Stress, depression, and suicide - molecular basis of the downward spiral

• Project/Area Number: 17H04249
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Yokohama City University (2019); Kobe University (2017-2018)
• Principal Investigator: Hishimoto Akitoyo 横浜市立大学, 医学研究科, 教授 (50529526)
• Co-Investigator(Kenkyū-buntansha): 泉 剛 北海道医療大学, 薬学部, 教授 (60312360) ; 白川 治 近畿大学, 医学部, 教授 (40243307) ; 曽良 一郎 神戸大学, 医学研究科, 教授 (40322713) ; 朴 秀賢 神戸大学, 医学研究科, 講師 (60455665) ; 辻井 農亜 近畿大学, 医学部, 准教授 (90460914)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
• Keywords: 自殺 / テロメア / ミトコンドリア / DNAメチル化 / バイオマーカー / テロメア短縮 / ストレス / 神経科学

Outline of Final Research Achievements

Our GWAS identified significant polygenicity for Japanese suicide. We found aberrant changes of various telomere-related factors (telomere length, DNA-methylation aging, methylation status of TERT promoter, mtDNAcn, SIRT1 SNP, and chemokine levels) in suicides, which may contribute to the establishment of "biomarker for suicide risk". We observed that the direction of the relationships between the oxy-Hb changes of the left frontopolar region and mtDNAcn was opposite in bipolar disorder (BD) and major depressive disorder (MDD), which may suggest the potential Potential as Diagnostic Marker for Distinguishing BD From MDD. By using mouse neural stem cells and stress-model rats, we indicated that stress can reduce TERT and some anti-depressant drugs may rescue stress-induced TERT reduction.

Academic Significance and Societal Importance of the Research Achievements

申請者らは本研究課題にて、気分障害や自殺に関連するバイオマーカーを既に多数同定し、今後、抗うつ作用や抗自殺作用とテロメア動態の関連を提示する論文を準備中である。COVID-19による様々な社会不安・ストレスにより、世界各国で今後数年に渡り自殺の増加が懸念される今だからこそ、自殺予防のバイオマーカーや創薬につながる生物学的機序を解明しようとする申請者らの研究は、社会に必ず貢献できると考える。

Research Products

• [Journal Article] Decelerated Epigenetic Aging Associated With Mood Stabilizers in the Blood of Patients With Bipolar Disorder. (2020)
  • Author(s): Okazaki S, Numata S, Otsuka I, Horai T, Kinoshita M, Sora I, Ohmori T, Hishimoto A.
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 129-129
  • DOI: 10.1038/s41398-020-0813-y
  • NAID: 120006850492
  • Peer Reviewed / Open Access
• [Journal Article] Whole-exome Sequencing in a Family With a Monozygotic Twin Pair Concordant for Schizophrenia and a Follow-Up Case-Control Study of Identified De-Novo Variants. (2020)
  • Author(s): Hoya S, Watanabe Y, Nunokawa A, Otsuka I, Shibuya M, Igeta H, Hishimoto A, Someya T.
  • Journal Title: Psychiatric Genetics Volume: 30 Issue: 2 Pages: 60-63
  • DOI: 10.1097/ypg.0000000000000250
  • Peer Reviewed
• [Journal Article] ATP and Repetitive Electric Stimulation Increases Leukemia Inhibitory Factor Expression in Astrocytes: A Potential Role for Astrocytes in the Action Mechanism of Electroconvulsive Therapy (2020)
  • Author(s): Maruyama S, Boku S, Okazaki S, Kikuyama H, Mizoguchi Y, Monji A, Otsuka I, Sora I, Kanazawa T, Hishimoto A, Yoneda H.
  • Journal Title: Psychiatry Clin Neurosci . Volume: . Issue: 5 Pages: 12986-12986
  • DOI: 10.1111/pcn.12986
  • Peer Reviewed / Open Access
• [Journal Article] Accelerated Extrinsic Epigenetic Aging and Increased Natural Killer Cells in Blood of Suicide Completers (2020)
  • Author(s): Okazaki S, Otsuka I, Horai T, Hirata T, Takahashi M, Ueno Y, Boku S, Sora I, Hishimoto A.
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry . Volume: 98 Pages: 109805-109805
  • DOI: 10.1016/j.pnpbp.2019.109805
  • Peer Reviewed / Open Access
• [Journal Article] Chemokine Alterations in the Postmortem Brains of Suicide Completers (2020)
  • Author(s): Shinko Y, Otsuka I, Okazaki S, Horai T, Boku S, Takahashi M, Ueno Y, Sora I, Hishimoto A.
  • Journal Title: J Psychiatr Res . Volume: 120 Pages: 29-33
  • DOI: 10.1016/j.jpsychires.2019.10.008
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association studies identify polygenic effects for completed suicide in the Japanese population. (2019)
  • Author(s): Otsuka I, Akiyama M, Shirakawa O, Okazaki S, Momozawa Y, Kamatani Y, Izumi T, Numata S, Takahashi M, Boku S, Sora I, Yamamoto K, Ueno Y, Toda T, Kubo M, Hishimoto A
  • Journal Title: Neuropsychopharmacology Volume: 44 Issue: 12 Pages: 2119-2124
  • DOI: 10.1038/s41386-019-0506-5
  • NAID: 120007027666
  • Peer Reviewed / Open Access
• [Journal Article] Major depressive disorder-associated SIRT1 locus affects the risk for suicide in women after middle age. (2019)
  • Author(s): Hirata T, Otsuka I, Okazaki S, Mouri K, Horai T, Boku S, Takahashi M, Ueno Y, Sora I, Shirakawa O, Hishimoto A.
  • Journal Title: Psychiatry Res Volume: 278 Pages: 141-145
  • DOI: 10.1016/j.psychres.2019.06.002
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial DNA copy number raises the potential of left frontopolar hemodynamic response as a diagnostic marker for distinguishing bipolar disorder from major depressive disorder. (2019)
  • Author(s): Tsujii N, Otsuka I, Okazaki S, Yanagi M, Numata S, Yamaki N, Kawakubo Y, Shirakawa O, Hishimoto A.
  • Journal Title: Frontiers in Psychiatry Volume: in press
  • NAID: 120006869526
  • Peer Reviewed / Open Access
• [Journal Article] Neurexin 3 transmembrane and soluble isoform expression and splicing haplotype are associated with neuron inflammasome and Alzheimer's disease. (2019)
  • Author(s): Hishimoto A, Pletnikova O, Lang DL, Troncoso JC, Egan JM, Liu QR.
  • Journal Title: Alzheimer's Research & Therapy Volume: 11 Issue: 1 Pages: 28-28
  • DOI: 10.1186/s13195-019-0475-2
  • NAID: 120006604676
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic clock analysis of blood samples from Japanese schizophrenia patients. (2019)
  • Author(s): Okazaki S, Otsuka I, Numata S, Horai T, Mouri K, Boku S, Ohmori T, Sora I, Hishimoto A.
  • Journal Title: NPJ Schizophrenia Volume: 5 Issue: 1 Pages: 4-4
  • DOI: 10.1038/s41537-019-0072-1
  • NAID: 120006629323
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of CYP2D6 polymorphisms and extrapyramidal symptoms in schizophrenia patients receiving risperidone: a retrospective study. (2018)
  • Author(s): Ito T, Yamamoto K, Ohsawa F, Otsuka I, Hishimoto A, Sora I, Hirai M, Yano I.
  • Journal Title: Journal of Pharmaceutical Health Care and Sciences Volume: 4 Issue: 1 Pages: 28-28
  • DOI: 10.1186/s40780-018-0126-y
  • NAID: 120006543322
  • Peer Reviewed / Open Access
• [Journal Article] Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde. (2018)
  • Author(s): Yamaki N, Matsushita S, Hara S, Yokoyama A, Hishimoto A, Higuchi S.
  • Journal Title: Journal of Psychiatric Research Volume: 109 Pages: 27-32
  • DOI: 10.1016/j.jpsychires.2018.11.007
  • Peer Reviewed
• [Journal Article] Investigation of chromosome Y loss in men with schizophrenia. (2018)
  • Author(s): Hirata T, Hishimoto A, Otsuka I, Okazaki S, Boku S, Kimura A, Horai T, Sora I.
  • Journal Title: Neuropsychiatr Dis Treat. Volume: 14 Pages: 2115-2122
  • DOI: 10.2147/ndt.s172886
  • NAID: 120006510199
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mitochondrial DNA copy number of peripheral blood in bipolar disorder: The present study and a meta-analysis. (2018)
  • Author(s): Yamaki N, Otsuka I, Numata S, Yanagi M, Mouri K, Okazaki S, Boku S, Horai T, Ohmori T, Shirakawa O, Sora I, Hishimoto A.
  • Journal Title: Psychiatry Research Volume: 269 Pages: 115-117
  • DOI: 10.1016/j.psychres.2018.08.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population. (2018)
  • Author(s): Zhang Y, Hishimoto A, Otsuka I, Watanabe Y, Numata S, Yamamori H, Boku S, Horai T, Someya T, Ohmori T, Hashimoto R, Sora I.
  • Journal Title: J Psychiatr Res Volume: 103 Pages: 161-166
  • DOI: 10.1016/j.jpsychires.2018.05.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia. (2018)
  • Author(s): Okazaki S, Hishimoto A, Otsuka I, Watanabe Y, Numata S, Boku S, Shimmyo N, Kinoshita M, Inoue E, Ohmori T, Someya T, Sora I.
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry. Volume: 83 Pages: 33-41
  • DOI: 10.1016/j.pnpbp.2018.01.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of chromosome Y in blood, but not in brain, of suicide completers (2018)
  • Author(s): Kimura A, Hishimoto A, Otsuka I, Okazaki S, Boku S, Horai T, Izumi T, Takahashi M, Ueno Y, Shirakawa O, Sora I
  • Journal Title: PLoS One Volume: 13 Issue: 1 Pages: e0190667-e0190667
  • DOI: 10.1371/journal.pone.0190667
  • NAID: 120006382347
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Loss of chromosome Y in blood, but not in brain, of suicide completers. (2018)
  • Author(s): Otsuka I, Okazaki S, Kimura A, Horai T, Izumi T, Takahashi M, Ueno Y, Shirakawa O, Sora I, Hishimoto A.
  • Organizer: WFSBP Asia Pacific Regional Congress
  • Int'l Joint Research
• [Presentation] Mitochondrial DNA copy number of peripheral blood in bipolar disorder:the present study and a meta-analysis. (2018)
  • Author(s): Yamaki N, Otsuka I, Mouri K, Boku S, Numata S, Yanagi M, Ohmori T, Shirakawa O, Sora I, Hishimoto A.
  • Organizer: WFSBP Asia Pacific Regional Congress
  • Int'l Joint Research
• [Presentation] Mosaic loss of chromosome Y in peripheral blood and its risk variants in men with schizophrenia. (2018)
  • Author(s): Hirata T, Okazaki S, Otsuka I, Boku S, Aoyama S, Eguchi N, Kimura A, Horai T, Sora I, Hishimoto A.
  • Organizer: WFSBP Asia Pacific Regional Congress
  • Int'l Joint Research
• [Presentation] Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia. (2018)
  • Author(s): Okazaki S, Otsuka I, Watanabe Y, Numata S, Boku S, Shimmyo N, Ohmori T, Someya T, Sora I, Hishimoto A.
  • Organizer: WFSBP Asia Pacific Regional Congress
  • Int'l Joint Research
• [Presentation] ALCOHOL-RELATED POLYMORPHISMS AND RISK FOR SUICIDE IN THE JAPANESE POPULATION. (2018)
  • Author(s): Otsuka I, Hishimoto A.
  • Organizer: The 19th Congress of the International Society for Biomedical Research on Alcoholism.
  • Int'l Joint Research / Invited
• [Presentation] ABERRANT TELOMERES IN ALCOHOL DEPENDENCE, MOOD DISORDER AND SUICIDEABERRANT TELOMERES IN ALCOHOL DEPENDENCE, MOOD DISORDER AND SUICIDE. (2018)
  • Author(s): Yamaki N, Hishimoto A.
  • Organizer: The 19th Congress of the International Society for Biomedical Research on Alcoholism.
  • Int'l Joint Research / Invited
• [Presentation] The cell cycle-related genes as biomarkers for schizophrenia. (2018)
  • Author(s): Okazaki S, Boku S, Otsuka I, Eguchi N, Sora I, Akitoyo Hishimoto A.
  • Organizer: Neuroscience 2018 Annual Meeting
  • Int'l Joint Research
• [Book] Facilitating Resilience After PTSD: A Translational Approach (2018)
  • Author(s): Ikuo Otsuka, Akitoyo Hishimoto（分担執筆）
  • Total Pages: 243
  • Publisher: Nova Science Pub Inc
  • ISBN: 1536130974