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

本课题通过收集和分析三环类抗抑郁药及其代谢物的血药浓度数据和三环类抗抑郁药代谢相关酶(S)的遗传数据，试图寻找难治性抑郁的生物学背景。我们测量了氯米帕明及其代谢物的血浆浓度，以及根据稳态药物浓度计算的脱甲基化、羟化和葡萄糖醛酸化的代谢率，它们的个体间差异分别为36、14和28倍。对57例DSM-III-R重度抑郁发作患者给予不同剂量的氯丙咪嗪治疗后，测定其血浆中氯米帕明及其脱甲基化、羟化和糖醛酸化代谢产物的浓度。药物浓度和临床反应的判别分析显示，大约79%的受试者可以正确预测临床结果。去甲替林是目前广泛用于治疗抑郁症的三环类抗抑郁药之一。研究了在亚洲常见的CYP2D6CH对去甲替林代谢的影响。与野生型纯合子(Wt/Wt)相比，携带CYP2D6CH纯合子(CH/CH)的受试者血浆去甲替林血药浓度升高约80%。在CH/CH组中，代表去甲替林羟化比率的去甲替林/反式-10-羟基去甲替林比Wt/Wt组高约240%。这些结果表明，CYP2D6CH纯合子降低去甲替林的羟化清除率。

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.