Personalized Treatment with Pharmacotherapy and CBT for Moderate Problem Drinking

描述(由申请人提供)：有问题的饮酒(其极端形式是酒精依赖)是一种病因和临床上不同的现象，很可能是由遗传易感性和环境暴露的相互作用造成的。对这种异质性的认识导致了发展酒精依赖(AD)的多变量、多维类型的各种尝试。多项研究表明，不同亚组的酗酒者对5-羟色胺能药物或纳曲酮(NTX)治疗的反应可能不同。这项建议的研究部分建立在NIAAA资助的一项正在进行的研究的基础上，该研究对纽约市及邻近地区与男性发生性行为的问题饮酒者(MSM)人群进行了为期12周的NTX或认知行为疗法(CBT)或两者结合的随机分配治疗的有效性。拟议的K奖将使候选人能够研究这一独特的风险群体中个体治疗反应的遗传基础，这一群体的社会环境和网络更有可能涉及饮酒。他们的疾病表现在许多方面与大多数隐藏问题饮酒者的相似，因为他们通常功能较高，通常不会寻求以完全戒酒为目标的治疗。这项拟议研究的目的是确定编码5-羟色胺转运体(5-HTTLPR)、阿片受体(OPRM1)和GABA-A受体亚单位(GABRA2)的基因变异是否与纳曲酮药物治疗和/或认知行为心理治疗在这一特殊人群中的疗程和结果有关。候选基因和多态是根据最近的研究选择的，这些研究表明，这些遗传变异对某些与酒精相关的临床特征有轻微到中度的影响。除了标准的结果测量外，我们还建议利用一种新的数据收集技术--交互式语音响应--来收集情绪、渴望、自我效能、动机和饮酒之间的日常关系的数据。为了加强实践，掌握为候选人设计和实施临床试验的技能，并测试一种新药物在特定人群中适度饮酒的潜在用途，研究计划还包括一项关于口服托吡酯(200 mg/天)在同一高功能MSM问题饮酒组的有效性和安全性的初步研究。总体而言，研究产生的数据和使用的方法将成为未来对澳门氏症个性化治疗研究的基础。这项以患者为导向的研究职业指导奖申请将为训练有素的精神病学家和分子神经学家Andrew C.Chen医学博士提供必要的时间、指导和培训，以进行高质量的临床翻译研究，包括药物遗传学方法，以开发针对酒精使用障碍(AUD)的个性化治疗。

DESCRIPTION (provided by applicant): Problematic alcohol drinking (the extreme form of which is alcohol dependence) is an etiologically and clinically heterogeneous phenomenon that is most likely caused by an interaction of genetic predisposition and environmental exposures. Recognition of this heterogeneity has led to a variety of attempts to develop multivariate, multi-dimensional typologies of alcohol dependence (AD). Several studies have shown that subgroups of alcoholics may respond differently to treatment with serotonergic medications and perhaps with naltrexone (NTX). The research component of this proposal is built upon on an on-going NIAAA-funded study on the efficacy of 12 weeks of randomly assigned treatment with NTX or cognitive behavioral therapy (CBT) or the two combined, in a population of problem-drinking men who have sex with men (MSM) in New York City and vicinity. The proposed K award will enable the candidate to study the genetic underpinnings of the individual treatment responses in this unique risk group whose social milieu and networks are more likely to involve the consumption of alcohol. Their disease manifestations are similar in many respects to those of the majority of hidden problem-drinkers in that they are generally high functioning and do not normally seek treatments that advocate complete abstinence as their goal. The objectives of the proposed study are to determine whether genetic variants in the genes encoding the serotonin transporter (5-HTTLPR), mu-opioid receptor (OPRM1), and GABA-A receptor subunit (GABRA2) are associated with the course and outcome of pharmacotherapy with naltrexone and/or cognitive behavioral psychotherapy treatment in this unique population. The candidate genes and polymorphisms were chosen based on recent studies showing small-to-moderate effects of these genetic variants on certain alcohol-related clinical characteristics. In addition to standard outcome measures, we propose to utilize a novel data collection technology, Interactive Voice Response, to collect data on daily relations among mood, craving, self-efficacy, motivation, and drinking. To augment the practicum in mastering the skills of design and implement of clinical trials for the candidate and to test the potential use of a new medication for moderation of drinking in a specific population, the research plan also includes a pilot study on the efficacy and safety of oral topiramate (200 mg/day) in the same high functioning MSM problem drinking group. Overall, the data generated from the studies and the methodology used will serve as a foundation for future studies of personalized treatments for AUD. This Mentored Patient-Oriented Research Career Award application will provide Andrew C. Chen, MD, PhD, a well trained psychiatrist and molecular neuroscientist, with the necessary time, mentorship and training to conduct high-quality clinical translational research, including pharmacogenetic approaches, to develop personalized treatments for alcohol use disorders (AUD).