (n = 15) (two-tailed t test: G/G and G/A= 51.2 +/- 16.6 and 59.0 +/- 17.6 ng/ml/mg/kg, respectively, df= 28, P = .22). The present study suggests that the genotyping of CYP1A2 cannot predict the steady state plasma levels or TIAL in male smoking schizophrenics. (C) 2001 Elsevier Science Inc. All rights reserved.

    DOI: 10.1016/S0278-5846(01)00263-9

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  • Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients Reviewed

    T Futamura, K Toyooka, S Iritani, K Niizato, R Nakamura, K Tsuchiya, T Someya, A Kakita, H Takahashi, H Nawa

    MOLECULAR PSYCHIATRY   7 ( 7 )   673 - 682   2002

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    Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFa were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia.

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  • The effect of CYP2C19 and CYP2D6 genotypes on the metabolism of clomipramine in Japanese psychiatric patients Reviewed

    A Yokono, S Morita, T Someya, G Hirokane, M Okawa, K Shimoda

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   21 ( 6 )   549 - 555   2001.12

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    In this study, the authors investigated the relationship between the metabolism of clomipramine (C) and the genotypes of cytochrome P450 (CYP) CYP2C19 and CYP2D6. Fifty-one Japanese patients (18 men and 33 women) were administered 10 to 250 mg/day of C by mouth and maintained on the same daily dose of C for at least 2 weeks to obtain steady-state concentrations. Plasma levels of C and its metabolites N-desmethylclomipramine (DC), 8-hydroxyclomipramine, and 8-hydroxy-N-desmethylclomipramine (HDC) were determined by high-performance liquid chromatography. The allele frequencies of CYP2C19*2, CYP2C19*3, CYP2D6*5, and CYP2D6*10 were 27.5%, 12.8%, 2.9%, and 43.1%, respectively. Subjects who were homozygous for mutated alleles of CYP2C19 showed approximately 75% higher concentrations of C corrected by dose and body weight compared with those who were homozygous for wild-type alleles. Also, subjects who were homozygous for mutated alleles of CYP2C19 showed an approximately 68% higher value of C/DC compared with those who were homozygous for wild-type alleles. No significant difference in the ratio of DC/HDC was observed between subjects who were homozygous for mutated alleles of CYP2D6 and those who were homozygous for wild-type alleles. These results suggest that genotyping CYP2C19 is useful for grossly predicting the risk of getting high plasma concentrations of C and the low individual capacity to demethylate C because there is marked interindividual variability within each genotype. However, the genotyping of CYP2D6 is not useful for predicting the individual capacity to hydroxylate DC.

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  • Differential judgement of static facial expressions of emotions in three cultures Reviewed

    YQ Huang, S Tang, D Helmeste, T Shioiri, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   55 ( 5 )   479 - 483   2001.10

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    Judging facial expressions of emotions has important clinical value in the assessment of psychiatric patients. Judging facial emotional expressions in foreign patients however, is not always easy. Controversy has existed in previous reports on cultural differences in identifying static facial expressions of emotions. While it has been argued that emotional expressions on the face are universally recognized, experimental data obtained were not necessarily totally supportive. Using the data reported in the literature, our previous pilot study showed that the Japanese interpreted many emotional expressions differently from USA viewers of the same emotions. In order to explore such discrepancies further, we conducted the same experiments on Chinese subjects residing in Beijing. The data showed that, similar to the Japanese viewers, Chinese viewers also judged many static facial emotional expressions differently from USA viewers. The combined results of the Chinese and the Japanese experiments suggest a major cross-cultural difference between American and Asian viewers in identifying some static facial emotional expressions, particularly when the posed emotion has negative connotations. The results have important implications for cross-cultural communications when facial emotional expressions are presented as static images.

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  • Is DSM widely accepted by Japanese clinicians?

    T Someya, M Takahashi, M Takahashi

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   55 ( 5 )   437 - 450   2001.10

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    The Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III), a new standardized diagnostic system with multiaxial diagnosis, operational criteria and renewed definitions of mental disorders, was introduced in 1980 and prompted movements to reform conventions in Japanese psychiatry. This review overviews the initial response of Japanese clinicians to accept DSM-III, and its effects on the development of systematic research of psychiatric diagnosis. These new research activities include those on reliability of psychiatric diagnosis, application of various evaluation tools, discussion on the concept of mental disorders, relation of personality disorders with depressive disorders, and Taijin-kyofusho, or culturally distinctive phobia in Japan. A reference database search to survey the latest trend on psychiatric research indicated that the number of papers published by Japanese workers increased sharply after 1987, and DSM apparently greatly influenced their internationalization. Twenty years after the publication of DSM-III, a questionnaire on the use of DSM-IV was set out in 2000 to survey how widely DSM is utilized in clinical practice in Japan. Two hundred and twelve psychiatrists answered the questionnaire, and the results show that DSM has been accepted positively by the younger generation, while the older generation (over 40s) has still less interest in DSM, and DSM is used mainly for research purposes rather than in daily practice.

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  • Importance of the cytochrome P450 2D6 genotype for the drug metabolic interaction between chlorpromazine and haloperidol Reviewed

    Y Suzuki, T Someya, K Shimoda, G Hirokane, S Morita, A Yokono, Y Inoue, S Takahashi

    THERAPEUTIC DRUG MONITORING   23 ( 4 )   363 - 368   2001.8

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    The authors studied the interactive effects of the coadministration of haloperidol and chlorpromazine on plasma concentrations of haloperidol and reduced haloperidol. The subjects were 43 Japanese male schizophrenic inpatients who were concomitantly treated with chlorpromazine before or after monotherapy with haloperidol. Coadministration of chlorpromazine produced significant increases in the plasma concentrations of haloperidol (P &lt; 0.01) and reduced haloperidol (P &lt; 0.001) by an average of 28.5% +/- 83.3% and 160.8% +/- 288.9%, respectively. However, there were marked interindividual variations in the interactive effects of chlorpromazine. The authors analyzed the importance of five CYP2D6 genotypes, *1/*1, *1/*10, *10/*10, *1/*5, and *5/*10 on the percentage of change in plasma concentrations of haloperidol and reduced haloperidol. Patients with the CYP2D6*5 allele (n = 4) showed a significantly smaller increase in plasma concentrations of haloperidol (P &lt; 0.05) and a slightly smaller increase in those of reduced haloperidol (P = 0.074) in response to the coadministration of chlorpromazine compared than those with the CYP2D6*1/*1 genotype (n = 8). Those with the CYP2D6*1/*1 genotype (n = 8) showed a trend toward greater increases in plasma concentrations of haloperidol than those with other genotypes (P = 0.087).

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  • Establishment of enzyme immunoassay for measuring serum sultopride levels Reviewed

    T Someya, K Shimoda, T Muratake, E Nakajima, A Shirai, H Funaoka, T Yashiki, H Ishii, N Sunahara, S Takahashi

    THERAPEUTIC DRUG MONITORING   23 ( 3 )   277 - 281   2001.6

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    Measurement of serum sultopride levels was performed using an enzyme immunoassay. Little or no cross-reactivity with metabolites of sultopride and other drugs was found. The results of reproducibility, recovery, and dilution testing were all good enough for clinical use, A comparison between the measurement values of this method (y) with that of high-performance liquid chromatography (x) showed high correlation (n = 211, r = 0.991, p &lt; 0.0001, y = 0.99x + 107.5). In a comparison between the sultopride dose and serum levels in 161 patients, interindividual differences were large (19 times for same doses), implying that the serum level cannot be predicted from the dosage. The method was found to be reliable for serum level measurements of sultopride and useful for monitoring compliance and assessing the optimal dose.

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  • Obsessional personality features in employed Japanese adults with a lifetime history of depression: assessment by the Munich Personality Test (MPT) Reviewed

    K Sakado, M Sakado, T Seki, H Kuwabara, M Kojima, T Sato, T Someya

    EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE   251 ( 3 )   109 - 113   2001.6

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    Background Although a number of studies have reported on the association between obsessional personality features as measured by the Munich Personality Test (MPT) "Rigidity" scale and depression, there has been no examination of these relationships in a non-clinical sample. Methods The dimensional scores on the MPT were compared between subjects with and without lifetime depression, using a sample of employed Japanese adults. The odds ratio for suffering from lifetime depression was estimated by multiple logistic regression analysis. To diagnose a lifetime history of depression, the Inventory to Diagnose Depression, Lifetime version (IDDL) was used. Results The subjects with lifetime depression scored significantly higher on the "Rigidity" scale than the subjects without lifetime depression. In our logistic regression analysis, three risk factors were identified as each independently increasing a person's risk for suffering from lifetime depression: higher levels of "Rigidity", being of the female gender, and suffering from current depressive symptoms. Conclusion The MPT "Rigidity" scale is a sensitive measure of personality features that occur with depression.

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  • The Japanese version of the Barratt Impulsiveness Scale, 11th version (BIS-11): Its reliability and validity Reviewed

    T Someya, K Sakado, T Seki, M Kojima, C Reist, SW Tang, S Takahashi

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   55 ( 2 )   111 - 114   2001.4

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    No instrument for assessing impulsiveness has been developed in Japan. Alter translating the Barratt impulsiveness Scale 11th version (BIS-11) into Japanese, we investigated reliability and validity in student (n = 34) and worker (n = 416) samples. To assess test-retest reliability, the intraclass coefficient between test and retest was calculated in the student sample. Internal consistency was examined by calculating Cronbach's alpha in the worker sample. To see factor validity, we examined by confirmatory factor analysis whether the three-factor model, proposed by a previous report, fit the data. The results showed that the Japanese version of the BIS-11 had excellent test-retest reliability and acceptable internal consistency reliability. In addition, the Japanese version was judged to have similar factor structure to the original one. The Japanese version of the BIS-11 is a reliable and valid measure and has possible utility for assessing impulsiveness.

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  • Psychoeducation for the families of patients with eating disorders and changes in expressed emotion: A preliminary study Reviewed

    T Uehara, Y Kawashima, M Goto, S Tasaki, T Someya

    COMPREHENSIVE PSYCHIATRY   42 ( 2 )   132 - 138   2001.3

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    Psychosocial variables such as expressed emotion (EE) have prognostic significance, and family psychoeducation has been developed to aid in the treatment of various psychiatric disorders. This study reports relationships among EE, family factors, and symptoms observed while conducting multifamily psychoeducation for eating disorders. Group sessions were held once a month for the relatives of patients with DSM-IV eating disorders, and the group met for five sessions that included both education and problem-solving. Thirty-seven relatives volunteered to participate in our program, and of these, 28 completed the program. EE (as measured by the Five-Minute Speech Sample [FMSS]), family function (as measured by the Family Adaptability and Cohesion Evaluation Scales [FACES]), the family's mental state (as measured by the Profile of Mood States [POMS]), and patient's symptoms (as measured by the Eating Disorder Evaluation Scales [EDES] and Global Assessment of Functioning [GAF] on clinician evaluations, and by the Anorexic Behavior Observation Scale [ABOS] assessment of the family) were administered at both the first and final sessions. The rates of high-EE relatives tended to decrease (especially high emotional over-involvement [EO1]), and families' assessment of symptoms was also significantly improved. Twice-repeated multivariate analysis of variance (MANCOVA) showed that EOI, ABOS, and POMS scores were changed significantiy during the sessions. Psychoeducation for the family members of patients with eating disorders might help lower distress and encourage positive interactions within the family. EE is an important measure in evaluations of psychoeducation. However, a randomized, controlled trial is needed to clarify the efficacy of this treatment. Copyright (C) 2001 by W.B. Saunders Company.

    DOI: 10.1053/comp.2001.21215

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  • A survey on the drug therapy for delirium Reviewed

    Toshiyuki Someya, Taro Endo, Takashi Hara, Gohei Yagi, Jiro Suzuki

    Psychiatry and Clinical Neurosciences   55 ( 4 )   397 - 401   2001

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    Delirium, which is experienced by 10-30% of inpatients, is commonly seen in daily practice. A survey was conducted of the delirium medications, and results were obtained from 28 psychiatric departments and related facilities. Haloperidol was used in 67% cases for the treatment of delirium. Ninety-seven per cent of facilities considered haloperidol as the drug of first choice, while 57% thought this drug had few side-effects and was easy to use. However, because the use of this drug is not covered by health insurance in Japan, its use is limited. We expect that this study on medication for the treatment of delirium will be a first step in increasing the approved indications for drugs used for the treatment of delirium, and to reduce off-label use.

    DOI: 10.1046/j.1440-1819.2001.00881.x

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  • The relationship between personality, dysfunctional parenting in childhood, and lifetime depression in a sample of employed Japanese adults Reviewed

    K Sakado, H Kuwabara, T Sato, T Uehara, M Sakado, T Someya

    JOURNAL OF AFFECTIVE DISORDERS   60 ( 1 )   47 - 51   2000.10

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    Background: Few studies have explored the relationship between personality, dysfunctional parenting in childhood, and adult depression. Methods: Pal ental rearing styles and personality scores as measured by the Parental Bonding Instrument (PBI) and the Interpersonal Sensitivity Measure (IPSM) were compared in a group of employed Japanese adults with and without a lifetime history of depression. The diagnosis was provided by the Inventory to Diagnose Depression, Lifetime version (IDDL). To estimate the effects of the PBI and the IPSM scores on lifetime depression, a multiple logistic regression analysis was performed. Results: Subjects with lifetime depression were seen to have significantly lower scores on the PBI 'care' and higher scores on the IPSM than the subjects without lifetime depression. Lower levels of maternal care and higher Levels of 'interpersonal sensitivity' each independently increased the risk for lifetime depression. Limitations: The findings of the present study may not be conclusive since the data were retrospectively obtained. Conclusion: Dysfunctional parenting and personality seem to be correlated by lifetime depression, but it is uncertain whether they are independent risk factors (C) 2000 Elsevier Science B.V. All rights reserved.

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  • Prevalence of anorexia nervosa and bulimia nervosa in a geographically defined area in Japan Reviewed

    Kazutoshi Nakamura, Masaharu Yamamoto, Osamu Yamazaki, Yoshiaki Kawashima, Kensuke Muto, Toshiyuki Someya, Koji Sakurai, Shinichi Nozoe

    International Journal of Eating Disorders   28 ( 2 )   173 - 180   2000.9

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    Objective: Little has been understood regarding the frequency of eating disorders in Japan. This study was designed to identify the prevalence of anorexia nervosa (AN) and bulimia nervosa (BN) in Japan. Method: We asked doctors in all of the relevant medical facilities (130 hospitals and 1,326 clinics) in Niigata Prefecture to report patients with DSM-IV-diagnosed eating disorders who appeared or were admitted between 20-24 October 1997. The response rate was 94.4%. Results: The estimated point prevalences of AN and BN were 4.79 and 1.02, respectively, per 100,000 females. Specifically for the age group of 15-29 years, the prevalence of AN was 17.10 and that of BN 5.79. Discussion: The prevalence of AN and BN in Japan is lower than that for European Caucasian populations. This result may be due to cultural and ethnic differences and/or it may be a transient phenomenon. (C) 2000 by John Wiley and Sons, Inc.

    DOI: 10.1002/1098-108X(200009)28:2<173::AID-EAT6>3.0.CO;2-I

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  • CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Asian patients Reviewed

    K Shimoda, S Morita, A Yokono, T Someya, G Hirokane, N Sunahara, S Takahashi

    THERAPEUTIC DRUG MONITORING   22 ( 4 )   392 - 396   2000.8

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    The authors we investigated the relationship between plasma levels of haloperidol (HAL) and the number of CYP2D6*10(*10) alleles in 66 Japanese inpatients with schizophrenia(male = 61, female = 5) on HAL. Plasma HAL level was determined by an enzyme immunoassay method. Daily dose of HAL was 1.5-36 (mean +/- SD = 12.3 +/- 7.6) mg or 0.02-0.49 (0.21 +/- 0.13) mg/kg body weight. Plasma HAL levels ranged from 1.4 to 47.4 (12.4 +/- 9.5) ng/mL. No significant difference in the plasma HAL levels was observed between the subjects with no, one, and two *10 alleles tone-way analysis of variance: 56.1 +/- 20.3, 61.0 +/- 20.3, and 63.3 +/- 20.3 ;ng/ml/mg/kg, respectively, F(2,63) = 0.65, p = 0.52). These results are not supportive of the previous report that plasma HAL levels can be predicted by the number of *10 alleles in Asian patients.

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  • Metabolism of desipramine in Japanese psychiatric patients: The impact of CYP2D6 genotype on the hydroxylation of desipramine Reviewed

    K Shimoda, S Morita, G Hirokane, A Yokono, T Someya, S Takahashi

    PHARMACOLOGY & TOXICOLOGY   86 ( 6 )   245 - 249   2000.6

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    We investigated the impact of the genotype of CYP2D6 on the hydroxylation of desipramine in eighteen patients who were administered desipramine hydrochloride per os. Significantly higher plasma concentration of desipramine/daily dose of desipramine/body weight was observed in the subjects with two mutated alleles than in the subjects with either no mutated alleles or one mutated allele (two mutated alleles versus no mutated alleles=530.4+/-215.2 versus 118.1+/-63.9 ng/ml/mg/kg, t=5.68, P&lt;0.001; two mutated alleles versus one mutated allele=530.4+/-215.2 versus 176.2+/-62.3 ng/ml/mg/kg, P&lt;0.001; One-way analysis of variance followed by Bonferroni's multiple comparison test, respectively). Significantly higher ratio of desipramine/2-hydroxy-desipramine was observed in the subjects with two mutated alleles compared to subjects with no mutated alleles or the subjects with one mutated allele (two mutated alleles versus one mutated allele=4.39+/-0.36 versus 2.00+/-0.64, t=5.12, P&lt;0.001; two mutated alleles versus no mutated alleles=4.39+/-0.36 versus 2.02+/-0.59, t=4.42, P&lt;0.01). The genotyping of CYP2D6 only grossly predicts the steady state concentration of desipramine, mainly predicts the risk of getting very high plasma levels. Within each genotype there is marked interindividual variability.

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  • Serum cholesterol levels and panic symptoms in patients with panic disorder: A preliminary study

    Toshiki Shioiri, Kumiko Fujii, Toshiyuki Someya, Saburo Takahashi

    Journal of Affective Disorders   58 ( 2 )   167 - 170   2000.5

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    Background: Although some previous research has focused on the relationship between panic disorder (PD) and a high total cholesterol (TC) level, it is still controversial. Recently, researchers have reported the heterogeneity of clinical symptoms in PD and the complexity of the correlations found among them. Therefore, the controversy on the TC level in PD may be due to the existence of clinical subgroups in PD. It is important to ascertain whether or not an elevated TC level in patients with PD is associated with specific panic symptoms. Methods: In 104 drug-free patients with PD, we examined the relationship between TC level and each of several panic symptoms occurring at the time of panic attacks (PAs), which included anticipatory anxiety, agoraphobia, and 13 panic symptoms based on the DSM- III-R. Results: Stepwise regression analysis revealed a significant effect of the presence of the symptom 'fear of dying' on TC levels. Patients with a fear of dying had a significantly higher TC level than those without it. Limitations: The relatively small sample size may limit the generalizability of our findings. Discussion: These data suggest that TC level may be associated with panic symptoms in patients with PD. (C) 2000 Elsevier Science B.V.

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  • Interindividual variation in bromperidol metabolism and relationship to therapeutic effects Reviewed

    T Someya, T Muratake, G Hirokane, M Shibasaki, K Shimoda, S Takahashi

    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY   20 ( 2 )   175 - 180   2000.4

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    Plasma concentrations of bromperidol (BRP) and reduced bromperidol (RBRP) were determined in 31 patients with schizophrenia who were administered BRP for their psychiatric symptoms. Activities of carbonyl reductase in red blood cells mere assayed using BRP as a substrate. Plasma concentrations of BRP and RBRP ranged from 2.2 to 23.5 ng/mL and from 0.2 to 8.2 ng/mL, respectively. RBRP-to-BRP ratios in plasma ranged from 0.01 to 0.94 (mean +/- SD: 0.31 +/- 0.20), values notably lower than the previously reported values of reduced haloperidol to haloperidol (HAL) in the plasma from patients on HAL. The activity of BRP reductase in red blood cells was determined as 6.8-12.3 pmol/hr/10(6) red blood cells, which was at approximately the same level as that of HAL reductase. Patients with positive responses to BRP treatment mere evaluated using the Brief Psychiatric Rating Scale. We found that the number of patients who had a positive response to BRP did not increase after BRP plasma levels had reached the level of 12 ng/mL. This finding suggests that a therapeutic plateau in BRP pharmacotherapy of schizophrenia occurs, and there is no advantage to raising the dose once this plateau is reached.

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  • Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in Japanese patients: Impact of CYP2D6 genotype on the hydroxylation of nortriptyline Reviewed

    Sachiyo Morita, Kazutaka Shimoda, Toshiyuki Someya, Yoshitaka Yoshimura, Kunitoshi Kamijima, Nobumasa Kato

    Journal of Clinical Psychopharmacology   20 ( 2 )   141 - 149   2000.4

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    The authors investigated the impact of the CYP2D6 genotype on steady- state concentrations of nortriptyline (NT) and its metabolites, trans-10- hydroxynortriptyline (EHNT) and cis-10-hydroxynortriptyline in a Japanese population of psychiatric patients. Forty-one patients (20 men and 21 women) were orally administered nortriptyline hydrochloride. The allele frequencies of the CYP2D6*5 and CYP2D6*10 were 4.9% and 34.1%, respectively. Significant differences in NT concentrations corrected for dose and weight were observed between the subjects with no mutated alleles and those with one mutated allele (mean ± SD for no mutated alleles vs. one mutated allele: 70.3 ± 25.4 vs. 98.4 ± 36.6 ng/mL·mg-1·kg-1
    t = 2.54, df = 33, p &lt
    0.05) and between the subjects with no mutated alleles and two mutated alleles (no mutated alleles vs. two mutated alleles: 70.3 ± 25.4 vs. 147 ± 31.1 ng/mL·mg-1·kg-1
    t = 5.87, df = 19, p &lt
    0.0001). Also, a significant difference in the NT/EHNT ratio, which is representative of the hydroxylation ratio of NT, was observed between the subjects with no mutated alleles and those with two mutated alleles (no mutated alleles vs. two mutated alleles: 0.82 ± 0.30 vs. 2.71 ± 0.84
    t = 7.86, df = 19, p &lt
    0.0001). Multiple regression analysis showed that the number of mutated alleles of CYP2D6, which was the only significant factor, accounted for 41% and 48% of the variability in log(NT corrected for dose and weight) and log(NT/EHNT), respectively.

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  • Involvement of CYP3A4 in the metabolism of bromperidol in vitro Reviewed

    S Sato, T Someya, T Shioiri, T Koitabashi, Y Inoue

    PHARMACOLOGY & TOXICOLOGY   86 ( 3 )   145 - 148   2000.3

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    In this study, human cytochrome P450 isoenzymes (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) expressed in a cell line were used to elucidate their roles in the metabolism of bromperidol. We found that CYP3A4 catalyzes the N-dealkylation of bromperidol and its metabolite, reduced bromperidol. CYP3A4 also catalyzes the dehydration of bromperidol to bromperidol 1,2,3,6-tetrahydropyridine, metabolizes bromperidol to bromperidol pyridinium, and catalyzes the oxidation of reduced bromperidol back to bromperidol. CYP1A2, CYP2C19, and CYP2D6 do not catalyze these reactions.

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  • Effects of gender difference and birth order on perceived parenting styles, measured by the EMBU scale, in Japanese two-sibling subjects Reviewed

    T Someya, T Uehara, M Kadowaki, SW Tang, S Takahashi

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   54 ( 1 )   77 - 81   2000.2

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    The relationship between Egna Minnen av Barndoms Uppforstran (EMBU) scaling and gender, birth order and parents' gender was previously investigated in a large volunteer sample; significant interactions among the variables were found. In the present study, 730 Japanese volunteers with one sibling were used as subjects in order to control the number of siblings: the effect of gender of subjects and siblings and birth order on the perceived parenting style was examined. Based on gender and birth orders, 730 subjects were grouped into the following categories: (i) male with a younger brother; (ii) male with a younger sister; (iii) male with an older brother; (iv) male with an older sister; (v) female with a younger brother; (vi) female with a younger sister; (vii) female with an older brother; and (viii) female with an older sister. One-way ANOVA was performed with each EMBU subscale used as a dependent variable and these eight groups as independent variables. The scores for rejection and emotional warmth of father were influenced significantly by the pattern of siblings (P &lt; 0.006 and P &lt; 0.0012, respectively), and scores for emotional warmth of mother were influenced significantly by the pattern of siblings (P &lt; 0.0012). The elder male children strongly experienced parenting style as more rejecting than others, and female children (elder sisters with brother, or younger sisters with sister) recognized parenting style as more caring and demonstrated more warmth than others. The results confirmed a significant interaction of gender of subjects and siblings and birth order of perceived parental rearing behavior.

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  • Recovery from catatonic stupor and change in cerebral perfusion.

    Uehara T, Kawamura T, Odano I, Muratake T, Kitamura H, Someya T

    Internal Medicine Journal   7 ( 3 )   197 - 199   2000.1

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  • Panic disorder and perceived parental rearing behavior investigated by the Japanese version of the EMBU scale Reviewed

    T Someya, H Kitamura, T Uehara, K Sakado, H Kaiya, SW Tang, S Takahashi

    DEPRESSION AND ANXIETY   11 ( 4 )   158 - 162   2000

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    Although recent studies have found dysfunctional parental rearing behaviour is associated with certain aspects of psychopathology of panic disorder (PD), the results are not in complete agreement By using a translated Japanese version of the EMBU (Egna Minnen Betraffande Uppfostran), we investigated the parental rearing behavior perceived by 103 normal subjects, 71 PD patients with agoraphobia, and 32 PD patients without agoraphobia. The PD patients scored both parents as more rejecting and over-protective than did the. controls. However, subgroup analysis showed that the patients with agoraphobia reported significantly more rejection from both parents and less emotional warmth from mothers, while the patients without agoraphobia, by contrast, reported more overprotection from both parents and more favouring subject from fathers than did the controls. Interestingly, these results were consistent with those documented in the Western literature, which reported "affectionless control" as a parenting style in PD, and furthermore, indicated a moss-cultural similarity of parental rearing factor. In addition, it was suggested that a lack of care might be associated with the development of agoraphobia in Japan. (C) 2000 Wiley-Liss, Inc.

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  • Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients Reviewed

    M. Takahashi, O. Shirakawa, K. Toyooka, N. Kitamura, T. Hashimoto, K. Maeda, S. Koizumi, K. Wakabayashi, H. Takahashi, T. Someya, H. Nawa

    Molecular Psychiatry   5 ( 3 )   293 - 300   2000

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    Previous neuropathological studies have revealed that the corticolimbic system of schizophrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we determined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influenced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. However, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither withdrawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness.

    DOI: 10.1038/sj.mp.4000718

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  • Frontal lobe membrane phospholipid metabolism and ventricle to brain ratio in schizophrenia: Preliminary 31P-MRS and CT studies Reviewed

    Toshiki Shioiri, Hiroshi Hamakawa, Tadafumi Kato, Kumiko Fujii, Jun Murashita, Toshiro Inubushi, Toshiyuki Someya

    European Archives of Psychiatry and Clinical Neuroscience   250 ( 4 )   169 - 174   2000

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    A number of studies employing in vivo phosphorous-31 magnetic resonance spectroscopy (31P-MRS) have demonstrated alterated measurements of frontal phospholipid and high energy phosphorus metabolism in schizophrenia. Enlargement of both the cerebroventricular system and the cortical sulci also has been reported as the most consistent pathological finding in schizophrenia by several investigators. To our knowledge, however, only two studies have simultaneously examined structural and functional aspects of the biological substrate of schizophrenia in the same patients. Moreover, they may have failed to find a significant correlation between these variables because of small sample sizes. The possible relationship between frontal lobe membrane phospholipid metabolism and ventricle-to-brain ratio (VBR) in patients with schizophrenia was investigated. In 31 schizophrenic patients, frontal lobe membrane phospholipid metabolism was measured by 31P-MRS, and VBR was measured by computed tomography (CT). Stepwise multiple regression analysis disclosed that VBR positively correlated only with increased phosphodiester (PDE) level (β = 0.381, p = 0.0345), but with no other metabolites. This finding may provide evidence for an association between structural brain abnormality and altered frontal lobe membrane metabolism in schizophrenic patients, although the p-value of the finding is not high.

    DOI: 10.1007/s004060070021

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    Other Link: http://orcid.org/0000-0001-7856-3952

  • Cultural difference in recognition of facial emotional expression: Contrast between Japanese and American raters Reviewed

    T Shioiri, T Someya, D Helmeste, SW Tang

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   53 ( 6 )   629 - 633   1999.12

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    Using the Japanese and Caucasian Facial Expressions of Emotion (JACFEE) photo set, the relationship between recognition and intensity ratings of universal facial expressions of emotions in 123 Japanese undergraduate students was examined and compared with data reported by American raters. In Japanese raters, although the intensity was rated as high for some of the poses, their correctness scores were poor, suggesting a serious misjudgment of the intended emotions as defined in the JACFEE photo set. Only in Japanese raters were significant relationships between the intensity scores and the percentage correctness scores for sadness detected (r = 0.97, P &lt; 0.0001), but no significant relationship was observed for other emotions. The robust correlation suggests the possibility that Japanese raters might be more responsive to certain emotional expressions when they are fully or intensely expressed. It is proposed that the facial emotional expression paradigm cannot be applied to the psychiatric setting without first refining for cultural differences.

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  • A pharmacotherapy algorithm for the treatment of dysthymia in Japan Reviewed

    H Kitamura, T Yokoyama, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   53   S49 - S53   1999.10

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    Based on randomized controlled trials conducted in western countries, we proposed a pharmacotherapy algorithm for DSM-IV dysthymia in Japan. The main strategy of the algorithm are: firstly, one of the antidepressants is selected for an initial agent, and secondly, efficacy of the selected antidepressant is evaluated at 8 to 12 weeks. The agent with sufficient efficacy is continued for at least 6 months, while ineffective agent is replaced to another antidepressant. The algorithm is preliminary mainly because of the lack of data from Japanese samples and the unavailability of some useful agents in Japan, for instance, selective serotonin reuptake inhibitors and monoamine oxidase inhibitors.

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  • The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: A preliminary study in a psychiatric population Reviewed

    T Someya, Y Suzuki, K Shimoda, G Hirokane, S Morita, A Yokono, Y Inoue, S Takahashi

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   53 ( 5 )   593 - 597   1999.10

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    We investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5, Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean +/- SD, 0.66+/-0.25, n=47) ng/mL/mg and 0.03-3.00 (mean+/-SD, 0.36+/-0.46, n=47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.85 (mean+/-SD, 0.48+/-0.32, n=47). The analysis was performed among the four genotype groups:CYP2D6*1/CYP206*1 (n=11), CYP2D6*1/CYP2D6*10 (n=11), CYP2D6*10/CYP2D6*10 (n=6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n=4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity.

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  • Factor analysis of the EMBU scale in a large sample of Japanese volunteers Reviewed

    T Someya, T Uehara, M Kadowaki, K Sakado, C Reist, SW Tang, S Takahashi

    ACTA PSYCHIATRICA SCANDINAVICA   100 ( 4 )   252 - 257   1999.10

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    Objective: The EMBU (Egna Minnen av Barndoms Uppfostran; tone's memories of upbringing') is a convenient and reliable instrument for the assessment of parental attitudes. The aim of the present study was to investigate the extent to which the factor structure of the EMBU, obtained in previous investigations, could be retrieved in a large Japanese sample.
    Method: The EMBU scale was administered to 1320 healthy Japanese volunteers. Both exploratory and confirmatory factor analyses were performed.
    Results: The first factor in the analysis, accounting for 9.9% (father) and 10.6% (mother) of the variance, consisted of rejection items. The second factor, accounting for 9.1% (father) and 8.6% (mother) of the variance, contained items relating to emotional warmth. The third factor appeared to represent overprotection, and accounted for 7.8% (father) and 7.8% (mother) of the variance. The fourth factor, which accounted for 3.7% (father) and 3.7% (mother) of the variance, included items classified under favouring subjects. Confirmatory factor analysis revealed that this four-factor structure fitted our data very well for both the father and the mother. The results of factor analysis for four subscales showed three major factors for the EMBU.
    Conclusion: The results of this study confirmed that the EMBU yielded a factor structure in Japan similar to that found in European countries. The EMBU is useful for comparison of parenting attitudes in different societies or countries.

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  • The association between the high interpersonal sensitivity type of personality and a lifetime history of depression in a sample of employed Japanese adults Reviewed

    K Sakado, T Sato, T Uehara, M Sakado, H Kuwabara, T Someya

    PSYCHOLOGICAL MEDICINE   29 ( 5 )   1243 - 1248   1999.9

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    Background, Although the 'high interpersonal sensitivity' type of personality has repeatedly been shown to be related to depression by case-control studies, no studies have confirmed whether this association also exists in a non-clinical sample.
    Methods. Scores on the Interpersonal Sensitivity Measure (IPSM)were compared between employed Japanese adults with and without a lifetime diagnosis of major depressive disorder. The diagnosis was provided by the Inventory to Diagnose Depression, Lifetime version. A multiple logistic regression analysis estimated the odds ratios for having a lifetime diagnosis of depression.
    Results. The scores on the IPSM were higher in the subjects with a lifetime history of depression than those without a lifetime history of depression. On the five subscales of the IPSM, the subjects with a lifetime history of depression showed higher scores on 'interpersonal awareness', 'need for approval', and 'separation anxiety' than those without a lifetime history of depression. The multiple logistic regression analysis showed that the subjects with the high interpersonal sensitivity type of personality had an increased risk for experiencing lifetime depression.
    Conclusions. The results suggest that high interpersonal sensitivity is a risk factor for depression even in a non-clinical sample from non-Western culture.

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  • Reliability of the 5-min speech sample for assessing expressed emotion in Japanese patients Reviewed

    T Uehara, T Yokoyama, M Goto, Y Nakano, Y Kawashima, T Someya

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   53 ( 4 )   511 - 514   1999.8

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    Expressed emotion (EE) has been shown in various countries to be a good predictor of the clinical course of a patient's mental illness, Because the traditional EE interview requires considerable time and effort, this study examined the reliability of a method called the five-minute speech sample (FMSS) for assessing EE. The samples of 65 subjects were rated by the FMSS-EE coding system, and the interrater reliability among four authorized raters was investigated. Of these 65 samples, 10 (15%) were rated as high-EE thigh critical, 6%; high emotional over-involvement (EOI), 9%), and 19 (29%) were rated as borderline (b-)-high-EE (b-critical, 15%; b-EOI, 14%). The intraclass correlation coefficient (ICC) was 0.91 for the overall category, 0.74 for criticism, 0.85 for EOI, 0.63 for b-critical and 0.54 for b-EOI. The FMSS was shown to be reliable for the assessment of EE, even outside of Western countries. However, the lower agreement in the subcategories of EOI and b-critical has to be considered as a limitation of this brief method.

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  • Do perceived parenting styles influence stress coping in patients with major depressive disorders? Reviewed

    T Uehara, K Sakado, T Sato, T Someya

    STRESS MEDICINE   15 ( 3 )   197 - 200   1999.7

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    Parenting styles can influence an individual's ability to cope with stress; consequently, coping strategies may moderate the interaction between stress and psychiatric disorders. The correlation between perceived parenting styles and stress-coping strategies in 50 outpatients in remission from major depressive disorders was investigated. Using multiple regression analysis including symptoms, gender and age of subjects as independent variables, maternal care and male gender were significant variables for predicting task-oriented coping strategies (p &lt; 0.05). Low maternal care and highly overprotective parenting were significant variables for predicting emotion-oriented coping strategies (p ( 0.05). These findings suggest that perceived parenting styles of the mother experienced in childhood may be related to stress-coping styles in adulthood. It should nevertheless be considered whether parents' actual childrearing methods affect their offspring's ability to cope with stress or whether an individual who retrospectively perceives a lack of parental affection tends to use more emotion-oriented coping and less task-oriented coping. Copyright (C) 1999 John Wiley & Sons, Ltd.

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  • Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients Reviewed

    K Shimoda, T Someya, S Morita, G Hirokane, G Noguchi, A Yokono, M Shibasaki, S Takahashi

    THERAPEUTIC DRUG MONITORING   21 ( 3 )   293 - 296   1999.6

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    The impact of smoking on plasma haloperidol (HAL) concentrations was investigated in 66 Japanese male schizophrenic inpatients treated orally with HAL. The subjects consisted of 22 nonsmokers and 44 smokers each smoking ten cigarettes per day. Plasma concentrations of HAL were determined by an enzyme immunoassay method. There were significant positive correlations between the plasma HAL concentration and the daily dose of HAL per kg body weight (Y = 58.1X - 0.01 (r = 0.86)). Smokers had significantly lower HAL concentrations per daily dose of HAL/kg body weight than nonsmokers (smokers vs. nonsmokers = 54.3 +/- 16.6 vs. 70.6 +/- 23.2 ng/mL/mg/kg). In doses less than 0.2 mg/kg of HAL, smokers showed significantly lower HAL concentrations per daily dose of HAL/kg body weight than nonsmokers (smokers vs. nonsmokers = 55.1 +/- 14.4 vs. 79.5 +/- 27.1 ng/mL/mg/kg), whereas no significant difference in HAL concentrations per daily dose of HAL/kg body weight was observed between smokers and nonsmokers when heated with more than 0.2 mg/kg (smokers vs, nonsmokers = 52.9 +/- 20.7 vs. 60.0 +/- 11.1 ng/mL/mg/kg). Our results indicate that smoking may induce the enzyme(s) metabolizing HAL, which results in lower plasma HAL concentrations in smokers than in nonsmokers, particularly at low doses of HAL.

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  • Schizophrenia: Is it time to replace the term?

    Yutaka Ono, Yuki Satsumi, Yoshiharu Kim, Toshiharu Iwadate, Kimio Moriyama, Yoshibumi Nakane, Teruo Nakata, Kazuo Okagami, Toshiaki Sakai, Mitsumoto Sato, Toshiyuki Someya, Shunsuke Takagi, Sadanobu Ushijima, Keita Yamauchi, Kimio Yoshimura

    Psychiatry and Clinical Neurosciences   53 ( 3 )   335 - 341   1999.6

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    The attitudes of Japanese psychiatrists toward their patients who suffer from schizophrenia were investigated. We were concerned specifically with whether the psychiatrists inform their patients of the suspected diagnosis. We discuss how the term 'schizophrenia' may influence a psychiatrist's decision to inform his patients of the diagnosis. A self-reported questionnaire was distributed to 150 executive board members of the Japanese Society of Psychiatry and Neurology and analysis of the data obtained from 110 respondents was carried out. The results showed that the concepts that psychiatrists use when they give a diagnosis of schizophrenia vary considerably. Fifty-nine per cent of the respondents informed their patients of a diagnosis of schizophrenia on a case-by-case basis, while 37% informed only the patients' families. A tree analysis showed that the most important predictors for informing the patients of the diagnosis were assumptions about the public image of schizophrenia and a negative impression of the term schizophrenia, translated as 'Seishin Bunretsu Byou' in Japanese. The results revealed that the Japanese term for schizophrenia influences a psychiatrist's decision to inform patients of the diagnosis and that, by changing the term to a less stigmatized one, the disclosure of information about schizophrenia to patients would be promoted.

    DOI: 10.1046/j.1440-1819.1999.00555.x

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  • Misinterpretation of facial expression: A cross-cultural study Reviewed

    T Shioiri, T Someya, D Helmeste, SW Tang

    PSYCHIATRY AND CLINICAL NEUROSCIENCES   53 ( 1 )   45 - 50   1999.2

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    Accurately recognizing facial emotional expressions is important in psychiatrist-versus-patient interactions. This might be difficult when the physician and patients are from different cultures. More than two decades of research on facial expressions have documented the universality of the emotions of anger, contempt, disgust, fear, happiness, sadness, and surprise. In contrast, some research data supported the concept that there are significant cultural differences in the judgment of emotion. In this pilot study, the recognition of emotional facial expressions in 123 Japanese subjects was evaluated using the Japanese and Caucasian Facial Expression of Emotion (JACFEE) photos. The results indicated that Japanese subjects experienced difficulties in recognizing some emotional facial expressions and misunderstood others as depicted by the posers, when compared to previous studies using American subjects. Interestingly, the sex and cultural background of the poser did not appear to influence the accuracy of recognition. The data suggest that in this young Japanese sample, judgment of certain emotional facial expressions was significantly different from the Americans. Further exploration in this area is warranted due to its importance in cross-cultural clinician-patient interactions.

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  • Interindividual variation of plasma haloperidol concentrations and the impact of concomitant medications: The analysis of therapeutic drug monitoring data Reviewed

    G Hirokane, T Someya, S Takahashi, S Morita, K Shimoda

    THERAPEUTIC DRUG MONITORING   21 ( 1 )   82 - 86   1999.2

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    We analyzed therapeutic drug monitoring (TDM) data from 231 schizophrenic inpatients (137 men, 94 women) and investigated interindividual differences of plasma haloperidol (HAL) concentrations and drug/drug interactions between HAL and various concomitant drugs. Plasma HAL concentrations were determined by an enzyme immunoassay (EIA) method. Plasma HAL concentrations per daily dose of HAL per body weight (HAL C/D ratio) demonstrated an approximately 11-fold interindividual variation. The patient subjects who received carbamazepine (CBZ) concomitantly had a mean HAL C/D ratio that was 37% lower than that of the patient subjects without CBZ. The patient subjects treated with concomitant phenobarbital (PB) also showed a mean HAL C/D ratio that was 22% lower than those without PB. We concluded that careful evaluation of HAL TDM data and consideration of the impact of concomitant medication such as CBZ or PB that might influence the metabolism of HAL is necessary in daily clinical settings to avoid insufficient clinical response because of lowered concentrations of HAL or adverse effects because of high concentrations of HAL.

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  • Relationship between stress coping and personality in patients with major depressive disorder Reviewed

    T Uehara, K Sakado, M Sakado, T Sato, T Someya

    PSYCHOTHERAPY AND PSYCHOSOMATICS   68 ( 1 )   26 - 30   1999.1

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    Stress coping is defined as a behavioral or cognitive response of an individual to uncomfortable or difficult situations. It has been suggested that coping, like personality, is related to the pathology and course of mental disorders. Accordingly, we here used a clinical sample to investigate the relationships between coping strategies and personality traits. Methods: Subjects were 60 outpatients who were in remission from major depressive disorder and who completed the Coping Inventory for Stressful Situations (CISS) and the Munich Personality Test (MPT). Results: Task-oriented coping showed a positive correlation with extraversion and frustration tolerance. Emotion-oriented coping was closely associated with neuroticism, esoteric tendencies a nd isolation tendency. Avoidance-oriented coping was related to extraversion. Principal component analysis indicated th ree corresponding factors between coping and personality; one was related to psychopathology (loading from the neuroticism, esoteric tendencies and isolation tendency scales of the MPT, and from the emotion-oriented coping scale of the CISS), a second was a social-adaptive ability component (loading from the frustration tolerance and extraversion scales of the MPT, and from the task-oriented coping and avoidance-oriented coping scales of the CISS), and a third was a passive-avoidance coping component (loaded from the emotion-oriented coping and avoidance-oriented coping scales of the CISS only). Conclusion: Some personality traits such as extraversion and frustration tolerance are significantly related to task-oriented coping, and psychopathological personality traits such as neuroticism are associated with emotional-oriented coping in major depressive disorder.

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  • Perceived parenting pattern and response to antidepressants in patients with major depression Reviewed

    K Sakado, T Sato, T Uehara, M Sakado, T Someya

    JOURNAL OF AFFECTIVE DISORDERS   52 ( 1-3 )   59 - 66   1999.1

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    Background: No systematic study has been conducted to explore the relationship of dysfunctional parenting early in life, as measured