Ethnic Variations in Antidepressant Response

抗抑郁药反应的种族差异

• 批准号: 6915499
• 负责人: Russell E. 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6915499
• 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：（由申请人提供）尽管近年来取得了显著进展， 在现代精神药物治疗的几十年中，患者在他们的 对抗抑郁药的反应，从完全缓解到完全治疗 失败不良反应通常令人烦恼，有时甚至危及生命， 对患者和临床医生来说仍然是重大的挑战。 对造成这种差异的机制仍然知之甚少。在 此外，尽管不太了解， 精神反应经常存在。领域的最新发展 药物遗传学表明，遗传因素可能占很大一部分， 这些不同的反应。特定的遗传多态性影响 5-羟色胺系统的功能已经被假定为预测 抗抑郁药类似地，基因突变已被证明会产生 主要影响一些药物代谢的表达， 酶，包括大多数细胞色素P-450酶（例如，cyp 2c 19和 CYP 3A 4）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强烈地 与各种副作用的倾向有关。资本化 根据这些新的发展，拟议的研究将审查预测价值， 400名患者（200名非裔美国人）中的一些遗传多态性 和200名高加索人）， 西酞普兰（CIT）。据推测，突变影响的功能， 5-羟色胺转运蛋白的多态性将预测对CU '的反应，而 CYP 2C 19将与副作用特征和药代动力学相关 的CIT。包括非洲裔美国人和高加索人，他们的基因 5-羟色胺转运体的分布彼此显著不同， 将使我们能够研究这些差异如何影响抗抑郁反应 模式，以及这种关联是否可以在不同种族之间“复制”。还有， 非洲裔美国人对抗抑郁药的反应很少被研究， 一个系统的方式，特别是在控制的临床背景下， 审判因此，除了解决与临床相关的问题之外， phannacogenetics，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 还应有助于弥合关于治疗 患有严重抑郁症的非裔美国人。