Updated on 2025/10/23

写真a

 
TAKAKI Manabu
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
Homepage
http://kaken.nii.ac.jp/d/r/60452570.ja.html
Profile
精神医学において統合失調症の臨床、基礎研究を行ってきました。最近は、自己免疫性脳炎と精神疾患の関連を中心に臨床、基礎研究を行っています。加えて、精神科薬理学の臨床と基礎の論文を執筆しています。
External link

Degree

  • 医学博士

Research Interests

  • 精神科薬理学

  • 包括脳ネットワーク

  • 自己免疫性脳炎

  • 抗NMDAR抗体

  • 神経発達障害

  • シナプス

  • 統合失調症

  • PCM-1

  • DISC-1

  • 認知機能

  • クロザピン

  • セントロソーム

  • カリリン

Research Areas

  • Life Science / Psychiatry

Research History

  • 岡山大学学術研究院 医歯薬学域   教授

    2022.10

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Papers

  • Alteration of perineuronal nets and parvalbumin interneurons in prefrontal cortex and hippocampus, and correlation with blood corticosterone in activity-based anorexia model mice. Reviewed International journal

    Hoang Duy Nguyen, Haruko Miyazaki, Hiroki Kawai, Ziyi Wang, Shinji Sakamoto, Manabu Takaki, Toshitaka Oohashi

    Neuroscience research   218   104922 - 104922   2025.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    Anorexia nervosa (AN) is an eating disorder characterized by restricted energy intake, severely underweight status, and frequent hyperactivity. Previous research has shown structural and functional alterations in the medial prefrontal cortex (mPFC) and hippocampus of AN patients. To investigate the pathological mechanism of AN, we analyzed the expression and distribution of parvalbumin (PV) interneurons and perineuronal nets (PNNs), which are implicated in the pathology of neuropsychiatric disorders, in the mPFC and hippocampus dorsal (HPCd) and ventral (HPCv) using an activity-based anorexia (ABA) mouse model. We found that PNN expression and density increased in the mPFC, with minor alterations in the HPCd and HPCv of ABA mice. The expression and distribution of PV neurons were unchanged in the brains of ABA mice, except for a regional decrease in PV-expressing neuron density in the HPCd. Co-localization analysis showed an increased number of PNNs enwrapping PV-negative neurons in the mPFC of ABA mice. Furthermore, the upregulation of PNN expression in the mPFC was positively correlated with elevated blood corticosterone levels, a well-known stress indicator, in ABA mice. Our findings suggest that the increased expression and distribution of PNNs surrounding PV-negative neurons in the mPFC may indicate the pathological mechanisms of AN.

    DOI： 10.1016/j.neures.2025.104922

    PubMed

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  • Occupational therapist-guided exercise increased white blood cell and neutrophil counts during clozapine treatment: A case report. Reviewed International journal

    Kenji Hinotsu, Shinji Sakamoto, Hiroki Kawai, Yoshio Ohya, Akiyoshi Yokode, Takahiro Asada, Yuko Okahisa, Manabu Takaki

    PCN reports : psychiatry and clinical neurosciences   4 ( 3 )   e70167   2025.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Moderate exercise increases white blood cells and neutrophils. However, there are no reports on the relationship between exercise intensity and these cells. We observed a patient taking clozapine whose white blood cell and neutrophil counts were borderline. Supervised exercise therapy with an occupational therapist stabilized these counts. CASE PRESENTATION: A 50-year-old woman with treatment-resistant schizophrenia was prescribed clozapine. By Day 63, the clozapine dosage had been increased to 450 mg/day. Additionally, she was advised to perform a 30-min walking exercise program 1 h before blood tests. Exercise therapy supervised by an occupational therapist was performed eight times, and self-training was performed five times. Exercise intensity was monitored using the Borg Scale for subjective evaluation and the Karvonen formula for objective evaluation. Supervised exercise therapy with an occupational therapist resulted in greater increases on the Borg Scale and Karvonen formula than did self-training. It also induced increases in white blood cells and neutrophils. Her psychiatric symptoms improved, and she was discharged on Day 71. A blood test taken after discharge revealed that her white blood cell and neutrophil counts were within the normal range and she continued to take clozapine for 2 years. She has since been able to enjoy a calm and relaxed life at home. CONCLUSION: Exercise involving subjective and objective evaluation by an occupational therapist effectively increased white blood cells and neutrophils during clozapine treatment. Supervised exercise therapy by an occupational therapist is important when self-exercise is insufficient for continuing clozapine treatment.

    DOI： 10.1002/pcn5.70167

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  • Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology. Reviewed International journal

    Toru Yamashita, Osamu Yokota, Daiki Ousaka, Hongming Sun, Takashi Haraguchi, Ricardo Satoshi Ota-Elliott, Chika Matsuoka, Tomohito Kawano, Hanae Nakashima-Yasuda, Yusuke Fukui, Yumiko Nakano, Ryuta Morihara, Masato Hasegawa, Yasuyuki Hosono, Seishi Terada, Manabu Takaki, Hiroyuki Ishiura

    Acta neuropathologica   150 ( 1 )   19 - 19   2025.8

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    Language：English   Publishing type：Research paper (scientific journal)  

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms, leading to the accumulation of misfolded proteins, particularly TAR DNA-binding protein 43 (TDP-43). TDP-43 aggregation is a central pathological feature of ALS. Maintaining protein homeostasis is critical and facilitated by heat shock proteins (HSPs), particularly the HSP40 family, which includes co-chaperones such as DNAJC7. Here, we report a family with three siblings affected by ALS who carry a homozygous c.518dupC frameshift variant in DNAJC7, a member of the HSP40 family. All three patients exhibited progressive muscle weakness, limb atrophy, bulbar palsy, and respiratory failure. Pathological examination revealed degeneration of both upper and lower motor neurons, with phosphorylated TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortices. Immunoblot analysis were consistent with a type B pattern of phosphorylated TDP-43 in the precentral gyrus. Immunohistochemistry and RNA sequencing analyses demonstrated a substantial reduction in DNAJC7 expression at both the protein and RNA levels in affected brain regions. In a TDP-43 cell model, DNAJC7 knockdown impaired the disassembly of TDP-43 following arsenite-induced stress, whereas DNAJC7 overexpression suppressed the assembly and promoted the disassembly of arsenite-induced TDP-43 condensates. Furthermore, in a zebrafish ALS model, dnajc7 knockdown resulted in increased TDP-43 aggregation in motor neurons and reduced survival. To the best of our knowledge, this study provides the first evidence linking biallelic loss-of-function variants in DNAJC7 to familial ALS with TDP-43 pathology.

    DOI： 10.1007/s00401-025-02899-y

    PubMed

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  • Effect modification in therapeutic impact of nalmefene on alcohol dependence by ADH1B polymorphism: A secondary analysis of a Japanese randomized clinical trial. Reviewed International journal

    Nozomu Hashimoto, Manabu Takaki, Yoshitsugu Kojima, Izuru Nakamura, Daisuke D Ikeda, Shinji Sakamoto, Yuko Okahisa, Soshi Takao, Keitaro Matsuo

    Addiction (Abingdon, England)   2025.8

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND AND AIMS: The association between alcohol-metabolizing enzyme polymorphisms and treatment response to nalmefene for alcohol dependence has not been studied. We aimed to determine whether alcohol-metabolizing enzyme polymorphisms, specifically ADH1B rs1229984 and ALDH2 rs671, modify the treatment response to nalmefene for alcohol dependence. DESIGN: Secondary analysis of a Japanese randomized clinical trial, in which participants were randomly assigned (4:3:4) to placebo, 10 mg nalmefene or 20 mg nalmefene groups for 24 weeks, accompanied by a brief psychosocial intervention. SETTING: 80 addiction outpatient clinics across Japan. PARTICIPANTS: A subset of 531 individuals (mean age 49.2 years, standard deviation 11.5; 69.9% male), including 196 in the placebo group and 335 in the nalmefene group, who agreed to DNA preservation and had available DNA data between February 2015 and July 2016. MEASUREMENTS: Genotyping was performed to determine ADH1B rs1229984 polymorphism (AA, AG, GG) and ALDH2 rs671 polymorphism (GG, GA, AA) in participants. Primary endpoint was change from baseline in monthly heavy drinking days (HDD, days/month) over the 24 treatment weeks. The key secondary endpoint was change from baseline in daily total alcohol consumption (TAC, g/day) over the 24 treatment weeks. FINDINGS: A mixed-effects model for repeated measures analyses showed a statistically significant gene-treatment interaction with ADH1B rs1229984 for TAC [10.71 (95% confidence interval = 4.03-17.39) g/day, P = 0.002], but not for HDD [1.65 (-0.38 to 3.67) days/month, P = 0.110]: as the G allele of rs1229984 increased, the efficacy regarding TAC decreased. In contrast, no statistically significant gene-treatment interaction was seen with ALDH2 rs671 for either TAC [4.46 (-7.88 to 16.80) g/day, P = 0.478] or HDD [-0.91 (-4.60 to 2.78) days/month, P = 0.630]. In the ADH1B rs1229984 variant, the number needed to treat for two category shifts in drinking risk level, as defined by the World Health Organization, was 3.7 for AA carriers, 6.6 for AG carriers and 18.5 for GG carriers. CONCLUSIONS: The ADH1B rs1229984 polymorphism appears to moderate the response to nalmefene in Japanese patients with alcohol dependence. Specifically, nalmefene appears to show efficacy in individuals with the ADH1B rs1229984 AA genotype.

    DOI： 10.1111/add.70160

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  • Correction: Cerebral Braak stage and amygdala granular fuzzy astrocyte status have independent effects on neuronal 3R-tau and 4R-tau accumulations in the olfactory bulb, respectively, in cases with low to intermediate AD neuropathologic change. Reviewed International journal

    Osamu Yokota, Tomoko Miki, Hanae Nakashima-Yasuda, Hideki Ishizu, Takashi Haraguchi, Akinori Miyashita, Takeshi Ikeuchi, Masato Hasegawa, Naoto Nishikawa, Shintaro Takenoshita, Seishi Terada, Manabu Takaki

    Acta neuropathologica   150 ( 1 )   9 - 9   2025.7

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  • Metaverse Support Groups for LGBTQ+ Youth: An Observational Study on Safety, Self-Expression, and Early Intervention Reviewed

    Joe Hasei, Yosuke Matsumoto, Hiroki Kawai, Yuko Okahisa, Manabu Takaki, Toshifumi Ozaki

    2025.6

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    This study assessed metaverse-based support groups designed to reduce social
    isolation and suicide risk among LGBTQ+ youths. Using the Cluster platform,
    enhanced anonymity, avatar-based self-expression, and accessibility were
    provided. Key findings showed that 79.2% chose avatars matching their gender
    identity, reporting high satisfaction (mean: 4.10/5) and low discomfort (mean:
    1.79/5). Social confidence significantly improved in virtual spaces compared to
    real-world interactions (p<0.001), particularly among participants with
    initially low confidence, averaging an increase of 2.08 points. About half of
    the first-time participants were 16 or younger, highlighting potential for
    early intervention. The metaverse scored higher than real-world environments
    for safety/privacy (3.94/5), self-expression (4.02/5), and accessibility
    (4.21/5). Additionally, 73.6% reported feeling more accepted virtually.
    However, some highly confident individuals offline experienced mild adaptation
    challenges, averaging a confidence decrease of 0.58 points, indicating virtual
    support complements rather than replaces in-person services. These findings
    suggest metaverse-based support effectively lowers psychological barriers and
    provides affirming spaces, potentially reducing severe outcomes such as
    suicidal ideation. Future studies should focus on integrating virtual support
    with existing community and clinical frameworks to enhance long-term impacts.

    DOI： 10.57019/jmv.1639701

    arXiv

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    Other Link： http://arxiv.org/pdf/2507.21079v1

  • Olanzapine enabled rechallenge after lorlatinib-induced psychosis: A case report. Reviewed International journal

    Akiyoshi Yokode, Masaki Fujiwara, Yuko Nakamura, Kadoaki Ohashi, Shinji Sakamoto, Manabu Takaki

    PCN reports : psychiatry and clinical neurosciences   4 ( 2 )   e70091   2025.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Lorlatinib is a third-generation tyrosine kinase inhibitor for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). While it has a high intracranial lesion control rate, it can also cause central nervous system complications, including psychotic symptoms. We present a case of lorlatinib-induced psychosis successfully managed with olanzapine, enabling lorlatinib rechallenge. CASE PRESENTATION: A 32-year-old woman with ALK-positive NSCLC and brain metastases was started on lorlatinib. After 18 months, she developed hallucinations and delusions. Despite treatment with risperidone, her psychotic symptoms persisted, leading to hospitalization. Her symptoms resolved upon lorlatinib discontinuation while risperidone was continued. Given the critical role of lorlatinib in controlling brain metastases, rechallenge was considered. To mitigate concerns regarding drug interactions, risperidone was replaced with olanzapine. Following lorlatinib rechallenge with olanzapine, no recurrence of psychiatric symptoms was observed, allowing continued lorlatinib treatment. Additionally, no progression of lung cancer was noted. CONCLUSION: Lorlatinib is an essential drug for controlling brain metastases in ALK-positive NSCLC. However, it can induce psychotic symptoms. When psychiatrists are involved in managing adverse effects during cancer treatment, close collaboration among oncologists, psychiatrists, and patients is essential.

    DOI： 10.1002/pcn5.70091

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  • A case report of ineffective electroconvulsive therapy for chronic pain. Reviewed International journal

    Takashi Fukao, Masaki Fujiwara, Yuto Yamada, Kazushi Asada, Takahiro Asada, Hirotoshi Ri, Shinji Sakamoto, Manabu Takaki

    PCN reports : psychiatry and clinical neurosciences   4 ( 2 )   e70108   2025.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Somatic symptom disorder (SSD), which includes chronic pain, is a common mental disorder characterized by significant functional impairment and other psychiatric comorbidities. Electroconvulsive therapy (ECT) has been proposed as a potential treatment for refractory chronic pain. However, evidence supporting its efficacy is limited and/or low quality. We present a case of SSD with chronic pain in which ECT was ineffective. CASE PRESENTATION: The patient was a 63-year-old man with chronic pain in the lower back, buttocks, thighs, and soles of the feet. The duration of his chronic pain was 3.8 years. He was diagnosed with Bertolotti's syndrome and SSD. He did not meet the criteria for major depressive disorder. He kept physically active by walking and doing exercises to distract himself from his pain. He strongly perceived pain as a physical issue and preferred ECT over psychotherapy. Despite undergoing 10 ECT sessions with adequate seizures, his pain persisted. After four sessions, he experienced despair over the lack of improvement in pain, which temporarily intensified his suicidal ideation. After undergoing ECT, he continued to maintain his activities, including walking and exercise, while his catastrophic thinking about pain persisted. CONCLUSION: The ineffectiveness of ECT in this case highlights the need for balanced counseling, particularly for patients who consider ECT a last-resort treatment. Psychological monitoring and depression screening are essential, especially given the risk of heightened despair or suicidal ideation when ECT is ineffective. Therefore, collaborative decision-making based on accurate information is vital.

    DOI： 10.1002/pcn5.70108

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  • [Autoimmune Encephalitis Centered on NMDAR Encephalitis from a Psychiatrist's Perspective]. Reviewed

    Manabu Takaki, Shinji Sakamoto

    Brain and nerve = Shinkei kenkyu no shinpo   77 ( 6 )   691 - 698   2025.6

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    Language：Japanese  

    Autoimmune encephalitis, within the psychiatric domain, encompasses two concepts involving psychiatric symptoms triggered by cell-membrane surface antibodies: NMDAR encephalitis, which manifests as encephalitis in neurology, and neuronal autoantibodies detected predominantly in the serum of patients with schizophrenia. Autoimmune encephalitis is associated with humoral immunity abnormalities caused by autoantibodies in the acute phase and cell-mediated immunity disruptions, including those in the chronic phase. Follow-up knowledge is required to provide evidence for immunotherapy in patients with mental illnesses.

    DOI： 10.11477/mf.188160960770060691

    PubMed

    J-GLOBAL

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  • Cerebral Braak stage and amygdala granular fuzzy astrocyte status have independent effects on neuronal 3R-tau and 4R-tau accumulations in the olfactory bulb, respectively, in cases with low to intermediate AD neuropathologic change. Reviewed International journal

    Osamu Yokota, Tomoko Miki, Hanae Nakashima-Yasuda, Hideki Ishizu, Takashi Haraguchi, Akinori Miyashita, Takeshi Ikeuchi, Masato Hasegawa, Naoto Nishikawa, Shintaro Takenoshita, Seishi Terada, Manabu Takaki

    Acta neuropathologica   149 ( 1 )   36 - 36   2025.4

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  • A case of invasive pulmonary aspergillosis associated with clozapine-induced agranulocytosis. Reviewed International journal

    Akiyoshi Yokode, Masaki Fujiwara, Toshiki Terao, Shinji Sakamoto, Yuto Yamada, Ryota Sato, Momoko Mishima, Yuji Yada, Ken-Ichi Matsuoka, Manabu Takaki

    PCN reports : psychiatry and clinical neurosciences   4 ( 1 )   e70077   2025.3

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Clozapine-induced agranulocytosis (CLIA) is a rare but serious complication. Fever associated with CLIA is typically treated with broad-spectrum antimicrobials, but empiric antifungal therapy is rarely used. While bacterial and viral infections have been reported in CLIA cases, no cases of fungal infections complicated by CLIA have been documented. We report the first case of CLIA complicated by invasive pulmonary aspergillosis (IPA) in a patient with schizophrenia. The diagnosis of IPA was made using serum β-D-glucan, Aspergillus galactomannan antigen tests, and chest computed tomography (CT). CASE PRESENTATION: We present a case of a 51-year-old man with schizophrenia who developed CLIA complicated by IPA. The patient, diagnosed with treatment-resistant schizophrenia, was started on clozapine, but 9 months later he presented with fever, cough, leukopenia, and neutropenia. Clozapine was discontinued, and empirical treatments with cefepime and filgrastim were initiated. Serum β-D-glucan and Aspergillus galactomannan antigen tests were positive, and chest CT showed well-circumscribed nodules, leading to a probable diagnosis of IPA. Antifungal therapy was switched from micafungin to voriconazole according to guidelines. His neutropenia and fever improved, and he was re-transferred to a psychiatric hospital. CONCLUSION: CLIA can be complicated by fungal infections. When patients with CLIA present with fever, fungal infections, including IPA, should be considered in the differential diagnosis. Serological tests, including β-D-glucan and Aspergillus galactomannan, are useful for the diagnosis of IPA as well as the appropriate use of antifungal agents in patients with CLIA.

    DOI： 10.1002/pcn5.70077

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  • Successful retreatment with clozapine combined with ursodeoxycholic acid after clozapine-induced hepatitis: A case report Reviewed International journal

    Ryota Sato, Yuto Yamada, Masaki Fujiwara, Yuji Yada, Yoshiki Kishi, Manabu Takaki

    Asian Journal of Psychiatry   102   104260 - 104260   2024.12

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.ajp.2024.104260

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  • Doctor Interview 自己免疫性脳炎などの適切な診断により,難治の疾患を治療可能な疾患に

    髙木 学

    精神科臨床legato / 「精神科臨床legato」編集委員会 編   10 ( 2 )   120 - 123   2024.8

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    Language：Japanese   Publisher：大阪 : メディカルレビュー社  

    CiNii Books

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    Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I033689943

  • 経ストーマ投与されたジアゼパム坐剤が自然排出されていたために、離脱症状を生じた1例 Reviewed

    山田 裕士, 藤原 雅樹, 鳥越 美沙子, 高木 学

    精神神経学雑誌   120th ( 2024特別号 )   S406 - S406   2024.6

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    Language：Japanese   Publisher：(公社)日本精神神経学会  

    J-GLOBAL

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  • Autoimmune Psychosis, Including Papers from and Cases at Okayama University Hospital Invited Reviewed

    高木学, 岡久祐子, 酒本真次, 樋之津健二, 河合弘樹, 来住由樹, 山田了士, 山田了士

    精神神経学雑誌   126 ( 2 )   114 - 125   2024.2

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    Authorship：Lead author   Language：Japanese  

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  • ダウン症のある人に生じた急激な生活機能変化の調査

    竹之下 慎太郎, 上地 玲子, 桑野 良三, 井上 友和, 黒住 卓, 楢原 幸二, 末光 茂, 西川 直人, 林 聡, 寺田 整司, 高木 学

    日本発達障害学会研究大会発表論文集   58回   130 - 130   2023.11

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    Language：Japanese   Publisher：(一社)日本発達障害学会  

    J-GLOBAL

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  • ダウン症候群における認知症の有病率と危険因子

    竹之下 慎太郎, 寺田 整司, 井上 友和, 黒住 卓, 西川 直人, 三木 知子, 横田 修, 高木 学, 末光 茂, 桑野 良三

    老年精神医学雑誌   34 ( 増刊II )   222 - 222   2023.10

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    Language：Japanese   Publisher：(株)ワールドプランニング  

    J-GLOBAL

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  • 相貌認知障害と左無視を呈し皮下質諸核に4リピートタウ蓄積を有したPick病の一例

    三木 知子, 横田 修, 石津 秀樹, 安田 華枝, 原口 俊, 竹之下 慎太郎, 寺田 整司, 高木 学

    老年精神医学雑誌   34 ( 増刊II )   210 - 210   2023.10

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    Language：Japanese   Publisher：(株)ワールドプランニング  

    J-GLOBAL

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  • 認知症患者の主観的QOLの予測 認知症外来における縦断研究

    西川 直人, 竹之下 慎太郎, 寺田 整司, 三木 知子, 横田 修, 林 聡, 矢部 真弓, 今井 奈緒, 堀内 真希子, 高木 学

    老年精神医学雑誌   34 ( 増刊II )   195 - 195   2023.10

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    Language：Japanese   Publisher：(株)ワールドプランニング  

    J-GLOBAL

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  • ダウン症候群を持つ施設入所者における認知症有病率の横断調査

    竹之下 慎太郎, 寺田 整司, 井上 友和, 黒住 卓, 西川 直人, 三木 知子, 横田 修, 高木 学, 末光 茂, 桑野 良三

    Dementia Japan   37 ( 4 )   683 - 683   2023.10

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    Language：Japanese   Publisher：(一社)日本認知症学会  

    J-GLOBAL

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  • 認知症患者のおける主観的QOLの予測因子

    西川 直人, 竹之下 慎太郎, 寺田 整司, 三木 知子, 横田 修, 林 聡, 矢部 真弓, 今井 奈緒, 堀内 真希子, 高木 学

    Dementia Japan   37 ( 4 )   671 - 671   2023.10

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    Language：Japanese   Publisher：(一社)日本認知症学会  

    J-GLOBAL

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  • 岡山大学病院におけるケタミンを使用したECT9例の検討

    馬場 悠花里, 山田 裕士, 酒本 真次, 竹之下 慎太郎, 寺田 整司, 高木 学

    精神神経学雑誌   ( 2023特別号 )   S554 - S554   2023.6

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    Language：Japanese   Publisher：(公社)日本精神神経学会  

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Books

  • 自己免疫性脳炎・関連疾患ハンドブック = Handbook of Autoimmune Encephalitis and Related Disorders

    下畑, 享良ら 高木学（ Role： Joint author）

    金芳堂  2023.5  （ ISBN:9784765319560 ）

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    Total pages：vii, 363p   Language：Japanese

    CiNii Books

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MISC

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Research Projects

  • Impact of cellular immunity on psychiatric disorders

    Grant number：25K10862  2025.04 - 2028.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    高木 学

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    Grant amount：\4680000 （ Direct expense: \3600000 、 Indirect expense：\1080000 ）

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  • Influence of neuronal autoantibodies to the onset and recurrence of psychosis

    Grant number：22K07616  2022.04 - 2025.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    高木 学

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    Grant amount：\4160000 （ Direct expense: \3200000 、 Indirect expense：\960000 ）

    脳炎症状を欠き精神症状を主症状とする患者の髄液中に神経伝達物質受容体に対する自己抗体が存在し、これら自己免疫性精神病患者に対する免疫療法の有効性が多く報告される。一方で、急性期、慢性期の精神疾患患者の血清中にも、自己抗体が比較的多く存在するが、これら血清中の抗体の産生機序、臨床経過に与える影響は未だ明らかではない。我々は抗NMDA受容体抗体を含む血清中の神経自己抗体が神経発達障害を引き起こすことを報告したが、本研究ではこれらの神経自己抗体が精神疾患の発症や再発の機序にどのように関わるかを解明するために、動物実験を用いた基礎的検討、患者の血清及び髄液を用いた臨床的検討を行い、精神疾患患者への免疫療法の可能性をさらに追及することを目的とする。血清、髄液の抗グルタミン酸受容体（抗NMDARなど）抗体、抗ドパミン受容体（抗ドパミンD2受容体：DRD2など）抗体、抗GABA受容体（抗GABAA, B受容体など）抗体などが、神経発達、精神疾患の発症と再発に与える影響、抗免疫療法の効果を、基礎、臨床両面から検討する。岡山大学病院他施設の約100名の抗体検査を行い、10例（女性8例，男性2例）で抗NMDA受容体抗体が陽性（髄液9例，血清2例）、2名（女性1例，男性1例）でLGI1抗体が陽性（髄液1例，血清2例）であった。他に血清NAE抗体陽性1例、Yo抗体陽性1例、AQP4抗体陽性1例のを認めた。免疫療法を行ったものは大半で症状の改善を認めた。また、日本独自の診断基準である非定型精神病の診断基準を認める患者の10％が抗NMDAR抗体を髄液で保有し、免疫療法が有効であること、加えて、脳波検査で徐波異常を認めた患者では25％に陽性率が上がり、精神科領域で興奮が激しい際などに施行困難な髄液検査を積極的に行う指標となることを報告し、Schizophrenia Researchにアクセプトされた。

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  • Dimensional approach to mental disease through autoantibodies

    Grant number：19K08019  2019.04 - 2022.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Takaki Manabu

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    Grant amount：\4420000 （ Direct expense: \3400000 、 Indirect expense：\1020000 ）

    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.

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  • Verification of the Effectiveness of a Relationship Developmental Intervention (RDI) for Children with Autism Spectrum Disorder

    Grant number：17K10332  2017.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Kishimoto Makiko

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    Eight children diagnosed with autism on the ADOS-2 received a one-year intervention using the Relationship Developmental Intervention (RDI), and pre- and post-intervention changes were assessed on the child's adaptive behavior scale, emotional and behavioral problems, and caregiver’s (mother) parenting stress. The Vineland-II Adaptive Behavior Scale showed significant improvement in the overall adaptive behavior score (p=0.034). Domain standardized scores showed significant improvement in Socialization Domain (p=0.018) and the sub-domain interpersonal relationships (p=0.018). However, no significant improvements were found for the Abnormal Behavior Checklist (ABC-J), the Child Strengths and Difficulties Questionnaire (SDQ), and the Parenting Stress Index (PSI).

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  • The influence of autoimmune antibodies on psychiatric diseases

    Grant number：16K10188  2016.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Takaki Manabu, Sakamoto Shinji, Kawai Hiroki

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    Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）

    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.

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  • Reclassification of schizophrenia by candidate gene and symptom

    Grant number：25461731  2013.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Takaki Manabu

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    Grant amount：\5070000 （ Direct expense: \3900000 、 Indirect expense：\1170000 ）

    We investigated the association between genetics and clinical or social outcomes of about 500 patients with schizophrenia at the critical period. Among 7 SNPs of 6 genes (SLC6A5, DTNBP1, GRM7, PPP3CC, EGR3, and PDE4B) which participated in NMDA receptor function, rs894747 of SLC6A5 gene was related to severity of illness and social outcome. Rs472952 of PDE4B gene was related to low score of letter fluency test. In 91SNPs of GWAS analysis of Japanese patients with schizophrenia, each 3SNPs including rs2623659 of CSMD1 was related to severity of illness or social outcome. 3SNPs ralated with severity of illness was also related to treatment resistance. It is interesting that the genetic factor also influenced to the clinical or social outcomes of the patients with schizophrenia.

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  • The functionalanalysis of the Pericentriolar material 1 (PCM1), one of the candidate genes of schizophrenia at synapse

    Grant number：22791125  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    TAKAKI Manabu

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    Grant amount：\4030000 （ Direct expense: \3100000 、 Indirect expense：\930000 ）

    Four functional polymorphism of the pericentriolar material 1 (PCM1) gene is not associated with the schizophrenia in a Japanese population. The PCM1 protein expresses more in E17 than in adult. The PCM1 protein exists at centrosome until D.I.V. 7 days, diminishes until D.I.V. 14 days, and doesn’t exist on spine in D.I.V. 28 days. The period of expression and the distribution of PCM1 are same with r-tubulin. The human Rho guanine nucleotide exchange factor 11 (ARHGEF11) gene has been reported to be associated with type 2 diabetes mellitus (T2DM). Four polymorphism of ARHGEF11 which was reported to be associated with T2DM were also associated with the paranoid subtype of schizophrenia in a Japanese population. ARHGEF11 has co-localized with PSD95, one of the post synaptic marker. ARHGEF11 may be one of the genetic links between schizophrenia and T2DM and have integrated the synaptic morphology through the interaction withDisrupted-In-Schizophrenia-1 (DISC-1).

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  • Disrupted in Schizophrenia-1 (Disc-1), a candidate gene of schizophrenia regulates kalirin and maintains synapse.

    Grant number：20790840  2008 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    TAKAKI Manabu

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    Grant amount：\4290000 （ Direct expense: \3300000 、 Indirect expense：\990000 ）

    Disrupted in Schizophrenia-1 (Disc-1) is a candidate gene of schizophrenia. Following to the development, Disc-1, dynein and BBS4, the binding protein of Disc-1 moved from centrosome to spine. On the other hand, r-tubulin and PCM-1 did not. Disc-1 regulates kalirin and maintains spine. Disc-1 inhibited the binding of Kalirin-7 and Rac1. Clozapine, one of the atypical psychotics, which is effective to intractable schizophrenia and related to NMDA receptor function, increased PSD95, a post synaptic marker.

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