A New Pharmacotherapy for Alcohol Dependence: Olanzapine

对酒精的渴望与饮酒失控有关，并且是生物学和心理学的主要目标。 酒精依赖的行为干预。我们以前的研究表明，奥氮平（a 多巴胺拮抗剂）减弱了对酒精的渴望，这是一种表达D4受体的基因变异 影响对酒精的渴望，奥氮平在减少对酒精的渴望方面特别有效， 有这种变异的人。最近一项为期12周的奥氮平试验的初步数据表明， 耐受性良好，奥氮平可减少饮酒，特别是在上述患者中 基因变异本申请的目的是检验奥氮平（5 mg/天），与奥氮平（2.5 mg/天）和安慰剂对照相比， 寻求治疗的酗酒者的饮酒行为。此外，本申请将研究 奥氮平对饮酒结果的影响是否是通过其对特定的假定的 机构（即，线索引起的对酒精的渴望），并确定DRD 4 VNTR多态性是否是 奥氮平有效性的标志物。为此，将随机抽取202名酒精依赖受试者; 分配到药物组并接受12周的药物治疗。受试者将完成随访 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天的治疗过程中，以剂量依赖的方式减少线索引起的渴望和酒精使用行为。 周试验和随访期，与安慰剂条件相比。此外，预计 奥氮平对酒精使用行为的影响将通过奥氮平对线索诱发的 渴望，奥氮平对线索诱发的渴望和酒精使用行为的影响将被缓和 通过DRD 4 VNTR，使得奥氮平在具有7个重复等位基因的个体中更有效。 这项拟议中的研究的成功完成有望推动一种治疗酒精的新药的开发 依赖性和先进的遗传标记，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.