Pharmacogenomics of Antidepressant Response

抗抑郁反应的药物基因组学

• 批准号: 7052047
• 负责人: Steven P. Hamilton
• 金额: $ 176.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-11 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052047
• 关键词: DNA; antidepressants; citalopram; clinical research; drug design /synthesis /production; drug metabolism; gene expression; genetic mapping; genetic markers; genetic screening; human genetic material tag; human subject; human therapy evaluation; major depression; mental disorder chemotherapy; neurotransmitter transport; patient oriented research; pharmacogenetics; pharmacokinetics; serotonin inhibitor

DESCRIPTION (provided by applicant): Major Depressive Disorder is a common and disabling psychiatric illness, usually treated with a selective serotonin reuptake inhibitor antidepressant. Studies to date suggest that there are associations between antidepressant response and genes in both neurotransmitter regulatory pathways and antidepressant metabolism pathways. Based on these observations, this application is designed to identify genetic determinants for antidepressant response in a clinical sample of unprecedented size, treated with a single antidepressant, whose treatment response has been carefully ascertained. The ultimate goal is to elucidate genetic determinants of response to antidepressants as an important prerequisite to understanding the mechanism of antidepressant action and development of novel therapeutic agents for depression. Our specific hypothesis is that important phenotypes involving response to citalopram are in part mediated by detectable genetic factors. We propose a large-scale genetic association study on a collection of DNA's (about 1,400) obtained during the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) protocol, a large multi-site treatment study involving about 4,000 persons with DSM-IV Major Depressive Disorder. We propose to: 1) genotype this sample for association between response phenotypes and variants in 20 antidepressant response candidate genes based on prior biological or genetic evidence, and 2) perform a whole genome association study between response phenotypes and about 100,000 gene-based DNA variants. Secondary specific aims are to: 1) sequence genes positively associated with response phenotypes identified using candidate gene or whole genome approaches to identify potential response-related alleles, and 2) develop refined phenotypes and novel hypotheses to test for association to treatment response outcomes. Power calculations suggest meaningful differences between phenotypic groupings can be detected. Detecting any association between DNA variations and antidepressant response could ultimately have a significant clinical impact if a genotype that accounts for a substantial portion of variance in response or tolerability of these medications is identified. These findings could provide steps toward our ability to define clinically useful genetic predictors of pharmacological treatment and apply them to patient populations.

描述（由申请人提供）：重度抑郁症是一种常见的致残性精神疾病，通常用选择性血清素再摄取抑制剂抗抑郁药治疗。迄今为止的研究表明，抗抑郁药反应与神经递质调节途径和抗抑郁药代谢途径中的基因之间存在关联。基于这些观察，该应用程序旨在在规模空前的临床样本中识别抗抑郁反应的遗传决定因素，该临床样本使用单一抗抑郁药治疗，其治疗反应已被仔细确定。最终目标是阐明抗抑郁药反应的遗传决定因素，这是了解抗抑郁药作用机制和开发新型抑郁症治疗药物的重要先决条件。我们的具体假设是，涉及西酞普兰反应的重要表型部分是由可检测的遗传因素介导的。我们提议对 STAR*D（缓解抑郁症的测序替代治疗方案）协议期间获得的 DNA 集合（约 1,400 个）进行大规模遗传关联研究，这是一项大型多中心治疗研究，涉及约 4,000 名 DSM-IV 重度抑郁症患者。我们建议：1) 根据先前的生物学或遗传证据，对该样本进行基因分型，以了解 20 个抗抑郁药反应候选基因的反应表型和变异之间的关联，2) 在反应表型和约 100,000 个基于基因的 DNA 变异之间进行全基因组关联研究。第二个具体目标是：1）对与使用候选基因或全基因组方法识别的反应表型呈正相关的基因进行测序，以识别潜在的反应相关等位基因，2）开发完善的表型和新的假设，以测试与治疗反应结果的关联。功效计算表明可以检测到表型分组之间有意义的差异。如果确定了导致这些药物反应或耐受性差异很大一部分的基因型，那么检测 DNA 变异与抗抑郁药反应之间的任何关联最终可能会产生重大的临床影响。这些发现可以为我们确定临床上有用的药物治疗遗传预测因子并将其应用于患者群体提供帮助。