A New Pharmacotherapy for Alcohol Dependence: Olanzapine

对酒精的渴求与饮酒失控有关，是生物和 酒精依赖的行为干预。我们之前的研究已经证明奥氮平(A) 多巴胺拮抗剂)减轻对酒精的渴望，酒精是表达D4受体的基因的一种变体 影响对酒精的渴望，奥氮平在减少 携带此变种的个体。最近奥氮平12周试验的试验数据表明，奥氮平是 耐受性良好，奥氮平减少饮酒，特别是在患有上述 基因变异。本申请的目的是检查奥氮平(5)的有效性 与奥氮平(2.5毫克/天)和安慰剂对照组相比，在减少饥饿感和 寻求治疗的酗酒者的酒精使用行为。此外，本申请将审查 奥氮平对饮酒结局的影响是否通过其对特定推定的 机制(即，线索引起的对酒精的渴求)，并确定DRD4 VNTR多态是否 奥氮平有效性的标记物。为此，将随机抽取202名酒精依赖受试者； 分配给药组，并接受12周的药物治疗。受试者将完成后续调查 在治疗结束后3个月和6个月进行评估。预计奥氮平将显著 在12个月的过程中，以剂量依赖的方式减少暗示引发的渴望和饮酒行为 周试验和随访期，与安慰剂条件相比较。此外，预计 奥氮平对酒精使用行为的影响可能是通过其对线索诱导的影响来实现的 奥氮平对线索诱导的渴望和饮酒行为的影响将得到缓解 因此，奥氮平对具有7个重复等位基因的个体更有效。 这项拟议中的研究的成功完成有望推进一种治疗酒精的新药 依赖和先进的遗传标记，预测这种药物的有效性。

Craving for alcohol has been related to loss of control drinking and is a major target of biological and behavioral interventions for alcohol dependence. Our previous research has demonstrated that olanzapine (a dopamine antagonist) attenuates craving for alcohol, that a variant in the gene that expresses D4 receptors influences craving for alcohol, and that olanzapine is particularly effective at reducing craving among individuals with this variant. Pilot data from a recent 12week trial of olanzapine indicates that olanzapine is well tolerated and that olanzapine reduces drinking, particularly among individuals with the aforementioned genetic variant. The objective of the present application is to examine the effectiveness of olanzapine (5 mg/day), as compared to olanzapine (2.5 mg/day) and a placebo control, in terms of reducing craving and alcohol use behavior among treatment seeking alcoholics. Furthermore, the present application will examine whether the effects of olanzapine on drinking outcomes are mediated by its effects on a specific putative mechanism (i.e., cue-elicited craving for alcohol) and determine whether the DRD4 VNTR polymorphism is a marker for the effectiveness of olanzapine. To that end, 202 alcohol dependent subjects will be randomly ; assigned to medication group and receive 12 weeks of medication. Subjects will complete follow-up assessments at 3 and 6 months after the end of the treatment. It is expected that olanzapine will significantly reduce cue-elicited craving and alcohol use behavior in a dose dependent fashion over the course of the 12 week trial and follow-up period, as compared to the placebo condition. Furthermore, it is expected that the effects of olanzapine on alcohol use behavior will be mediated by the effect of olanzapine on cue-elicited craving and that the effects of olanzapine on cue-elicted craving and alcohol use behavior will be moderated by the DRD4 VNTR, such that olanzapine will be more effective among individuals with the 7 repeat allele. The successful completion of the proposed research is expected to advance a new medication for alcohol dependence and advance genetic markers that predict the effectiveness of this medication.