Ethnic Variations in Antidepressant Response

抗抑郁药反应的种族差异

• 批准号: 6399285
• 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/6399285
• 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)尽管最近取得了显著的进展 在现代精神药物治疗的几十年中，患者在他们的 对抗抑郁药物的反应，从完全缓解到完全治疗 失败了。负面影响，通常令人烦恼，有时还会危及生命， 仍然是患者和临床医生面临的重大挑战。 造成这种差异的机制仍然知之甚少。在……里面 此外，尽管不太受重视，但在 精神药物反应经常存在。……领域的最新发展 药物遗传学表明遗传因素可能在很大程度上解释了 这些不同的反应。特定的遗传多态影响 5-羟色胺系统的功能已被推测为预测 抗抑郁药。类似地，基因突变已被证明会产生 对多种药物代谢产物表达的主导影响 酶，包括大多数细胞色素P-450酶(例如，CYP2C19和 对大多数抗抑郁药物的生物转化起作用。 控制这些酶的基因的多态已经被发现是强烈的 与各种副作用的倾向有关。大写字母 关于这些新的发展，拟议的研究将检验其预测价值 在400名患者(200名非裔美国人)中发现其中一些基因多态 和200名高加索人)与DSM-IV重度抑郁症前瞻性治疗 西酞普兰(CIT)。据推测，影响细胞功能的突变 5-羟色胺转运体将预测对CU‘的反应，而 CYP2C19将与副作用谱和药代动力学相关 CIT的。包括非洲裔美国人和白人，他们的基因 5-羟色胺转运体的特征彼此之间有很大的不同， 将使我们能够研究这些差异如何影响抗抑郁药物的反应 模式，以及这种关联是否可以在不同种族之间“复制”。另外， 非裔美国人对抗抑郁药物的反应很少在 一种系统性的方式，特别是在受控临床的背景下 审判。因此，除了解决与临床相关的问题外， 来自这三个站点的数据(港湾-加州大学洛杉矶分校， 加州大学洛杉矶分校\King-Drew和Cedars-Sinai医疗中心)合作R01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人。