New Pharmacotherapy for Alcohol Dependence: Olanzapine

治疗酒精依赖的新药物疗法：奥氮平

• 批准号: 7039315
• 负责人: KENT E. HUTCHISON
• 金额: $ 52.12万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039315
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; alcoholism /alcohol abuse chemotherapy; antipsychotic agents; behavioral /social science research tag; clinical research; craving; cues; dopamine antagonists; dosage; drug screening /evaluation; genetic markers; genetic polymorphism; human subject; human therapy evaluation; longitudinal human study; mental disorder chemotherapy; patient oriented research; pharmacogenetics; psychopharmacology; serotonin inhibitor; substance abuse related behavior

DESCRIPTION (provided by applicant): 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 12 week 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.

描述（由申请人提供）：对酒精的渴望与饮酒失控有关，并且是酒精依赖生物和行为干预的主要目标。我们之前的研究表明，奥氮平（一种多巴胺拮抗剂）可以减弱对酒精的渴望，表达 D4 受体的基因变异会影响对酒精的渴望，并且奥氮平对于减少具有这种变异的个体的渴望特别有效。最近一项为期 12 周的奥氮平试验的初步数据表明，奥氮平具有良好的耐受性，并且奥氮平可以减少饮酒，特别是在具有上述遗传变异的个体中。本申请的目的是检验奥氮平（5mg/天）与奥氮平（2.5mg/天）和安慰剂对照相比在减少寻求治疗的酗酒者的渴望和酒精使用行为方面的有效性。此外，本申请将检查奥氮平对饮酒结果的影响是否是通过其对特定推定机制（即提示引发的对酒精的渴望）的影响来介导的，并确定DRD4 VNTR多态性是否是奥氮平有效性的标记。 。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。受试者将在治疗结束后 3 个月和 6 个月完成随访评估。预计在 12 周的试验和随访期间，与安慰剂条件相比，奥氮平将以剂量依赖的方式显着减少提示引发的渴望和饮酒行为。此外，预计奥氮平对酒精使用行为的影响将通过奥氮平对提示引发的渴望的影响来介导，并且奥氮平对提示引发的渴望和酒精使用行为的影响将由DRD4 VNTR调节，这样奥氮平对于具有 7 个重复等位基因的个体会更有效。拟议研究的成功完成预计将推出一种治疗酒精依赖的新药物，并推进预测这种药物有效性的遗传标记。