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

将精神病理学的新颖框架与精准医学方法相结合，以了解戒酒的异质反应

• 批准号: 10473770
• 负责人: Eva Argyriou
• 金额: $ 4.54万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473770
• 关键词: ARHGEF5 gene; Abstinence; Address; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Behavioral; Categories; Characteristics; Clinical; Complement; Complex; Data; Decision Making; Development; Dimensions; Electrophysiology (science); Family history of; Fellowship; Female; Funding; Genetic; Goals; Grant; Guidelines; Heterogeneity; Human; Individual; Individual Differences; Intervention; Laboratories; Life; Measurement; Mentorship; Methodology; Methods; Modeling; Modernization; Neurobiology; Patients; Pattern; Population; Psychopathology; Recommendation; Relapse; Reporting; Research; Risk Factors; Secondary to; Subgroup; Substance Use Disorder; Symptoms; Syndrome; Taxonomy; United States National Institutes of Health; Woman; alcohol abstinence; alcohol abuse therapy; alcohol research; alcohol response; alcohol seeking behavior; alcohol use disorder; base; career; clinical decision-making; clinical practice; comorbidity; cost; design; drinking; follow-up; hospital readmission; individualized medicine; innovation; men; neurobiological mechanism; novel; personalized medicine; precision medicine; predicting response; relating to nervous system; response; sex; trait; treatment choice; treatment effect; treatment planning; treatment response

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.

项目摘要 尽管以禁欲为导向的干预措施仍然是酒精使用障碍的典型治疗方法 （aud），继电器很常见。对动物和人类的研究表明，在某些群体中，短期 禁欲，然后恢复饮酒的升级，而不是减少随后的酒精使用。这 异质性反应可以部分解释AUD治疗效果不佳，警告个性化治疗 何时准备戒酒的干预措施的规则。共同出现的心理病理学使AUD复杂， 使其成为基于临床决策的主要因素。该项目的总体目标是利用 一种新颖的心理病理学框架，即精神病理学的等级分类学（HITOP），以预测 对短期戒酒的异质反应，并检查共同的神经生物学和遗传 这种反应的基础机制。本应用的具体目的是1）表征个人 谁受益于或受到基于Hitop维度的短期强制禁欲的伤害 良好控制的实验室范式中的基本神经生物学和遗传机制和2） 表征的个人表现出自然时期后表现出不断升级的酒精消费方式 基于Hitop维度和基础神经生物学和遗传的一年中的禁欲 机制。现代尖端的亚组发现方法将被利用 类似地，与复杂的非线性建模大量的治疗调节剂相互作用 适度效应，以准确估计禁欲响应。这种尖端的方法直接 告知临床决策，从而创建指南来预测对禁欲的反应 实践。拟议的项目具有创新性和重要意义，因为1）研究禁欲的异质性 反应，这可能解释了酒精使用的升级，这是一个高度重大且昂贵的问题。 2）杠杆 个性化酒精治疗建议的新型Hitop框架，很容易评估 并且可以轻松地应用于临床环境； 3）应用最先进的现代统计方法论 解决精确医学中传统方法的局限性以及对个性化的迫切需求 治疗计划； 4）完成数据驱动的方法，并具有潜在的潜在神经生物学和 遗传机制； 5）在生态上整合了一个小说，控制良好的人类实验室范式 现实世界中有效的纵向随访报告了酒精模式，以进一步提供丰富而健壮的发现。 这项研究线的长期目标是制定准则，以促进临床从业者的决策 - 涉及何时利用基于禁欲的干预措施。