臨床薬理・ゲ ノム薬理グループ

グループリーダー：緒方 治彦

精神科治療において、今日その中心的役割を担う薬物療法の個別化医療（プレシジョン・メディシン）を目指し研究を行っています。個別化医療とは、患者の遺伝的背景・生理的状態・疾患の状態などを考慮して、患者個々に最適な治療法を設定する医療と定義されます。

うつ病、統合失調症を対象として継続して行っている無作為化割り付け試験のデータより、比較した治療薬の有用性（効果・副作用）を検討するとともに、ある治療薬で改善した人、しなかった人、副作用が出現した人などの反応性の個人差の原因（因子）を検討します。それらの因子を投与する前に評価することで、各薬剤の反応性を予測し、個人に最適な治療法を選択可能にすることを目指しています。

探索する因子としては、遺伝子(DNA, miRNA, mtDNA)や、そのメチル化、治療に影響する血中蛋白などのバイオマーカー、性格、生活環境などの患者背景や中間表現型（定量脳波やMRI）を対象としています。これらのたくさんの因子が、どのように薬剤の治療反応に影響しているかを詳細に解析することで、各患者に最適な治療を導くアルゴリズムを構築していきます。DNA、miRNA、mtDNA、メチル化は網羅的ゲノミクス、トランスクリプトミクス、エピゲノミクス解析と候補遺因子解析にて行っております。

これまでに、すでに多くの成果を世界に発信していますが、進化する解析技術を使用し、さらなる質と精度の向上を目指し、知識とデータを蓄積し続けています。

精神科領域において、本邦には無作為化割り付け試験をゲノム薬理的な方法論を用いて継続している研究グループはほとんどなく、我々のグループが蓄積しているデータは重要であり、その特徴を活かしたさらなる研究成果を発信したいと考えております。

このような研究に関わりたい方（医師、研究者、大学院生）も随時募集しております。

イタリアのボローニャ大学生物医学・神経運動科学教室（グループリーダー；Alessandro Serretti）と研究交流があり、主要な留学先の一つとなっております。他にも主に、産業医科大学精神医学教室、理化学研究所脳科学総合研究センター、広島大学細胞分子生物学教室、兵庫医療大学薬学部医療薬学科、The International SSRI Pharmacogenomics Consortium (ISPC)等の施設と共同研究を進めています。

業績

論文

  • Adachi N, Azekawa T, Edagawa K, Goto E, Hongo S, Kato M, Katsumoto E, Kikuchi T, Kubota Y, Miki K, Nakagawa A, Tsuboi T, Ueda H, Watanabe K, Watanabe Y, Yasui-Furukori N, Yoshimura R. Estimated model of psychotropic polypharmacy for bipolar disorder: Analysis using patients’ and practitioners’ parameters in the MUSUBI study. Hum Psychopharmacol. 2021 Mar;36(2):e2764.
  • Takekita Y, Hiraoka S, Iwama Y, Sunada N, Aoki N, Ogata H, Funatsuki T, Takano C, Yanagida T, Koshikawa Y, Naito M, Yamamoto A, Kato M, Kinoshita T. Divergence of dose-response with asenapine: a cluster analysis of randomized, double-blind, and placebo control study. CNS Spectr. 2022 Jun;27(3):369-377.
  • Kato M, Hori H, Inoue T, Iga J, Iwata M, Inagaki T, Shinohara K, Imai H, Murata A, Mishima K, Tajika A. Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry. 2021 Jan;26(1):118-133.
  • Sakurai H, Yasui-Furukori N, Suzuki T, Uchida H, Baba H, Watanabe K, Inada K, Kikuchi YS, Kikuchi T, Katsuki A, Kishida I, Kato M. Pharmacological Treatment of Schizophrenia: Japanese Expert Consensus. Pharmacopsychiatry. 2021 Mar;54(2):60-67.
  • Shinozaki M, Yasui-Furukori N, Adachi N, Ueda H, Hongo S, Azekawa T, Kubota Y, Katsumoto E, Edagawa K, Goto E, Miki K, Kato M, Nakagawa A, Kikuchi T, Tsuboi T, Watanabe K, Shimoda K, Yoshimura R. Differences in prescription patterns between real-world outpatients with bipolar I and II disorders in the MUSUBI survey. Asian J Psychiatr. 2022 Jan;67:102935.
  • Takeuchi H, Takekita Y, Hori H, Oya K, Miura I, Hashimoto N, Yasui-Furukori N. Pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia: Japanese Society of Clinical Neuropsychopharmacology treatment algorithms. Hum Psychopharmacol. 2021 Nov;36(6):e2804.
  • Ishigooka J, Iwata N, Kusumi I, Nakagawa A, Miyamoto S, Kishi T, Matsuda Y, Miyake N, Iga J, Kato M, Tajika A, Hori H, Ito K, Kanazawa T, Kishimoto T, Takeuchi H, Hishimoto A, Enomoto T, Suwa T, Takekita Y, Hashimoto R, Misawa F, Miyada R, Inada K, Sato S, Tsujino N, Yamada H, Watanabe H, Ikebuchi E, Kasai K, Goto M, Fukuda M, Murai T, Kimura H, Nemoto K, Numata S, Ochi S, Sato H, Tarutani S, Uchida H. Japanese Society of Neuropsychopharmacology: “Guideline for Pharmacological Therapy of Schizophrenia”. Neuropsychopharmacol Rep. 2021 Sep;41(3):266-324.
  • Tokumitsu K, Norio YF, Adachi N, Kubota Y, Watanabe Y, Miki K, Azekawa T, Edagawa K, Katsumoto E, Hongo S, Goto E, Ueda H, Kato M, Nakagawa A, Kikuchi T, Tsuboi T, Watanabe K, Shimoda K, Yoshimura R. Real-world clinical predictors of manic/hypomanic episodes among outpatients with bipolar disorder. PLoS One. 2021 Dec 31;16(12):e0262129.
  • Kato M, Ogata H, Tahara H, Shimamoto A, Takekita Y, Koshikawa Y, Nishida K, Nonen S, Higasa K, Kinoshita T. Multiple Pre-Treatment miRNAs Levels in Untreated Major Depressive Disorder Patients Predict Early Response to Antidepressants and Interact with Key Pathways. Int J Mol Sci. 2022 Mar 31;23(7):3873.
  • Kawamata Y, Yasui-Furukori N, Adachi N, Ueda H, Hongo S, Azekawa T, Kubota Y, Katsumoto E, Edagawa K, Goto E, Miki K, Kato M, Nakagawa A, Kikuchi T, Tsuboi T, Yoshimura R, Shimoda K, Watanabe K. Effect of age and sex on prescriptions for outpatients with bipolar disorder in the MUSUBI study: a cross‑sectional study. Ann Gen Psychiatry. 2022 Sep 12;21(1):37.
  • Pain O, Hodgson K, Trubetskoy V, Ripke S, Marshe VS, Adams MJ, Byrne EM, Campos AI, Carrillo-Roa T, Cattaneo A, Als TD, Souery D, Dernovsek MZ, Fabbri C, Hayward C, Henigsberg N, Hauser J, Kennedy JL, Lenze EJ, Lewis G, Müller DJ, Martin NG, Mulsant BH, Mors O, Perroud N, Porteous DJ, Rentería ME, Reynolds CF 3rd, Rietschel M, Uher R, Wigmore EM, Maier W, Wray NR, Aitchison KJ, Arolt V, Baune BT, Biernacka JM, Bondolfi G, Domschke K, Kato M, Li QS, Liu YL, Serretti A, Tsai SJ, Turecki G, Weinshilboum R; GSRD Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; McIntosh AM, Lewis CM. Identifying the Common Genetic Basis of Antidepressant Response. Biol Psychiatry Glob Open Sci. 2022 Apr;2(2):115-126.
  • Takekita Y, Hiraoka S, Iwama Y, Sunada N, Aoki N, Ogata H, Funatsuki T, Takano C, Yanagida T, Koshikawa Y, Naito M, Yamamoto A, Kato M, Kinoshita T. Divergence of dose-response with asenapine: a cluster analysis of randomized, double-blind, and placebo control study. CNS Spectr. 2022 Jun;27(3):369-377.
  • Naito M, Kato M, Koshikawa Y, Bandou H, Sakai S, Takekita Y, Nishida K, Kinoshita T. Personality as a basis for antidepressant selection for patients with depression: A two-point outcome study at 4 and 8 weeks. J Affect Disord. 2022 Oct 1;314:27-33.
  • Aoki Y, Takaesu Y, Baba H, Iga JI, Hori H, Inoue T, Mishima K, Tajika A, Kato M. Development and acceptability of a decision aid for major depressive disorder considering discontinuation of antidepressant treatment after remission. Neuropsychopharmacol Rep. 2022 Sep;42(3):306-314.
  • Tajika A, Hori H, Iga JI, Koshikawa Y, Ogata H, Ogawa Y, Watanabe K, Kato T, Matsuo K, Kato M. Mood Stabilizers and Antipsychotics for Acute Mania: Systematic Review and Meta-Analysis of Augmentation Therapy vs Monotherapy From the Perspective of Time to the Onset of Treatment Effects. Int J Neuropsychopharmacol. 2022 Oct 25;25(10):839-852.
  • Atake K, Hori H, Kageyama Y, Koshikawa Y, Igata R, Tominaga H, Katsuki A, Bando H, Sakai S, Nishida K, Takekita Y, Kato T, Kinoshita T, Kato M. Pre-treatment plasma cytokine levels as potential predictors of short-term remission of depression. World J Biol Psychiatry. 2022 Dec;23(10):785-793.
  • Kanahara N, Kimura H, Kinoshita T, Iyo M, Takekita Y. Efficacy of Asenapine in Drug-resistant Psychotic Patients with Dopamine Supersensitivity Psychosis: Two Cases. Clin Psychopharmacol Neurosci. 2023 Feb 28;21(1):197-201.
  • Kishi T, Sakuma K, Hatano M, Okuya M, Matsuda Y, Kato M, Iwata N. Relapse and its modifiers in major depressive disorder after antidepressant discontinuation: meta-analysis and meta-regression. Mol Psychiatry. 2023 Mar;28(3):974-976.
  • Adachi N, Kubota Y, Goto E, Watanabe K, Yoshimura R, Tsuboi T, Yasui-Furukori N, Kato M, Hongo S, Azekawa T, Katsumoto E, Edagawa K, Nakagawa A, Kikuchi T, Ueda H, Miki K. Costs of psychotropics for outpatients with bipolar disorder in Japan; the MUSUBI 2016 survey. Ann Med. 2023 Dec;55(1):2224047.
  • Kato M, Baba H, Takekita Y, Naito M, Koshikawa Y, Bandou H, Kinoshita T. Usefulness of mirtazapine and SSRIs in late-life depression: post hoc analysis of the GUNDAM study. Eur J Clin Pharmacol. 2023 Nov;79(11):1515-1524.
  • Takano C, Kato M, Adachi N, Kubota Y, Azekawa T, Ueda H, Edagawa K, Katsumoto E, Goto E, Hongo S, Miki K, Tsuboi T, Yasui-Furukori N, Nakagawa A, Kikuchi T, Watanabe K, Kinoshita T, Yoshimura R. Clinical characteristics and prescriptions associated with a 2-year course of rapid cycling and euthymia in bipolar disorder: a multicenter treatment survey for bipolar disorder in psychiatric clinics. Front Psychiatry. 2023 May 17;14:1183782.
  • Funatsuki T, Ogata H, Tahara H, Shimamoto A, Takekita Y, Koshikawa Y, Nonen S, Higasa K, Kinoshita T, Kato M. Changes in Multiple microRNA Levels with Antidepressant Treatment Are Associated with Remission and Interact with Key Pathways: A Comprehensive microRNA Analysis. Int J Mol Sci. 2023 Jul 30;24(15):12199.
  • Ogata H, Higasa K, Kageyama Y, Tahara H, Shimamoto A, Takekita Y, Koshikawa Y, Nonen S, Kato T, Kinoshita T, Kato M. Relationship between circulating mitochondrial DNA and microRNA in patients with major depression. J Affect Disord. 2023 Oct 15;339:538-546.
  • Kato M, Masuda T, Sano F, Kato T. The efficacy and safety of lurasidone in bipolar I depression with and without rapid cycling: A pooled post-hoc analysis of two randomized, placebo-controlled trials. J Affect Disord. 2023 Sep 15;337:150-158.
  • Kato M, Hori H, Tajika A. Appropriate duration of antidepressant medications for prevention of depressive relapse and the impact of life stage. Mol Psychiatry. 2023 Dec;28(12):4937-4938.
  • Yamamoto A, Tsukuda B, Minami S, Hayamizu S, Naito M, Koshikawa Y, Funatsuki T, Takano C, Ogata H, Takekita Y, Nishida K, Ikeda S, Kinoshita T, Kato M. Effectiveness and Changes in Brain Functions by an Occupational Therapy Program Incorporating Mindfulness in Outpatients with Anxiety and Depression: A Randomized Controlled Trial. Neuropsychobiology. 2023;82(5):306-318.
  • Aoki Y, Takaesu Y, Matsui K, Tokumasu T, Tani H, Takekita Y, Kanazawa T, Kishimoto T, Tarutani S, Hashimoto N, Takeuchi H, Mishima K, Inada K. Development and acceptability testing of a decision aid for considering whether to reduce antipsychotics in individuals with stable schizophrenia. Neuropsychopharmacol Rep. 2023 Sep;43(3):391-402.
  • Kinoshita T, Takekita Y, Hiraoka S, Tamura F, Iwama Y. Long-term safety and efficacy of sublingual asenapine for the treatment of schizophrenia: A phase III extension study with follow-up for 52 weeks (P06125)-Secondary publication. Neuropsychopharmacol Rep. 2023 Sep;43(3):328-337.
  • Kato M, Nakagome K, Baba T, Sonoyama T, Okutsu D, Yamanaka H, Shimizu R, Motomiya T, Inoue T. Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double-blind, randomized, placebo-controlled, phase 2 clinical trial. Psychiatry Clin Neurosci. 2023 Sep;77(9):497-509.
  • Kishi T, Sakuma K, Hatano M, Okumura T, Kato M, Baba H, Iwata N. Antidepressants available in Japan for older people with major depressive disorder: A systematic review and meta-analysis. Neuropsychopharmacol Rep. 2024 Mar;44(1):267-271.
  • Takekita Y, Hiraoka S, Iwama Y, Matsui D, Aoki N, Ogata H, Funatsuki T, Shimizu T, Murase Y, Koshikawa Y, Kato M, Kinoshita T. Optimal dose for the efficacy of asenapine in patients with schizophrenia: Real-world data. Neuropsychopharmacol Rep. 2024 Mar;44(1):234-239.
  • Kishi T, Sakuma K, Hatano M, Matsuda Y, Esumi S, Miyake N, Miura I, Hori H, Kato M, Iwata N. Newer antidepressant for Japanese adults with major depressive disorder: A systematic review and meta-analysis. Neuropsychopharmacol Rep. 2024 Mar;44(1):216-220.
  • Kishi T, Sakuma K, Saito T, Nakagawa A, Kato M, Iwata N. Comparison of brexpiprazole, aripiprazole, and placebo for Japanese major depressive disorder: A systematic review and network meta-analysis. Neuropsychopharmacol Rep. 2024 Mar;44(1):165-175.
  • Kishi T, Ikuta T, Sakuma K, Hatano M, Matsuda Y, Esumi S, Miyake N, Miura I, Kato M, Iwata N. Safety profile of antidepressant for Japanese adults with major depressive disorder: A systematic review and network meta-analysis. Psychiatry Clin Neurosci. 2024 Feb;78(2):142-144.
  • Kato M, Shiosakai M, Kuwahara K, Iba K, Shimada Y, Saito M, Isogai Y, Sekine D, Aoki K, Koga N, Higuchi T. Adjunctive brexpiprazole 1 mg and 2 mg daily for Japanese patients with major depressive disorder following inadequate response to antidepressants: a phase 2/3, randomized, double-blind (BLESS) study. Psychiatry Clin Neurosci. 2024 Feb;78(2):113-122.
  • Takekita Y, Hiraoka S, Iwama Y, Matsui D, Aoki N, Ogata H, Funatsuki T, Shimizu T, Murase Y, Shimamoto Y, Koshikawa Y, Kato M. Predictors of continuation for asenapine from real-world data in patients with schizophrenia. Ann Gen Psychiatry. 2024 Aug 2;23(1):29.
  • Kato M, Shiosakai M, Kuwahara K, Iba K, Shimada Y, Saito M, Sekine D, Aoki K, Shiomi Y, Higuchi T. A Multicenter, Open-Label Study to Evaluate the Long-term Safety and Efficacy of Adjunctive Brexpiprazole 2 mg Daily in Japanese Patients with Major Depressive Disorder. CNS Drugs. 2024 Dec;38(12):1003-1016.
  • Takekita Y, Matsumoto Y, Masuda T, Yoshida K, Koshikawa Y, Kato M. Association between treatment response and dose of blonanserin transdermal patch in patients with acute schizophrenia: A post hoc cluster analysis based on baseline psychiatric symptoms. Neuropsychopharmacol Rep. 2024 Dec;44(4):784-791.
  • Kato T, Ogasawara K, Motomura K, Kato M, Tanaka T, Takaesu Y, Nio S, Kishi T, So M, Nemoto K, Suzuki E, Watanabe K, Matsuo K; JSMD Bipolar Disorder Guidelines Revision Working Group; JSMD Bipolar Disorder Committee; JSMD Guidelines Committee. Practice Guidelines for Bipolar Disorder by the JSMD (Japanese Society of Mood Disorders). Psychiatry Clin Neurosci. 2024 Nov;78(11):633-645.
  • Murase Y, Kato M, Kinoshita T, Takekita Y. Lithium-induced cognitive dysfunction assessed over 1-year hospitalisation: A case report. S Afr J Psychiatr. 2024 Sep 26;30:2314.
  • Li D, Pain O, Fabbri C, Wong WLE, Lo CWH, Ripke S, Cattaneo A, Souery D, Dernovsek MZ, Henigsberg N, Hauser J, Lewis G, Mors O, Perroud N, Rietschel M, Uher R, Maier W, Baune BT, Biernacka JM, Bondolfi G, Domschke K, Kato M, Liu YL, Serretti A, Tsai SJ, Weinshilboum R; GSRD Consortium, the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; McIntosh AM, Lewis CM. Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis. Transl Psychiatry. 2024 Jul 19;14(1):296.
  • Takekita Y, Suwa T, Yasuda K, Kawashima H, Omori W, Kurimoto N, Tsuboi T, Noda T, Aoki N, Wada K, Inada K, Takebayash M; Expert Consensus Development Working Group; Electroconvulsive Therapy Committee; Japanese Society of General Hospital Psychiatry. Approaches for difficult-to-induce-seizures electroconvulsive therapy cases (DEC): a Japanese expert consensus. Ann Gen Psychiatry. 2025 Jan 12;24(1):2.
  • Urata M, Sakurai H, Ueno F, Maruki T, Tada T, Uchida T, Matsumoto Y, Murao M, Tomita M, Baba H, Kato M, Tsuboi T, Watanabe K. Efficacy of Pharmacological Interventions in Milder Depression: A Systematic Review and Meta-Analysis. Neuropsychopharmacol Rep. 2025 Mar;45(1):e70008.
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