Predicting Alcoholics' Treatment Responses to an SSRI

预测酗酒者对 SSRI 的治疗反应

• 批准号: 7059992
• 负责人: ROBERT M ANTHENELLI
• 金额: $ 51.04万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059992
• 关键词: alcoholism /alcohol abuse; alcoholism /alcohol abuse therapy; behavior therapy; behavioral /social science research tag; citalopram; clinical research; gel electrophoresis; gene expression; genotype; human subject; motivation; pharmacogenetics; polymerase chain reaction; relapse /recurrence; serotonin inhibitor; serotonin transporter; therapy compliance

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.

描述（由申请人提供）：酗酒仍然是一个烦人的临床和国家健康问题。基于其临床特征将依赖酒精的患者与特定治疗相匹配的努力产生了不同的结果。药物遗传学（对对药物治疗反应的遗传影响的研究）提供了一种强大的新工具，可将单个患者复杂遗传蓝图的特定元素与靶向药物疗法相匹配，该元素可以对其进行最佳反应。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依赖酒精的患者将对选择性5-羟色胺再摄取抑制剂（SSRI）的试验有利，以防止酒精中毒复发。我们的中心假设是影响5-羟色胺转运蛋白功能的遗传差异将影响依赖性人对SSRI Citalopram的治疗反应。为了检验这一假设，我们将在治疗中对西妥位丙醇和安慰剂进行14周，随机，双盲，平行组的比较，以寻求符合DSM-IV符合酒精依赖标准的门诊患者。所有受试者都将获得一次动机访谈，并进行9次简短的课程，旨在提高治疗依从性并增强戒酒或减少饮酒的动机。治疗后随访评估将在4、12和24周进行。将对受试者的DNA进行基因分型，以确定5-羟色胺转运蛋白基因的启动子区域中的等位基因变异，这些变体已被发现显着影响5-羟色胺再摄取并影响对SSRIS的治疗治疗反应能力。我们预测，与短变体等位基因（S/S纯合子）纯合患者相比，这种多态性的两个长变异等位基因（1/1个纯合子）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-羟色胺转运蛋白功能的药物遗传学差异（这些药物的作用部位）是否会影响不抑郁的男女对SSRI的治疗反应。该研究旨在通过排除严重酒精依赖的受试者和明显的脉冲性状，在这些受试者中发现尚未发现SSRI有效，从而控制了辅助的心理干预措施，从而最大程度地减少了精神疗法的效果，从而使潜在的效果最大程度地减少了性，这项研究旨在通过排除具有严重酒精依赖的受试者和明显的冲动性状，从而最大程度地发现SSRI有效，从而最大程度地减少了性能效果，并通过控制性效果，并通过效果最小化，从而控制了SSRIS，从而最大程度地减少了性能，该研究旨在最大程度地提高对Citalopram而不是安慰剂的治疗效率的可能性。这项单一中心研究的成功完成可能会导致更异质的人群中的未来多中心试验，并使用5-羟色胺受体亚型特异性药物进行研究。