Genomic Predictors of Placebo response in Phase II AUD trials

项目摘要 安慰剂反应是一种重要的治疗反应现象，但人们对其了解甚少。一个庞大而 在长达十年的安慰剂对照双盲临床试验中， 测试了酒精使用障碍（AUD）的各种治疗方法。大的安慰剂效应使检测复杂化 研究药物的可量化治疗效果，特别是对于中度有效的精神病患者 毒品安慰剂反应是由患者、临床试验工作人员和治疗之间复杂的相互作用引起的 环境因素因为安慰剂反应是错综复杂的，复杂的和可变的个体，它是 在临床试验中招募之前识别这些个体具有挑战性。拟议项目旨在 探索基因组学在确定安慰剂应答者方面的实用性，以在III期AUD治疗试验中进行。迄今为止， 据我们所知，还没有进行全面的基因组研究来评估遗传变异， 与AUD治疗结局或安慰剂应答的关系。基因组分析需要大样本量， 在寻求治疗的个体中进行的中小型临床试验中不容易收集 AUD或其他药物使用障碍。为了解决这个问题，我们将利用六个方面的资源， 已完成和两项正在进行的NIAAA资助的AUD治疗试验。我们将首先研究 入组的寻求治疗的AUD患者在接受 安慰剂（Aim）。然后，我们将探讨饮酒的这些变化如何影响基因的表达， 每个个体的整个基因组（Aim基因组）。这些基因的表达水平被发现根据 一个人的饮酒行为或如何频繁的人能够戒酒，将罚款- 梳理，以确定DNA序列（遗传）变异，使他们容易受到不同数量的 酒精（Aim酒精）。接下来，我们将探讨这些遗传变异及其表达模式是否与基因组的表达有关。 基因，可以预测安慰剂反应（通过戒烟率测量）在人群与AUD一起， 其他精神疾病（可卡因成瘾和创伤后应激障碍;探索性目标）。最后，我们将探讨 所鉴定的遗传变异体和基因在那些接受过免疫治疗的人中以相同的方式表达， 活性药物（昂丹司琼/托吡酯/纳曲酮）用于治疗其AUD（探索性目的性心律失常）， 这可能有助于我们理解安慰剂成分嵌入对活性药物的反应中， 分子水平。总之，我们提出的项目在概念和方法上都是创新的， 通过检测与饮酒量相关的基因表达差异来探索遗传变异 在安慰剂治疗期间。作为第一项描述AUD III期安慰剂应答基因组学特征的研究 试验，研究结果将为未来的翻译研究提供丰富的信息，并传播 个性化医疗利用安慰剂反应并知道如何优化它将使我们能够：a） 改善总体结果; B）确定谁需要额外治疗，以及c）表征 特定AUD亚组的治疗指数（疗效/副作用）。

PROJECT SUMMARY Placebo response is an important and poorly understood phenomenon of treatment response. A large and variable placebo response has been evident in decade’s long placebo-controlled double blind clinical trials that tested various treatments for alcohol use disorders (AUD). Large placebo effects complicate detection of quantifiable treatment effects for investigational medications, especially for the modestly effective psychiatric drugs. Placebo response arise from a complex interaction of patient, clinical trial staff, and treatment environment factors. Because the placebo response is intricate, complex and variable among individuals, it is challenging to identify these individuals prior to enrollment in a clinical trial. The proposed project seeks to explore the utility of genomics to identify placebo responders in phase ІІ AUD treatment trials. To date, to the best of our knowledge, comprehensive genomic studies have not been conducted to assess genetic variation in relation to outcomes of AUD treatment or placebo response. Genomic analyses require large sample sizes that are not easy to gather in small to medium scale clinical trials conducted with treatment seeking individuals with an AUD or other drug use disorder. To address this issue, we will leverage the resources from six completed and two ongoing NIAAA-funded phase ІІ AUD treatment trials. We will first examine changes in patterns of drinking among the enrolled treatment-seeking individuals with AUD, during treatment with a placebo (Aim І). We will then explore how these changes in drinking affect expression of genes, perusing the entire genome of each individual (Aim ІІ). The genes whose expression levels are found to be changed according to a person’s drinking behavior or how frequent the person was able to abstain from alcohol, will be fine- combed to identify DNA sequence (genetic) variations that rendered them susceptible to varying amounts of alcohol (Aim ІІІ). Next, we will explore whether these genetic variations and the expression patterns of their genes, can predict placebo response (as measured by abstinence rates) in populations with AUD together with other psychiatric conditions (cocaine addiction and PTSD; Exploratory Aim І). Finally, we will explore whether the identified genetic variants and genes are expressed in the same manner in those who have received an active medication (ondansetron/topiramate/naltrexone) for the treatment of their AUD (Exploratory Aim ІІ), which may help us understand the placebo component embedded within response to an active medication, at a molecular level. In summary, our proposed project is conceptually and methodologically innovative in exploring genetic variations by examining gene expression differences associated with amounts of drinking during placebo treatment. As the first study to characterize genomics of placebo response in phase ІІ AUD trials, findings will provide a wealth of information for future translational research and propagate personalized medicine. Harnessing the placebo response and knowing how to optimize it will allow us to: a) improve overall outcomes; b) determine who is in need of additional treatment, and c) characterize the therapeutic index (efficacy/side effects) for particular subgroups with AUD.