Ethnic Variations in Antidepressant Response

抗抑郁药反应的种族差异

• 批准号: 6943945
• 负责人: IRA Marc LESSER
• 金额: $ 47.6万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6943945
• 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）尽管在 近几十年来，在现代精神药物治疗中，患者在以下方面存在很大差异： 他们对抗抑郁药物的反应，从完全缓解到完全缓解 治疗失败。不良影响，经常令人烦恼，偶尔也会发生 危及生命，继续对患者构成重大挑战 临床医生。造成这种变异的机制仍然很薄弱 明白了。此外，虽然不太受重视，但大量的跨种族 精神药物反应常常存在差异。最近的发展 药物遗传学领域表明，遗传因素可能占很大一部分 反应差异的一部分。影响特定基因多态性 血清素（SERT）系统的功能被假设为预测 抗抑郁药的作用。同样，基因突变已被证明 对许多表达有重要影响 药物代谢酶，包括大多数细胞色素 P-450 酶 （例如 CYP2C 19 和 CYP3A4）负责生物转化 大多数抗抑郁药。控制这些酶的基因多态性 研究发现与各种倾向密切相关 副作用。利用这些新的发展，拟议的研究将 第 400 章 患有 DSM-LV 重度抑郁症的患者（200 名非裔美国人和 200 名白种人） 前瞻性地用西酞普兰（CIT）治疗。假设突变 影响 SERT 功能将预测对 CIT 的反应， CYP2C 19 将与副作用特征和药代动力学相关 企业所得税。纳入两个比较组：非裔美国人和 白种人的基因突变模式彼此之间存在显着差异 其他，将使我们能够研究这些差异如何影响他们 抗抑郁药反应模式以及这种关联是否“可复制” 跨种族。此外，非裔美国人对抗抑郁药物的反应 很少以系统的方式进行研究，特别是在 对照临床试验。因此，除了解决与 临床药物遗传学，来自这三个站点的数据（Harbor-UCLA， UCLA\King-Drew 和 Cedars-Sinai 医疗中心）协作 R0l 项目 还应有助于弥合有关治疗的关键知识差距 患有严重抑郁症的非裔美国患者。