2/2 Pharmacogenetic Treatment for Alcoholism

描述（由申请人提供）：尽管开发了治疗酒精依赖（AD）的新药，但药物治疗仍然是酒精治疗的一种未充分利用的方法。在很大程度上，这是与FDA批准的AD药物相关的适度效应量的函数。目前的建议是扩展来自一项随机双盲临床试验的结果，昂丹司琼，一种特异性5-羟色胺-3（5-HT 3）拮抗剂，在欧洲， 美国（EA）和西班牙裔AD患者。在该试验中，该药物可有效减少5-羟色胺转运蛋白基因（SLC 6A 4）中52-HTTLPR L等位基因纯合子个体的饮酒量，这种效果在同一基因中32-UTR SNP（rs 1042173）的T纯合子个体中得到增强。所提出的研究将通过在LL基因型中平衡具有32-UTR SNP的个体来解决该研究的重要局限性，使得有可能准确地表征昂丹司琼的治疗效果被TT基因型增强的程度，并确定昂丹司琼在具有TT基因型的个体中与其基因型对应物相比的独立治疗效果（即，TG和GG）。此外，我们将与同等数量的EA和非洲裔美国人（AA）进行拟议的研究，以提高研究结果对一般人群的普遍性。最后，我们将使用52-HTTLPR的三等位基因型（L2与S2等位基因），以避免低估与使用双等位基因52-HTTLPR基因型（L与S等位基因）相关的药物遗传学效应。我们的总体假设是，昂丹司琼，通过调节突触后5-HT 3受体下调的SLC 6A 4多态性变异的影响，将减少在52-HTTLPR和32-UTR SNP的L2和T等位基因纯合子的个人酗酒的频率。这种效应将在两个不同的人群中观察到：EA和AA。也就是说，L2 L2/TT个体将表现出最强的治疗反应。为了检验这一假设，我们将仅招募具有L2 L2基因型的寻求治疗的AD个体，其将被分配到2组4个细胞（总N = 8），每组包含32个个体（总N=256）。由于需要招募一个非常大的样本（N=~ 1，000），从中仅随机化L2纯合子，因此本研究将在弗吉尼亚大学和宾夕法尼亚大学进行。受试者将被分配到2个组之一-AA和EA。在为期16周的临床试验中，仅包含L2纯合子的每组将以2（TT vs. TG或GG）x 2（昂丹司琼4 mg/kg每日两次vs.安慰剂）析因设计进行随机化。受试者还将接受每周一次的简短行为依从性增强治疗（BBCET）作为其心理社会辅助治疗。昂丹司琼的作用的遗传调节的成功证明，可以预期产生中等的效应大小，将有助于个性化AD的治疗，并证明在该疾病的药理学治疗中的巨大潜在益处。 公共卫生相关性：这项提议是为了扩展昂丹司琼的随机双盲临床试验的结果，在该试验中，发现该药物可以减少某些基因型个体的饮酒（即，DNA的形式，控制遗传特征的物质）。这项拟议中的研究将解决先前工作中的一些局限性，包括在欧洲裔美国人和非洲裔美国人样本中测试药物。为了确保有足够数量的参与者，这项研究将在弗吉尼亚大学和宾夕法尼亚大学进行，由在进行这类研究方面具有丰富经验的研究人员进行。

DESCRIPTION (provided by applicant): Despite the development of new medications to treat alcohol dependence (AD), pharmacotherapy remains an underutilized approach to alcohol treatment. This is, in large measure, a function of modest effect sizes associated with the FDA-approved medications for AD. The present proposal is to extend findings from a randomized double-blind clinical trial of ondansetron, a specific serotonin-3 (5-HT3) antagonist, in European- American (EA) and Hispanic individuals with AD. In that trial, the medication was efficacious in reducing drinking among individuals homozygous for the L allele of the 52-HTTLPR in the serotonin transporter gene (SLC6A4), an effect that was enhanced in individuals who were T homozygotes for the 32-UTR SNP (rs1042173) in the same gene. The proposed study will address important limitations to that study by balancing individuals with the 32-UTR SNP across the LL genotype, making it possible to characterize accurately the degree to which ondansetron's therapeutic effect was enhanced by the TT genotype and to determine the independent therapeutic effect of ondansetron in individuals with the TT genotype compared with their genotypic counterparts (i.e., TG and GG). In addition, we will do the proposed study with an equal number of EAs and African-Americans (AAs) to enhance the generalizability of the findings to the general population. Finally, we will use the tri-allelic genotype (L2 vs. S2 allele) for the 52-HTTLPR to avoid underestimation of the pharmacogenetic effect associated with the use of the bi-allelic 52-HTTLPR genotype (L vs. S alleles). Our overarching hypothesis is that ondansetron, by modulating the effects of polymorphic variation at SLC6A4 through postsynaptic 5-HT3 receptor down-regulation, will decrease the frequency of heavy drinking in individuals homozygous for the L2 and T alleles at the 52-HTTLPR and the 32-UTR SNP, respectively. This effect will be seen in two distinct populations: EAs and AAs. That is, individuals who are L2L2/TT will exhibit the most robust therapeutic response. To test this hypothesis, we will enroll only treatment-seeking, AD individuals with the L2L2 genotype, who will be assigned to 2 sets of 4 cells (total N = 8), each containing 32 individuals (total N=256). Because of the need to recruit a very large sample (N=~1,000) from which to randomize only L2 homozygotes, the study will be conducted at both the University of Virginia and the University of Pennsylvania. Subjects will be allocated into one of 2 groups-AAs and EAs. Each group, containing only L2 homozygotes, will be randomized in a 2 (TT vs. TG or GG) x 2 (ondansetron 4 mg/kg twice daily vs. placebo) factorial design in a 16-week clinical trial. Subjects also will receive weekly brief behavioral compliance enhancement treatment (BBCET) as their psychosocial adjunct. The successful demonstration of genetic moderation of the effects of ondansetron, which can be expected to yield a moderate effect size, will help to personalize the treatment of AD and demonstrate the great potential benefit in the pharmacological treatment of the disorder. PUBLIC HEALTH RELEVANCE: This proposal is to extend findings from a randomized double-blind clinical trial of ondansetron, in which the medication was found to reduce drinking among individuals with certain genotypes (i.e., forms of DNA, the material that controls the inheritance of characteristics). The proposed study will address a number of limitations in the prior work, including testing the medication in both European-American and African-American samples. To ensure an adequate number of participants, the study will be conducted at both the University of Virginia and the University of Pennsylvania, by researchers with considerable experience in the conduct of such studies.