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Molecular pharmacogenetic investigation of pharmacotherapeutic strategy for treatment-resistant depression.

Research Project

Project/Area Number 07671064
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionShiga University of Medical Science

Principal Investigator

SOMEYA Toshiyuki  Shiga University of Medical Science, Health Administration Center, Lecturer, 保健管理センター, 講師 (50187902)

Co-Investigator(Kenkyū-buntansha) SHIMODA Kazutaka  Shiga University of Medical Science, Department of Psychiatry, Instructor, 医学部, 助手 (30196555)
村下 淳  滋賀医科大学, 医学部, 助手 (80252386)
成田 実  滋賀医科大学, 医学部, 助手 (20273401)
Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1997: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1996: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
KeywordsTreatment-resistant depression. / Tricyclic antidepressant. / Metabolism. / Genotyping
Research Abstract

In this project, we tried to search the biological background of resistant depression by collecting and analyzing the data of plasma levels of tricyclic antidepressants and their metabolites and the genetic data of enzyme (s) which is responsible for metabolism of tricyclic antidepressants. We measured the plasma concentrations of clomipramine and its metabolites, and the metabolic ratios for desmethylation, hydroxylation, and glucuronidation that were calculated from steady-state drug concentrations varied substantially with 36-, 14, and 28-fold interindividual variations, respectively. Plasma levels of clomipramine and its desmethylated, hydroxylated and glucuronidated metabolites were determined in fifty-seven patients who were suffered from DSM-III-R major depressive episode and treated with various daily dose of clomipramine. Discriminant analysis of drug concentrations and clinical response revealed that clinical outcome of approximately 79% of the subjects could be correctly predicted. Nortriptyline is one of the prevalent tricyclic antidepressants that is widely used for treatment of depression. The impact of CYP2D6Ch that is frequently found in Asian, on the metabolism of nortriptyline was investigated. The subjects with homozygote of CYP2D6Ch (Ch/Ch) show approximately 80% higher plasma concentrations of nortriptyline compared with the subjects with homozygote of wild type (Wt/Wt). In Ch/Ch group, nortriptyline/trans-10-hydroxynortriptyline, which is representative of the hydroxylation ratio of nortriptyline, is approximately 240% higher than that of Wt/Wt group. These results suggest that homozygote of CYP2D6Ch decrease the hydroxylation clearance of nortriptyline.

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Shimada K et al: "Interindividual variation of desmethylation and hydroxylation of amitriptyline in a Japanese psychiotric population" Journal of Clinical Psychopharmacology. 15. 175-181 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shimoda K et al: "Metabolism of clomipramine in a Japanese psychiotric population : Significance of hydroxylation,desmethylation and glucuronilati" Neuropsychopharmacology. 12. 323-333 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 森田 幸代 ら: "Clomipramineとその水酸化・脱メチル化代謝物およびグルクロン酸抱合体の血漿中濃度モニタリングによる気分障害の臨床改善疫の予測" 精神医学. 38(2). 181-185 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 下田 和孝 ら: "選択的セロトニン取り込み阻害薬(SSRI)の薬物交互作用について-SSRI時代の夜明け前に-" 精神医学. 39(12). 1329-1336 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 染矢 俊幸 ら: "TDMはなぜ有用なのか" 臨床精神薬理. 1(1). 39-45 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 下田 和孝 ら: "抗うつ薬血中濃度モニタリングの現状と問題点" 臨床精神薬理. 1(4)(印刷中). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shimoda, K.et al: "Interindividual variations of desmethylation and hydroxylation of amitriptyline in a Japanese psychiatric population." Journal of Clinical Psychopharmacology. 15. 175-181

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shimoda, K.et al: "Metabolism of clomipramine in a Japanese psychiatric population significance of hydroxylation, desmethylation and hydroxylation." Neuropsychopharmacology.12. 323-333 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Morita, S.et al: "Prediction of clinical response in mood disorders by monitoring of plasma levels of clomipramine, its hydroxylated and desmethylated metabolites and glucuronide conjugates of its hydroxylated metabolites." Seishin Igaku. 38. 1329-1336 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shimoda, K.et al: "Drug interaction of selective serotonin reuptake inhibitor (SSRI) : before the dawn of the era of SSRI." Seishin Igaku.39. 1329-1336 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Someya, T.et al: "Why is TDM useful in treatment for schizophrenia?" Rinsyo Seishin Yakuri. 1. 39-45 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shimoda, K.et al: "Current status and problems of therapeutic drug monitoring of antidepressants." Rinsyo Seishin Yakuri. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 下田和孝ら: "選択的セロトニン取り込み阻害薬(SSRZ)の薬物交互作用について-SSRI時代の夜明け前〜-" 精神医学. 39(12). 1329-1336 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 染矢俊幸ら: "TDMはなぜ有用なのか" 臨床精神薬理. 1(1). 39-45 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 下田和孝ら: "抗うつ薬血中濃度モニタリングの現状と問題点" 臨床精神薬理. 1(4)(印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 森田幸代ら: "Clomipramineとその水酸化・脱メチル化代謝物およびグルクロン酸抱合体の血漿中濃度モニタリングによる気分障害の臨床改善度の予測" 精神医学. 38(2). 181-185 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Shimoda,K.,et al: "Interindividual variations of desmethylation and hydroxylation of amitriptyline in a Japanese psychiatric population" Journal of Clinical Psychopharmacology. 15. 175-181 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shimoda,K.,et al: "Metabolism of clomipramine in a Japanese psychiatric population:significance of hydroxylation,desmethylation and glucuronidation." Neuropsychopharmacology. 12. 323-333 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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