Dimensional approach to mental disease through autoantibodies

• Project/Area Number: 19K08019
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Okayama University
• Principal Investigator: Takaki Manabu 岡山大学, 大学病院, 講師 (60452570)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 自己免疫性脳炎 / 自己抗体 / 精神疾患 / 免疫療法 / 抗NMDA受容体抗体脳炎 / VGKC複合体抗体 / LGI-1抗体 / cell based assay法 / 抗NMDAR抗体脳炎 / 抗DRD2抗体脳炎 / 統合失調症 / 気分障害 / てんかん精神病 / 非定型精神病 / 神経発達障害 / 抗VGKC複合体抗体 / 抗NMDA受容体抗体 / ディメンジョナルアプローチ

Outline of Research at the Start

精神疾患の病態仮説は、グルタミン酸、ドパミン、GABA仮説があり、各受容体への自己抗体が存在する。精神疾患と診断された患者の中に、抗NMDA受容体抗体の陽性例が増えているが、他の受容体抗体の検討はない。精神疾患の発症の原因として神経発達障害仮説があるが、我々は自己抗体が神経発達や精神疾患の発症脆弱性に与える影響の検討を世界で初めて行ってきた。本研究では、抗NMDA受容体抗体を含む神経伝達物質受容体自己抗体の、動物実験を用いた基礎的検討、患者髄液を用いた臨床的検討を行い、神経発達、臨床症状、治療効果の違いを検討し、精神疾患を神経伝達物質障害別に新分類するディメンジョナルアプローチに寄与する。

Outline of Final Research Achievements

Anti-NMDA receptor antibodies were measured in about 260 patients with suspected schizophrenia, mood disorders, and epilepsy, and more than 10 were positive. The patient was ineffective with psychotropic medications and was in complete or partial remission with immunotherapy including rituximab. In eleven patients with epilepsy each two patient was positive for anti-NMDA receptor antibodies or VGKC complex antibodies (LGI-1 antibody), and in 3 patients, the symptoms including epilepsy were in complete or partial remission by immunotherapy. In a basic study using rat cerebral cortex primary culture neurons, patient anti-NMDA receptor antibodies impaired neurite outgrowth, delayed central body disappearance, and dendrite formation and were irreversible even if the antibodies were removed. Prolonged exposure to neurons of anti-NMDA receptor antibodies impaired neurodevelopment.

Academic Significance and Societal Importance of the Research Achievements

統合失調症、気分障害、てんかんなど初期診断される患者で神経自己抗体の存在が確認され、免疫療法の有効性が示唆された。抗NMDA受容体抗体脳炎は早期発見治療によって予後が良い疾患であるが、発見が遅れれば致死的または後遺症を生じる。今回の基礎的研究で抗NMDA受容体抗体の直接の神経発達障害が証明され、抗NMDA受容体抗体を含む各種神経自己抗体検査を積極的に行い、自己免疫性脳炎の典型的経過で致死的な症状を示す患者だけでなく、精神症状のみの抗体陽性者に対しても、発症早期や再発予防に免疫療法を行う根拠や、向精神薬抵抗性の難治で自己抗体が陽性の患者に免疫療法を積極的に行う可能性が示唆された。

Research Products

• [Journal Article] Inconsistency of Antibody Testing in a Patient with Anti-N-Methyl-D-Aspartate Receptor Encephalitis. (2022)
  • Author(s): Mino S, Hinotsu K, Fujiwara M, Sakamoto S, Sasaki R, Yada Y, Yamada Y, Fukao T, Takaki M, Yamada N.
  • Journal Title: Asian J Psychiatr. Volume: in press
  • Peer Reviewed
• [Journal Article] Association between depression in chronic phase and future clinical outcome of patients with schizophrenia. (2022)
  • Author(s): Yamada Y, Yamauchi Y, Sakamoto S, Fujiwara M, Okahisa Y, Takao S, Takaki M, Yamada N.
  • Journal Title: Psychopharmacology (Berl) Volume: 239 Issue: 3 Pages: 965-975
  • DOI: 10.1007/s00213-022-06099-4
  • Peer Reviewed
• [Journal Article] Impairment of early neuronal maturation in anti-NMDA-receptor encephalitis. (2022)
  • Author(s): Okamoto S, Takaki M, Hinotsu K, Kawai H, Sakamoto S, Okahisa Y, Takao S, Tsutsui K, Kanbayashi T, Tanaka K, Yamada N.
  • Journal Title: Psychopharmacology (Berl) Volume: 239 Issue: 2 Pages: 525-531
  • DOI: 10.1007/s00213-021-06036-x
  • Peer Reviewed
• [Journal Article] Clinical moderators of response to nalmefene in a randomized-controlled trial for alcohol dependence: An exploratory analysis. (2022)
  • Author(s): Hashimoto N, Habu H, Takao S, Sakamoto S, Okahisa Y, Matsuo K, Takaki M, Kishi Y, Yamada N.
  • Journal Title: Drug Alcohol Depend. Volume: in press Pages: 109365-109365
  • DOI: 10.1016/j.drugalcdep.2022.109365
  • Peer Reviewed
• [Journal Article] A Decrease of Neutrophils After COVID-19 Vaccination in a Treatment-Resistant Patient With Schizophrenia Taking Clozapine. (2022)
  • Author(s): Takaki M, Yada Y, Sakamoto S, Fujiwara M, Okahisa Y, Yamada N.
  • Journal Title: J Clin Psychopharmacol. Volume: in press Issue: 3 Pages: 324-325
  • DOI: 10.1097/jcp.0000000000001527
  • Peer Reviewed
• [Journal Article] Mirtazapine Was Effective for a Patient With Benzodiazepine Dependence. (2022)
  • Author(s): Takaki M, Ishikawa R, Sakamoto S, Hashimoto N, Okahisa Y, Yamada N.
  • Journal Title: Clin Neuropharmacol. Volume: 45 Issue: 1 Pages: 11-12
  • DOI: 10.1097/wnf.0000000000000488
  • Peer Reviewed
• [Journal Article] 統合失調症における抗精神病薬の使い分け (2022)
  • Author(s): 髙木学, 矢田勇慈, 酒本真次, 岡久祐子, 児玉匡史, 来住由樹, 武田俊彦, 山田了士
  • Journal Title: 精神科 Volume: 40 Pages: 283-290
• [Journal Article] The relationship between plasma clozapine concentration and clinical outcome: a cross-sectional study. (2021)
  • Author(s): Yada Y, Kitagawa K, Sakamoto S, Ozawa A, Nakada A, Kashiwagi H, Okahisa Y, Takao S, Takaki M, Kishi Y, Yamada N.
  • Journal Title: Acta Psychiatr Scand. Volume: 143 Issue: 3 Pages: 227-237
  • DOI: 10.1111/acps.13264
  • Peer Reviewed / Open Access
• [Journal Article] Rituximab was effective for treatment of anti-NMDAR encephalitis in early adolescence in initially suspected dissociative disorder (2021)
  • Author(s): Takashi Shibata, Hiroki Kawai, Shinji Sakamoto, Ko Tsutsui, Takashi Kanbayashi, Keiko Tanaka, Manabu Takaki
  • Journal Title: Clin Neuropharmacol. Volume: in press Issue: 3 Pages: 000-000
  • DOI: 10.1097/wnf.0000000000000443
  • Peer Reviewed
• [Journal Article] 精神疾患の病因における抗NMDA受容体抗体 (2021)
  • Author(s): 髙木学, 酒本真次, 岡久祐子, 山田了士
  • Journal Title: 医学のあゆみ Volume: 227 Pages: 964-969
• [Journal Article] 【特集】精神科で見落とされやすい身体疾患, 自己免疫性脳炎・脳症と精神症状. (2021)
  • Author(s): 山田了士, 髙木学, 岡久祐子, 酒本真次
  • Journal Title: 精神科治療学 Volume: 34 Pages: 1239-1245
• [Journal Article] Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus (2020)
  • Author(s): Mizuki Yutaka、Sakamoto Shinji、Okahisa Yuko、Yada Yuji、Hashimoto Nozomu、Takaki Manabu、Yamada Norihito
  • Journal Title: International Journal of Neuropsychopharmacology Volume: in press Issue: 5 Pages: 000-000
  • DOI: 10.1093/ijnp/pyaa097
  • NAID: 120007045004
  • Peer Reviewed / Open Access
• [Journal Article] Electroconvulsive Therapy Is Effective and Safe for Serious Catatonia-Related Ileus: Two Case Reports (2020)
  • Author(s): Yuto Yamada, Masaki Fujiwara, Ryuhei So, Satoru Edahiro, Yukiko Matsui, Shinji Sakamoto, Kiyohiro Kawada, Manabu Takaki, Suguru Ishizu, Keiko Kanazawa, Yoshiki Kishi, Norihito Yamada
  • Journal Title: J ECT. Volume: 36(4) Issue: 4 Pages: e49-e51
  • DOI: 10.1097/yct.0000000000000686
  • Peer Reviewed
• [Journal Article] Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder (2020)
  • Author(s): Kato Hidekazu、Kushima Itaru、Mori Daisuke、Yoshimi Akira、Aleksic Branko、Nawa Yoshihiro、Toyama Miho、Furuta Sho、Yu Yanjie、Ishizuka Kanako、Kimura Hiroki、Arioka Yuko、Tsujimura Keita、Morikawa Mako、Okada Takashi、Inada Toshiya、Nakatochi Masahiro、Shinjo Keiko、Kondo Yutaka、Kaibuchi Kozo、Egawa Jun et al
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 421-421
  • DOI: 10.1038/s41398-020-01107-7
  • Peer Reviewed / Open Access
• [Journal Article] 自己抗体を通した精神疾患のディメンジョナルアプローチ (2020)
  • Author(s): 髙木 学
  • Journal Title: Medical Science Digest Volume: 46(6) Pages: 58-59
  • Peer Reviewed
• [Journal Article] Switching strategies for antipsychotic monotherapy in schizophrenia: a multi-center cohort study of aripiprazole (2020)
  • Author(s): Obayashi Y, Mitsui S, Sakamoto S, Minao N, Yoshimura B, Kono T, Yada Y, Okahisa Y, Takao S, Kishi Y, Takeda T, Takaki M, Yamada N.
  • Journal Title: Psychopharmacology Volume: 237(1) Issue: 1 Pages: 167-175
  • DOI: 10.1007/s00213-019-05352-7
  • Peer Reviewed
• [Journal Article] Anti-NMDA-receptor antibody in initial diagnosis of mood disorder. (2019)
  • Author(s): Kawai H, Takaki M, Sakamoto S, Shibata T, Tsuchida A, Yoshimura B, Yada Y, Matsumoto N, Sato K, Abe K, Okahisa Y, Kishi Y, Takao S, Tsutsui K, Kanbayashi T, Tanaka K, Yamada N.
  • Journal Title: Eur Neuropsychopharmacol. Volume: 29(9) Issue: 9 Pages: 1041-1050
  • DOI: 10.1016/j.euroneuro.2019.07.137
  • Peer Reviewed
• [Journal Article] Anti-N-Methyl-D-Aspartate Receptor Encephalitis in Psychiatry (2019)
  • Author(s): Sakamoto S, Kawai H, Okahisa Y, Tsutsui K, Kanbayashi T, Tanaka K, Mizuki Y, Takaki M, Yamada N.
  • Journal Title: Acta Medica Okayama Volume: 73 Issue: 3 Pages: 189-195
  • DOI: 10.18926/AMO/56860
  • NAID: 120006647996
  • URL: https://ousar.lib.okayama-u.ac.jp/56860
  • Peer Reviewed / Open Access
• [Journal Article] 【特集】精神科で見落とされやすい身体疾患.自己免疫性脳炎・脳症と精神症状. (2019)
  • Author(s): 山田了士、髙木学、岡久祐子、酒本真次
  • Journal Title: 精神科治療学 Volume: 34 Pages: 1239-1245
  • Peer Reviewed
• [Journal Article] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect (2018)
  • Author(s): Ikeda M,Takahashi A,Kamatani Y,Momozawa Y,Saito T,Kondo K,Shimasaki A,Kawase K,Sakusabe T,Iwayama Y,Toyota T,Wakuda T,Kikuchi M,Kanahara N,Yamamori H,Yasuda Y,Watanabe Y,Hoya S,Aleksic B,Kushima I,Arai H,Takaki M,Hattori K,Kunugi H,Okahisa Y,Ohnuma T,Ozaki N,Someya T,Hashimoto R,Yoshikawa T,Kubo M,Iwata N
  • Journal Title: Schizophrenia Bulletin Volume: 印刷中 Issue: 4 Pages: 824-834
  • DOI: 10.1093/schbul/sby140
  • Peer Reviewed / Open Access
• [Presentation] 自己免疫性精神病: 発症機序と多彩な精神症状 (2021)
  • Author(s): 髙木学
  • Organizer: 第117回日本精神神経学会学術総会シンポジウム
  • Invited
• [Presentation] 睡眠相後退症候群に対しアリピプラゾールが有効であった一例.適用外使用を考える (2021)
  • Author(s): 髙木学, 氏家寛
  • Organizer: 第46回日本睡眠学会
  • Invited
• [Presentation] 成人期自閉症スペクトラム症の中核症状・感覚処理困難に対するSafe and sound protocolの効果―探索的介入研究. (2021)
  • Author(s): 河合弘樹、岸本真希子、髙木学、岡久祐子、酒本真次、寺田整司、山田了士.
  • Organizer: 第31回日本臨床精神神経薬理学会
• [Presentation] 初期診断が気分障害であった患者における 抗NMDA受容体抗体保有率の検討 (2020)
  • Author(s): 河合弘樹、髙木学、酒本真次、柴田敬、土田彩加、吉村文太、矢田勇慈、松本奈見子、佐藤恒太、阿部康二、岡久祐子、来住由樹、高尾総司、筒井幸、神林崇、田中恵子、山田了士
  • Organizer: 第116回日本精神神経学会学術総会
• [Presentation] 精神疾患のディメンショナルアプローチ (2020)
  • Author(s): 髙木学
  • Organizer: 第116回日本精神神経学会学術総会
  • Invited
• [Presentation] 自己抗体を通した精神疾患の ディメンジョナルアプローチ (2020)
  • Author(s): 髙木学
  • Organizer: Psychiatric Reserch Web Semnar
  • Invited
• [Presentation] 慢性統合失調症患者におけるアリピプラゾール単剤治療への切替方法についての検討（多施設コホート研究） (2020)
  • Author(s): 大林芳明, 光井 聡，酒本真次，皆尾 望, 吉村文太, 耕野敏樹, 矢田勇慈, 岡久祐子, 高尾総司, 来住由樹, 武田俊彦, 髙木 学, 山田了士
  • Organizer: 第116回日本精神神経学会学術総会9月28日（月）～30日
• [Presentation] 非定型精神病における抗NMDA受容体抗体の陽性率の検討 (2020)
  • Author(s): 樋之津健二、髙木学、河合弘樹、酒本真次、岡久祐子、山田了士
  • Organizer: 第42回日本生物学的精神医学会
• [Presentation] 精神疾患と自己抗体の基礎研究と臨床 ～抗NMDA受容体から他受容体へ. (2019)
  • Author(s): 髙木学
  • Organizer: 第115回 日本精神神経学会学術総会, 新潟市
  • Invited
• [Presentation] 細胞膜表面抗原への抗体による自己免疫性脳炎と精神疾患. (2019)
  • Author(s): 髙木学, 神林崇, 田中惠子, 来住由樹, 山田了士
  • Organizer: 第32回 日本総合病院精神医学会総会, 倉敷市
  • Invited
• [Presentation] 精神疾患と抗NMDAR抗体 (2019)
  • Author(s): 髙木学
  • Organizer: てんかんと精神症状セミナー, 東京