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  2. 岩田 仲生

岩田 仲生

イワタ ナカオ  (Nakao Iwata)

基本情報

所属
藤田医科大学 医学部 教授
学位
博士（医学）(名古屋大学)
J-GLOBAL ID
200901048638344557
researchmap会員ID
5000024641
外部リンク
1989年 名古屋大学医学部卒業
1993年 名古屋大学大学院修了 博士（医学）
1994年 名古屋大学医学部付属病院精神科 医員
1996年 National Institute of Health Visiting Fellow
1998年 藤田医科大学医学部精神神経科学 講師
2002年 藤田医科大学医学部精神神経科学 助教授
2003年 藤田医科大学医学部精神神経科学 教授（現職）
2011年 藤田医科大学研究支援推進本部 本部長（現職）
2015年 藤田医科大学医学部 医学部長（現職）
2016年 藤田医科大学 副学長（現職）
専門分野： 精神疾患の分子遺伝学、神経生化学、薬理遺伝学、臨床精神薬理学

研究キーワード

 11

研究分野

 1

経歴

 5

学歴

 2

論文

 613
  • Taro Kishi, Yuki Matsuda, Shinji Matsunaga, Masatsugu Moriwaki, Yoichiro Otake, Kaku Akamatsu, Tomo Okochi, Shigeki Hirano, Toshihiko Funahashi, Momoko Okuda, Hideaki Tabuse, Kiyoshi Fujita, Nakao Iwata
    Neuropsychiatric disease and treatment 13 117-125 2017年  査読有り
    OBJECTIVE: There are no direct comparisons between escitalopram and paroxetine controlled release in patients with major depressive disorder (MDD). METHODS: We conducted a 24-week, rater-masked, randomized trial of escitalopram (5-20 mg/day) versus paroxetine controlled release (12.5-50 mg/day) in patients with MDD (UMIN000011191). Patients with the diagnosis of moderate-to-severe MDD (a 17-item Hamilton Rating Scale for Depression [HAMD-17], with total score at baseline being ≥20) were recruited to participate in a parallel, randomized, controlled trial. The primary outcome for efficacy was an improvement in the 21-item HAMD (HAMD-21) total score at 24 weeks. The secondary outcomes were the response, remission, and discontinuation rates and the incidence of individual adverse events. RESULTS: A total of 88 patients with MDD (males, 61.4%; mean age, 40.8±13.4 years) were recruited. The discontinuation rate was 58.0% (escitalopram, 55.8%; paroxetine controlled release, 60.0%). Both escitalopram and paroxetine controlled-release treatment groups exhibited significant reduction in the HAMD-21 total score at 2, 4, 8, 12, and 24 weeks from the baseline. However, there were no significant differences in the HAMD-21 total score, response rate, remission rate, and discontinuation rate at any time point between the groups. In addition, there were no significant differences in the incidence of any individual adverse events (eg, nausea, vomiting, and somnolence) between the treatment groups. CONCLUSION: Our results suggest that escitalopram and paroxetine controlled release had similar efficacy and safety profiles in patients with MDD. One of the primary limitations of this study is the small sample size.
  • Yuichi Esaki, Tsuyoshi Kitajima, Ippei Takeuchi, Soji Tsuboi, Osamu Furukawa, Masatsugu Moriwaki, Kiyoshi Fujita, Nakao Iwata
    Chronobiology international 34(6) 753-761 2017年  査読有り
    Blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We hypothesized that wearing blue-blocking (BB) glasses in the evening may influence circadian rhythm disturbances in patients with major depressive disorder (MDD), resulting in improved sleep and mood. We used a randomized placebo-controlled double-blinded design. Patients with MDD with sleep onset insomnia were randomly assigned to wearing either BB glasses or clear glasses (placebo). Patients were instructed to wear the glasses from 20:00 hours until bedtime for 2 weeks. We assessed sleep state (sleep quality on a visual analog scale, the Morningness-Eveningness Questionnaire [MEQ], and a sleep diary) and depressive symptoms at baseline and after 2 weeks. Data were analyzed with a full analysis set. In total, 20 patients were randomly assigned to the BB and placebo groups (BB group, n = 10; placebo group, n = 10). There were three dropouts (BB group, n = 1; placebo group, n = 2). At baseline, sleep quality, sleep latency (assessed via a sleep diary), and antipsychotics use differed between the groups. To take account of these differences, the baseline sleep state or depressive symptoms and antipsychotics use were used as covariates in the later analysis. The change scores for sleep quality did not show a significant improvement in the BB group compared with the placebo group (mean [standard deviation, SD] scores for BB versus placebo: 36.1 [31.7] versus 16.2 [15.1], p = 0.43), although half of the BB group showed a clear improvement in sleep quality. The change in MEQ scores did not significantly differ between the groups (p = 0.14), although there was a trend of a shift to morning type in the BB group (3.10 [4.95] points) and to evening type in the placebo group (0.50 [3.89] points). There were no statistically significant changes in depressive symptoms in either group. Across both groups, 40% of the participants reported pain or discomfort from wearing the glasses, which were available in only one size. Thus, the failure to find significant differences may have resulted from the glasses used in this study. Glasses fitted to individual patients may improve efficacy and safety. Replication of the study with a larger sample size and size-adjustable glasses is needed.
  • Taro Kishi, Toshikazu Ikuta, Shinji Matsunaga, Yuki Matsuda, Kazuto Oya, Nakao Iwata
    Neuropsychiatric disease and treatment 13 1281-1302 2017年  査読有り
    BACKGROUND: The relative efficacy and tolerability of antipsychotics for schizophrenia are considerably well studied. This study aimed to examine whether previous findings could be replicated in a genetically distinct and homogenous group (ie, Japanese patients with schizophrenia) and whether previous findings could be extended to a broader range of antipsychotics with previously unclear relative efficacy and tolerability. METHODS: Bayesian network meta-analysis was performed in which randomized trials comparing any of the following interventions were included: second-generation antipsychotics, haloperidol, or placebo. The primary outcomes for efficacy and acceptability were the response rate and all-cause discontinuation. The secondary outcomes included the improvement of Positive and Negative Syndrome Scale scores, discontinuation because of adverse events, and individual adverse events. RESULTS: Eighteen relevant studies were identified (total n=3,446; aripiprazole =267, blonanserin =285, clozapine =47, clocapramine =295, haloperidol =857, mosapramine =493, olanzapine =179, paliperidone =136, perospirone =146, placebo =138, quetiapine =212, and risperidone =338; mean study duration =8.33±1.41 weeks). In primary outcomes, olanzapine and paliperidone showed efficacy than placebo, and olanzapine and paliperidone showed superior acceptability compared with placebo. There were differences in the incidences of individual adverse events (the best antipsychotic: extrapyramidal symptoms = olanzapine, hyperprolactinemia- related symptoms = quetiapine, sedation = paliperidone, and weight change = blonanserin) among antipsychotics. CONCLUSION: Although the current analysis exclusively included Japanese patients with schizophrenia, no remarkable differences were observed in efficacy and safety compared with previous meta-analyses. Diverse hierarchies in safety outcomes also support the implication that individual risk expectations for adverse events can guide clinical decisions. However, the sample size was relatively limited. Additional efficacy and safety data are required to fully obtain a conclusive understanding.
  • Taro Kishi, Shinji Matsunaga, Nakao Iwata
    Neuropsychiatric disease and treatment 13 1909-1928 2017年  査読有り
    BACKGROUND: Memantine is effective in the treatment of behavioral disturbances in patients with Alzheimer's disease. It has not yet been fully determined which behavioral disturbances respond best to memantine. METHODS: We conducted a meta-analysis of memantine vs control (placebo or usual care) for the treatment of individual behavioral disturbances (delusion, hallucination, agitation/aggression, dysphoria, anxiety/phobia, euphoria, apathy, disinhibition, irritability/lability, aberrant motor activity/activity disturbances, nighttime disturbance/diurnal rhythm disturbances, and eating disturbances). Randomized controlled studies of memantine in patients with Alzheimer's disease were included in this study. To evaluate these outcomes, standardized mean difference (SMD), with 95% confidence intervals (95% CIs), based upon a random-effects model was evaluated in the meta-analysis. RESULTS: A total of 11 studies (n=4,261; memantine vs placebo: N=4, n=1,500; memantine + cholinesterase inhibitors [M + ChEIs] vs ChEIs: N=7, n=2,761) were included in the meta-analysis. Compared to control, memantine showed significant improvement in agitation/aggression (SMD =-0.11; 95% CIs =-0.20, -0.03; P=0.01; I2=47%), delusion (SMD =-0.12; 95% CIs =-0.18, -0.06; P=0.0002; I2=0%), disinhibition (SMD =-0.08; 95% CIs =-0.15, -0.00; P=0.04; I2=0%), and nighttime disturbance/diurnal rhythm disturbances (SMD =-0.10; 95% CIs =-0.18, -0.02; P=0.02; I2=36%). Memantine was also marginally superior to control in hallucination (SMD =-0.06; 95% CIs =-0.12, 0.01; P=0.07; I2=0%) and irritability/lability (SMD =-0.09; 95% CIs =-0.19, 0.01; P=0.07; I2=42%). Memantine is similar to control in dysphoria, anxiety/phobia, euphoria, apathy, and eating disturbance. CONCLUSION: The meta-analysis suggest that memantine has benefits for the treatment of most of the behavioral disturbances in patients with Alzheimer's disease. Memantine does not deteriorate negative symptoms as behavioral disturbances in patients with Alzheimer's disease.
  • Taro Kishi, Shinji Matsunaga, Kazuto Oya, Ikuo Nomura, Toshikazu Ikuta, Nakao Iwata
    Journal of Alzheimer's disease : JAD 60(2) 401-425 2017年  査読有り
    BACKGROUND: The clinical benefit of memantine for Alzheimer's disease (AD) remains inconclusive. OBJECTIVE: We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD. METHODS: We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses. RESULTS: Thirty studies (n = 7,567; memantine versus placebo: N = 11, n = 3,298; memantine + cholinesterase inhibitors (M+ChEIs) versus ChEIs: N = 17, n = 4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD) = -0.24, 95% confidence intervals (95% CIs) = -0.34, -0.15, p < 0.00001, I2 = 35% ] and BD (SMD = -0.16, 95% CIs = -0.29, -0.04, p = 0.01, I2 = 52%) compared with placebo. In the sensitivity analysis including only patients with moderate-severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMD = -0.20, 95% CIs = -0.34, -0.07, p = 0.003, I2 = 36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMD = -0.20, 95% CIs = -0.36, -0.03, p = 0.02, I2 = 77%) and a trend of CF improvement (SMD = -0.11, 95% CIs = -0.22, 0.01, p = 0.06, I2 = 56%). However, in the sensitivity analysis of double-blind, placebo-controlled studies only, M+ChEIs showed a significant reduction in BD compared with ChEIs without considerable heterogeneity (SMD = -0.11, 95% CIs = -0.21, -0.01, p = 0.04, I2 = 40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMD = -0.18, 95% CIs = -0.31, -0.05, p = 0.006, I2 = 49%). No differences were detected in all-cause discontinuation between the groups. CONCLUSIONS: The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs.
  • Tomiki Sumiyoshi, Atsuhito Toyomaki, Naoko Kawano, Tomoko Kitajima, Ichiro Kusumi, Norio Ozaki, Nakao Iwata, Kazuki Sueyoshi, Kazuyuki Nakagome
    Frontiers in psychiatry 8 168-168 2017年  査読有り
    BACKGROUNDS: Several domains of cognitive function, including learning memory and executive function, are impaired in mood disorders. Also, the relationship between disturbances of these two cognitive domains has been suggested. In line with the recent initiative to establish a standard measure of cognitive decline in bipolar disorder, the present study was conducted to (1) test the criterion-related validity and test-retest reliability of the California Verbal Learning Test (CVLT)-II Japanese version, and (2) determine if type of word learning tasks (i.e., with or without a category structure) affects severity of verbal memory deficits in patients with subsyndromal bipolar disorder. METHODS: Thirty-six patients with bipolar disorder with mild symptoms and 42 healthy volunteers participated in the study. We first compared effect sizes for memory deficits in patients among the CVLT-II, Brief Assessment of Cognition in Schizophrenia (BACS), and Hopkins Verbal Memory Tests-Revised (HVLT-R). We next evaluated the correlations between scores of the CVLT-II vs. those of the BACS and HVLT-R. Bipolar patients were re-assessed with the same (standard) or alternate forms of the CVLT-II and HVLT-R 1 month later. RESULTS: Scores on the CVLT-II 1-5 Free Recall and Long-delay Free Recall, as well as the HVLT-R Immediate Recall, but not the BACS List Learning were significantly lower for patients compared to control subjects. The effect sizes for cognitive decline due to the illness were comparable when measured by the CVLT-II and HVLT-R, ranging from 0.5 to 0.6. CVLT-II scores were significantly correlated with those of the HVLT-R and BACS. Test-retest reliability of the CVLT-II was acceptable, and no significant practice effect was observed when the alternate form was used. There was no consistent relationship between mood symptoms and performance on the CVLT-II. CONCLUSION: These results suggest the CVLT-II Japanese version is able to discriminate between bipolar disorder patients and healthy controls with good sensitivity and validity. Data in this study also indicate that the degree of verbal memory deficits in bipolar disorder may be influenced by memory organizational strategy.
  • Taro Kishi, Reiji Yoshimura, Toshikazu Ikuta, Nakao Iwata
    Frontiers in psychiatry 8 308-308 2017年  査読有り
    Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) is associated with the pathophysiology of major depressive disorder (MDD). In this mini review, we explored the association between BDNF and MDD using meta-analytic evidence. Our findings indicated that the Val66Met polymorphism in the BDNF gene was not associated with MDD or hippocampal volume in patients with MDD. However, plasma/serum levels of BDNF were decreased in patients with acute MDD compared with healthy controls. Both antidepressant treatment and electroconvulsive therapy increased plasma and serum levels of BDNF in patients with MDD. Val66Met polymorphism in the BDNF gene was associated with an antidepressant response in patients with MDD. Taken together, we did not detect any plausible evidence regarding Val66Met polymorphism in the BDNF gene contributing to a risk of MDD. However, peripheral BDNF levels are decreased in patients with MDD, and the polymorphisms are associated with treatment response. In conclusion, BDNF is best understood to be a biomarker for the state of MDD and its treatment response rather than a risk factor for MDD.
  • Taro Kishi, Toshikazu Ikuta, Shinji Matsunaga, Yuki Matsuda, Kazuto Oya, Nakao Iwata
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 13 1281-1301 2017年  査読有り
    Background: The relative efficacy and tolerability of antipsychotics for schizophrenia are considerably well studied. This study aimed to examine whether previous findings could be replicated in a genetically distinct and homogenous group (ie, Japanese patients with schizophrenia) and whether previous findings could be extended to a broader range of antipsychotics with previously unclear relative efficacy and tolerability. Methods: Bayesian network meta-analysis was performed in which randomized trials comparing any of the following interventions were included: second-generation antipsychotics, haloperidol, or placebo. The primary outcomes for efficacy and acceptability were the response rate and all-cause discontinuation. The secondary outcomes included the improvement of Positive and Negative Syndrome Scale scores, discontinuation because of adverse events, and individual adverse events. Results: Eighteen relevant studies were identified (total n=3,446; aripiprazole =267, blonanserin =285, clozapine =47, clocapramine =295, haloperidol =857, mosapramine =493, olanzapine =179, paliperidone =136, perospirone =146, placebo =138, quetiapine =212, and risperidone =338; mean study duration =8.33 +/- 1.41 weeks). In primary outcomes, olanzapine and paliperidone showed efficacy than placebo, and olanzapine and paliperidone showed superior acceptability compared with placebo. There were differences in the incidences of individual adverse events (the best antipsychotic: extrapyramidal symptoms = olanzapine, hyperprolactinemia-related symptoms = quetiapine, sedation = paliperidone, and weight change = blonanserin) among antipsychotics. Conclusion: Although the current analysis exclusively included Japanese patients with schizophrenia, no remarkable differences were observed in efficacy and safety compared with previous meta-analyses. Diverse hierarchies in safety outcomes also support the implication that individual risk expectations for adverse events can guide clinical decisions. However, the sample size was relatively limited. Additional efficacy and safety data are required to fully obtain a conclusive understanding.
  • Taro Kishi, Yuki Matsuda, Shinji Matsunaga, Masatsugu Moriwaki, Yoichiro Otake, Kaku Akamatsu, Tomo Okochi, Shigeki Hirano, Toshihiko Funahashi, Momoko Okuda, Hideaki Tabuse, Kiyoshi Fujita, Nakao Iwata
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 13 117-125 2017年  査読有り
    Objective: There are no direct comparisons between escitalopram and paroxetine controlled release in patients with major depressive disorder (MDD). Methods: We conducted a 24-week, rater-masked, randomized trial of escitalopram (5-20 mg/day) versus paroxetine controlled release (12.5-50 mg/day) in patients with MDD (UMIN000011191). Patients with the diagnosis of moderate-to-severe MDD (a 17-item Hamilton Rating Scale for Depression [HAMD-17], with total score at baseline being &gt;= 20) were recruited to participate in a parallel, randomized, controlled trial. The primary outcome for efficacy was an improvement in the 21-item HAMD (HAMD-21) total score at 24 weeks. The secondary outcomes were the response, remission, and discontinuation rates and the incidence of individual adverse events. Results: A total of 88 patients with MDD (males, 61.4%; mean age, 40.8 +/- 13.4 years) were recruited. The discontinuation rate was 58.0% (escitalopram, 55.8%; paroxetine controlled release, 60.0%). Both escitalopram and paroxetine controlled-release treatment groups exhibited significant reduction in the HAMD-21 total score at 2, 4, 8, 12, and 24 weeks from the baseline. However, there were no significant differences in the HAMD-21 total score, response rate, remission rate, and discontinuation rate at any time point between the groups. In addition, there were no significant differences in the incidence of any individual adverse events (eg, nausea, vomiting, and somnolence) between the treatment groups. Conclusion: Our results suggest that escitalopram and paroxetine controlled release had similar efficacy and safety profiles in patients with MDD. One of the primary limitations of this study is the small sample size.
  • Taro Kishi, Shinji Matsunaga, Nakao Iwata
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 13 1909-1928 2017年  査読有り
    Background: Memantine is effective in the treatment of behavioral disturbances in patients with Alzheimer's disease. It has not yet been fully determined which behavioral disturbances respond best to memantine. Methods: We conducted a meta-analysis of memantine vs control (placebo or usual care) for the treatment of individual behavioral disturbances (delusion, hallucination, agitation/aggression, dysphoria, anxiety/phobia, euphoria, apathy, disinhibition, irritability/lability, aberrant motor activity/activity disturbances, nighttime disturbance/diurnal rhythm disturbances, and eating disturbances). Randomized controlled studies of memantine in patients with Alzheimer's disease were included in this study. To evaluate these outcomes, standardized mean difference (SMD), with 95% confidence intervals (95% CIs), based upon a random-effects model was evaluated in the meta-analysis. Results: A total of 11 studies (n=4,261; memantine vs placebo: N=4, n=1,500; memantine + cholinesterase inhibitors [M + ChEIs] vs ChEIs: N=7, n=2,761) were included in the meta-analysis. Compared to control, memantine showed significant improvement in agitation/aggression (SMD=-0.11; 95% CIs=-0.20, -0.03; P=0.01; I-2=47%), delusion (SMD =-0.12; 95% CIs=-0.18, -0.06; P=0.0002; I-2=0%), disinhibition (SMD=-0.08; 95% CIs=-0.15, -0.00; P=0.04; I-2=0%), and nighttime disturbance/diurnal rhythm disturbances (SMD=-0.10; 95% CIs=-0.18, -0.02; P=0.02; I-2=36%). Memantine was also marginally superior to control in hallucination (SMD=-0.06; 95% CIs=-0.12, 0.01; P=0.07; I-2=0%) and irritability/lability (SMD=-0.09; 95% CIs=-0.19, 0.01; P=0.07; I-2=42%). Memantine is similar to control in dysphoria, anxiety/phobia, euphoria, apathy, and eating disturbance. Conclusion: The meta-analysis suggest that memantine has benefits for the treatment of most of the behavioral disturbances in patients with Alzheimer's disease. Memantine does not deteriorate negative symptoms as behavioral disturbances in patients with Alzheimer's disease.
  • Taro Kishi, Kazuto Oya, Nakao Iwata
    Psychiatry research 246 750-755 2016年12月30日  査読有り
    This meta-analysis of randomized controlled trials (RCTs) investigated the advantages of long-acting injectable antipsychotics (LAI-APs) over oral antipsychotics (OAPs) with regard to efficacy and safety for patients with recent-onset psychotic disorders. Effect sizes and 95% confidence intervals (95%CIs) were calculated. We identified five RCTs (1022 patients, mean study duration=18±7.59 months) that compared LAI-APs (paliperidone or risperidone) with OAPs. Pooled LAI-APs did not outperform OAPs in terms of the preventing of relapse (N=3, n=875). However, there was significant heterogeneity (I2=76%), with one study showing no superiority of LAI-APs over OAPs [Malla 2013: risk ratio (RR)=1.83, 95%CI=0.70-4.77, n=77] and the other two studies showing LAI-APs to be superior [Schreiner 2015: [RR=0.71, 95%CI=0.51-0.97, number needed to treat (NNT)=-17, n=715, Subotnik 2015: RR=0.15, 95%CI=0.04-0.63, NNT=-4, n=83]. Pooling the studies, there were no significant differences between LAI-APs and OAPs in the improvement of Positive and Negative Syndrome Scale scores or in discontinuation due to all-cause, adverse events (AEs), and death, but LAI-APs outperformed OAPs in terms of discontinuation due to inefficacy (RR=0.34, NNT=-50) and nonadherence (RR=0.30, NNT=-33). However, the LAI-APs were associated with a higher incidence of at least one AE (RR=1.13) and tremor (RR=2.38) compared with OAPs.
  • Hiroki Kimura, Chenyao Wang, Kanako Ishizuka, Jingrui Xing, Yuto Takasaki, Itaru Kushima, Branko Aleksic, Yota Uno, Takashi Okada, Masashi Ikeda, Daisuke Mori, Toshiya Inada, Nakao Iwata, Norio Ozaki
    Schizophrenia research 178(1-3) 104-106 2016年12月  査読有り
  • Dragana Bugarski-Kirola, Nakao Iwata, Snjezana Sameljak, Carol Reid, Thomas Blaettler, Laurie Millar, Tiago Reis Marques, George Garibaldi, Shitij Kapur
    LANCET PSYCHIATRY 3(12) 1115-1128 2016年12月  査読有り
    Background Many patients with schizophrenia require high doses of medication for their ongoing psychotic symptoms. Glutamate theories and findings from studies showing efficacy of sarcosine, an endogenous, non-selective glycine-reuptake inhibitor mediated by GlyT1, off er an alternative approach. We undertook the SearchLyte trial programme to examine the efficacy of bitopertin, a selective GlyT1-mediated glycine-reuptake inhibitor, as an adjunctive treatment to ongoing antipsychotic treatment. Methods SearchLyte consisted of three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies done in outpatient clinics in Asia, Europe, and North and South America (TwiLyte done at 109 sites, NightLyte at 84, and MoonLyte at 87). Participants were male and female outpatients, aged at least 18 years, meeting DSM-IV criteria for schizophrenia with suboptimally controlled positive symptoms despite treatment with antipsychotics. Inclusion criteria included a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and antipsychotic treatment stability for the past 12 weeks before randomisation. Key exclusion criteria included meeting criteria for symptomatic remission or previous treatment with a GlyT1 inhibitor or any other investigational drug. After a screening or 4-week prospective stabilisation period, we randomly assigned participants (1: 1: 1) to a 12-week, double-blind treatment of either placebo or one of two fixed doses of oral, once-daily bitopertin (10 or 20 mg in TwiLyte and NightLyte; 5 or 10 mg in MoonLyte) added to their current antipsychotic medicine. After completion of 12 weeks' treatment, the study design allowed for additional double-blind treatment for 40 weeks to assess maintenance of the effect, followed by a randomised 4-week washout period to assess withdrawal effects. Subsequently, all patients were offered the opportunity to receive bitopertin treatment in a 3-year follow-up. The primary efficacy endpoint was the mean change from baseline in the PANSS Positive Symptom Factor Score (PSFS) at week 12, analysed in the modified intention-to-treat population. The trials were registered at ClinicalTrials.gov (numbers NCT01235520 [TwiLyte], NCT01235585 [MoonLyte], and NCT01235559 [NightLyte]). Findings Between Nov 19, 2010, and Dec 12, 2014, we randomly assigned 1794 patients to treatment, of whom 1772 were treated and analysed. MoonLyte was discontinued in September, 2014, on the basis of results from futility analyses. Across studies and treatment arms, most patients completed 12 weeks of treatment (505 in TwiLyte, 517 in NightLyte, and 506 in MoonLyte). Only one study, NightLyte, met the primary endpoint where the PANSS PSFS significantly differed from placebo at week 12, and only in the 10-mg arm: mean difference in score -1.37, 95% CI -2.27 to -0.47; p = 0.0028. Improvements from baseline for the bitopertin 20-mg arm in Nightlyte were not significant compared with placebo: -3.77, 95% CI -4.40 to -3.14; p = 0.3142. Results from the other two studies also did not differ from placebo (TwiLyte 0.58, 95% CI -0.34 to 1.50, p = 0.22 for 10 mg and 0.43, -0.49 to 1.36, p = 0.36 for 20 mg; MoonLyte 0.06, 95% CI -0.79 to 0.92, p = 0.88 for 5 mg and 0.44, -0.41 to 1.28, p = 0.31 for 10 mg). Placebo responses varied across studies and might have contributed to the differences in efficacy between studies. Four deaths occurred during the 12-week treatment period, three in NightLyte (upper gastrointestinal haemorrhage, alcohol poisoning and related head injury, and a completed suicide) and one in MoonLyte (myocardial infarction in a patient with pre-existing risk factors). Only the death by suicide was deemed related to the study drug. The incidence of serious adverse events was low across treatment groups in all three studies; psychiatric disorders were the most frequently reported serious adverse events and the most frequent cause of adverse events leading to discontinuation. Interpretation Only one of six active treatment arms across the three studies offered an advantage of adjunctive bitopertin over placebo for the treatment of suboptimally controlled symptoms of schizophrenia. The small improvement associated with bitopertin together with the varying placebo response suggests that adjunctive bitopertin treatment might off er only modest benefit to suboptimal responders to antipsychotics, if any.
  • Akiko Tsuchiya, Tsuyoshi Kitajima, Satoe Tomita, Yuichi Esaki, Marina Hirose, Nakao Iwata
    Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 12(11) 1471-1476 2016年11月15日  査読有り
    STUDY OBJECTIVES: Patients with circadian rhythm sleep disorders (CRSDs) often have coincidence of orthostatic dysregulation (OD). Both disorders have many common clinical features. However, the prevalence of OD in patients with CRSD has not been examined. METHODS: Thirty-eight patients with CRSD with either delayed sleep phase disorder or free-running disorder were tested for OD using the new orthostatic test, which was originally established by Tanaka et al. (< 20 years) and the Schellong test, i.e., the active standing test (≥ 20 years). RESULTS: The overall prevalence of OD in patients with CRSD was 57.9% (22/38), and prevalence of OD was 70% in patients under 20 years of age (14/20). These rates exceed the previously reported values in adolescents aged 14-15 years (15%), regarded as the age with highest OD prevalence. Prevalence was not significantly associated with CRSD severity and medications used. CONCLUSIONS: We observed a high prevalence of OD in patients with CRSD, suggesting some relationship between CRSD and OD. Large-scale case-control studies are warranted to investigate the underlying mechanisms for this comorbidity.
  • Taro Kishi, Shinji Matsunaga, Nakao Iwata
    Schizophrenia bulletin 42(6) 1438-1445 2016年11月  査読有り
    Long-acting injectable (LAI) antipsychotics (LAI-APs) have several advantages over oral medications, but deaths reported in Japan during the early post-marketing phase vigilance period have raised safety concerns. We conducted a series of meta-analyses to assess whether LAI-APs affect the mortality of patients with schizophrenia. Three categorical meta-analyses of randomized controlled trials (RCTs) were performed to compare all-cause death (primary outcome) and death due to suicide: individual and pooled LAI-APs vs placebo, individual and pooled LAI-APs vs oral antipsychotics (OAPs), and head-to-head comparisons of LAI-APs. The risk ratios (RRs) and 95% CIs were calculated. We identified 52 RCTs (53 comparisons; total participants = 17 416, LAI-APs = 11 360, OAP = 3910, and placebo = 2146; mean study duration [wk]: LAI-APs vs placebo = 28.9, LAI-APs vs OAPs = 64.5). Neither pooled nor individual LAI-APs (aripiprazole, fluphenazine, olanzapine, paliperidone, and risperidone) differed from the placebo regarding the incidences of all-cause death (pooled LAI-APs: RR = 0.64, P = .37) and death due to suicide (pooled LAI-APs: RR = 0.98, P = .98). However, in a subgroup meta-analysis of only short-duration RCTs (≤13wk), pooled LAI-APs exhibited a trend toward lower incidence of all-cause death than placebo (RR = 0.29, P = .08). Pooled LAI-APs (aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol) did not differ from pooled OAPs regarding all-cause death (pooled LAI-APs: RR = 0.71, P = .30) and death due to suicide (pooled LAI-APs: RR = 0.94, P = .91). Individual LAI-APs and OAPs were associated with similar risks of death. Data for head-to-head comparisons of individual LAI-APs were insufficient. In conclusion, there was no significant difference between LAI-APs and placebo or OAPs regarding all-cause death and death due to suicide.
  • Kohei Kawase, Kenji Kondo, Takeo Saito, Ayu Shimasaki, Atsushi Takahashi, Yoichiro Kamatani, Naoto Kawabe, Senju Hashimoto, Masashi Ikeda, Michiaki Kubo, Kentaro Yoshioka, Nakao Iwata
    Psychiatry and clinical neurosciences 70(11) 489-497 2016年11月  査読有り
    AIM: Pegylated interferon (PegIFN) therapies for hepatitis C virus (HCV) infection often induce a depressive state. This study aimed to identify the risk factors for and clinical characteristics of PegIFN-induced depressive state. METHODS: Sixty-nine subjects with HCV who received PegIFN therapy were enrolled. Before beginning therapy, all subjects were evaluated using the Neuroticism-Extraversion-Openness Five-Factor Inventory and the List of Threatening Events Questionnaire. Beck Depression Inventory (BDI) scores were also evaluated at baseline, 2-4 weeks after initiating therapy, and every 4 weeks thereafter. RESULTS: During the study, 18 subjects (24.3%) developed a depressive state (BDI ≥ 10). A bimodal peak of onset was observed during the early (2-8 weeks) and late (after 20 weeks) therapy phases. Moreover, we observed that baseline BDI scores (odds ratio [OR] = 1.40, P  = 0.0104) and neuroticism (OR = 1.14, P  = 0.0275) were significant risk factors for developing a depressive state. To determine the specific characteristics of this condition, we compared the BDI subscales between the 'PegIFN-induced' and 'general' depressive state reported previously. We found that the score at 'somatic symptoms' was higher in the 'PegIFN-induced' group. CONCLUSION: Our results indicate the following: (i) PegIFN-induced depressive state most frequently develops during the first 8 weeks of therapy; (ii) baseline BDI and neuroticism scores are risk factors for PegIFN-induced depressive state; and (iii) the core symptoms of PegIFN-induced depressive state are different from those of 'general' depression.
  • Matsunaga S, Kishi T, Iwata N
    Journal of the American Medical Directors Association 17(11) 1061-1062 2016年11月1日  査読有り
  • Takeo Saito, Masashi Ikeda, Taisei Mushiroda, Takeshi Ozeki, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Shuji Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kazutaka Ohi, Masatoshi Takeda, Yoichiro Kamatani, Shusuke Numata, Tetsuro Ohmori, Shu-Ichi Ueno, Manabu Makinodan, Yosuke Nishihata, Masaharu Kubota, Takemi Kimura, Nobuhisa Kanahara, Naoki Hashimoto, Kiyoshi Fujita, Kiyotaka Nemoto, Taku Fukao, Taro Suwa, Tetsuro Noda, Yuji Yada, Manabu Takaki, Naoya Kida, Taku Otsuru, Masaru Murakami, Atsushi Takahashi, Michiaki Kubo, Ryota Hashimoto, Nakao Iwata
    Biological psychiatry 80(8) 636-42 2016年10月15日  査読有り
    BACKGROUND: Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. METHODS: To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. RESULTS: We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. CONCLUSIONS: Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.
  • 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年9月12日  査読有り
    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.
  • Shinji Matsunaga, Taro Kishi, Nakao Iwata
    Journal of Alzheimer's disease : JAD 54(2) 635-43 2016年9月6日  査読有り
    BACKGROUND: Previous clinical studies found that yokukansan has a therapeutic effect on behavioral and psychological symptoms of dementia (BPSD) in dementia patients. OBJECTIVE: To perform an updated meta-analysis of randomized controlled trials (RCTs) testing yokukansan for patients with BPSD. METHODS: Primary efficacy and safety endpoints were BPSD total scores and all-cause discontinuation, respectively. Secondary outcomes were BPSD subscales, cognitive function scores [Mini-mental state examination (MMSE)], activities of daily living (ADL) scores, discontinuation due to adverse events (AEs), and incidences of AEs. RESULTS: Five RCTs with 381 patients with BPSD were included. Compared with controls [placebo+usual care (UC)], yokukansan significantly decreased BPSD total scores [standardized mean difference (SMD) = -0.32, 95% confidence interval (CI) = -0.53 to -0.11, p = 0.003, I2 = 0%, N = 5 studies, n = 361]. Yokukansan was more efficacious in reducing BPSD subscale scores (delusions: SMD = -0.51, 95% CI = -0.98 to -0.04, hallucinations: SMD = -0.54, 95% CI = -0.96 to -0.12, agitation/aggression: SMD = -0.37, 95% CI = -0.60 to -0.15) than placebo+UC. However, yokukansan was not superior to placebo+UC for BPSD total as well as any subscales scores only in Alzheimer's disease patients. Compared with UC, yokukansan treatment improved ADL scores (SMD = -0.32, 95% CI = -0.62 to -0.01). MMSE scores did not differ between the yokukansan and placebo+UC treatment groups. No significant differences were found in all-cause discontinuation, discontinuation due to AEs, and incidences of AEs between yokukansan and placebo+UC treatments. CONCLUSIONS: Our results suggest that yokukansan is beneficial for the treatment of patients with BPSD and is well-tolerated; it was not beneficial for BPSD total and any subscale scores only in Alzheimer's disease patients.
  • 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 : the official publication of the International Society of Psychiatric Genetics 171(6) 797-805 2016年9月  査読有り
    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. © 2016 Wiley Periodicals, Inc.
  • Taro Kishi, Kazuto Oya, Nakao Iwata
    The international journal of neuropsychopharmacology 19(9) 2016年9月  査読有り
    BACKGROUND: This meta-analysis of randomized controlled trials aimed to examine the advantages of long-acting injectable antipsychotics over placebo or oral medications regarding efficacy and safety for patients with bipolar disorder. METHODS: Two categorical meta-analyses of randomized controlled trials were performed to compare study-defined relapse rate (primary), discontinuation rates, and individual adverse events: (1) risperidone-long-acting injectable vs placebo, and (2) long-acting injectable antipsychotics vs oral medications. RESULTS: We identified 7 randomized controlled trials (n=1016; long-acting injectable antipsychotics [flupenthixol (1 randomized controlled trial) and risperidone (6 randomized controlled trials)=449]; oral medications [mood stabilizers, antidepressants, antipsychotic, or any combination of these agents=283]; and placebo=284). Risperidone-long-acting injectable antipsychotic was superior to placebo for study-defined relapse rate (risk ratio=0.63, P<.0001), relapse of manic symptoms (risk ratio=0.42, P<.00001), and all-cause discontinuation (risk ratio=0.75, P=.007). Risperidone-long-acting injectable was associated with higher incidence of prolactin-related adverse events (risk ratio=4.82, P=.001) and weight gain (risk ratio=3.80, P<.0001) than placebo. The pooled long-acting injectable antipsychotics did not outperform oral medications regarding primary outcome but with significant heterogeneity (I2=74%). Sensitivity analysis, including only studies with rapid cycling or high frequency of relapse patients, revealed that long-acting injectable antipsychotics were superior compared to oral medications (I2=0%, RR=0.58, P=.0004). However, the comparators in this sensitivity analysis did not include second-generation antipsychotic monotherapy. In sensitivity analysis, including only studies with second-generation antipsychotic monotherapy as the comparator, long-acting injectable antipsychotics did not outperform second-generation antipsychotic monotherapy. Risperidone-long-acting injectable was also associated with higher incidence of prolactin-related adverse events than oral medications (RR=2.66, P=.03). CONCLUSIONS: Long-acting injectable antipsychotics appear beneficial for relapse prevention in patients with rapid cycling. Furthermore, randomized controlled trials comparing long-acting injectable antipsychotics and oral second-generation antipsychotic using larger samples of rapid cycling patients are warranted.
  • Kazuto Oya, Yuki Matsuda, Shinji Matsunaga, Taro Kishi, Nakao Iwata
    European archives of psychiatry and clinical neuroscience 266(5) 439-50 2016年8月  査読有り
    The aim of this study was to perform a systematic review and an updated and comprehensive meta-analysis of oxytocin augmentation therapy in patients with schizophrenia who received antipsychotic agents. Data published up to 07/11/2015 were obtained from PubMed, PsycINFO, and Cochrane Library databases. We conducted a systematic review and meta-analysis of patients' data from randomized controlled trials (RCTs) comparing oxytocin with placebo. Relative risk (RR), standardized mean difference (SMD), and 95 % confidence intervals (95 % CI) based on the random-effects model were calculated. We included seven RCTs; the total sample size was 206 patients. Oxytocin was superior to placebo for decreasing the Positive and Negative Syndrome Scale (PANSS) general subscale scores (SMD = -0.44, 95 % CI -0.82 to -0.06, p = 0.02, I (2) = 0 %, N = 4, n = 112); however, it was not different from placebo for total symptoms (SMD = -0.46, 95 % CI -1.20 to 0.28, p = 0.22, I (2) = 80 %, N = 6, n = 162), positive symptoms (SMD = -0.18, 95 % CI -0.87 to 0.51, p = 0.60, I (2) = 81 %, N = 6, n = 192), and negative symptoms (SMD = -0.34, 95 % CI -0.76 to 0.08, p = 0.12, I (2) = 55 %, N = 7, n = 214). However, a sensitivity analysis including only oxytocin administration on consecutive days studies was superior to placebo in negative symptoms (SMD = -0.44, 95 % CI -0.87 to -0.01, p = 0.04, I (2) = 51 %, N = 6 n = 192). There were no significant differences for all-cause discontinuation (RR = 1.02) and individual side effects such as headache and dizziness between oxytocin and placebo. Oxytocin may improve PANSS general subscale scores in schizophrenia and seems to be well tolerated. However, because the number of studies in the current analysis was small, further study will be required using larger sample sizes.
  • Kazutaka Ohi, Masataka Kikuchi, Masashi Ikeda, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Haruo Fujino, Kenichiro Miura, Masaki Fukunaga, Akihiro Nakaya, Nakao Iwata, Ryota Hashimoto
    Schizophrenia research 175(1-3) 226-229 2016年8月  査読有り
  • Taro Kishi, Tomoya Hirota, Shinji Matsunaga, Nakao Iwata
    Journal of neurology, neurosurgery, and psychiatry 87(7) 767-74 2016年7月  査読有り
    OBJECTIVES: We performed an updated meta-analysis of antipsychotic treatment in patients with delirium, based on a previous meta-analysis published in 2007. METHODS: Included in this study were randomised, placebo-controlled or usual care (UC) controlled trials of antipsychotics in adult patients with delirium. Our primary outcome measure was response rate at the study end point. The secondary outcome measures included improvement of severity of delirium, Clinical Global Impression-Severity Scale (CGI-S), time to response (TTR), discontinuation rate and individual adverse effects. The risk ratio (RR), the number-needed-to-treat/harm (NNT/NNH), 95% CIs and standardised mean difference (SMD), were calculated. RESULTS: We identified 15 studies (mean duration: 9.8 days) for the systematic review (total n=949, amisulpride=20, aripiprazole=8, chlorpromazine=13, haloperidol=316, intramuscular olanzapine or haloperidol injection=62, olanzapine=144, placebo=75, quetiapine=125, risperidone=124, UC=30 and ziprasidone=32), 4 of which were conference abstracts and unpublished. When pooled as a group, antipsychotics were superior to placebo/UC in terms of response rate (RR=0.22, NNT=2), delirium severity scales scores (SMD=-1.27), CGI-S scores (SMD=-1.57) and TTR (SMD=-1.22). The pooled antipsychotic group was associated with a higher incidence of dry mouth (RR=13.0, NNH=5) and sedation (RR=4.59, NNH=5) compared with placebo/UC. Pooled second-generation antipsychotics (SGAs) were associated with shorter TTR (SMD=-0.27) and a lower incidence of extrapyramidal symptoms (RR=0.31, NNH=7) compared with haloperidol. CONCLUSIONS: Our results suggested that SGAs have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol. However, further study using larger samples is required.
  • Ikeda M, Hashimoto M, Matsushita M, Miyagawa Y, Ijichi D, Ueno Y, Iwata N, Kazui H
    2016年6月  
  • Masatoshi Inoshita, Shusuke Numata, Atsushi Tajima, Makoto Kinoshita, Hidehiro Umehara, Masahito Nakataki, Masashi Ikeda, Souichiro Maruyama, Hidenaga Yamamori, Tetsufumi Kanazawa, Shinji Shimodera, Ryota Hashimoto, Issei Imoto, Hiroshi Yoneda, Nakao Iwata, Tetsuro Ohmori
    Scientific reports 6 26105-26105 2016年5月19日  査読有り
    Many observational studies have shown elevated blood CRP levels in schizophrenia compared with controls, and one population-based prospective study has reported that elevated plasma CRP levels were associated with late- and very-late-onset schizophrenia. Furthermore, several clinical studies have reported the efficacy of anti-inflammatory drugs on the symptoms in patients with schizophrenia. However, whether elevated CRP levels are causally related to schizophrenia is not still established because of confounding factors and reverse causality. In the present study, we demonstrated that serum CRP levels were significantly higher in patients with schizophrenia than in the controls by conducting a case-control study and a meta-analysis of case-control studies between schizophrenia and serum CRP levels. Furthermore, we provided evidence for a causal association between elevated CRP levels and increased schizophrenia risk by conducting a Mendelian randomization analysis. Our findings suggest that elevated CRP itself may be a causal risk factor for schizophrenia.
  • Yuichi Esaki, Tsuyoshi Kitajima, Shigefumi Koike, Hiroshige Fujishiro, Yasuyo Iwata, Akiko Tsuchiya, Marina Hirose, Nakao Iwata
    Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 12(5) 689-93 2016年5月15日  査読有り
    STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by REM sleep without atonia and elaborate motor activity in association with dream mentation. The melatonin receptor agonist ramelteon has been documented as being effective in two patients with secondary RBD. However, there are no reports on ramelteon treatment for idiopathic RBD. METHODS: In an open-labeled trial, we treated 12 consecutive patients with idiopathic RBD for at least 4 w with 8 mg ramelteon given within 30 min before bedtime. RESULTS: Ramelteon treatment did not have a clear effect on REM sleep without atonia or an RBD severity scale measured by video-supported polysomnography. However, clinical assessment using a visual analog scale showed a trend toward significance and there were also definitely positive changes in some individual cases. Ramelteon was well tolerated in most patients, with minor side effects. CONCLUSIONS: Considering that ramelteon is associated with few side effects, further study may ascertain whether patients with RBD could be effectively treated by ramelteon, especially when clonazepam may not be suitable due to its side effects. COMMENTARY: A commentary on this article appears in this issue on page 643.
  • Anthony R Isles, Andrés Ingason, Chelsea Lowther, James Walters, Micha Gawlick, Gerald Stöber, Elliott Rees, Joanna Martin, Rosie B Little, Harry Potter, Lyudmila Georgieva, Lucilla Pizzo, Norio Ozaki, Branko Aleksic, Itaru Kushima, Masashi Ikeda, Nakao Iwata, Douglas F Levinson, Pablo V Gejman, Jianxin Shi, Alan R Sanders, Jubao Duan, Joseph Willis, Sanjay Sisodiya, Gregory Costain, Thomas M Werge, Franziska Degenhardt, Ina Giegling, Dan Rujescu, Stefan J Hreidarsson, Evald Saemundsen, Joo Wook Ahn, Caroline Ogilvie, Santhosh D Girirajan, Hreinn Stefansson, Kari Stefansson, Michael C O'Donovan, Michael J Owen, Anne Bassett, George Kirov
    PLoS genetics 12(5) e1005993 2016年5月  査読有り
    Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.
  • Takanobu Nakazawa, Ryota Hashimoto, Kazuto Sakoori, Yuki Sugaya, Asami Tanimura, Yuki Hashimotodani, Kazutaka Ohi, Hidenaga Yamamori, Yuka Yasuda, Satomi Umeda-Yano, Yuji Kiyama, Kohtarou Konno, Takeshi Inoue, Kazumasa Yokoyama, Takafumi Inoue, Shusuke Numata, Tohru Ohnuma, Nakao Iwata, Norio Ozaki, Hitoshi Hashimoto, Masahiko Watanabe, Toshiya Manabe, Tadashi Yamamoto, Masatoshi Takeda, Masanobu Kano
    Nature communications 7 11466-11466 2016年4月20日  査読有り
  • Shinji Sakamoto, Manabu Takaki, Yuko Okahisa, Yutaka Mizuki, Masatoshi Inagaki, Hiroshi Ujike, Toshiharu Mitsuhashi, Soshi Takao, Masashi Ikeda, Yosuke Uchitomi, Nakao Iwata, Norihito Yamada
    Journal of human genetics 61(4) 329-34 2016年4月  査読有り
    Many patients with schizophrenia have poor clinical and social outcomes. Some risk alleles closely related to the onset of schizophrenia have been reported to be associated with their clinical phenotypes, but the direct relationship between genetic vulnerability to schizophrenia and clinical/social outcomes of schizophrenia, as evaluated by both practical clinical scales and 'real-world' function, has not been investigated. We evaluated the clinical and social outcomes of 455 Japanese patients with schizophrenia by severity of illness according to the Clinical Global Impression-Severity Scale (CGI-S) and social outcomes by social adjustment/maladjustment at 5 years after the first visit. We examined whether 46 single nucleotide polymorphisms (SNPs) selected from a Japanese genome-wide association study of susceptibility to schizophrenia were associated with clinical and social outcomes. We also investigated the polygenic risk scores of 46 SNPs. Allele-wise association analysis detected three SNPs, including rs2623659 in the CUB and Sushi multiple domains-1 (CSMD1) gene, associated with severity of illness at end point. The severity of illness at end point was associated with treatment response, but not with the severity of illness at baseline. Three SNPs, including rs2294424 in the C6orf105 gene, were associated with social outcomes. Point estimates of odds ratios showed positive relationships between polygenic risk scores and clinical/social outcomes; however, the results were not statistically significant. Because these results are exploratory, we need to replicate them with a larger sample in a future study.
  • Ryoko Higashiyama, Tohru Ohnuma, Yuto Takebayashi, Ryo Hanzawa, Nobuto Shibata, Hidenaga Yamamori, Yuka Yasuda, Itaru Kushima, Branko Aleksic, Kenji Kondo, Masashi Ikeda, Ryota Hashimoto, Nakao Iwata, Norio Ozaki, Heii Arai
    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 171B(3) 447-57 2016年4月  査読有り
    Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size. Eight SNPs and 10 CNVs were investigated using Taqman SNP and CNV quantitative real-time polymerase chain reaction method. For the first-stage analysis, 513 unrelated Japanese patients with schizophrenia and 705 healthy controls were examined. For the second-stage replication study, positive findings from the first stage were further investigated using a larger sample size, namely 1,854 patients with schizophrenia and 2,137 controls. The first-stage analysis showed significant associations among schizophrenia, intronic SNP rs165774, CNV6 situated at promoter 1, CNV8 at exon 6, and CNV9 at exon 7. The second-stage study showed that intronic SNP rs165774 (χ(2)  = 8.327, P = 0.0039), CNV6 (χ(2)  = 19.66, P = 0.00005), and CNV8 (χ(2)  = 16.57, P = 0.00025) were significantly associated with schizophrenia. Large and rare CNVs as well as low-frequency CNVs and relatively small CNVs, namely <30 kb in COMT, may be genetic risk factors for schizophrenia.
  • Akihiro Mouri, Masashi Ikeda, Takenao Koseki, Nakao Iwata, Toshitaka Nabeshima
    Neuroscience letters 617 22-6 2016年3月23日  査読有り
    There is insufficient serotonergic neuronal function in the pathophysiology of major depressive disorder (MDD). Serotonin transporter (SERT) plays a critical role in terminating the function of serotoninergic neurons. SERT is linked to vulnerability to MDD and is an important target for antidepressants. The expression of SERT in lymphocytes and platelets is associated with their expression in central nervous system. Most of the clinical studies that have analyzed the role of SERT in depression have focused on absolute expression of SERT in the brain or peripheral tissue. Our study has shown that the SERT protein is ubiquitinated, which has been implicated through the SERT stability and depressive behaviors in mice. In our study, we have used lymphoblasts derived from the peripheral blood lymphocytes to quantitatively examine SERT protein expression and ubiquitination in fluvoxamine-responsive and fluvoxamine-resistant MDD patients. We found that the protein levels of SERT were higher in the fluvoxamine-resistant MDD patients. Ubiquitinated protein levels of SERT were lower in the fluvoxamine-resistant MDD patients. The proteasome inhibitor failed to increase the protein levels of SERT in both fluvoxamine-responsive and fluvoxamine-resistant MDD patients. In sum, these findings suggest that the downregulation of the ubiquitination of SERT protein induces insufficient degradation of SERT by proteasome, which resulted in the upregulation of SERT protein in fluvoxamine-resistant MDD patients. Although further studies with various populations will be required to generalize results, SERT protein expression, ubiquitination, and the responsiveness of SERT expression to proteasome inhibitor are potential biomarkers for the diagnosis of MDD and antidepressant efficacy.
  • Eiji Harada, Hirofumi Tokuoka, Shinji Fujikoshi, Jumpei Funai, Madelaine M Wohlreich, Michael H Ossipov, Nakao Iwata
    Pain 157(3) 577-584 2016年3月  査読有り
    In treating Major Depressive Disorder with associated painful physical symptoms (PPS), the effect of duloxetine on PPS has been shown to decompose into a direct effect on PPS and an indirect effect on PPS via depressive symptoms (DS) improvement. To evaluate the changes in relative contributions of the direct and indirect effects over time, we analyzed pooled data from 3 randomized double-blind studies comparing duloxetine 60 mg/d with placebo in patients with major depressive disorder and PPS. Changes from baseline in Montgomery-Åsberg Depression Rating Scale total and Brief Pain Inventory-Short Form average pain score were assessed over 8 weeks. Path analysis examined the (1) direct effect of treatment on PPS and/or indirect effect on PPS via DS improvement and (2) direct effect of treatment on DS and/or indirect effect on DS via PPS improvement. At week 1, the direct effect of duloxetine on PPS (75.3%) was greater than the indirect effect through DS improvement (24.7%) but became less (22.6%) than the indirect effect (77.4%) by week 8. Initially, the direct effect of duloxetine on PPS was markedly greater than its indirect effect, whereas later the indirect effect predominated. Conversely, at week 1, the direct effect of treatment on DS (46.4%) was less than the indirect effect (53.6%), and by week 8 it superseded (62.6%) the indirect effect (37.4%). Thus, duloxetine would relieve PPS directly in the initial phase and indirectly via improving DS in the later phase.
  • Tim B. Bigdeli, Stephan Ripke, Silviu Alin Bacanu, Sang Hong Lee, Naomi R. Wray, Pablo V. Gejman, Marcella Rietschel, Sven Cichon, David St Clair, Aiden Corvin, George Kirov, Andrew Mcquillin, Hugh Gurling, Dan Rujescu, Ole A. Andreassen, Thomas Werge, Douglas H.R. Blackwood, Carlos N. Pato, Michele T. Pato, Anil K. Malhotra, Michael C. O'Donovan, Kenneth S. Kendler, Ayman H. Fanous
    American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics 171(2) 276-289 2016年3月1日  
    © 2016 Wiley Periodicals, Inc. Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N=978), cases reporting no such family history (N=4,503), and unscreened controls (N=8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R2=0.0021; P=0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P=0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.
  • Barbara Franke, Kimm J.E. van Hulzen, Alejandro Arias-Vasquez, Janita Bralten, Martine Hoogman, Marieke Klein, Marjolein M.J. van Donkelaar, Marina M.H. Hakobjan, Angelien J.G.A.M. Heister, Remco R.R. Makkinje, Marlies A.M. Naber, Saskia S.L. van der Marel, Jeanette C. Mostert, Han G. Brunner, Hans van Bokhoven, Marcel P. Zwiers, Jan K. Buitelaar, Guillén Fernández, Simon E. Fisher, Clyde Francks, Jason L. Stein, Derrek P. Hibar, Paul M. Thompson, Stephan Ripke, Verneri Anttila, Benjamin M. Neale, Kai-How Farh, Brendan Bulik-Sullivan, Hailiang Huang, Menachem Fromer, Jacqueline I. Goldstein, Mark J. Daly, Raymond K. Walters, Jordan W. Smoller, Phil Lee, Richard A. Belliveau, Sarah E. Bergen, Elizabeth Bevilacqua, Kimberley D. Chambert, Giulio Genovese, Colm O'Dushlaine, Edward M. Scolnick, Steven A. McCarroll, Jennifer L. Moran, Aarno Palotie, Tracey L. Petryshen, Susanne Erk, Andreas Heinz, Sebastian Mohnke, Nina Romanczuk-Seiferth, Henrik Walter, Lynn E. DeLisi, Robert W. McCarley, Raquelle I. Mesholam-Gately, Larry J. Seidman, Thomas E. Nichols, Michael C. Neale, Andrew M. McIntosh, Martina Papmeyer, Emma Sprooten, Stephen M. Lawrie, Jessika E. Sussmann, Francis J. McMahon, Yin Yao, Andreas Meyer-Lindenberg, Emanuel Schwarz, Oliver Grimm, Manuel Mattheisen, Esben Agerbo, Ditte Demontis, Thomas Hansen, Ole Mors, Line Olsen, Henrik B. Rasmussen, Anders D. Børglum, Preben B. Mortensen, Thomas Werge, Ole A. Andreassen, Andrew A. Brown, Lavinia Athanasiu, Cecilie B. Hartberg, Unn Haukvik, Ingrid Melle, Oliver Gruber, Bernd Kraemer, Maria Keil, Perminder S. Sachdev, Karen A. Mather, Anbupalam Thalamuthu, Nicola J. Armstrong, Amelia A. Assareh, Henry Brodaty, Simone Reppermund, Wei Wen, Roberto Roiz-Santiañez, Rocio Perez-Iglesias, Andrew J. Saykin, Sungeun Kim, Kwangsik Nho, Shannon L. Risacher, Li Shen, Tatiana M. Foroud, Stefan Ehrlich, Johanna Hass, Esther Walton, Jessica A. Turner, Yvonne Y.W. Ho, Nicholas G. Martin, Margaret J. Wright, Miguel E. Renteria, Gabriel Cuellar-Partida, Lachlan T. Strike, Narelle K. Hansell, Grant W. Montgomery, Sarah E. Medland, Greig I. de Zubicaray, James T.R. Walters, Peter A. Holmans, Noa Carrera, Nick Craddock, Valentina Escott-Price, Lyudmila Georgieva, Marian L. Hamshere, David Kavanagh, Sophie E. Legge, Andrew J. Pocklington, Alexander L. Richards, Douglas M. Ruderfer, Nigel M. Williams, George Kirov, Michael J. Owen, Michael C. O'Donovan, Tune H. Pers, Joel N. Hirschhorn, Alkes Price, Eli A. Stahl, Tõnu Esko, Anna K. Kähler, Patrik K.E. Magnusson, Christina M. Hultman, Patrick F. Sullivan, James J. Crowley, Martilias S. Farrell, Paola Giusti-Rodríguez, Yunjung Kim, Jin P. Szatkiewicz, Stephanie Williams, Diana O. Perkins, Aiden Corvin, Paul Cormican, Gary Donohoe, Derek W. Morris, Michael Gill, Emma J. Rose, Margaret Needham, David A. Collier, Ingrid Agartz, Srdjan Djurovic, Morten Mattingsdal, Erik G. Jönsson, Erik Söderman, Margot Albus, Madeline Alexander, Claudine Laurent, Douglas F. Levinson, Farooq Amin, Silviu A. Bacanu, Tim B. Bigdeli, Mark A. Reimers, Bradley T. Webb, Aaron R. Wolen, Brandon K. Wormley, Kenneth S. Kendler, Brien P. Riley, Martin Begemann, Christian Hammer, Sergi Papiol, Hannelore Ehrenreich, Judit Bene, Bela Melegh, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, Joshua L. Roffman, Avram J. Holmes, Randy L. Gollub, William F. Byerley, Wiepke Cahn, René S. Kahn, Eric Strengman, Roel A. Ophoff, Guiqing Cai, Kenneth L. Davis, Elodie Drapeau, Joseph I. Friedman, Vahram Haroutunian, Elena Parkhomenko, Abraham Reichenberg, Jeremy M. Silverman, Joseph D. Buxbaum, Murray J. Cairns, Vaughan J. Carr, Stanley V. Catts, Frans A. Henskens, Carmel M. Loughland, Patricia T. Michie, Christos Pantelis, Ulrich Schall, Rodney J. Scott, Paul A. Tooney, Jing Qin Wu, Assen V. Jablensky, Brian J. Kelly, Dominique Campion, Rita M. Cantor, Raymond C.K. Chan, Eric Y.H. Chen, Miaoxin Li, Pak C. Sham, Ronald Y.L. Chen, Hon-Cheong So, Emily H.M. Wong, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, Jimmy Lee Chee Keong, Kang Sim, Mythily Subramaniam, C. Robert Cloninger, Dragan M. Svrakic, David Cohen, Nadine Cohen, Benedicto Crespo-Facorro, David Curtis, Jonathan Pimm, Hugh Gurling, Andrew McQuillin, Michael Davidson, Mark Weiser, Franziska Degenhardt, Stefan L. Herms, Per Hoffmann, Andrea Hofman, Sven Cichon, Markus M. Nöthen, Jurgen Del Favero, Dimitris Dikeos, George N. Papadimitriou, Timothy Dinan, Jubao Duan, Alan R. Sanders, Pablo V. Gejman, Frank Dudbridge, Peter Eichhammer, Johan Eriksson, Veikko Salomaa, Laurent Essioux, Ayman H. Fanous, Josef Frank, Thomas G. Schulze, Stephanie H. Witt, Marcella Rietschel, Lude Franke, Juha Karjalainen, Robert Freedman, Ann Olincy, Nelson B. Freimer, Elliot S. Gershon, Ina Giegling, Annette M. Hartmann, Bettina Konte, Dan Rujescu, Stephanie Godard, Srihari Gopal, Dai Wang, Qingqin S. Li, Jacob Gratten, S. Hong Lee, Naomi R. Wray, Peter M. Visscher, Lieuwe de Haan, Carin J. Meijer, Mark Hansen, Pamela Sklar, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Nakao Iwata, Inge Joa, Antonio Julià, Sara Marsal, Luba Kalaydjieva, Sena Karachanak-Yankova, Matthew C. Keller, James L. Kennedy, Clement C. Zai, Jo Knight, Andrey Khrunin, Svetlana Limborska, Petr Slominsky, Janis Klovins, Liene Nikitina-Zake, James A. Knowles, Michele T. Pato, Carlos N. Pato, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Bernard Lerer, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, T. Scott Stroup, Jouko Lönnqvist, Jaana Suvisaari, Jan Lubinski, Milan Macek Jr, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Colm McDonald, Sandra Meier, Jana Strohmaier, Andres Metspalu, Lili Milani, Mari Nelis, Vihra Milanova, Younes Mokrab, Bertram Müller-Myhsok, Kieran C. Murphy, Robin M. Murray, John Powell, Inez Myin-Germeys, Jim Van Os, Igor Nenadic, Deborah A. Nertney, Bryan J. Mowry, Gerald Nestadt, Ann E. Pulver, Kristin K. Nicodemus, Laura Nisenbaum, Annelie Nordin, Rolf Adolfsson, Eadbhard O'Callaghan, F. Anthony O'Neill, Sang-Yun Oh, Tiina Paunio, Olli Pietiläinen, Shaun M. Purcell, Panos Roussos, Digby Quested, Simon Lovestone, Christian R. Schubert, Jens R. Wendland, Knut Schnell, Sibylle G. Schwab, Jianxin Shi, Psychosis Endophenotypes International Consortium, Chris C.A. Spencer, Elisabeth Stogmann, Fritz Zimprich, Richard E. Straub, Daniel R. Weinberger, Qiang Chen, Aaron L. Goldman, Venkata S. Mattay, Srinivas Thirumalai, Draga Toncheva, Juha Veijola, John Waddington, Dermot Walsh, Qiang Wang, Dieter B. Wildenauer, Hualin Simon Xi, Xuebin Zheng, Jianjun Liu, Douglas H.R. Blackwood, Elvira Bramon, Thomas W. Mühleisen, Ariel Darvasi, Enrico Domenici, Todd Lencz, Anil K. Malhotra, Danielle Posthuma, David St Clair, Sylvane Desrivières, Tianye Jia, Christine Macare, Gunter Schumann, Neda Jahanshad, Christopher R.K. Ching, Roberto Toro, Katharina Wittfeld, Wolfgang Hoffmann, Deborah Janowitz, Hans J. Grabe, Lucija Abramovic, Marc M. Bohlken, Marco P. Boks, Kristel R. van Eijk, Neeltje E.M. van Haren, Rachel M. Brouwer, Hilleke E. Hulshoff Pol, Micael Andersson, Alireza Salami, Lars G. Nilsson, Lars Nyberg, Benjamin S. Aribisala, Natalie A. Royle, Mark E. Bastin, Joanna M. Wardlaw, Manon Bernard, Jean Shin, Zdenka Pausova, M. Mallar Chakravarty, Anouk den Braber, Iryna O. Fedko, Jouke-Jan Hottenga, Dennis van 't Ent, Dorret I. Boomsma, Eco J.C. de Geus, Sudheer Giddaluru, Vidar M. Steen, Stephanie LeHellard, Tulio Guadalupe, Girma Woldehawariat, Allison C. Nugent, Xinmin Liu, Wayne C. Drevets, Dara M. Cannon, Loes M. Olde Loohuis, Michelle Luciano, David C.M. Liewald, Lorna M. Lopez, Ian J. Deary, Yuri Milaneschi, Lianne Schmaal, Dick J. Veltman, Brenda W.J.H. Penninx, Adaikalavan Ramasamy, Mina Ryten, Michael E. Weale, Daniah Trabzuni, Raphael Gibbs, Sebastian Guelfi, Dena G. Hernandez, John Hardy, Philipp G. Sämann, David Höhn, Benno Pütz, Christiane Wolf, Michael Czisch, Florian Holsboer, Andrew J. Schork, Alexander Teumer, Henry Völzke, Lars T. Westlye, Thomas Espeseth, Ivar Reinvang, Christopher D. Whelan, Saud Alhusaini, Gianpiero L. Cavalleri, Norman Delanty, Anderson M. Winkler, Dalia Kasperaviciute, Mar Matarin, Sanjay M. Sisodiya, David R. McKay, David C. Glahn, Laura Almasy, Melanie A. Carless, Joanne E. Curran, Ravi Duggirala, Thomas D. Dyer, Harald H.H. Göring, Jack W. Kent, John Blangero, David Ames, Sampath Arepalli, Allissa Dillman, Michael A. Nalls, Bryan Traynor, Mark R. Cookson, Andrew Singleton, Maria C. Valdés Hernández, Kazima B. Bulayeva, Luigi Ferrucci, Peter T. Fox, Rene L. Olvera, Masaki Fukunaga, Robert C. Green, Catharina A. Hartman, Pieter J. Hoekstra, Katrin Hegenscheid, Norbert Hosten, Dirk J. Heslenfeld, Georg Homuth, Clifford R. Jack, Mark Jenkinson, Robert Johnson, Ronald H. Zielke, Ryota Kanai, Peter Kochunov, John B. Kwok, Peter R. Schofield, Dan L. Longo, Katie L. McMahon, Eva Meisenzahl, Kazutaka Ohi, G. Bruce Pike, Steven G. Potkin, Glenn D. Rosen, Colin Smith, Arthur W. Toga, Juan Troncoso, Marcel van der Bruggeman, Nic J.A. van der Wee, Marie-Jose van Tol, Thomas H. Wassink, Eric Westman, Alan Zonderman, David G. Ashbrook, Reinmar Hager, Lu Lu, Robert W. Williams, Vince D. Calhoun, Anders M. Dale, Gareth E. Davies, Chantal Depondt, Massimo Pandolfo, Beng-Choon Ho, Matthias Nauck, Michael W. Weiner, Tonya White, Hieab H.H. Adams, M. Arfan Ikram, Ryota Hashimoto, Iwona Kloszewska, Patrizia Mecocci, Tomas Paus, Andy Simmons, Hilkka Soininen, Sven J. van der Lee, Cornelia M. van Duijn, Lenore J. Launer, Stephan Seiler, Reinhold Schmidt, Ganesh Chauhan, Claudia L. Satizabal, Sudha Seshadri, James T. Becker, Lisa Yanek, Maritza Ebling, Bruce Fischl, Douglas Greve, Louis N. Vinke, W. T. Longstreth, Helena Schmidt, Paul Nyquist, Xue Luting, Bernard Mazoyer, Joshua C. Bis, Vilmundur Gudnason, Jimmy Lee Chee Keong, M. Mallar Chakravarty, G. Bruce Pike, Marcel van der Brug, M. Arfan Ikram
    Nature Neuroscience 19(3) 420-431 2016年2月23日  査読有り
    Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.
  • Aswin Sekar, Allison R Bialas, Heather de Rivera, Avery Davis, Timothy R Hammond, Nolan Kamitaki, Katherine Tooley, Jessy Presumey, Matthew Baum, Vanessa Van Doren, Giulio Genovese, Samuel A Rose, Robert E Handsaker, Mark J Daly, Michael C Carroll, Beth Stevens, Steven A McCarroll
    Nature 530(7589) 177-83 2016年2月11日  
    Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
  • Takanobu Nakazawa, Ryota Hashimoto, Kazuto Sakoori, Yuki Sugaya, Asami Tanimura, Yuki Hashimotodani, Kazutaka Ohi, Hidenaga Yamamori, Yuka Yasuda, Satomi Umeda-Yano, Yuji Kiyama, Kohtarou Konno, Takeshi Inoue, Kazumasa Yokoyama, Takafumi Inoue, Shusuke Numata, Tohru Ohnuma, Nakao Iwata, Norio Ozaki, Hitoshi Hashimoto, Masahiko Watanabe, Toshiya Manabe, Tadashi Yamamoto, Masatoshi Takeda, Masanobu Kano
    Nature communications 7 10594-10594 2016年2月3日  査読有り
    Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.
  • 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 13-8 2016年1月30日  査読有り
    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 (NWD1 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.
  • Ichiro Yasue, Shinji Matsunaga, Taro Kishi, Kiyoshi Fujita, Nakao Iwata
    Journal of Alzheimer's disease : JAD 50(3) 733-40 2016年  査読有り
    BACKGROUND: There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT2A) receptor negative modulators for Parkinson's disease psychosis (PDP). OBJECTIVE: This is the first meta-analysis of randomized placebo-controlled trials (RCTs) testing negative modulators of the 5-HT2A receptor as a treatment for PDP. METHODS: The primary outcome was the Scale for Assessment of Positive Symptoms (SAPS)-hallucinations (H) and -delusions (D) scores (SAPS-H+D). Other outcome measures were SAPS-H, SAPS-D, the Unified Parkinson's Disease Rating Scale Part II and III (UPDRS-II+III), discontinuation rates, and individual adverse events. RESULTS: Four RCTs were identified that met inclusion criteria, all assessing the 5-HT2A inverse agonist pimavanserin (including 417 drug-treated and 263 placebo-treated PDP patients). Pimavanserin significantly decreased SAPS-H+D scores compared to placebo [weighted mean differences (WMD) = -2.26, 95% confidence interval (95% CI) = -3.86 to -0.67, p = 0.005, I2 = 30% , N = 4 studies, n = 502 patients]. Moreover, pimavanserin was superior to placebo for reducing SAPS-H (WMD = -2.15, 95% CI = -3.45 to -0.86, p = 0.001, I2 = 0% , N = 2, n = 237) and SAPS-D scores (WMD = -1.32, 95% CI = -2.32 to -0.32, p = 0.010, I2 = 0% , N = 2, n = 237). Pimavanserin was associated with less orthostatic hypotension than placebo (risk ratio = 0.33, 95% CI = 0.15-0.75, p = 0.008, I2 = 0% , number needed to harm = 17, p = 0.01, N = 3, n = 476). There were no significant differences in rates of all-cause discontinuation, adverse events, and death, UPDRS-II+III scores, and incidences of individual adverse events (other than orthostatic hypotension) between pimavanserin and placebo groups. CONCLUSIONS: Pooled RCT results suggest that pimavanserin is beneficial for the treatment of PDP and is well tolerated. We did not identify other negative modulators of the 5-HT2A receptor for the treatment of PDP.
  • Masashi Ikeda, Ayu Shimasaki, Atsushi Takahashi, Kenji Kondo, Takeo Saito, Kohei Kawase, Kosei Esaki, Yasuyo Otsuka, Keiko Mano, Michiaki Kubo, Nakao Iwata
    The Journal of clinical psychiatry 77(1) e29-30-+ 2016年1月  査読有り
  • Issei Ueda, Shingo Kakeda, Keita Watanabe, Reiji Yoshimura, Taro Kishi, Osamu Abe, Satoru Ide, Junji Moriya, Asuka Katsuki, Hikaru Hori, Nakao Iwata, Jun Nakamura, Yukunori Korogi
    PloS one 11(3) e0150712 2016年  査読有り
    BACKGROUND: Earlier studies implicated norepinephrine transporter (NET) gene (SLC6A2) polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide SLC6A2 polymorphisms, G1287A in exon 9 and T-182C in the promoter region, were found to be associated with MDD in different populations. We investigated the relationship between the brain volume and these two polymorphisms of the SLC6A2 in MDD patients. METHODS: We obtained 3D high-resolution T1-weighted images of 30 first-episode MDD patients and 48 age- and sex-matched healthy subjects (HS). All were divided into 4 groups based on polymorphism of either the G1287A or the T-182C genotype. VBM analysis examined the effects of diagnosis, genotype, and genotype-diagnosis interactions. RESULTS: Diagnosis effects on the brain morphology were found in the left superior temporal cortex. No significant genotype effects were found in the T-182C and the G1287A. A significant genotype (G1287A)-diagnosis interaction was found in the left dorsolateral prefrontal cortex. No significant genotype (T-182C)-diagnosis interaction effects were observed in any brain region. CONCLUSIONS: In MDD patients there seems to be a relationship between the volume of the dorsolateral prefrontal cortex and polymorphism of the SLC6A2 G1287A gene.
  • Yuichi Esaki, Tsuyoshi Kitajima, Yasuhiro Ito, Shigefumi Koike, Yasumi Nakao, Akiko Tsuchiya, Marina Hirose, Nakao Iwata
    Chronobiology international 33(8) 1037-44 2016年  査読有り
    It has been recently discovered that blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We investigated the effect of blue light-blocking glasses in subjects with delayed sleep phase disorder (DSPD). This open-label trial was conducted over 4 consecutive weeks. The DSPD patients were instructed to wear blue light-blocking amber glasses from 21:00 p.m. to bedtime, every evening for 2 weeks. To ascertain the outcome of this intervention, we measured dim light melatonin onset (DLMO) and actigraphic sleep data at baseline and after the treatment. Nine consecutive DSPD patients participated in this study. Most subjects could complete the treatment with the exception of one patient who hoped for changing to drug therapy before the treatment was completed. The patients who used amber lens showed an advance of 78 min in DLMO value, although the change was not statistically significant (p = 0.145). Nevertheless, the sleep onset time measured by actigraph was advanced by 132 min after the treatment (p = 0.034). These data suggest that wearing amber lenses may be an effective and safe intervention for the patients with DSPD. These findings also warrant replication in a larger patient cohort with controlled observations.
  • Taro Kishi, Yuki Matsuda, Shinji Matsunaga, Tomohiko Mukai, Masatsugu Moriwaki, Hideaki Tabuse, Kiyoshi Fujita, Nakao Iwata
    Neuropsychiatric disease and treatment 12 3041-3049 2016年  査読有り
    OBJECTIVE: There has been no direct comparison of aripiprazole and blonanserin for schizophrenia treatment. We conducted a 24-week, rater-masked, randomized trial of aripiprazole (6-30 mg/d) vs blonanserin (4-24 mg/d) in schizophrenia patients who were not taking any antipsychotic medication for more than 2 weeks before enrollment (UMIN000011194). METHODS: The primary outcome measure for efficacy was improvement of Positive and Negative Syndrome Scale (PANSS) total score at week 24. Secondary outcomes were PANSS subscale scores, 21-item Hamilton Rating Scale for Depression (HAMD-21) score, response rate, discontinuation rate, and individual adverse events. RESULTS: Forty-four patients were recruited. The discontinuation rate was 86.4% in the aripiprazole group and 68.2% in the blonanserin treatment group. There was no significant difference in mean time to discontinuation between the groups. Although both treatment groups showed significant reductions in the PANSS total score, PANSS subscale scores, and HAMD-21 scores at week 24, the magnitudes of the changes did not differ between the groups. There were no significant differences in the incidences of adverse events including somnolence, extrapyramidal symptoms, prolactin-related adverse events, and weight change between the groups. CONCLUSION: Our results suggest similar efficacy and safety profiles of aripiprazole and blonanserin in the patients with schizophrenia. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole and blonanserin in schizophrenia.
  • Yuji Okuyama, Kazuto Oya, Shinji Matsunaga, Taro Kishi, Nakao Iwata
    Neuropsychiatric disease and treatment 12 3221-3236 2016年  査読有り
    This study aimed to perform a comprehensive meta-analysis of topiramate-augmentation therapy in patients with schizophrenia receiving antipsychotic agents. Data published up to June 20, 2016 were obtained from the PubMed, PsycINFO, and Cochrane Library databases. Twelve randomized controlled trials comparing topiramate to placebo or antipsychotic only were included (n=676 patients). The primary outcome was change in overall symptoms. Relative risk (RR) and standardized mean difference (SMD), along with 95% confidence intervals, were calculated using random effects model for each outcome. Topiramate-augmentation therapy was superior to the control for decreasing overall symptoms (SMD -0.55, 95% confidence interval -0.86 to -0.24; P=0.001; I2=55%, eight comparisons, n=380), positive symptoms (SMD -0.4), negative symptoms (SMD -0.47), and Positive and Negative Syndrome Scale general subscale scores (SMD -0.67). Furthermore, topiramate-augmentation therapy decreased weight (SMD -0.69) and body mass index (SMD -0.95) compared with the control. Topiramate was similar to the control with respect to discontinuation due to all causes (RR 1.19), inefficacy (RR 1.71), and adverse events (RR 1.09). Topiramate was associated with higher incidence of paresthesia (RR 2.67) and attention difficulty (RR 8.97) compared with the control. Our results seemed to suggest that topiramate-augmentation therapy improves the psychopathology of schizophrenia with good tolerability and has the additional advantage of weight maintenance. However, because there were some limitations (numbers of studies and patients included in the meta-analysis were small, some studies used completer analysis, Chinese studies were included in the meta-analysis, and studies that had a risk of bias were included in the meta-analysis) in this study, we cannot apply the results of this study in daily clinical practice.
  • Yuji Okuyama, Kazuto Oya, Shinji Matsunaga, Taro Kishi, Nakao Iwata
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 12 3221-3236 2016年  査読有り
    This study aimed to perform a comprehensive meta-analysis of topiramate-augmentation therapy in patients with schizophrenia receiving antipsychotic agents. Data published up to June 20, 2016 were obtained from the PubMed, PsycINFO, and Cochrane Library databases. Twelve randomized controlled trials comparing topiramate to placebo or antipsychotic only were included (n=676 patients). The primary outcome was change in overall symptoms. Relative risk (RR) and standardized mean difference (SMD), along with 95% confidence intervals, were calculated using random effects model for each outcome. Topiramate-augmentation therapy was superior to the control for decreasing overall symptoms (SMD -0.55, 95% confidence interval -0.86 to -0.24; P= 0.001; I-2 = 55%, eight comparisons, n= 380), positive symptoms (SMD -0.4), negative symptoms (SMD -0.47), and Positive and Negative Syndrome Scale general subscale scores (SMD -0.67). Furthermore, topiramate-augmentation therapy decreased weight (SMD -0.69) and body mass index (SMD -0.95) compared with the control. Topiramate was similar to the control with respect to discontinuation due to all causes (RR 1.19), inefficacy (RR 1.71), and adverse events (RR 1.09). Topiramate was associated with higher incidence of paresthesia (RR 2.67) and attention difficulty (RR 8.97) compared with the control. Our results seemed to suggest that topiramate-augmentation therapy improves the psychopathology of schizophrenia with good tolerability and has the additional advantage of weight maintenance. However, because there were some limitations (numbers of studies and patients included in the meta-analysis were small, some studies used completer analysis, Chinese studies were included in the meta-analysis, and studies that had a risk of bias were included in the meta-analysis) in this study, we cannot apply the results of this study in daily clinical practice.
  • Taro Kishi, Yuki Matsuda, Shinji Matsunaga, Tomohiko Mukai, Masatsugu Moriwaki, Hideaki Tabuse, Kiyoshi Fujita, Nakao Iwata
    NEUROPSYCHIATRIC DISEASE AND TREATMENT 12 3041-3049 2016年  査読有り
    Objective: There has been no direct comparison of aripiprazole and blonanserin for schizophrenia treatment. We conducted a 24-week, rater-masked, randomized trial of aripiprazole (6-30 mg/d) vs blonanserin (4-24 mg/d) in schizophrenia patients who were not taking any antipsychotic medication for more than 2 weeks before enrollment (UMIN000011194). Methods: The primary outcome measure for efficacy was improvement of Positive and Negative Syndrome Scale (PANSS) total score at week 24. Secondary outcomes were PANSS subscale scores, 21-item Hamilton Rating Scale for Depression (HAMD-21) score, response rate, discontinuation rate, and individual adverse events. Results: Forty-four patients were recruited. The discontinuation rate was 86.4% in the aripiprazole group and 68.2% in the blonanserin treatment group. There was no significant difference in mean time to discontinuation between the groups. Although both treatment groups showed significant reductions in the PANSS total score, PANSS subscale scores, and HAMD-21 scores at week 24, the magnitudes of the changes did not differ between the groups. There were no significant differences in the incidences of adverse events including somnolence, extrapyramidal symptoms, prolactin-related adverse events, and weight change between the groups. Conclusion: Our results suggest similar efficacy and safety profiles of aripiprazole and blonanserin in the patients with schizophrenia. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole and blonanserin in schizophrenia.
  • Hiroki Kimura, Satoshi Tanaka, Itaru Kushima, Takayoshi Koide, Masahiro Banno, Tsutomu Kikuchi, Yukako Nakamura, Tomoko Shiino, Akira Yoshimi, Tomoko Oya-Ito, Jingrui Xing, Chenyao Wang, Yuto Takasaki, Branko Aleksic, Takashi Okada, Masashi Ikeda, Toshiya Inada, Tetsuya Iidaka, Nakao Iwata, Norio Ozaki
    Scientific reports 5 15705-15705 2015年10月23日  査読有り
    B-cell CLL/lymphoma 9 (BCL9) is located within the schizophrenia (SCZ) suspected locus chr1q21.1. A recent study reported that a single nucleotide polyphormism (SNP) within BCL9 (rs583583) is associated with negative symptoms of Schizophrenia, as measured by the Positive and Negative Syndrome Scale (PANSS), in the Caucasian population. We therefore investigated genetic association of rs583583, and its effect on negative symptoms in the Japanese patients. For association analysis, we used a Japanese sample set comprising 1089 SCZ and 950 controls (CON). Analysis of the effect of rs586586 on negative symptoms as examined by PANSS was investigated using 280 SCZ. Furthermore, for analysis of cognitive performance, we investigated 90 SCZ and 51 CON using the Continuous Performance Test (CPT-IP) and the Wisconsin Card Sorting Test (WCST) Keio version. We did not detect association between rs583583 and SCZ. Furthermore, rs583583 was not associated with PANSS negative scores or with CPT-IT or WCST cognitive tests. Considering the results of our previous study, combined with the results of the current study of rs583583, we argue that BCL9 most likely does not harbor a common genetic variant that can increase the risk for SCZ in the Japanese population.
  • Taro Kishi, Shinji Matsunaga, Nakao Iwata
    Journal of psychiatric research 68 198-209 2015年9月  査読有り
    We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs) of intramuscular (IM)-olanzapine (OLA-IM) versus controls in agitated patients. The risk ratio, number-needed-to-treat/harm, and standardized mean difference based on a random effects model were calculated. We identified 13 RCTs (19 comparisons) as follows: 7 comparisons with 1059 patients for OLA-IM versus placebo; 5 comparisons with 613 patients for OLA-IM versus haloperidol (HAL)-IM; 2 comparisons with 108 patients for OLA-IM versus ziprasidone (ZIP)-IM; 2 comparisons with 110 patients for OLA-IM versus HAL-IM plus midazolam; and 3 comparisons with 412 patients for OLA-IM versus HAL-IM plus promethazine, 2 comparisons with 355 patients for OLA-IM versus lorazepam-IM (LOR-IM); and 1 comparison with 67 patients for OLA-IM versus HAL-IM plus LOR-IM. OLA-IM was superior to placebo in both Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) and Agitation-Calmness Evaluation Scale (ACES) scores 2 h after first injection, and had a comparable side effect profile, including over sedation, extrapyramidal symptoms, akathisia, and anticholinergic use. While there was no significant difference in PANSS-EC scores after 2 h between OLA-IM and HAL-IM, OLA-IM outperformed HAL-IM in ACES after 2 h. Compared with HAL-IM, OLA-IM was associated with fewer side effects, including anticholinergic use, akathisia, extrapyramidal symptoms, and dystonia, and marginally less QT prolongation compared with HAL-IM. Based on our findings, OLA-IM is preferable to HAL-IM for the treatment of agitated patients. However, comparator data for ZIP-IM, LOR-IM and HAL-IM combination therapy were insufficient.
  • Satoru Ide, Shingo Kakeda, Keita Watanabe, Reiji Yoshimura, Osamu Abe, Kenji Hayashi, Issei Ueda, Taro Kishi, Asuka Katsuki, Wakako Umene-Nakano, Nakao Iwata, Jun Nakamura, Yukunori Korogi
    Psychiatry research 233(2) 120-4 2015年8月30日  査読有り
    The brain-derived neurotrophic factor (BDNF) relates to basic neuronal functions, such as cell survival, axonal outgrowth, and dendritic growth. The Val66Met polymorphism of the BDNF gene may affect genetic susceptibility to major depressive disorder (MDD). We prospectively investigated the relationship between the Val66Met BDNF genotype and voxel-based morphometry (VBM) findings for first episode and drug-naïve MDD patients and healthy subjects (HS). Participants comprised 38 MDD patients and 42 age- and sex-matched HS were divided into groups based on their BDNF genotype. The effects of diagnosis and genotype, as well as the genotype-diagnosis interaction, in relation to brain morphology were evaluated using a voxel-by-voxel statistical analysis of high-resolution magnetic resonance imaging (MRI) findings. Among the Met-carriers, the volume of the left middle frontal gyrus (composition of the prefrontal cortex [PFC]) was significantly smaller for MDD patients than for the HS, i.e., there was a significant genotype-diagnosis interaction effect on brain morphology noted in the left PFC. The BDNF polymorphism was associated with atrophy of the PFC in MDD patients, which suggests that the BDNF Val66Met polymorphism may play an important role in the pathogenesis of early stages of MDD.

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