The influence of autoimmune antibodies on psychiatric diseases

• Project/Area Number: 16K10188
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Okayama University
• Principal Investigator: Takaki Manabu 岡山大学, 大学病院, 講師 (60452570)
• Research Collaborator: Sakamoto Shinji ; Kawai Hiroki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 抗NMDA受容体抗体脳炎 / 統合失調症 / 気分障害 / 抗体価と精神症状 / 神経発達障害 / プライマリーカルチャーニューロン / 免疫療法 / cell based assay法 / 自己免疫性脳炎 / 抗 NMDA 受容体抗体 / 臨床転帰 / 抗免疫療法 / 双極性障害 / Cell Based Assay

Outline of Final Research Achievements

The patients with anti-NMDA receptor encephalitis show only psychiatric symptoms before or without neurological findings. Anti-NMDA receptor antibodies is supposed to be involved in the pathogenesis of psychiatric disorders. The 190 patients with psychiatric disorders were tested anti-NMDA receptor antibodies by cell based assay. Seven patients with initially suspected schizophrenia and mood disorder had anti-NMDA receptor antibodies. The immunotherapy including methylprednisolone pulse, plasma exchange, intravenous immunoglobulin or rituximab were effective and the psychotropic medications were not. There was a correlation between anti-NMDA receptor antibody titers and psychiatric symptoms scored by Brief Psychiatric Rating Scale. In rat primary cerebral culture neurons, anti-NMDA receptor antibodies impaired neurite outgrowth, disappearance of centrosome (failure of neuronal migration), dendrite formation, and these phenotypes were not reversible even after removal of antibodies.

Academic Significance and Societal Importance of the Research Achievements

抗NMDA受容体抗体脳炎は抗体除去により予後良好であるが治療が遅れた場合など時に重篤となる。精神症状のみで精神疾患として慢性の経過をたどっている場合や妊婦が抗NMDA受容体抗体脳炎に罹患した際の胎児の場合、抗NMDA受容体抗体に神経細胞が長期間暴露されることで、神経発達に不可逆な影響を及ぼす可能性が示唆された。今後、抗NMDA受容体以外に対する自己抗体の検索も行っていく必要がある。精神疾患に対して、早期の免疫療法（ステロイドパルス療法、血漿交換療法、免疫グロブリン大量療法、リツキシマブによる抗腫瘍療法）が有効である可能性が示唆された。

Research Products

• [Journal Article] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect (2019)
  • 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: Schizophr Bull Volume: 印刷中 Pages: 824-834
  • DOI: 10.1093/schbul/sby140
  • Peer Reviewed / Open Access
• [Journal Article] Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine. (2018)
  • Author(s): Takaki M, Kodama M, Mizuki Y, Kawai H, Yoshimura B, Kishimoto M, Sakamoto S, Okahisa Y, Yamada N.
  • Journal Title: Eur Neuropsychopharmacol. Volume: 28(5) Pages: 610-619
  • DOI: 10.1016/j.euroneuro.2018.03.004
  • Peer Reviewed / Open Access
• [Journal Article] Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation. (2018)
  • Author(s): Omori Y, Kanbayashi T, Sagawa Y, Imanishi A, Tsutsui K, Takahashi Y, Takeshima M, Takaki M, Nishino S, Shimizu T.
  • Journal Title: Neuropsychiatr Dis Treat. Volume: 18 Pages: 1281-1286
  • DOI: 10.2147/ndt.s158865
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility (2018)
  • Author(s): Yu Yanjie、Lin Yingni、Takasaki Yuto、Wang Chenyao、Kimura Hiroki、Xing Jingrui、Ishizuka Kanako、Toyama Miho、Kushima Itaru、Mori Daisuke、Arioka Yuko、Uno Yota、Shiino Tomoko、Nakamura Yukako、Okada Takashi、Morikawa Mako、Ikeda Masashi、Iwata Nakao、Okahisa Yuko、Takaki Manabu、Sakamoto Shinji、et al.
  • Journal Title: Transl Psychiatry Volume: 8 Pages: 12-12
  • DOI: 10.1038/s41398-017-0061-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 精神医学のフロンティア 統合失調症患者における認知機能障害の推定 多施設共同研究 (2018)
  • Author(s): 藤野 陽生, 住吉 チカ, 安田 由華, 山森 英長, 藤本 美智子, 福永 雅喜, 三浦 健一郎, 竹林 佑人, 岡田 直大, 磯村 周一, 河野 直子, 豊巻 敦人, 久我 弘典, 磯部 昌憲, 大矢 一登, 岡久 祐子, 高木 学, 橋本 直樹, 加藤 正樹, 鬼塚 俊明, 上野 雄文, 大沼 徹, 笠井 清登, 尾崎 紀夫, 住吉 太幹, 井村 修, 橋本 亮太, COCORO
  • Journal Title: 精神経誌 Volume: 120 Pages: 255-261
  • Peer Reviewed / Open Access
• [Journal Article] Restless Genital Syndrome Induced by Milnacipran. (2018)
  • Author(s): Miyake K, Takaki M, Sakamoto S, Kawada K, Inoue S, Yamada N.
  • Journal Title: Clin Neuropharmacol. Volume: 41 Pages: 109-110
  • DOI: 10.1097/wnf.0000000000000279
  • Peer Reviewed / Open Access
• [Journal Article] Augmentation with blonanserin for schizophrenia patient with insufficient response to clozapine (2018)
  • Author(s): Takaki M, Takahashi S, Yada Y, Kitagawa K, Kishi Y, Yamada N.
  • Journal Title: Open Journal of Psychiatry Volume: 8 Pages: 131-136
  • DOI: 10.4236/ojpsych.2018.82012
  • Peer Reviewed / Open Access
• [Journal Article] N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection. (2017)
  • Author(s): Tsutsui K, Kanbayashi T, Takaki M, Omori Y, Imai Y, Nishino S, Tanaka K, Shimizu T.
  • Journal Title: Neuropsychiatric Disease and Treatment Volume: 13 Pages: 339-345
  • DOI: 10.2147/ndt.s125800
  • Peer Reviewed / Open Access
• [Journal Article] Anti-NMDA Receptor Antibody Positivity and Presentations Without Seizure, Involuntary Movement, Hypoventilation, or Tumor: A Systematic Review of the Literature. (2017)
  • Author(s): Yoshimura B, Takaki M.
  • Journal Title: J Neuropsychiatry Clin Neurosci. Volume: 29 Pages: 267-274
  • DOI: 10.1176/appi.neuropsych.16050101
  • Peer Reviewed / Open Access
• [Journal Article] The critical treatment window of clozapine in treatment-resistant schizophrenia: secondary analysis of an observational study. (2017)
  • Author(s): Yoshimura B, Yada Y, So R, Takaki M, Yamada N.
  • Journal Title: Psychiatry Res. Volume: 250 Pages: 65-70
  • DOI: 10.1016/j.psychres.2017.01.064
  • Peer Reviewed / Open Access
• [Journal Article] Estimated cognitive decline in patients with schizophrenia: A multicenter study. (2017)
  • Author(s): Fujino H, Sumiyoshi C, Yasuda Y, Yamamori H, Fujimoto M, Fukunaga M, Miura K, Takebayashi Y, Okada N, Isomura S, Kawano N, Toyomaki A, Kuga H, Isobe M, Oya K, Okahisa Y, Takaki M, Hashimoto N, Kato M, Onitsuka T, Ueno T, Ohnuma T, Kasai K, Ozaki N, Sumiyoshi T, Imura O, Hashimoto R
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 印刷中 Pages: 294-300
  • DOI: 10.1111/pcn.12474
  • Peer Reviewed / Open Access
• [Journal Article] Algorithm-based pharmacotherapy for first-episode schizophrenia involuntarily hospitalized: A retrospective analysis of real-world practice. (2017)
  • Author(s): Yoshimura B, Sato K, Takaki M, Yamada N.
  • Journal Title: Early Interv Psychiatry. Volume: in press
  • DOI: 10.1111/eip.12442
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of remission during acute treatment of first-episode schizophrenia patients involuntarily hospitalized and treated with algorithm-based pharmacotherapy: secondary analysis of an observational study. (2017)
  • Author(s): Yoshimura B, Sakamoto S, Sato K, Takaki M, Yamada N.
  • Journal Title: Early Interv Psychiatry Volume: in press
  • DOI: 10.1111/eip.12531
  • Peer Reviewed / Open Access
• [Journal Article] Transethnic Replication Study to Assess the Association Between Clozapine-Induced Agranulocytosis/Granulocytopenia and Genes at 12p12.2 in a Japanese Population (2017)
  • Author(s): Saito T, Ikeda M, Hashimoto R, Iwata N; Members of the Clozapine Pharmacogenomics Consortium of Japan
  • Journal Title: Biol Psychiatry Volume: in press
  • DOI: 10.1016/j.biopsych.2016.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Human Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) Regulates Dendritic Morphogenesis (2017)
  • Author(s): Mizuki Y, Takaki M, Sakamoto S, Okamoto S, Kishimoto M, Okahisa Y, Itoh M, Yamada N
  • Journal Title: Int J Mol Sci. Volume: 18(1) Pages: 1-11
  • DOI: 10.3390/ijms18010067
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Individual risk alleles of susceptibility to schizophrenia are associated with poor clinical and social outcomes. (2016)
  • Author(s): Sakamoto S, Takaki M, Okahisa Y, Mizuki Y, Inagaki M, Ujike H, Mitsuhashi T, Takao S, Ikeda M, Uchitomi Y, Iwata N, Yamada N.
  • Journal Title: J Hum Genet. Volume: 61 Pages: 329-334
  • DOI: 10.1038/jhg.2015.153
  • NAID: 40020802866
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population (2016)
  • Author(s): Saito T, Ikeda M, Mushiroda T, Ozeki T, Kondo K, Shimasaki A, Kawase K, Hashimoto S, Yamamori H, Yasuda Y, Fujimoto M et al
  • Journal Title: BIol Psychiatry Volume: in press Pages: 636-42
  • DOI: 10.1016/j.biopsych.2015.12.006
  • NAID: 120007129309
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-Inflammatory Therapy and Immunotherapy Were Partially Effective in a Patient With Anti-N-Methyl-D-Aspartate Receptor Antibodies and a Special Subgroup of Treatment-Resistant Schizophrenia. (2016)
  • Author(s): Senda M, Bessho K, Oshima E, Sakamoto S, Tanaka K, Tsutsui K, Kanbayashi T,Takaki M, Yoshimura B.
  • Journal Title: J Clin Psychopharmacol Volume: 36 Pages: 92-3
  • DOI: 10.1097/jcp.0000000000000439
  • Peer Reviewed / Open Access
• [Presentation] The relationship of N-methyl-D-aspartate receptor antibody and psychiatric disorders (2018)
  • Author(s): Kawai H, Sakamoto S, Kishimoto M, Okahisa Y, Takaki M, Yamada N.
  • Organizer: CINP 31st World Congress, Vienna, Austria
  • Int'l Joint Research
• [Presentation] Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine (2018)
  • Author(s): Takaki M, Kodama M, Mizuki Y, Kawai H, Yoshimura B, Kishimoto M, Sakamoto S, Okahisa Y, Yamada N.
  • Organizer: CINP 31st World Congress, Vienna, Austria
  • Int'l Joint Research
• [Presentation] Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine (2018)
  • Author(s): Takaki M, Kodama M, Mizuki Y, Kawai H, Yoshimura B, Kishimoto M, Sakamoto S, Okahisa Y, Yamada N.
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry, WFSBP 2018 KOBE, Kobe, Japan
  • Int'l Joint Research
• [Presentation] 自己免疫てんかんから見たてんかんと精神症状 (2018)
  • Author(s): 酒本真次, 髙木学
  • Organizer: 第114回 日本精神神経学会学術総会, 神戸
  • Invited
• [Presentation] 精神科救急病院との連携からみた自己免疫性脳炎の検討 (2018)
  • Author(s): 髙木学, 酒本真次
  • Organizer: 第114回 日本精神神経学会学術総会, 神戸
  • Invited
• [Presentation] 精神疾患における抗NMDA受容体抗体保有率の検討 (2018)
  • Author(s): 酒本真次, 河合弘樹, 岸本真希子, 岡久祐子, 髙木学, 筒井幸, 神林崇, 田中惠子,山田了士
  • Organizer: 第114回 日本精神神経学会学術総会, 神戸
• [Presentation] The potential causal relationship between anti-NMDAR antibody and mood disorders (2018)
  • Author(s): Kawai H, Sakamoto S, Kishimoto M, Okahisa Y, Takaki M, Yamada N
  • Organizer: 第40回日本生物学的精神医学会, 第61回日本神経化学会大会, 神戸
• [Presentation] 岡山における自己免疫脳症の検討 (2017)
  • Author(s): 髙木学, 来住由樹, 吉村文太
  • Organizer: 第113回日本精神神経学会
  • Invited
• [Presentation] マイコプラズマ感染後の小児急性精神神経症候群に続発した緊張病状態に対してmECTが奏功した一例 (2017)
  • Author(s): 枝廣 暁, 酒本 真次, 川田 清宏, 高木 学, 山田 了士
  • Organizer: 第113回 日本精神神経学会総会
• [Presentation] 髄液抗NMDA受容体抗体と血清AQP4抗体陽性の自己免疫性脳炎の一例 (2017)
  • Author(s): 李大賢, 岸本真希子, 酒本真次, 高木学, 山田了士
  • Organizer: 第58回 中国・四国精神神経学会
• [Presentation] 自己免疫性脳炎の精神症状に対する免疫療法の可能性（臨床と基礎研究） (2016)
  • Author(s): 髙木学、吉村文太、矢田勇慈
  • Organizer: 第112回日本精神神経学会学術集会
  • Place of Presentation: 幕張
• [Presentation] 自己免疫性脳症の精神症状に対する免疫療法の可能性 (2016)
  • Author(s): 髙木学
  • Organizer: 第49回岡山臨床薬理研究会
  • Place of Presentation: 岡山
  • Invited
• [Presentation] 統合失調症と診断されていた自閉スペクトラム症の1例～岡山大学病院「心のリスク専門外来」の取り組みから～ (2016)
  • Author(s): 李大賢、酒本真次、枝廣暁、大島悦子、髙木学、山田了士
  • Organizer: 第57回中国四国精神神経学会
  • Place of Presentation: 松山