Combining a novel framework for psychopathology with a precision medicine approach to understand the heterogeneous response to abstinence from alcohol

项目摘要 虽然戒酒为导向的干预仍然是酒精使用障碍的典型治疗选择， (AUD)复发是常见的。对动物和人类的研究表明，在某些群体中， 戒酒后再恢复饮酒会加剧而不是减少随后的饮酒。这 反应的异质性可以部分解释AUD治疗效果差， 规定何时采取禁欲干预措施。共同发生的精神病理学使AUD复杂化， 使其成为临床决策的主要因素。该项目的总体目标是利用 一个新的精神病理学框架，精神病理学的层次分类（HiTOP），预测 对短期禁欲的异质反应，并检查共同的神经生物学和遗传学 这一反应背后的机制。本申请的具体目的是1）表征个体 受益于或受到基于HiTOP维度的短期强制禁欲的人， 在良好控制的实验室范例中的潜在神经生物学和遗传机制，以及2） 描述那些在自然的饮酒期后表现出酒精消费升级模式的人的特征。 基于HiTOP维度和潜在的神经生物学和遗传学， 机制等将利用现代尖端的亚组发现方法， 同时对大量的治疗-调节剂相互作用进行建模， 适度效应，以准确估计禁欲反应。这种先进的方法直接 为临床决策提供信息，从而能够创建预测对禁欲反应的指南， 实践该项目是创新和重要的，因为它1）研究禁欲的异质性 反应，这可能解释了酒精使用的升级，这是一个非常重要和昂贵的问题; 2）利用 用于个性化酒精治疗建议的新型HiTOP框架，易于评估 并且可以很容易地应用于临床环境; 3）应用尖端的现代统计方法， 解决了传统方法在精准医学中的局限性和个性化治疗的迫切需要。 治疗计划; 4）补充数据驱动的方法与潜在的基础神经生物学和 遗传机制;和5）整合了一个新的，良好控制的人类实验室范式与生态 对真实世界报告的酒精模式进行有效的纵向随访，以进一步提供丰富和可靠的发现。 这项研究的长期目标是制定指导方针，以促进临床医生的决定- 关于何时使用基于禁欲的干预措施。

Project Summary Although abstinence-oriented interventions remain the typical treatment choice for alcohol use disorder (AUD), relapse is common. Research in animals and humans shows that, in certain groups, short-term abstinence followed by reinstatement of drinking escalates, instead of reduces, subsequent alcohol use. This heterogeneity in response can in part explain poor AUD treatment effects, warranting personalized treatment rules for when to prescribe abstinence-oriented interventions. Co-occurring psychopathology complicates AUD, making it a prime factor on which to base clinical decision-making. The overall goal of this project is to utilize a novel psychopathology framework, the Hierarchical Taxonomy of Psychopathology (HiTOP), to predict the heterogeneous response to short-term abstinence and to examine shared neurobiological and genetic mechanisms underlying this response. The specific aims of this application are to 1) characterize individuals who benefit from, or are harmed by, short-term enforced abstinence based on HiTOP dimensions and underlying neurobiological and genetic mechanisms in a well-controlled laboratory paradigm and 2) Characterize individuals who show escalating patterns of alcohol consumption after natural periods of abstinence over a one-year period based on HiTOP dimensions and underlying neurobiological and genetic mechanisms. Modern cutting-edge subgroup discovery methodology will be leveraged which enables simultaneously modeling a large number of treatment-moderator interactions with complex, nonlinear moderation effects, to accurately estimate abstinence response. This cutting-edge methodology directly informs clinical decision making, enabling the creation of guidelines for predicting response to abstinence in practice. The proposed project is innovative and significant as it 1) studies heterogeneity in abstinence response, which might explain escalation in alcohol use, a highly significant and costly problem; 2) leverages the novel HiTOP framework for personalized alcohol treatment recommendations, which is easily assessed and can be easily applied to clinical settings; 3) applies cutting edge modern statistical methodology that addresses limitations of traditional methods in precision medicine and the urgent need for individualized treatment planning; 4) complements data-driven approaches with potential underlying neurobiological and genetic mechanisms; and 5) integrates a novel, well-controlled human laboratory paradigm with ecologically valid longitudinal follow-up of real-world reported alcohol patterns to further provide rich and robust findings. The long-term goal of this line of research is to develop guidelines to facilitate clinical practitioners’ decision- making concerning when to utilize abstinence-based interventions.