Ethnic Variations in Antidepressant Response

抗抑郁药反应的种族差异

• 批准号: 6398110
• 负责人: KEH-MING LIN
• 金额: $ 42.17万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-22 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6398110
• 关键词: African American; antidepressants; caucasian American; cytochrome P450; drug metabolism; gene mutation; genetic polymorphism; human subject; human therapy evaluation; major depression; mental disorder chemotherapy; patient oriented research; pharmacogenetics; psychopharmacology; racial /ethnic difference; serotonin

DESCRIPTION: (provided by applicant) Despite remarkable progress in recentdecades in modern psychopharmacotherapy, patients vary substantially in their response to antidepressants, ranging from total remission to complete treatment failure. Adverse effects, often bothersome and occasionally life-threatening, continue to represent significant challenges to patients and clinicians. Mechanisms responsible for such variability remain poorly understood. In addition, although less appreciated, substantial cross-ethnic variations in psychotropic responses often exist. Recent developments in the field of pharmacogenetics indicate that genetic factors may account for a large part of these differences in response. Specific genetic po'ymorphisms affecting the function of the serotonin (SERT) system has been postulated to predict the effect of antidepressants. Similarly, genetic mutations have been shown to exert a predominant influence on the expression of a number of drug-metabolizing enzymes, including most of the cytochrome P-450 enzymes (e.g., CYP2C 19 and CYP3A4) that are responsible for the biotransformation of most antidepressants. Polymorphisms of genes controlling these enzymes have been found to be strongly associated with the propensity for various kinds of side effects. Capitalizing on these new developments, the proposed study will examine the predictive value of some of these genetic polymorphisms in 400 patients (200 African Americans and 200 Caucasians) with DSM-LV majordepression prospectively treated with citalopram (CIT). It is postulated that mutations affecting the function of SERT will predict responses to CIT, polymorphism of CYP2C 19 will be associated with the side effect profiles and pharmacokinetics of CIT. The inclusion of the two comparison groups, African Americans and Caucasians, whose genetic mutation patterns diverge significantly from each other, will allow us to examine how these differences affect their antidepressant response patterns and whether the associations are 'replicable' across ethnicity. Also, African Americans' response to antidepressants has rarely been studied in a systematic fashion, particularly in the context of controlled clinical trials. Thus, in addition to addressing issues related to clinical pharmacogenetics, data derived from this three-site (Harbor-UCLA, UCLA\King-Drew and Cedars-Sinai Medical Centers) collaborative R0l project should also serve to bridge crucial knowledge gaps regarding the treatment of African American patients suffering from major depression.

描述：（由申请人提供）尽管取得了显著进展， 近几十年来，在现代精神药物治疗中， 他们对抗抑郁药的反应，从完全缓解到完全缓解， 治疗失败。不良反应，通常令人烦恼，偶尔 危及生命，继续对患者构成重大挑战， 临床医生造成这种变化的机制仍然很差 明白此外，虽然不太受重视，但大量的跨族裔 精神反应的变化经常存在。最近的事态发展 药物遗传学领域的研究表明，遗传因素可能占很大比例， 这些差异的一部分。特定的遗传多态性影响 5-羟色胺（SERT）系统的功能已被假定为预测 抗抑郁药的效果。同样，基因突变也被证明 对一些国家的表达产生重大影响， 药物代谢酶，包括大多数细胞色素P-450酶 (e.g., CYP 2C 19和CYP 3A 4），负责 大多数抗抑郁药控制这些酶的基因的多态性 被发现与各种各样的倾向密切相关， 副作用.根据这些新的发展，拟议的研究将 研究这些遗传多态性的预测价值，在400 患有DSM-LV重度抑郁症的患者（200名非洲裔美国人和200名白人） 西酞普兰（CIT）前瞻性治疗。据推测，突变 影响SERT的功能将预测对CIT的反应， CYP 2C 19将与副作用特征和药代动力学相关 的CIT。包括两个比较组，非洲裔美国人和 高加索人，其基因突变模式与每个人都有显著差异， 其他，将使我们能够研究这些差异如何影响他们的 抗抑郁药反应模式以及相关性是否“可复制” 跨越种族。此外，非裔美国人对抗抑郁药的反应 很少被系统地研究，特别是在 对照临床试验。因此，除了解决与下列方面有关的问题外， 临床药物遗传学，来自这三个位点的数据（Harbor-UCLA， UCLA\King-Drew和Cedars-Sinai医疗中心）合作项目 还应有助于弥合治疗艾滋病毒/艾滋病方面的关键知识差距， 患有严重抑郁症的非裔美国人。