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: 10259703
• 负责人: Eva Argyriou
• 金额: $ 4.47万
• 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/10259703
• 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.

项目概要 尽管以戒酒为导向的干预措施仍然是酒精使用障碍的典型治疗选择 (AUD)，对动物和人类的研究表明，在某些群体中，复发是常见的。 戒酒后恢复饮酒会增加而不是减少随后的饮酒量。 反应的异质性可以部分解释 AUD 治疗效果不佳的原因，需要个性化治疗 何时制定以禁欲为导向的干预措施的规则 AUD， 使其成为临床决策的主要因素 该项目的总体目标是利用。 一种新颖的精神病理学框架，即精神病理学层次分类法（HiTOP），用于预测 对短期禁欲的异质反应并检查共同的神经生物学和遗传 该响应的具体机制是 1) 表征个体。 谁从基于 HiTOP 维度的短期强制禁欲中受益或受到伤害， 在良好控制的实验室范式中研究潜在的神经生物学和遗传机制；2) 描述在自然饮酒期后表现出不断增加的饮酒模式的个体的特征 根据 HiTOP 维度和潜在的神经生物学和遗传学，在一年内禁欲 将利用现代尖端的亚组发现方法，从而实现 同时对大量复杂的、非线性的治疗-调节剂相互作用进行建模 这种尖端方法可以直接准确地估计戒断反应。 为临床决策提供信息，从而能够制定预测戒断反应的指南 拟议的项目具有创新性和意义，因为它 1）研究了禁欲的异质性。 反应，这可能解释酒精使用的升级，这是一个非常重要且代价高昂的问题 2) 杠杆； 用于个性化酒精治疗建议的新颖 HiTOP 框架，易于评估 并且可以轻松应用于临床环境；3）应用尖端的现代统计方法 精准医疗传统方法的解决和个体化的迫切需求 治疗计划；4）用潜在的神经生物学和数据驱动方法来补充 遗传机制；5）将新颖的、控制良好的人类实验室范式与生态学相结合 对现实世界报告的酒精模式进行有效的纵向随访，以进一步提供丰富而可靠的发现。 该研究的长期目标是制定指导方针，以促进临床医生的决策 考虑何时使用基于禁欲的干预措施。