Personalized Treatment with Pharmacotherapy and CBT for Moderate Problem Drinking

描述（由申请人提供）：问题性饮酒（极端形式为酒精依赖）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，多维的酒精依赖（AD）的类型学。几项研究表明，酗酒者的亚组可能对β-羟色胺能药物和纳洛酮（NTX）的治疗反应不同。该提案的研究部分是建立在一项正在进行的NIAAA资助的研究的基础上的，该研究是在纽约市及其附近的问题饮酒男性同性恋人群中随机分配12周的NTX或认知行为疗法（CBT）或两者结合治疗的疗效。拟议的K奖将使候选人能够研究这个独特风险群体中个体治疗反应的遗传基础，这些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的问题饮酒者相似，因为他们通常是高功能的，并且通常不会寻求以完全戒酒为目标的治疗。 这项研究的目的是确定编码5-羟色胺转运蛋白（5-HTTLPR）、μ阿片受体（OPRM 1）和GABA-A受体亚单位（GABRA 2）的基因中的遗传变异是否与这一独特人群中纳洛酮药物治疗和/或认知行为心理治疗的过程和结果相关。候选基因和多态性的选择是基于最近的研究，这些研究表明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。除了标准的结果措施，我们建议利用一种新的数据收集技术，交互式语音应答，收集数据的日常关系之间的情绪，渴望，自我效能，动机和饮酒。为了加强实习，掌握技能的设计和实施的临床试验的候选人和测试的潜在用途的一种新的药物在特定人群中适度饮酒，研究计划还包括一个试点研究的有效性和安全性口服托吡酯（200毫克/天）在同一个高功能的男男性接触者问题饮酒组。总的来说，这些研究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。这个指导病人为导向的研究职业奖申请将提供安德鲁C。Chen，医学博士，博士，训练有素的精神病学家和分子神经科学家，有必要的时间，指导和培训进行高质量的临床转化研究，包括药物遗传学方法，以开发酒精使用障碍（AUD）的个性化治疗。 公共卫生相关性：最近的研究表明，有问题的饮酒者可能对治疗有不同的反应。拟议的K奖将使候选人能够研究个体治疗反应的遗传基础。从研究中产生的数据和使用的方法将作为未来开发酒精使用障碍个性化治疗的基础。

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). PUBLIC HEALTH RELEVANCE: Recent studies have shown that individuals with problematic alcohol drinking may respond to treatments differently. The proposed K award will enable the candidate to study the genetic underpinnings of the individual treatment responses. The data generated from the study and the methodology used will serve as a foundation for future development of personalized treatments of alcohol use disorders.