研究者業績
  1. 研究者検索結果一覧
  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, Toshikazu Ikuta, Kenji Sakuma, Masakazu Hatano, Yuki Matsuda, Jonas Wilkening, Roberto Goya-Maldonado, Martin Tik, Nolan R Williams, Shinsuke Kito, Nakao Iwata
    Molecular psychiatry 2024年6月6日  
    In clinical practice, theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial magnetic stimulation (rTMS), as it allows for the delivery of more stimuli in less time and at similar intensities. To date, accelerated treatment plans according to various continuous (cTBS) and intermittent TBS (iTBS) protocols for depression have been proposed. To investigate which of the TBS protocols provided a favorable risk-benefit balance for individuals with depression, this systematic review and random-effects model network meta-analysis was conducted. The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence of switch to mania, and incidence of headache/discomfort at treatment site. In this meta-analysis, a total of 23 randomized controlled trials (n = 960, mean age = 41.88 years, with 60.78% females) were included. Approximately 69.57% of the trials included individuals with an exclusive diagnosis of major depressive disorder. The following six TBS protocols (target) were evaluated: cTBS (right-dorsolateral prefrontal cortex [R-DLPFC]), cTBS (R-DLPFC) + iTBS (left-DLPFC [L-DLPFC]), iTBS (L-DLPFC), iTBS (L-DLPFC) + iTBS (R-DLPFC), iTBS (left-dorsomedial prefrontal cortex) + iTBS (right-dorsomedial prefrontal cortex), and iTBS (occipital lobe). Compared to sham, cTBS (R-DLPFC) + iTBS (L-DLPFC), iTBS (L-DLPFC), and iTBS (occipital lobe) had a higher response rate (k = 23); cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) dominated in the depression symptom improvement (k = 23); and iTBS (L-DLPFC) had a higher remission rate (k = 15). No significant differences were found for all-cause discontinuation rate (k = 17), incidence of switch to mania (k = 7), and incidence of headache/discomfort at treatment site (k = 10) between any TBS protocols and sham. Thus, cTBS (R-DLPFC) + iTBS (L-DLPFC) and iTBS (L-DLPFC) demonstrate favorable risk-benefit balance for the treatment of depression.
  • Yupeng He, Kenji Sakuma, Taro Kishi, Yuanying Li, Masaaki Matsunaga, Shinichi Tanihara, Nakao Iwata, Atsuhiko Ota
    Journal of Clinical Medicine 13(10) 2970-2970 2024年5月17日  
    Background and Objective: Excellent generalizability is the precondition for the widespread practical implementation of machine learning models. In our previous study, we developed the schizophrenia classification model (SZ classifier) to identify potential schizophrenia patients in the Japanese population. The SZ classifier has exhibited impressive performance during internal validation. However, ensuring the robustness and generalizability of the SZ classifier requires external validation across independent sample sets. In this study, we aimed to present an external validation of the SZ classifier using outpatient data. Methods: The SZ classifier was trained by using online survey data, which incorporate demographic, health-related, and social comorbidity features. External validation was conducted using an outpatient sample set which is independent from the sample set during the model development phase. The model performance was assessed based on the sensitivity and misclassification rates for schizophrenia, bipolar disorder, and major depression patients. Results: The SZ classifier demonstrated a sensitivity of 0.75 when applied to schizophrenia patients. The misclassification rates were 59% and 55% for bipolar disorder and major depression patients, respectively. Conclusions: The SZ classifier currently encounters challenges in accurately determining the presence or absence of schizophrenia at the individual level. Prior to widespread practical implementation, enhancements are necessary to bolster the accuracy and diminish the misclassification rates. Despite the current limitations of the model, such as poor specificity for certain psychiatric disorders, there is potential for improvement if including multiple types of psychiatric disorders during model development.
  • Taro Kishi, Kenji Sakuma, Takeo Saito, Atsuo Nakagawa, Masaki Kato, Nakao Iwata
    Neuropsychopharmacology Reports 44(1) 165-175 2024年3月  
    Aim: This systematic review and frequentist network meta-analysis used random-effects models is conducted to determine whether there are differences in the efficacy, acceptability, tolerability, and safety profiles of brexpiprazole (BRE) and aripiprazole (ARI) for Japanese with major depressive disorder (MDD) who were inadequately responsive to antidepressants. Methods: Outcome measures were scores on the Montgomery Åsberg Depression Rating Scale (primary), the Clinical Global Impression severity scale, and social functioning scale; the non-response rate; the non-remission rate; all-cause discontinuation; discontinuation due to adverse events (DAE); at least one adverse event (1AE); serious adverse event, akathisia; tremor; weight gain. Results: A literature search identified three double-blind, randomized, placebo-controlled trials. These comprised one BRE study (with a 1 mg/day [BRE1] and a 2 mg/day [BRE2]) and two ARI studies (with a 3 mg/day arm and a flexible-dose arm[within the dosage range approved in Japan]) (n = 1736). Both BRE and ARI demonstrated better efficacy than the placebo. BRE but not ARI had a higher DAE than the placebo. ARI but not BRE had a higher 1AE than the placebo. BRE and ARI had a higher risk of akathisia and weight gain than the placebo. There were no significant differences between BRE and ARI for any of the outcomes. Although BRE1 had good efficacy, it carried risk of weight gain. Although BRE2 also had efficacy, it carried risks of DAE, akathisia, and weight gain. However, the risk of akathisia in BRE2 was reduced by an initial dose of 0.5 mg/day rather than 1.0 mg/day. Conclusions: Overall BRE showed similar utility to ARI and a good risk–benefit balance.
  • Taro Kishi, Kenji Sakuma, Masakazu Hatano, Takenori Okumura, Masaki Kato, Hajime Baba, Nakao Iwata
    Neuropsychopharmacology reports 2024年2月6日  
    AIM: To update the major depressive disorder (MDD) treatment guidelines of the Japanese Society of Mood Disorders, we conducted a systematic review and pairwise meta-analysis of double-blind, randomized, placebo-controlled trials of available antidepressants in Japan for older adults with MDD. METHODS: Outcome measures included response rate (primary), improvement in depressive symptom scale score, remission rate, all-cause discontinuation, discontinuation due to adverse events, and at least one adverse event. A random-effects model was used to calculate the risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (95% CI). RESULTS: Nine double-blind, randomized, placebo-controlled trials (n = 2145) were identified. No study has been conducted in Japan. Our meta-analysis included the following antidepressants: duloxetine, escitalopram, imipramine, sertraline, venlafaxine, and vortioxetine. Antidepressants have significantly higher response rates than placebo (RR [95% CI] = 1.38 [1.04, 1.83], p = 0.02). Antidepressants outperformed placebo in terms of improving depressive symptom scale score (SMD [95% CI] = -0.62 [-0.92, -0.33], p < 0.0001). However, antidepressants were associated with a higher discontinuation rate due to adverse events (RR [95% CI] = 1.94 [1.30, 2.88], p = 0.001) and a higher incidence of at least one adverse event (RR [95% CI] = 1.11 [1.02, 1.21], p = 0.02) compared to placebo. The groups did not differ significantly in terms of remission rate or all-cause discontinuation. CONCLUSIONS: Our meta-analysis concluded that treatment with antidepressants available in Japan is only weakly recommended for moderate to severe MDD in older adults.
  • Taro Kishi, Toshikazu Ikuta, Kenji Sakuma, Masakazu Hatano, Yuki Matsuda, Satoru Esumi, Nobumi Miyake, Itaru Miura, Masaki Kato, Nakao Iwata
    Psychiatry and clinical neurosciences 2023年11月20日  
  • Yupeng He, Masaaki Matsunaga, Yuanying Li, Taro Kishi, Shinichi Tanihara, Nakao Iwata, Takahiro Tabuchi, Atsuhiko Ota
    JMIR Formative Research 7 e50193-e50193 2023年11月15日  
    Background In Japan, challenges were reported in accurately estimating the prevalence of schizophrenia among the general population. Retrieving previous studies, we investigated that patients with schizophrenia were more likely to experience poor subjective well-being and various physical, psychiatric, and social comorbidities. These factors might have great potential for precisely classifying schizophrenia cases in order to estimate the prevalence. Machine learning has shown a positive impact on many fields, including epidemiology, due to its high-precision modeling capability. It has been applied in research on mental disorders. However, few studies have applied machine learning technology to the precise classification of schizophrenia cases by variables of demographic and health-related backgrounds, especially using large-scale web-based surveys. Objective The aim of the study is to construct an artificial neural network (ANN) model that can accurately classify schizophrenia cases from large-scale Japanese web-based survey data and to verify the generalizability of the model. Methods Data were obtained from a large Japanese internet research pooled panel (Rakuten Insight, Inc) in 2021. A total of 223 individuals, aged 20-75 years, having schizophrenia, and 1776 healthy controls were included. Answers to the questions in a web-based survey were formatted as 1 response variable (self-report diagnosed with schizophrenia) and multiple feature variables (demographic, health-related backgrounds, physical comorbidities, psychiatric comorbidities, and social comorbidities). An ANN was applied to construct a model for classifying schizophrenia cases. Logistic regression (LR) was used as a reference. The performances of the models and algorithms were then compared. Results The model trained by the ANN performed better than LR in terms of area under the receiver operating characteristic curve (0.86 vs 0.78), accuracy (0.93 vs 0.91), and specificity (0.96 vs 0.94), while the model trained by LR showed better sensitivity (0.63 vs 0.56). Comparing the performances of the ANN and LR, the ANN was better in terms of area under the receiver operating characteristic curve (bootstrapping: 0.847 vs 0.773 and cross-validation: 0.81 vs 0.72), while LR performed better in terms of accuracy (0.894 vs 0.856). Sleep medication use, age, household income, and employment type were the top 4 variables in terms of importance. Conclusions This study constructed an ANN model to classify schizophrenia cases using web-based survey data. Our model showed a high internal validity. The findings are expected to provide evidence for estimating the prevalence of schizophrenia in the Japanese population and informing future epidemiological studies.
  • Tzuyao Lo, Itaru Kushima, Hiroki Kimura, Branko Aleksic, Takashi Okada, Hidekazu Kato, Toshiya Inada, Yoshihiro Nawa, Youta Torii, Maeri Yamamoto, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Shusuke Numata, Kiyoto Kasai, Tsukasa Sasaki, Shigeru Yokoyama, Toshio Munesue, Ryota Hashimoto, Yuka Yasuda, Michiko Fujimoto, Masahide Usami, Masanari Itokawa, Makoto Arai, Kazutaka Ohi, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Tsutomu Takahashi, Michio Suzuki, Hidenori Yamasue, Nakao Iwata, Masashi Ikeda, Norio Ozaki
    Neuropsychopharmacology reports 2023年11月1日  
    AIM: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case-control sample. METHOD: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD. RESULTS: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. CONCLUSION: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.
  • Shun Hamanaka, Taro Kishi, Kenji Sakuma, Yasufumi Nishii, Masakazu Hatano, Nakao Iwata
    Journal of psychiatric research 167 132-138 2023年10月16日  
    The benefits of serotonin 3 receptor antagonists (5-HT3R-As) in obsessive-compulsive disorder (OCD) treatment remain unclear. Thus, this study aimed to perform a systematic review and a random-effects meta-analysis, including double-blind, randomized, placebo-controlled trials (DBRPCTs). The outcomes include the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score (primary), Y-BOCS obsession subscale score, Y-BOCS compulsive subscale score, treatment response, remission rate, all-cause discontinuation, and incidence of individual adverse events (nervousness/restlessness/anxiety, insomnia, headache, dizziness/lightheadedness, decreased appetite, constipation, nausea/vomiting, diarrhea, dry mouth, sweating/increased perspiration, itching/pruritus, tremor, and sexual dysfunction/decreased libido). The mean differences (MD) for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals (CIs) were calculated. Our study included 10 DBRPCTs (n = 628). Pooled 5-HT3R-As outperformed placebo regarding Y-BOCS total score (MD = -5.08, 95% CI = -7.04, -3.12, N = 9, n = 560), Y-BOCS obsession subscale score, Y-BOCS compulsive subscale score, treatment response, and remission rate. Individually, all 5-HT3R-As outperformed placebo regarding Y-BOCS total score (granisetron: MD = -5.59, 95% CI = -8.79, -2.39, N = 3, n = 178, ondansetron: MD = -5.72, 95% CI = -8.06, -3.37, N = 6, n = 331, tropisetron: MD = -2.87, 95% CI = -5.19, -0.550, N = 1, n = 96). However, all-cause discontinuation and incidence of individual adverse events between pooled 5-HT3R-As and placebo were not significantly different. In conclusion, our meta-analysis suggested 5-HT3R-As as efficacious for symptom improvement in individuals with OCD. However, the number of individuals included in each study was small; thus, a replication randomized trial of 5-HT3R-As should be conducted using a larger sample size.
  • Taro Kishi, Kenji Sakuma, Masakazu Hatano, Yuki Matsuda, Satoru Esumi, Nobumi Miyake, Itaru Miura, Hikaru Hori, Masaki Kato, Nakao Iwata
    Neuropsychopharmacology reports 2023年8月30日  
    INTRODUCTION: The question remains to be elucidated: "Is treatment with antidepressants at doses approved in Japan effective for Japanese patients with MDD?" It is crucial to confirm this in order to provide appropriate treatments for Japanese patients with major depressive disorder (MDD). Therefore, we conducted a systematic review and random-effects pairwise meta-analysis including these nine double-blind, randomized, placebo-controlled trials. METHODS: We calculated the standardized mean difference (SMD) and risk ratio (RR) with a 95% confidence interval (95% CI). RESULTS: Pooled newer antidepressants outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = -0.20 (-0.27, -0.12), p < 0.00001], response to treatment [RR (95% CI) = 1.23 (1.13, 1.32), p < 0.00001], and remission rate [RR (95% CI) = 1.30 (1.16, 1.45), p < 0.00001]. Although all-cause discontinuation was not significantly different between the treatment groups, the pooled antidepressant group showed a higher discontinuation rate due to adverse event [RR (95% CI) = 1.60 (1.13, 2.26), p = 0.007] and a higher incidence of at least one adverse event than the placebo group [RR (95% CI) = 1.13 (1.08, 1.18), p < 0.00001]. DISCUSSION: We concluded that newer antidepressants are effective for Japanese adults with MDD although the clinicians must monitor the health conditions of these individuals.
  • Taro Kishi, Kenji Sakuma, Yuki Matsuda, Shinsuke Kito, Nakao Iwata
    Psychiatry research 328 115452-115452 2023年8月28日  
    Our meta-analysis demonstrated that intermittent theta burst stimulation (iTBS)/bilateral-TBS (Bi-TBS) and high-frequency repetitive transcranial magnetic stimulation (HF-rTMS)/bilateral-rTMS (Bi-rTMS) had similar efficacy, acceptability, and safety profiles for antidepressant treatment-resistant major depressive disorder (AD-TRD). In our sensitivity analysis that excluded a study that compared Bi-TBS with Bi-rTMS for older adults, all efficacy outcomes were also comparable between iTBS and HF-rTMS. Because iTBS does not require higher stimulation intensity and a longer stimulus time than conventional HF-rTMS protocols, we speculated that for those with AD-TRD, iTBS/Bi-TBS is a more helpful therapeutic modality in clinical practice than HF-rTMS/Bi-rTMS.
  • Rina Yokoi, Masakazu Hatano, Hiroyuki Kamei, Aoi Morita, Manako Hanya, Nakao Iwata, Shigeki Yamada
    Fujita medical journal 9(3) 231-235 2023年8月  
    OBJECTIVES: To investigate the subjective assessments of an antipsychotic treatment with brexpiprazole. METHODS: This was a 14-week prospective observational study. Nineteen patients participated in the study between February 2019 and January 2020. RESULTS: Patients had a mean age of 40.6±14.2 years and a Clinical Global Impressions-Severity of Illness scale (CGI-S) score of 4.6±1.2 at the initiation of brexpiprazole treatment. The Subjective Well-being under Neuroleptic drug treatment Short form, Japanese version (SWNS-J) total score significantly improved from 68.1±22.3 in week 2 to 79.5±21.0 in week 14 (p=0.0084). The SWNS-J subscales of self-control and social integration status also significantly improved from 14.0±4.7 and 13.9±6.0 in week 2 to 17.0±4.7 and 16.0±5.1 in week 14, respectively (p=0.0053 and 0.012, respectively). No significant improvements were observed in any other SWNS-J subscales or the Drug Attitude Inventory-10 (DAI-10) in the 14-week observation period. Moreover, the SWNS-J total score did not correlate with the DAI-10 (r=0.31, p=0.19), or CGI-S (r=-0.18, p=0.47) scores. CONCLUSIONS: The present results suggest that brexpiprazole might improve subjective well-being, although this may not necessarily reflect psychopathological improvements. To enhance medication adherence, it is important to perform subjective assessments on patients over time.
  • Hiroyuki Kamei, Tsuyoshi Kitajima, Masakazu Hatano, Ippei Takeuchi, Manako Hanya, Kiyoshi Fujita, Nakao Iwata
    Research in Clinical Pharmacy 1(1) 10-21 2023年6月30日  
  • Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chan, Eric Y.H. Chen, Wei Cheng, Eric FC. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm O'Dushlaine, F. Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O'Donovan, Hailiang Huang, Shengying Qin, Akira Sawa, Sibylle G. Schwab, Rene Kahn, Kyung Sue Hong, Wenzhao Shi, Ming Tsuang, Masanari Itokawa, Gang Feng, Jianjun Liu, Stephen J. Glatt, Nakao Iwata, Masashi Ikeda, Xiancang Ma, Jimmy Lee, Jinsong Tang, Yunfeng Ruan, Ruize Liu, Feng Zhu, Yasue Horiuchi, Byung Dae Lee, Eun-Jeong Joo, Woojae Myung, Kyooseob Ha, Hong-Hee Won, Ji Hyung Baek, Young Chul Chung, Sung-Wan Kim, Dieter B. Wildenauer, Agung Kusumawardhani, Wei J. Chen, Hai-Gwo Hwu, Kang Sim, Akitoyo Hishimoto, Ikuo Otsuka, Ichiro Sora, Tomoko Toyota, Takeo Yoshikawa, Hiroshi Kunugi, Kotaro Hattori, Sayuri Ishiwata, Shusuke Numata, Tetsuro Ohmori, Makoto Arai, Yuji Ozeki, Kumiko Fujii, Se Joo Kim, Heon-Jeong Lee, Yong Min Ahn, Se Hyun Kim, Kazufumi Akiyama, Kazutaka Shimoda, Makoto Kinoshita
    iScience 26(5) 106701-106701 2023年5月  
  • Yuichi Esaki, Kenji Obayashi, Keigo Saeki, Kiyoshi Fujita, Nakao Iwata, Tsuyoshi Kitajima
    Psychiatry and clinical neurosciences 2023年4月24日  
    AIM: Sleep disturbance, a core feature of bipolar disorder, is closely associated with mood symptoms. We examined the association between actigraphy sleep parameters and mood episode relapses in patients with bipolar disorder. METHODS: This prospective cohort study analyzed 193 outpatients with bipolar disorder who participated in the Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. The participants' sleep was objectively evaluated via actigraphy over 7 consecutive days for the baseline assessment and then at the 2-year follow-up appointment for mood episode relapses. The actigraphy sleep parameters were presented using the mean and variability (standard deviation) of each sleep parameter for 7 days. RESULTS: Of the 193 participants, 110 (57%) experienced mood episodes during follow-up. The participants with higher variability in total sleep time had a significantly shorter mean estimated time to mood episode relapses than those with lower variability (12.5 vs. 16.8 months; P < 0.001). The Cox proportional hazards model, when adjusted for potential confounders, demonstrated that variability in total sleep time was significantly associated with an increase in the mood episode relapses (per hour; hazard ratio [HR], 1.407; 95% confidence interval (CI), 1.057-1.873), mainly in the depressive episodes (per hour; HR, 1.477; 95% CI, 1.088-2.006). CONCLUSIONS: Our findings suggest that consistency in sleep time might be useful, as an adjunct therapy, in preventing the recurrence or relapse of mood episodes in bipolar disorder. This article is protected by copyright. All rights reserved.
  • Taro Kishi, Toshikazu Ikuta, Kenji Sakuma, Masakazu Hatano, Yuki Matsuda, Shinsuke Kito, Nakao Iwata
    Molecular psychiatry 2023年4月5日  
  • Masaaki Matsunaga, Yuanying Li, Yupeng He, Taro Kishi, Shinichi Tanihara, Nakao Iwata, Takahiro Tabuchi, Atsuhiko Ota
    International Journal of Environmental Research and Public Health 20(5) 4336-4336 2023年2月28日  
    The physical, psychiatric, and social comorbidities interfere with the everyday activities of community-dwelling individuals with schizophrenia and increase the risk of their readmission. However, these comorbidities have not been investigated comprehensively in Japan. We conducted a self-reported internet survey in February 2022 to identify individuals aged 20–75 years with and without schizophrenia using a prevalence case-control study. The survey compared physical comorbidities such as being overweight, hypertension, and diabetes; psychiatric comorbidities such as depressive symptoms and sleep disturbances; social comorbidities such as employment status, household income, and social support between participants with and without schizophrenia. A total of 223 participants with schizophrenia and 1776 participants without schizophrenia were identified. Participants with schizophrenia were more likely to be overweight and had a higher prevalence of hypertension, diabetes, and dyslipidemia than participants without schizophrenia. Additionally, depressive symptoms, unemployment, and non-regular employment were more prevalent in participants with schizophrenia than those without schizophrenia. These results highlight the necessity of comprehensive support and interventions addressing physical, psychiatric, and social comorbidities in individuals with schizophrenia in the community. In conclusion, effective interventions for managing comorbidities in individuals with schizophrenia are necessary to enable them to continue to live in the community.
  • Kenji Sakuma, Taro Kishi, Shohei Sanji, Ikuo Nomura, Masakazu Hatano, Makoto Okuya, Nakao Iwata
    Psychiatry and clinical neurosciences 77(5) 297-299 2023年2月21日  
  • Hirona Yamamoto, Hyeon-Cheol Lee-Okada, Masashi Ikeda, Takumi Nakamura, Takeo Saito, Atsushi Takata, Takehiko Yokomizo, Nakao Iwata, Tadafumi Kato, Takaoki Kasahara
    Molecular Psychiatry 28(7) 2848-2856 2023年2月21日  
    Abstract Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.
  • Taro Kishi, Kenji Sakuma, Masakazu Hatano, Makoto Okuya, Nakao Iwata
    Asian journal of psychiatry 82 103502-103502 2023年2月3日  
  • Yuki Matsuda, Kenji Sakuma, Taro Kishi, Kosei Esaki, Shinsuke Kito, Masahiro Shigeta, Nakao Iwata
    Brain stimulation 2023年2月1日  
  • Taro Kishi, Kenji Sakuma, Yuki Matsuda, Shinsuke Kito, Nakao Iwata
    Bipolar disorders 2023年1月20日  
  • Taro Kishi, Kenji Sakuma, Masakazu Hatano, Makoto Okuya, Yuki Matsuda, Masaki Kato, Nakao Iwata
    Molecular psychiatry 28(3) 974-976 2022年12月23日  
  • Yuichi Esaki, Kenji Obayashi, Keigo Saeki, Kiyoshi Fujita, Nakao Iwata, Tsuyoshi Kitajima
    Journal of affective disorders 323 762-769 2022年12月17日  
    BACKGROUND: Circadian activity rhythm disruption is a core feature in bipolar disorder. We investigated whether light exposure in daily life is associated with circadian activity rhythms in patients with bipolar disorder. METHODS: In a cross-sectional study, we enrolled 194 outpatients with bipolar disorder who were participants of the Association between Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. The participants' physical activity and daytime illuminance were measured using an actigraph over 7 consecutive days. Nighttime illuminance in the bedroom was measured using a portable photometer. Circadian activity rhythm parameters were calculated using cosinor analysis and a nonparametric circadian rhythm analysis. RESULTS: The median daytime illuminance and nighttime illuminance were 224.5 lx (interquartile range, 154.5-307.5 lx) and 2.3 lx (0.3-9.4 lx), respectively. Multivariable linear regression analysis, adjusted for potential confounding factors, showed that higher daytime illuminance was significantly associated with higher amplitude and most active continuous 10-hour period, advanced acrophase, higher interdaily stability, and lower intradaily variability. Higher nighttime illuminance was significantly associated with lower relative amplitude, delayed onset of the least active continuous 5-hour period, and higher intradaily variability. LIMITATIONS: As this was a cross-sectional study, the results do not necessarily imply that light exposure alters circadian activity rhythms. CONCLUSIONS: Daytime light exposure was associated with a positive effect and nighttime light exposure with a negative effect on circadian activity rhythms in bipolar disorder.
  • 岸 太郎, 佐久間 健二, 波多野 正和, 横井 里奈, 岩田 仲生
    臨床精神薬理 25(12) 1319-1322 2022年12月  
    双極性障害は躁病エピソードやうつ病エピソードに代表される急性期と急性期症状が改善し臨床的に安定した維持期に大別される。最新のメタ解析研究では,各病期に対して様々な薬物治療の使用が提案されているが,薬物の種類に加え,それら薬物の用量にも着目した診療が重要である。本稿では,2017年に発表されたThe International College of Neuro-Psychopharmacology(CINP)Treatment Guidelines for Bipolar Disorder in Adults(CINP-BD-2017)で推奨されている各薬剤の推奨用量を各病期別にまとめる。(著者抄録)
  • Taro Kishi, Kenji Sakuma, Masakazu Hatano, Nakao Iwata
    Psychiatry and clinical neurosciences 77(2) 119-121 2022年11月4日  
  • Motoi Terabe, Tsuyoshi Kitajima, Atsuhiko Ota, Hiroshi Yatsuya, Nakao Iwata
    Fujita medical journal 8(4) 103-107 2022年11月  
    OBJECTIVES: The influence of habitual alcohol consumption on insomnia symptoms in healthy workers remains unclear. In this study, we evaluated the association between habitual alcohol consumption among civil servants and insomnia symptoms such as difficulty falling asleep, difficulty staying asleep, and tiredness after sleep, using longitudinal data. METHODS: We enrolled civil servants in a prospective cohort study who completed questionnaires at baseline. Of those, 2861 participants were revaluated in a 5-year follow-up survey. Insomnia symptoms during the past month were assessed using self-reporting. Alcohol drinking habits were assessed by querying the frequency of drinking alcohol as well as the amount of alcohol usually consumed per one occasion. RESULTS: Drinking alcohol every day was less likely to have difficulty falling asleep (odds ratio, 0.42 95% confidence interval, 0.20-0.89), and drinking alcohol 3 or more days a week was associated with difficulty staying asleep (odds ratio, 1.48; 95% confidence interval, 1.16-1.90). CONCLUSIONS: Drinking alcohol every day may produce subjective improvement in sleep onset. However, drinking alcohol 3 or more days a week may increase arousal during sleep, which contributes to reduced sleep quality. These results suggest the possibility that long-term daily habitual drinking may reinforce a sense of improvement in subjective sleep onset but may possibly induce sleep disturbance.
  • Masashi Ikeda, Takeo Saito, Tetsufumi Kanazawa, Taro Kishi, Nakao Iwata
    Psychiatry and clinical neurosciences 76(11) 596-598 2022年11月  
  • Takeo Saito, Masashi Ikeda, Chikashi Terao, Takuma Ashizawa, Masami Miyata, Satoshi Tanaka, Tetsufumi Kanazawa, Tadafumi Kato, Taro Kishi, Nakao Iwata
    Psychiatry and clinical neurosciences 77(2) 118-119 2022年10月25日  
  • Taro Kishi, Toshikazu Ikuta, Kenji Sakuma, Makoto Okuya, Masakazu Hatano, Yuki Matsuda, Nakao Iwata
    Molecular psychiatry 28(1) 402-409 2022年10月17日  
    A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.
  • Itaru Kushima, Masahiro Nakatochi, Branko Aleksic, Takashi Okada, Hiroki Kimura, Hidekazu Kato, Mako Morikawa, Toshiya Inada, Kanako Ishizuka, Youta Torii, Yukako Nakamura, Satoshi Tanaka, Miho Imaeda, Nagahide Takahashi, Maeri Yamamoto, Kunihiro Iwamoto, Yoshihiro Nawa, Nanayo Ogawa, Shuji Iritani, Yu Hayashi, Tzuyao Lo, Gantsooj Otgonbayar, Sho Furuta, Nakao Iwata, Masashi Ikeda, Takeo Saito, Kohei Ninomiya, Tomo Okochi, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenichiro Miura, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Kazuya Toriumi, Kazutaka Ohi, Toshiki Shioiri, Kiyoyuki Kitaichi, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Tsutomu Takahashi, Michio Suzuki, Tsukasa Sasaki, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Hitoshi Kuwabara, Tomoyasu Wakuda, Takahiro A Kato, Shigenobu Kanba, Hideki Horikawa, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Takeo Yoshikawa, Tomoko Toyota, Shigeru Yokoyama, Toshio Munesue, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Minyoung Jung, Kiyoto Kasai, Tempei Ikegame, Seiichiro Jinde, Shusuke Numata, Makoto Kinoshita, Tadafumi Kato, Chihiro Kakiuchi, Kazuhiro Yamakawa, Toshimitsu Suzuki, Naoki Hashimoto, Shuhei Ishikawa, Bun Yamagata, Shintaro Nio, Toshiya Murai, Shuraku Son, Yasuto Kunii, Hirooki Yabe, Masumi Inagaki, Yu-Ichi Goto, Yuto Okumura, Tomoya Ito, Yuko Arioka, Daisuke Mori, Norio Ozaki
    Biological psychiatry 92(5) 362-374 2022年9月1日  
    BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.
  • 亀井 浩行, 竹内 一平, 波多野 正和, 清水 侑真, 飯田 優美, 當真 菜央, 横井 里奈, 半谷 眞七子, 宇野 準二, 山田 成樹, 藤田 潔, 岩田 仲生
    日本精神薬学会誌 6(1) 32-40 2022年9月  
    2019年9月から2021年8月までに、藤田医科大学病院、桶狭間病院藤田こころケアセンターで統合失調症と診断され、ブロナンセリン(BNS)貼付剤4週間以上の使用経験がある20歳以上の患者32名(入院患者22名、外来患者10名)に効果の実感度、副作用等が患者の満足度や薬剤の継続意思に及ぼす影響について検討した。23名(男性10名、女性13名、平均年齢52.6±12.6歳)から質問紙への調査協力を得た。罹病期間は平均26.0±16.0年であり、DAI-10の合計スコアは平均5.7±3.9であった。BNS貼付剤の投与量は40mgが7名、80mgが16名であった。BNS貼付剤の投与は前薬からの切り替えが15名、前薬への上乗せ処方が8名であった。BNS貼付剤の効果については「大変効果がある」6名、「大体効果がある」12名との回答で、78.3%の対象者が効果を感じていた。皮膚症状や使用方法の負担を強く感じている場合でも、薬剤の効果を実感している患者は使用満足度が高いことが示唆された。
  • Yupeng He, Ayako Tanaka, Taro Kishi, Yuanying Li, Masaaki Matsunaga, Shinichi Tanihara, Nakao Iwata, Atsuhiko Ota
    Neuropsychopharmacology Reports 42(4) 430-436 2022年8月2日  
  • Takeo Saito, Toru Usui, Hiroshi Inada, Izuru Miyawaki, Kentaro Mizuno, Masashi Ikeda, Nakao Iwata
    Journal of psychopharmacology (Oxford, England) 36(9) 2698811221112937-2698811221112937 2022年7月21日  
    BACKGROUND: Although clozapine-induced granulocytopenia (CIG) is less severe than clozapine-induced agranulocytosis (CIA), and some patients with CIG may not go on to develop serious complications, clozapine is discontinued in cases of both CIA and CIG. Understanding the pathogenic mechanisms of CIA/CIG could provide better management of clozapine therapy. Recently, as a mechanistic insight into adaptive immune systems, European groups reported clozapine-specific proliferative responses and clozapine-specific T cells using blood taken from patients with CIA and/or CIG. AIMS: The aims of our study are to support this mechanistic evidence and to investigate the difference in the lymphocyte response to clozapine between patients with CIG and those with CIA. METHODS: Lymphocyte stimulation tests (LSTs) were conducted using CD25-positive cell-depleted peripheral blood-derived mononuclear cells (PBMCs) isolated from blood of four Japanese patients with CIA, four patients with CIG, and nine clozapine-tolerant subjects. RESULTS: Three of four patients with CIA and one of four patients with CIG showed proliferative responses to clozapine with a stimulation index of greater than 2. In contrast, none of the nine clozapine-tolerant subjects showed any response to clozapine. Olanzapine did not stimulate PBMCs of patients with CIA, patients with CIG, or clozapine-tolerant subjects. CONCLUSIONS: Clozapine- and CIA-specific lymphocyte reactions in a Japanese population provided supportive evidence that the pathogenesis of CIA is based on adaptive immune reactions. In addition, patients with CIG who show a positive response to an LST may at the very least not be chosen for clozapine-rechallenge and further prospective studies are desirable to verify this hypothesis.
  • Rei Aoki, Takeo Saito, Kohei Ninomiya, Ayu Shimasaki, Takuma Ashizawa, Kenta Ito, Masashi Ikeda, Nakao Iwata
    Psychiatry and clinical neurosciences 76(8) 361-366 2022年5月10日  
    AIM: The genetic relationship between schizophrenia (SCZ) and other nonpsychiatric disorders remains largely unknown. We examined the shared genetic components between these disorders based on multipopulation data sets. METHODS: We used two data sets for East Asian (EAS) and European (EUR) samples. SCZ data was based on the Psychiatric Genomics Consortium Asia with our own genome-wide association study for EAS and Psychiatric Genomics Consortium for EUR. Nonpsychiatric data (20 binary traits [mainly nonpsychiatric complex disorders] and 34 quantitative traits [mainly laboratory examinations and physical characteristics]) were obtained from Biobank Japan and UK Biobank for EAS and EUR samples, respectively. To evaluate genetic correlation, linkage disequilibrium score regression analysis was utilized with further meta-analysis for each result from EAS and EUR samples to obtain robust evidence. Subsequent mendelian randomization analysis was also included to examine the causal effect. RESULTS: A significant genetic correlation between SCZ and several metabolic syndrome (MetS) traits was detected in the combined samples (meta-analysis between EAS and EUR data) (body mass index [rg  = -0.10, q-value = 1.0 × 10-9 ], high-density-lipoprotein cholesterol [rg  = 0.072, q-value = 2.9 × 10-3 ], blood sugar [rg  = -0.068, q-value = 1.4 × 10-2 ], triglycerides [rg  = -0.052, q-value = 2.4 × 10-2 ], systolic blood pressure [rg  = -0.054, q-value = 3.5 × 10-2 ], and C-reactive protein [rg  = -0.076, q-value = 7.8 × 10-5 ]. However, no causal relationship on SCZ susceptibility was detected for these traits based on the mendelian randomization analysis. CONCLUSION: Our results indicate shared genetic components between SCZ and MetS traits and C-reactive protein. Specifically, we found it interesting that the correlation between MetS traits and SCZ was the opposite of that expected from clinical studies: this genetic study suggests that SCZ susceptibility was associated with reduced MetS. This implied that MetS in patients with SCZ was not associated with genetic components but with environmental factors, including antipsychotics, lifestyle changes, poor diet, lack of exercise, and living conditions.
  • Yunfeng Ruan, Yen-Feng Lin, Yen-Chen Anne Feng, Chia-Yen Chen, Max Lam, Zhenglin Guo, Yong Min Ahn, Kazufumi Akiyama, Makoto Arai, Ji Hyun Baek, Wei J. Chen, Young-Chul Chung, Gang Feng, Kumiko Fujii, Stephen J. Glatt, Kyooseob Ha, Kotaro Hattori, Teruhiko Higuchi, Akitoyo Hishimoto, Kyung Sue Hong, Yasue Horiuchi, Hai-Gwo Hwu, Masashi Ikeda, Sayuri Ishiwata, Masanari Itokawa, Nakao Iwata, Eun-Jeong Joo, Rene S. Kahn, Sung-Wan Kim, Se Joo Kim, Se Hyun Kim, Makoto Kinoshita, Hiroshi Kunugi, Agung Kusumawardhani, Jimmy Lee, Byung Dae Lee, Heon-Jeong Lee, Jianjun Liu, Ruize Liu, Xiancang Ma, Woojae Myung, Shusuke Numata, Tetsuro Ohmori, Ikuo Otsuka, Yuji Ozeki, Sibylle G. Schwab, Wenzhao Shi, Kazutaka Shimoda, Kang Sim, Ichiro Sora, Jinsong Tang, Tomoko Toyota, Ming Tsuang, Dieter B. Wildenauer, Hong-Hee Won, Takeo Yoshikawa, Alice Zheng, Feng Zhu, Lin He, Akira Sawa, Alicia R. Martin, Shengying Qin, Hailiang Huang, Tian Ge
    Nature Genetics 54(5) 573-580 2022年5月  査読有り
    Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) have been conducted predominantly in individuals of European descent, the limited transferability of PRS reduces their clinical value in non-European populations, and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research have expanded the scale of non-European GWAS, although most remain underpowered. Here, we present a new PRS construction method, PRS-CSx, which improves cross-population polygenic prediction by integrating GWAS summary statistics from multiple populations. PRS-CSx couples genetic effects across populations via a shared continuous shrinkage (CS) prior, enabling more accurate effect size estimation by sharing information between summary statistics and leveraging linkage disequilibrium diversity across discovery samples, while inheriting computational efficiency and robustness from PRS-CS. We show that PRS-CSx outperforms alternative methods across traits with a wide range of genetic architectures, cross-population genetic overlaps and discovery GWAS sample sizes in simulations, and improves the prediction of quantitative traits and schizophrenia risk in non-European populations.
  • Naomichi Okamoto, Keita Watanabe, Hirofumi Tesen, Atsuko Ikenouchi, Ryohei Igata, Yuki Konishi, Tomoya Natsuyama, Rintaro Fujii, Shingo Kakeda, Taro Kishi, Nakao Iwata, Reiji Yoshimura
    Neurology international 14(2) 378-390 2022年4月15日  
    The amygdala is a prominent region of the brain that plays a critical role in the pathophysiology of major depressive disorder (MDD). The amygdala is formed from a collection of interconnected substructures (nuclei) that relay signals from multiple brain areas, which suggests that the amygdala has different functions depending on its subregion. There are two main alleles of serotonin transporter gene polymorphism (5-HTTLPR): a 44-bp insertion (l-allele) or deletion (s-allele). The transcriptional activity of the l-allele of the gene is twice that of the s-allele. The present study aimed to investigate the association between the volume of the whole amygdala and subregions of the amygdala in 25 first-episode and drug-naive patients with MDD and 46 healthy controls (HCs) with the s/s genotype of 5-HTTLPR and plasma levels of brain-derived neurotrophic factor (BDNF) or cortisol. No significant difference was observed in the amygdala total and subregion volumes between the HC and MDD groups. No significant difference was found in the plasma levels of BDNF and cortisol between the two groups. In addition, no correlations were found between the total and subregion amygdala volume and plasma levels of cortisol or BDNF.
  • 松田 勇紀, 山崎 龍一, 岸 太郎, 岩田 仲生, 繁田 雅弘, 鬼頭 伸輔
    精神神経学雑誌 124(4付録) S-539 2022年4月  
  • Vassily Trubetskoy, Antonio F Pardiñas, Ting Qi, Georgia Panagiotaropoulou, Swapnil Awasthi, Tim B Bigdeli, Julien Bryois, Chia-Yen Chen, Charlotte A Dennison, Lynsey S Hall, Max Lam, Kyoko Watanabe, Oleksandr Frei, Tian Ge, Janet C Harwood, Frank Koopmans, Sigurdur Magnusson, Alexander L Richards, Julia Sidorenko, Yang Wu, Jian Zeng, Jakob Grove, Minsoo Kim, Zhiqiang Li, Georgios Voloudakis, Wen Zhang, Mark Adams, Ingrid Agartz, Elizabeth G Atkinson, Esben Agerbo, Mariam Al Eissa, Margot Albus, Madeline Alexander, Behrooz Z Alizadeh, Köksal Alptekin, Thomas D Als, Farooq Amin, Volker Arolt, Manuel Arrojo, Lavinia Athanasiu, Maria Helena Azevedo, Silviu A Bacanu, Nicholas J Bass, Martin Begemann, Richard A Belliveau, Judit Bene, Beben Benyamin, Sarah E Bergen, Giuseppe Blasi, Julio Bobes, Stefano Bonassi, Alice Braun, Rodrigo Affonseca Bressan, Evelyn J Bromet, Richard Bruggeman, Peter F Buckley, Randy L Buckner, Jonas Bybjerg-Grauholm, Wiepke Cahn, Murray J Cairns, Monica E Calkins, Vaughan J Carr, David Castle, Stanley V Catts, Kimberley D Chambert, Raymond C K Chan, Boris Chaumette, Wei Cheng, Eric F C Cheung, Siow Ann Chong, David Cohen, Angèle Consoli, Quirino Cordeiro, Javier Costas, Charles Curtis, Michael Davidson, Kenneth L Davis, Lieuwe de Haan, Franziska Degenhardt, Lynn E DeLisi, Ditte Demontis, Faith Dickerson, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Jubao Duan, Giuseppe Ducci, Frank Dudbridge, Johan G Eriksson, Lourdes Fañanás, Stephen V Faraone, Alessia Fiorentino, Andreas Forstner, Josef Frank, Nelson B Freimer, Menachem Fromer, Alessandra Frustaci, Ary Gadelha, Giulio Genovese, Elliot S Gershon, Marianna Giannitelli, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I Goldstein, Javier González Peñas, Ana González-Pinto, Srihari Gopal, Jacob Gratten, Michael F Green, Tiffany A Greenwood, Olivier Guillin, Sinan Gülöksüz, Raquel E Gur, Ruben C Gur, Blanca Gutiérrez, Eric Hahn, Hakon Hakonarson, Vahram Haroutunian, Annette M Hartmann, Carol Harvey, Caroline Hayward, Frans A Henskens, Stefan Herms, Per Hoffmann, Daniel P Howrigan, Masashi Ikeda, Conrad Iyegbe, Inge Joa, Antonio Julià, Anna K Kähler, Tony Kam-Thong, Yoichiro Kamatani, Sena Karachanak-Yankova, Oussama Kebir, Matthew C Keller, Brian J Kelly, Andrey Khrunin, Sung-Wan Kim, Janis Klovins, Nikolay Kondratiev, Bettina Konte, Julia Kraft, Michiaki Kubo, Vaidutis Kučinskas, Zita Ausrele Kučinskiene, Agung Kusumawardhani, Hana Kuzelova-Ptackova, Stefano Landi, Laura C Lazzeroni, Phil H Lee, Sophie E Legge, Douglas S Lehrer, Rebecca Lencer, Bernard Lerer, Miaoxin Li, Jeffrey Lieberman, Gregory A Light, Svetlana Limborska, Chih-Min Liu, Jouko Lönnqvist, Carmel M Loughland, Jan Lubinski, Jurjen J Luykx, Amy Lynham, Milan Macek Jr, Andrew Mackinnon, Patrik K E Magnusson, Brion S Maher, Wolfgang Maier, Dolores Malaspina, Jacques Mallet, Stephen R Marder, Sara Marsal, Alicia R Martin, Lourdes Martorell, Manuel Mattheisen, Robert W McCarley, Colm McDonald, John J McGrath, Helena Medeiros, Sandra Meier, Bela Melegh, Ingrid Melle, Raquelle I Mesholam-Gately, Andres Metspalu, Patricia T Michie, Lili Milani, Vihra Milanova, Marina Mitjans, Espen Molden, Esther Molina, María Dolores Molto, Valeria Mondelli, Carmen Moreno, Christopher P Morley, Gerard Muntané, Kieran C Murphy, Inez Myin-Germeys, Igor Nenadić, Gerald Nestadt, Liene Nikitina-Zake, Cristiano Noto, Keith H Nuechterlein, Niamh Louise O'Brien, F Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Vanessa Kiyomi Ota, Christos Pantelis, George N Papadimitriou, Mara Parellada, Tiina Paunio, Renata Pellegrino, Sathish Periyasamy, Diana O Perkins, Bruno Pfuhlmann, Olli Pietiläinen, Jonathan Pimm, David Porteous, John Powell, Diego Quattrone, Digby Quested, Allen D Radant, Antonio Rampino, Mark H Rapaport, Anna Rautanen, Abraham Reichenberg, Cheryl Roe, Joshua L Roffman, Julian Roth, Matthias Rothermundt, Bart P F Rutten, Safaa Saker-Delye, Veikko Salomaa, Julio Sanjuan, Marcos Leite Santoro, Adam Savitz, Ulrich Schall, Rodney J Scott, Larry J Seidman, Sally Isabel Sharp, Jianxin Shi, Larry J Siever, Engilbert Sigurdsson, Kang Sim, Nora Skarabis, Petr Slominsky, Hon-Cheong So, Janet L Sobell, Erik Söderman, Helen J Stain, Nils Eiel Steen, Agnes A Steixner-Kumar, Elisabeth Stögmann, William S Stone, Richard E Straub, Fabian Streit, Eric Strengman, T Scott Stroup, Mythily Subramaniam, Catherine A Sugar, Jaana Suvisaari, Dragan M Svrakic, Neal R Swerdlow, Jin P Szatkiewicz, Thi Minh Tam Ta, Atsushi Takahashi, Chikashi Terao, Florence Thibaut, Draga Toncheva, Paul A Tooney, Silvia Torretta, Sarah Tosato, Gian Battista Tura, Bruce I Turetsky, Alp Üçok, Arne Vaaler, Therese van Amelsvoort, Ruud van Winkel, Juha Veijola, John Waddington, Henrik Walter, Anna Waterreus, Bradley T Webb, Mark Weiser, Nigel M Williams, Stephanie H Witt, Brandon K Wormley, Jing Qin Wu, Zhida Xu, Robert Yolken, Clement C Zai, Wei Zhou, Feng Zhu, Fritz Zimprich, Eşref Cem Atbaşoğlu, Muhammad Ayub, Christian Benner, Alessandro Bertolino, Donald W Black, Nicholas J Bray, Gerome Breen, Nancy G Buccola, William F Byerley, Wei J Chen, C Robert Cloninger, Benedicto Crespo-Facorro, Gary Donohoe, Robert Freedman, Cherrie Galletly, Michael J Gandal, Massimo Gennarelli, David M Hougaard, Hai-Gwo Hwu, Assen V Jablensky, Steven A McCarroll, Jennifer L Moran, Ole Mors, Preben B Mortensen, Bertram Müller-Myhsok, Amanda L Neil, Merete Nordentoft, Michele T Pato, Tracey L Petryshen, Matti Pirinen, Ann E Pulver, Thomas G Schulze, Jeremy M Silverman, Jordan W Smoller, Eli A Stahl, Debby W Tsuang, Elisabet Vilella, Shi-Heng Wang, Shuhua Xu, Rolf Adolfsson, Celso Arango, Bernhard T Baune, Sintia Iole Belangero, Anders D Børglum, David Braff, Elvira Bramon, Joseph D Buxbaum, Dominique Campion, Jorge A Cervilla, Sven Cichon, David A Collier, Aiden Corvin, David Curtis, Marta Di Forti, Enrico Domenici, Hannelore Ehrenreich, Valentina Escott-Price, Tõnu Esko, Ayman H Fanous, Anna Gareeva, Micha Gawlik, Pablo V Gejman, Michael Gill, Stephen J Glatt, Vera Golimbet, Kyung Sue Hong, Christina M Hultman, Steven E Hyman, Nakao Iwata, Erik G Jönsson, René S Kahn, James L Kennedy, Elza Khusnutdinova, George Kirov, James A Knowles, Marie-Odile Krebs, Claudine Laurent-Levinson, Jimmy Lee, Todd Lencz, Douglas F Levinson, Qingqin S Li, Jianjun Liu, Anil K Malhotra, Dheeraj Malhotra, Andrew McIntosh, Andrew McQuillin, Paulo R Menezes, Vera A Morgan, Derek W Morris, Bryan J Mowry, Robin M Murray, Vishwajit Nimgaonkar, Markus M Nöthen, Roel A Ophoff, Sara A Paciga, Aarno Palotie, Carlos N Pato, Shengying Qin, Marcella Rietschel, Brien P Riley, Margarita Rivera, Dan Rujescu, Meram C Saka, Alan R Sanders, Sibylle G Schwab, Alessandro Serretti, Pak C Sham, Yongyong Shi, David St Clair, Hreinn Stefánsson, Kari Stefansson, Ming T Tsuang, Jim van Os, Marquis P Vawter, Daniel R Weinberger, Thomas Werge, Dieter B Wildenauer, Xin Yu, Weihua Yue, Peter A Holmans, Andrew J Pocklington, Panos Roussos, Evangelos Vassos, Matthijs Verhage, Peter M Visscher, Jian Yang, Danielle Posthuma, Ole A Andreassen, Kenneth S Kendler, Michael J Owen, Naomi R Wray, Mark J Daly, Hailiang Huang, Benjamin M Neale, Patrick F Sullivan, Stephan Ripke, James T R Walters, Michael C O'Donovan
    Nature 604(7906) 502-508 2022年4月  
    Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
  • Ryo Morikawa, Yuichiro Watanabe, Hirofumi Igeta, Reza K Arta, Masashi Ikeda, Satoshi Okazaki, Satoshi Hoya, Takeo Saito, Ikuo Otsuka, Jun Egawa, Takaki Tanifuji, Nakao Iwata, Toshiyuki Someya
    Psychiatry research 310 114481-114481 2022年4月  
    SETD1A has been identified as a substantial risk gene for schizophrenia. To further investigate the role of SETD1A in the genetic etiology of schizophrenia in the Japanese population, we performed resequencing and association analyses. First, we resequenced the SETD1A coding regions of 974 patients with schizophrenia. Then, we genotyped variants, prioritized via resequencing, in 2,027 patients with schizophrenia and 2,664 controls. Next, we examined the association between SETD1A and schizophrenia in 3,001 patients with schizophrenia and 2,664 controls. Finally, we performed a retrospective chart review of patients with prioritized SETD1A variants. We identified two novel missense variants (p.Ser575Pro and p.Glu857Gln) via resequencing. We did not detect these variants in 4,691 individuals via genotyping. These variants were not significantly associated with schizophrenia in the association analysis. Additionally, we found that a schizophrenia patient with the p.Glu857Gln variant had developmental delays. In conclusion, novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia. However, our study does not provide evidence for the contribution of these variants to the genetic etiology of schizophrenia in the Japanese population.
  • Yuichi Esaki, Kenji Obayashi, Keigo Saeki, Kiyoshi Fujita, Nakao Iwata, Tsuyoshi Kitajima
    Acta psychiatrica Scandinavica 146(1) 64-73 2022年3月6日  
    OBJECTIVE: A previous cross-sectional study reported that nighttime light is associated with increased occurrence of manic symptoms in bipolar disorder; however, the longitudinal association between nighttime light and subsequent mood episode relapses remains unclear. We determined whether bedroom nighttime light was associated with mood episode relapses in patients with bipolar disorder. METHODS: This prospective cohort study included 172 outpatients with bipolar disorder who participated in an Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. A portable photometer was used to measure illuminance in the bedroom from bedtime to rising time during 7 consecutive nights for baseline assessment. Then, the participants were assessed at a 2-year follow-up for mood episode relapses. RESULTS: Of the 172 participants, 157 (91%) completed the 2-year follow-up, and 39 (22%) experienced manic or hypomanic episodes (with or without mixed features), during that time. In the Cox proportional-hazards model, the hazard ratio (HR) for manic/hypomanic episode relapses was significantly higher when the average nighttime illuminance was ≥3 lux (n = 71) than when it was <3 lux (n = 101; HR, 2.54; 95% confidence interval (CI), 1.33-4.84). In the multivariable model adjusted for a propensity score in relation to nighttime light, the relationship remained significant (HR, 2.17; 95% CI, 1.04-4.52). The association between nighttime light and depressive episode relapses was not significantly different. CONCLUSIONS: Keeping the bedroom dark at night may prevent hypomanic and manic episodes.
  • 飯田 優美, 竹内 一平, 波多野 正和, 當真 菜央, 横井 里奈, 半谷 眞七子, 宇野 準二, 山田 成樹, 藤田 潔, 岩田 仲生, 亀井 浩行
    日本精神薬学会誌 5(2) 63-63 2022年3月  
  • Chenyao Wang, Shin-Ichiro Horigane, Minoru Wakamori, Shuhei Ueda, Takeshi Kawabata, Hajime Fujii, Itaru Kushima, Hiroki Kimura, Kanako Ishizuka, Yukako Nakamura, Yoshimi Iwayama, Masashi Ikeda, Nakao Iwata, Takashi Okada, Branko Aleksic, Daisuke Mori, Takashi Yoshida, Haruhiko Bito, Takeo Yoshikawa, Sayaka Takemoto-Kimura, Norio Ozaki
    Translational psychiatry 12(1) 84-84 2022年2月26日  
    Several large-scale whole-exome sequencing studies in patients with schizophrenia (SCZ) and autism spectrum disorder (ASD) have identified rare variants with modest or strong effect size as genetic risk factors. Dysregulation of cellular calcium homeostasis might be involved in SCZ/ASD pathogenesis, and genes encoding L-type voltage-gated calcium channel (VGCC) subunits Cav1.1 (CACNA1S), Cav1.2 (CACNA1C), Cav1.3 (CACNA1D), and T-type VGCC subunit Cav3.3 (CACNA1I) recently were identified as risk loci for psychiatric disorders. We performed a screening study, using the Ion Torrent Personal Genome Machine (PGM), of exon regions of these four candidate genes (CACNA1C, CACNA1D, CACNA1S, CACNA1I) in 370 Japanese patients with SCZ and 192 with ASD. Variant filtering was applied to identify biologically relevant mutations that were not registered in the dbSNP database or that have a minor allele frequency of less than 1% in East-Asian samples from databases; and are potentially disruptive, including nonsense, frameshift, canonical splicing site single nucleotide variants (SNVs), and non-synonymous SNVs predicted as damaging by five different in silico analyses. Each of these filtered mutations were confirmed by Sanger sequencing. If parental samples were available, segregation analysis was employed for measuring the inheritance pattern. Using our filter, we discovered one nonsense SNV (p.C1451* in CACNA1D), one de novo SNV (p.A36V in CACNA1C), one rare short deletion (p.E1675del in CACNA1D), and 14 NSstrict SNVs (non-synonymous SNV predicted as damaging by all of five in silico analyses). Neither p.A36V in CACNA1C nor p.C1451* in CACNA1D were found in 1871 SCZ cases, 380 ASD cases, or 1916 healthy controls in the independent sample set, suggesting that these SNVs might be ultra-rare SNVs in the Japanese population. The neuronal splicing isoform of Cav1.2 with the p.A36V mutation, discovered in the present study, showed reduced Ca2+-dependent inhibition, resulting in excessive Ca2+ entry through the mutant channel. These results suggested that this de novo SNV in CACNA1C might predispose to SCZ by affecting Ca2+ homeostasis. Thus, our analysis successfully identified several ultra-rare and potentially disruptive gene variants, lending partial support to the hypothesis that VGCC-encoding genes may contribute to the risk of SCZ/ASD.
  • Taro Kishi, Toshikazu Ikuta, Yuki Matsuda, Kenji Sakuma, Makoto Okuya, Ikuo Nomura, Masakazu Hatano, Nakao Iwata
    Molecular psychiatry 27(2) 1136-1144 2022年2月  
    A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo.
  • Kohei Ninomiya, Takeo Saito, Masashi Ikeda, Nakao Iwata, François R Girardin
    Frontiers in pharmacology 13 1016669-1016669 2022年  
    The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration.
  • Marina Hirose, Toru Nakamura, Akiko Watanabe, Yuichi Esaki, Shigefumi Koike, Yoshiharu Yamamoto, Nakao Iwata, Tsuyoshi Kitajima
    Frontiers in psychiatry 13 933690-933690 2022年  
    Delayed sleep phase disorder (DSPD) and mood disorders have a close relationship. However, the shared mechanisms by DSPD and mood disorders have not been well-elucidated. We previously found that micro-fluctuations in human behaviors are organized by robust statistical laws (behavioral organization), where the cumulative distributions of resting and active period durations take a power-law distribution form and a stretched exponential functional form, respectively. Further, we found that the scaling exponents of resting period distributions significantly decreased in major depressive disorder (MDD). In this study, we hypothesized that DSPD had similar characteristics of the altered behavioral organization to that of MDD. Locomotor activity data were acquired for more than 1 week from 17 patients with DSPD and 17 age- and gender-matched healthy participants using actigraphy. We analyzed the cumulative distributions of resting and active period durations in locomotor activity data and subsequently derived fitting parameters of those distributions. Similar to patients with MDD, we found that resting period distributions took a power-law form over the range of 2-100 min, with significantly lower values of scaling exponents γ in patients with DSPD compared with healthy participants. The shared alteration in γ suggests the existence of similar pathophysiology between DSPD and MDD.
  • Jun Ishigooka, Kazuyuki Nakagome, Tetsuro Ohmori, Nakao Iwata, Ken Inada, Jun-Ichi Iga, Taro Kishi, Kiyoshi Fujita, Yuka Kikuchi, Toshiaki Shichijo, Hideaki Tabuse, Shotatsu Koretsune, Hiroshi Terada, Haruko Terada, Toshifumi Kishimoto, Yuichiro Tsutsumi, Yoshiki Kanda, Kazutaka Ohi, Kanji Sekiyama
    Psychiatry and clinical neurosciences 76(1) 22-31 2022年1月  
    AIM: Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone). METHODS: JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality-of-life scores [Personal and Social Performance Scale (PSP) and EuroQol-5 dimensions], and safety. RESULTS: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin. CONCLUSION: All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan.
  • Akari Fujita, Yuichi Esaki, Kenji Obayashi, Keigo Saeki, Kiyoshi Fujita, Nakao Iwata, Tsuyoshi Kitajima
    Journal of psychiatric research 145 190-196 2021年12月13日  
    BACKGROUND: Sleep disturbance is a core feature of bipolar disorder; hence, sleep must be accurately assessed in patients with bipolar disorder. Subjective sleep assessment tools such as sleep diary and questionnaires are often used clinically for assessing sleep in these patients. However, the insight into whether these tools are as accurate as objective tools, such as actigraphy, remains controversial. METHODS: This cross-sectional study included 164 outpatients with a diagnosis of bipolar disorder, including patients who had euthymic and residual symptomatic periods. Objective sleep assessment was conducted prospectively using actigraphy for 7 consecutive days, whereas subjective sleep assessment was conducted prospectively using a sleep diary. RESULTS: The correlations were high and moderate between sleep diary and actigraphy when assessing the total sleep time and sleep onset latency, respectively (r = 0.81 and 0.47). These correlations remained significant after correction for multiple testing (both p < 0.001) and in both euthymic and residual symptomatic states (total sleep time: r = 0.86 and 0.77; sleep onset latency: r = 0.51 and 0.40, respectively). The median (interquartile ranges) of the percentage difference (sleep diary parameters minus actigraphy parameters divided by actigraphy parameter) in the total sleep time was relatively small (6.2% [-0.2% to 13.6%]). CONCLUSIONS: Total sleep time assessment using a sleep diary could be clinically useful in the absence of actigraphy or polysomnography.
  • 芦澤 琢磨, 伊藤 健太, 二宮 光平, 齋藤 竹生, 池田 匡志, 岩田 仲生
    精神科臨床Legato 7(3) 140-144 2021年12月  
    統合失調症の病態は依然として不明のままであり、現在に至るまでさまざまな切り口から多くの研究がなされてきた。近年、全ゲノム関連研究(genome-wide association study;GWAS)は疾患感受性遺伝子同定に大きく寄与し、病態研究の新たなヒントを与えている。本稿では統合失調症GWASの成果について触れる。(著者抄録)
  • Masakazu Hatano, Ippei Takeuchi, Kanade Yamashita, Aoi Morita, Kaori Tozawa, Takashi Sakakibara, Genta Hajitsu, Manako Hanya, Shigeki Yamada, Nakao Iwata, Hiroyuki Kamei
    Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 19(4) 610-617 2021年11月30日  
    Objective: To identify factors affecting adherence to medication, a subjective questionnaire survey was administered to schizophrenia patients regarding the prescribed antipsychotic formulations. Methods: We evaluated the patients' satisfaction and dissatisfaction with prescribed antipsychotic formulations, and patients answered the Drug Attitude Inventory-10 Questionnaire (DAI-10). Inclusion criteria for patients are as follows: age between 20 and 75 years and taking antipsychotic agents containing the same ingredients and formulations, for at least 1 month. Results: In total, 301 patients answered the questionnaire survey. Tablets were found to be the most commonly used antipsychotic formulations among schizophrenia patients (n = 174, 57.8%), followed by long-acting injections (LAIs, n = 93, 30.9%). No significant differences in the formulation satisfaction level and DAI-10 scores were observed between all formulations. Formulations, except for LAI, were selected by physicians in more than half of the patients. Patients who answered "Decided by consultation with physicians" had significantly higher satisfaction levels and DAI-10 scores compared to those who answered "Decided by physicians" (4.11 ± 0.77 vs. 3.80 ± 1.00, p = 0.0073 and 6.20 ± 3.51 vs. 4.39 ± 4.56, p < 0.001, respectively). Satisfaction levels moderately correlated with DAI-10 scores (r = 0.48, p < 0.001). Conclusion: No formulation had a high satisfaction level in all patients, and it is important to be reflect the patients' individual preferences in pharmacotherapy. Shared decision-making in the selection of the formulations is seen to be useful for improving medication adherence.
  • 岸 太郎, 佐久間 健二, 奥谷 理, 岩田 仲生, 早川 ひろみ, 野村 郁雄, 波多野 正和
    精神科Resident 2(4) 257-263 2021年11月  
    ＜Key Point＞・統合失調症治療の大黒柱は抗精神病薬を用いた薬物治療である・各抗精神病薬間で、有効性に大差はないが、安全性には大きな違いがある・維持期を見据えて患者さんと一緒に急性期に用いる抗精神病薬を選択することが望まれる(著者抄録)

MISC

 625
もっとみる

書籍等出版物

 6
もっとみる

共同研究・競争的資金等の研究課題

 15
もっとみる

産業財産権

 3
一覧へ戻る