Personalized Treatment with Pharmacotherapy and CBT for Moderate Problem Drinking

描述（由申请人提供）：问题性饮酒（其极端形式是酒精依赖）是一种病因学和临床异质性现象，最有可能由遗传易感性和环境暴露的相互作用引起。认识到这种异质性导致了各种尝试，以发展多元，多维类型的酒精依赖（AD）。几项研究表明，不同亚群的酗酒者对血清素类药物和纳曲酮（NTX）治疗的反应可能不同。该提案的研究部分是建立在niaaa资助的一项正在进行的研究的基础上的，该研究是在纽约市及附近地区的男男性行为者（MSM）中，随机分配12周的NTX或认知行为疗法（CBT）或两者结合的治疗效果。拟议的K奖将使候选人能够研究这一独特风险群体中个体治疗反应的遗传基础，该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性问题饮酒者相似，因为他们通常是高功能的，通常不寻求以完全戒酒为目标的治疗。本研究的目的是确定编码5-羟色胺转运体（5-HTTLPR）、mu-阿片受体（OPRM1）和GABA-A受体亚基（GABRA2）的基因的遗传变异是否与纳曲酮和/或认知行为心理治疗在这一独特人群中的药物治疗过程和结果相关。候选基因和多态性是根据最近的研究选择的，这些研究显示这些遗传变异对某些酒精相关的临床特征有小到中度的影响。除了标准的结果测量，我们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。为了加强对候选人临床试验设计和实施技能的掌握，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毫克/天）在同一高功能MSM饮酒问题组中的有效性和安全性的试点研究。总的来说，从研究中产生的数据和使用的方法将作为未来AUD个性化治疗研究的基础。这项以患者为导向的指导研究职业奖申请将为训练有素的精神病学家和分子神经科学家Andrew C. Chen博士提供必要的时间、指导和培训，以进行高质量的临床转化研究，包括药物遗传方法，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).