Predicting Alcoholics' Treatment Responses to an SSRI

描述(由申请人提供)：酗酒仍然是一个令人头疼的临床和国家健康问题。根据酒精依赖患者的临床特征将他们与特定治疗相匹配的努力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，可以将个体复杂基因蓝图的特定元素与该个体可能最佳反应的靶向药物疗法相匹配。这项拟议的研究的目的是应用药物遗传学技术来预测哪些酒精依赖患者对选择性5-羟色胺再摄取抑制剂(SSRI)的试验反应良好，以防止酒精中毒复发。我们的中心假设是，影响5-羟色胺转运体功能的遗传差异将影响酒精依赖个体对SSRI西酞普兰的治疗反应。为了验证这一假设，我们将对西酞普兰和安慰剂进行为期14周的随机、双盲、平行组比较，以寻找符合DSM-IV酒精依赖标准的门诊患者。所有受试者将接受一次激励性访谈和9次简短的手动指导顺从疗法，旨在促进治疗依从性并增强戒酒或减少饮酒的动力。治疗后的随访评估将在4周、12周和24周进行。受试者的DNA将进行基因分型，以确定5-羟色胺转运体基因启动子区的等位基因变异，这些变异已被发现显著影响5-羟色胺的再摄取，并影响对SSRIs的治疗反应。我们预测携带这种多态的两个长变异等位基因(1/1纯合子)的个体与携带短变异等位基因纯合子(S/S纯合子)的患者相比，西酞普兰的饮酒天数将显着减少。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5-羟色胺转运体(这些药物的作用部位)功能的药物遗传学差异是否会影响非抑郁女性和男性对SSRI的治疗反应。这项研究旨在通过排除有严重酒精依赖和明显冲动特征的受试者，控制伴随的心理社会干预的暴露，将心理治疗的天花板效应降至最低，并控制性行为和吸烟的潜在缓和效应，最大限度地提高西酞普兰相对于安慰剂的治疗效果的可能性。这项单中心研究的成功完成可能会导致未来在更多异质人群中进行多中心试验，并使用5-羟色胺受体亚型特异性药物进行研究。

DESCRIPTION (provided by applicant): 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 reuptake 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.