Predicting Alcoholics' Treatment Responses to an SSRI

酗酒仍然是一个令人头疼的临床和国家健康问题。努力匹配酒精依赖 患者根据自己的临床特点进行具体治疗，产生了好坏参半的结果。药物遗传学 (研究基因对药物治疗反应的影响)提供了一种强大的新工具来匹配特定的 个体患者复杂的基因蓝图的元素，具有针对性的药物治疗 个体可能以最佳方式作出反应。这项拟议的研究的目的是将药物遗传学技术应用于 预测哪些酒精依赖患者对选择性5-羟色胺再摄取抑制剂的试验反应良好 (SSRI)用于预防酒精中毒复发。我们的中心假设是影响5-羟色胺的遗传差异 转运体功能将影响酒精依赖者对西酞普兰的治疗反应。至 为了验证这一假设，我们将对西酞普兰进行为期14周的随机、双盲、平行组比较 在寻求符合DSM-IV酒精依赖标准的门诊患者时使用安慰剂。所有受试者都将 接受一次激励性访谈和9次简短的手动指导顺从强化疗法 旨在促进坚持治疗并增强戒酒或减少饮酒的动力。后处理 后续评估将在第4、12和24周进行。受试者的DNA将进行基因分型以确定等位基因 5-羟色胺转运体基因启动子区域的变异已被发现显著影响5-羟色胺再摄取 摄取并影响对SSRIs的治疗反应性。我们预测携带两个长变种的个体 这种多态的等位基因(1/1纯合子)将显示出饮酒天数的显著减少 西酞普兰与短变异等位基因纯合子(S/S纯合子)患者比较。据我们所知， 这将是在酒精依赖患者中进行的第一项研究，以测试药物遗传学在 5-羟色胺转运体(这些药物的作用部位)的功能影响对 SSRI在非抑郁女性和男性中的应用。这项研究旨在最大限度地提高找到治疗的可能性。 排除严重酒精依赖和明显冲动的受试者西酞普兰的疗效优于安慰剂 尚未发现SSRI有效的特征，控制暴露于伴随的心理社会 干预措施，以尽量减少心理治疗的天花板效应，并通过控制性和 抽烟。这项单中心研究的成功完成可能导致未来更多的多中心试验 不同的人群，以及使用5-羟色胺受体亚型特异性药物的研究。

Relapse to alcoholism remains a vexing clinical and national health problem. Efforts to match alcohol dependent patients to specific treatments based on their clinical characteristics have produced mixed results. Pharmacogenetics (the study of genetic influences on therapeutic response to drugs) offers a powerful new tool to match specific elements of an individual patient's complex genetic blueprint with targeted pharmacotherapies to which that individual may optimally respond. The purpose of this proposed research is to apply pharmacogenetic techniques to predict which alcohol dependent patients will respond favorably to a trial of a selective serotonin re-uptake inhibitor (SSRI) for the prevention of alcoholism relapse. Our central hypothesis is that genetic differences affecting serotonin transporter function will influence an alcohol dependent individual's treatment response to the SSRI, citalopram. To test this hypothesis, we will perform a 14-week, randomized, double blind, parallel group comparison of citalopram and placebo in treatment seeking outpatients who meet DSM-IV criteria for alcohol dependence. All subjects will receive a single Motivational Interview and 9 brief sessions of a manual-guided Compliance Enhancement Therapy designed to promote treatment adherence and enhance motivation to quit or cut down on drinking. Post-treatment follow-up assessments will be conducted at 4, 12 and 24 weeks. Subjects' DNA will be genotyped to determine allelic variants in the promoter region of the serotonin transporter gene that have been found to markedly affect serotonin re- uptake and influence treatment responsiveness to SSRIs. We predict that individuals who carry two long variant alleles (1/1 homozygotes) of this polymorphism will exhibit a significant reduction in drinking days in response to citalopram compared with patients homozygous for the short variant allele (s/s homozygotes). To our knowledge, this will be the first study conducted in alcohol dependent patients to test whether pharmacogenetic differences in the function of the serotonin transporter (the site of action of these medications) influence the treatment response to a SSRI in nondepressed women and men. The study is designed to maximize the likelihood of finding treatment efficacy for citalopram over placebo by excluding subjects with severe alcohol dependence and marked impulsive traits in which SSRIs have not been found to be effective, controlling the exposure to the concomitant psychosocial intervention to minimize a psychotherapy ceiling effect, and by controlling the potential moderating effects of sex and cigarette smoking. The successful completion of this single center study may lead to future multicenter trials in more heterogeneous populations, and to studies using serotonin receptor subtype-specific medications.