Development of A Novel Transdiagnostic Intervention for Anhedonia

项目摘要 缺乏动力和快感，共同被称为快感缺乏症，与许多精神病有关 疾病，包括情绪和焦虑障碍，物质使用障碍，精神分裂症和注意力- 缺陷/多动障碍。因此，与快感缺失相关的结构是NIMH研究的核心 域标准(RDoC)项目。快感缺失通常是最难治疗的精神症状之一。 这代表了一系列精神疾病的关键内表型和易感性因素。给定 以快感缺失为中心的大量精神障碍，改善了治疗动机的干预 和愉悦是这些障碍的关键。这个R61/R33项目的总体目标是开发一种新颖的 快感障碍的跨诊断治疗，称为行为激活治疗快感障碍(BATA)。这 新的干预措施旨在通过强调支持与个人接触来治疗快感缺乏症 相关目标和减少回避行为。符合中概述的目标和里程碑 RFA-MH-16-406(“精神疾病新干预措施的探索性临床试验”)，在#年的R61阶段 在这项试验中，我们建议使用一种实验治疗学的方法来首先评估中皮质边缘靶点 通过这种治疗参与以临床损害快感缺乏为特征的跨诊断样本(AIM 1)。具体地说，我们将检查这种治疗相对于积极的对照治疗对 奖赏期待时尾状核的激活和头侧扣带回前部皮质的激活 使用超高场(7T)功能磁共振成像奖励结果。在这一阶段， 在这一项目中，我们还将使用功能磁共振成像来确定干预的最佳剂量(目标2)。如果是定量的 目标接洽的里程碑已实现，在本计划书的R33阶段，我们计划评估 这一新疗法的最佳剂量与积极对照疗法对快感缺乏症的影响 症状和功能结果(目标3)、奖励敏感性的行为指标(目标4)和神经 奖励处理指标(目标5)。如果假设得到支持，这个项目的结果将会改变 现实世界的临床实践，因为目前还没有经过经验验证的治疗方法，心理社会或 否则，目标是快感缺乏症。考虑到临床上快感缺乏症的高比率 在一系列精神障碍中，以及BATA相对容易传播的情况下，这 新的干预措施有可能迅速而有意义地影响专门从事 一系列障碍和状况，包括情绪障碍诊所、焦虑症诊所和普通 精神科门诊服务。此处建议的应用程序跨越多个NIMH优先级，并且 倡议，包括治疗发展的实验性治疗方法(NOT-MH-14-007：政策 用于提交包含临床试验的申请)，使用标准化的表型测量(非- MH-15-009：通过PhenX工具包进行NIMH人类受试者研究的数据协调)、严格性和 研究中的透明度(NOT-OD-16-011：NIH和AHRQ研究拨款中的严格性和透明度 应用程序)和与科学界的数据共享(NOT-MH-14-015：数据共享期望 NIMH资助的临床试验和NOT-MH-15-012：资助的临床研究的数据共享期望 NIMH)。

Project Summary Deficits in motivation and pleasure, together referred to as anhedonia, are implicated in a number of psychiatric illnesses, including mood and anxiety disorders, substance-use disorders, schizophrenia, and attention- deficit/hyperactivity disorder. As a result, constructs related to anhedonia are central to the NIMH Research Domain Criteria (RDoC) project. Anhedonia is often one of the most difficult psychiatric symptoms to treat and thus represents a critical endophenotype and vulnerability factor for a range of psychiatric disorders. Given the centrality of anhedonia to a large number of psychiatric disorders, improved interventions to treat motivation and pleasure are critical for these disorders. The overall goal of this R61/R33 project is to develop a novel transdiagnostic treatment for anhedonia, called Behavioral Activation Treatment for Anhedonia (BATA). This new intervention is designed to treat anhedonia by emphasizing supported engagement with personally relevant goals and reducing avoidance behaviors. Consistent with the objectives and milestones outlined in RFA-MH-16-406 (“Exploratory Clinical Trials of Novel Interventions for Mental Disorders”), in the R61 phase of this trial we propose to use an experimental therapeutics approach to first evaluate mesocorticolimbic target engagement by this treatment in a transdiagnostic sample characterized by clinically impairing anhedonia (Aim 1). Specifically, we will examine the effects of this treatment, relative to an active comparison treatment, on caudate nucleus activation during reward anticipation and rostral anterior cingulate cortex activation during reward outcomes using ultra-high field (7T) functional magnetic resonance imaging. In this phase of the project, we will also use fMRI to determine the optimal dose of the intervention (Aim 2). If quantitative milestones for target engagement are achieved, in the R33 phase of this proposal we plan to evaluate the effects of the optimal does of this new treatment, versus an active comparison treatment, on anhedonic symptoms and functional outcomes (Aim 3), behavioral indicators of reward sensitivity (Aim 4), and neural indicators of reward processing (Aim 5). If hypotheses are supported, the results of this project will change real-world clinical practice given that there are currently no empirically-validated treatments, psychosocial or otherwise, that target anhedonia transdiagnostically. Given the high rates of clinically impairing anhedonia across a range of psychiatric disorders, as well as the relative ease with which BATA can be disseminated, this novel intervention has the potential to rapidly and meaningfully impact patient care in clinics that specialize in a range of disorders and conditions, including mood disorder clinics, anxiety disorder clinic, and general outpatient psychiatry services. The application proposed here cuts across multiple NIMH priorities and initiatives, including an experimental therapeutics approach to treatment development (NOT-MH-14-007: Policy for Submission of Applications Containing Clinical Trials), the use of standardized phenotype measures (NOT- MH-15-009: Data Harmonization for NIMH Human Subjects Research via the PhenX Toolkit), rigor and transparency in research (NOT-OD-16-011: Rigor and Transparency in NIH & AHRQ Research Grant Applications), and data sharing with the scientific community (NOT-MH-14-015: Data Sharing Expectations for NIMH-funded Clinical Trials and NOT-MH-15-012: Data Sharing Expectations for Clinical Research Funded by NIMH).