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）尽管最近取得了显着进展 在现代精神药物治疗的数十年中，患者的治疗方法差异很大 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， 仍然对患者和临床医生构成重大挑战。 造成这种变异的机制仍然知之甚少。在 此外，尽管较少受到重视，但种族间的显着差异 精神反应经常存在。该领域的最新进展 药物遗传学表明遗传因素可能占很大一部分 这些差异的反应。影响特定基因多态性 血清素系统的功能已被假设为预测效果 抗抑郁药。同样，基因突变已被证明可以发挥 对多种药物代谢因子的表达有显着影响 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。 已发现控制这些酶的基因的多态性对 与各种副作用的倾向有关。大写 关于这些新的发展，拟议的研究将检验预测价值 400 名患者（200 名非洲裔美国人）中的一些基因多态性 和 200 名白人）患有 DSM-IV 重度抑郁症，前瞻性治疗 西酞普兰（CIT）。据推测，影响功能的突变 血清素转运蛋白将预测对 CU' 的反应，而 CU' 的多态性 CYP2C 19 将与副作用特征和药代动力学相关 企业所得税。将非裔美国人和白种人纳入其中，他们的基因 血清素转运蛋白的概况彼此显着不同， 将使我们能够研究这些差异如何影响抗抑郁反应 模式，以及这些关联是否可以跨种族“复制”。还， 非洲裔美国人对抗抑郁药的反应很少被研究 系统化的方式，特别是在受控临床的背景下 试验。因此，除了解决与临床相关的问题外， phannaco Genetics，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知识差距 患有严重抑郁症的非裔美国患者。