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

难治性抑郁症药物治疗策略的分子药理学研究。

基本信息

批准号：
07671064
负责人：
SOMEYA Toshiyuki
金额：
$ 1.54万
依托单位：
Shiga University of Medical Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671064/
关键词：
Treatment-resistant depression.Tricyclic antidepressant.Metabolism.Genotyping

项目摘要

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.

在本项目中，我们试图通过收集和分析三环类抗抑郁药物及其代谢物的血浆水平数据和三环类抗抑郁药物代谢酶的遗传数据来寻找耐药抑郁症的生物学背景。我们测量了氯丙咪嗪及其代谢物的血浆浓度，并根据稳态药物浓度计算出去甲基化、羟基化和葡萄糖醛酸化的代谢比率，个体间差异分别为36倍、14倍和28倍。对57例患有DSM-III-R重度抑郁发作并接受不同日剂量氯丙帕明治疗的患者，测定氯丙帕明及其去甲基化、羟化和葡萄糖醛酸化代谢物的血浆水平。药物浓度和临床反应的判别分析显示，大约79%的受试者的临床结果可以正确预测。去甲替林是一种流行的三环抗抑郁药，广泛用于治疗抑郁症。CYP2D6Ch在亚洲经常发现，对去甲替林代谢的影响进行了研究。CYP2D6Ch纯合子受试者（Ch/Ch）的血浆去甲替林浓度比野生型纯合子受试者（Wt/Wt）高约80%。在Ch/Ch组中，去甲替林/反式-10-羟基去甲替林的羟基化比率比Wt/Wt组高约240%。这些结果表明CYP2D6Ch纯合子降低了去甲替林的羟基化清除率。