Ethnic Variations in Antidepressant Response

抗抑郁药反应的种族差异

• 批准号: 6647056
• 负责人: RUSSELL Elliott POLAND
• 金额: $ 22.95万
• 依托单位: CEDARS-SINAI 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: 2001-09-21 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6647056
• 关键词: African American; alleles; antidepressants; behavioral /social science research tag; biotransformation; caucasian American; clinical trials; cytochrome P450; drug adverse effect; genetic polymorphism; genotype; human subject; human therapy evaluation; longitudinal human study; major depression; mental disorder chemotherapy; outcomes research; patient oriented research; pharmacogenetics; pharmacokinetics; polymerase chain reaction; psychopharmacology; racial /ethnic difference; serotonin transporter; social psychology; socioeconomics

DESCRIPTION: (provided by applicant) Despite remarkable progress in recent decades 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 polymorphisms affecting the function of the serotonin 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., CYP2C19 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-IV major depression prospectively treated with citalopram (CIT). It is postulated that mutations affecting the function of the serotonin transporter will predict responses to CU', whereas polymorphism of CYP2C 19 will be associated with the side effect profiles and pharmacokinetics of CIT. The inclusion of African Americans and Caucasians, whose genetic profiles for the serotonin transporter differ significantly from each other, will allow us to examine how these differences affect antidepressant response patterns, and whether the associations are 'replicable' across ethnicity. Also, the response of African Americans 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 phannacogenetics, data derived from this three-site (Harbor-UCLA, UCLA\King-Drew and Cedars-Sinai Medical Centers) collaborative R0l project should also serve to bridge the knowledge gap regarding the treatment of African American patients suffering from major depression.

描述：（申请人提供）尽管最近取得了显着进展 在现代心理药物治疗中数十年，患者的差异很大 对抗抑郁药的反应，从总缓解到完整治疗不等 失败。不良反应，通常是令人困扰的，偶尔威胁生命的， 继续对患者和临床医生面临重大挑战。 导致这种可变性的机制仍然很少理解。在 此外，尽管不太赞赏，但对跨种族的大量变化 经常存在精神反应。该领域的最新发展 药物遗传学表明，遗传因素可能是很大一部分 这些反应差异。特定的遗传多态性影响 已经假定5-羟色胺系统的功能来预测 抗抑郁药。同样，遗传突变已被证明施加 主要影响许多药物代谢的表达 酶，包括大多数细胞色素P-450酶（例如CYP2C19和 CYP3A4），负责大多数抗抑郁药的生物转化。 已经发现控制这些酶的基因的多态性很强 与各种副作用的倾向有关。大写 在这些新的发展中，拟议的研究将研究预测价值 其中一些遗传多态性中有400名患者（200名非裔美国人 和200名高加索人）有前瞻性治疗的DSM-IV重大抑郁症 西妥位（CIT）。据推测，影响的突变影响了 5-羟色胺转运蛋白将预测对Cu'的反应，而多态性 CYP2C 19将与副作用曲线和药代动力学有关 cit。包括非裔美国人和高加索人的遗传 5-羟色胺转运蛋白的轮廓彼此之间有显着差异， 将使我们能够检查这些差异如何影响抗抑郁反应 模式，以及整个种族之间的协会是否“可复制”。还， 很少研究非裔美国人对抗抑郁药的反应 一种系统的方式，尤其是在受控临床的背景下 试验。因此，除了解决与临床有关的问题外 Phannacogenetics，来自此三个位点的数据（Harbour-Ucla，， UCLA \ King-Drew和Cedars-Sinai Medical Centers）合作R0L项目 还应该有助于弥合有关治疗的知识差距 非裔美国人患者患有严重抑郁症。