1/2-Pharmacogenetic Treatments for Alcoholism

描述(申请人提供)：尽管开发了治疗酒精依赖(AD)的新药，但药物疗法仍然是一种未得到充分利用的酒精治疗方法。在很大程度上，这是与FDA批准的AD药物相关的适度效应大小的作用。目前的建议是扩大恩丹西酮的随机双盲临床试验的结果，恩丹西酮是一种特定的5-羟色胺3(5-HT3)拮抗剂，在欧洲- 美国(EA)和西班牙裔AD患者。在该试验中，该药物在5-羟色胺转运体基因(SLC6A4)52-HTTLPR52-HTTLPR纯合子(SLC6A4)L纯合子个体中有效地减少饮酒，在同一基因32-UTRSNP(Rs1042173)T纯合子个体中效果增强。这项拟议的研究将解决这项研究的重要局限性，通过平衡个人与LL基因中的32-UTRSNP，使其能够准确地描述TT基因对昂丹西酮疗效的增强程度，并确定与其基因型别(即TG和GG)相比，TT基因个体的昂丹西酮的独立疗效。此外，我们将在同等数量的EA和非裔美国人(AA)中进行拟议的研究，以增强研究结果对普通人群的普适性。最后，我们将使用52-HTTLPR的三等位基因(L2和S2等位基因)，以避免低估与使用双等位基因52-HTTLPR相关的药物遗传效应(L和S等位基因)。我们的主要假设是，昂丹西酮通过突触后5-HT3受体下调来调节SLC6A4的多态变异的影响，将减少分别位于52-HTTLPR和32-UTRSNP的L2和T等位基因纯合个体的重度饮酒频率。这种影响将在两个不同的种群中看到：东亚和北美。也就是说，L2L2/TT的个体将表现出最强烈的治疗反应。为了验证这一假设，我们将只招募具有L2L2基因的寻求治疗的AD患者，他们将被分配到2组4细胞(总N=8)，每组包含32个个体(总N=256)。由于需要招募非常大的样本(N=~1,000)，以便只对L2纯合子进行随机化，这项研究将在弗吉尼亚大学和宾夕法尼亚大学进行。受试者将被分配到两组中的一组-AAS和EAS。在为期16周的临床试验中，每组只包含L2纯合子的人将在2(TT与TG或GG)×2(恩丹西酮4 mg/kg每日两次与安慰剂对照)因子设计中被随机分配。受试者还将接受每周简短的行为依从性增强治疗(BBCET)，作为他们的心理社会辅助。恩丹西酮的疗效基因调节的成功证明将产生适度的效应大小，这将有助于AD的个人化治疗，并展示在该疾病的药物治疗中的巨大潜在益处。 与公共卫生相关：这项提议是扩大昂丹西酮随机双盲临床试验的结果，在该试验中，该药物被发现可以减少具有某些基因类型(即，控制特征遗传的DNA形式)的个体的饮酒。这项拟议的研究将解决之前工作中的一些限制，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，研究人员在进行此类研究方面具有相当的经验。

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.