Improving Therapeutic Learning in Depression: Proof of Concept

项目概要/摘要 尽管药物治疗和心理治疗在治疗抑郁症方面都取得了进展，但无反应和 部分反应仍然是相对常见的结果，促使人们寻找新的治疗方法。这 本申请涉及一种这样的新型治疗的开发，其基于一种特定的 转化研究的成功：基于认知行为疗法（CBT）的增强 D-环丝氨酸（DCS）。在这个应用中，我们提出了一个研究的DCS的功效， 与抑郁症治疗相关的治疗性学习（即，在灭绝学习之外， 已取得成功）。具体而言，对于R-21机制（PA-11 - 261），我们 研究DCS在增强抑郁症患者陈述性记忆中的作用， 标准化测试和认知治疗课程材料的保留。在寻求扩大治疗 为了达到DCS增强的目标，我们还建议研究一种活性比较剂。这个特工 莫达非尼似乎在睡眠剥夺和非睡眠剥夺中均提供认知增强作用 个人，但似乎也有药物状态（例如，情绪和副作用）不是DCS的特征 增强因此，药物环境效应可能会随着时间的推移影响记忆力。因此，我们将 评价药物作用期间以及一周后无记忆增强作用时的记忆增强作用。 药物被拿走了。总体而言，我们建议在4项研究中检查认知功能和记忆表现， 在96名患有严重抑郁症的男性和女性中，他们将以双盲方式随机 分配至：（1）50 mg DCS，（2）250 mg DCS，（3）100 mg莫达非尼，或（4）安慰剂 第二周和第三周。记忆测试包括给定学习周特有的两个项目（即，项目分类， HVLT和数字向后），以及随时间重复的存储器任务（逻辑存储器任务和 认知治疗内容），允许在一周内评估记忆和保持效果 (i.e.,从第2周到第3周和从第3周到第4周）。我们相信这项研究是下一个合乎逻辑的步骤 旨在扩大CBT对抑郁症的增强作用。如果在本R21中实现了研究目标 研究，我们将在资助期结束时继续进行R01申请，以证明是否 治疗性学习的增强导致抑郁症患者更早和/或更强的治疗反应。 接受CBT的患者。

PROJECT SUMMARY/ABSTRACT Despite advances in both pharmacotherapy and psychotherapy for major depression, non-response and partial-response remain relatively common outcomes, motivating the search for new treatments. This application is concerned with the development of one such novel treatment, based on one of the particular successes of translational research: the augmentation of exposure-based cognitive-behavior therapy (CBT) with d-cycloserine (DCS). In this application, we propose a study of the efficacy of DCS for augmenting therapeutic learning relevant for the treatment of depression (i.e., outside the extinction learning where DCS has been shown to have success). Specifically, appropriate to an R-21 mechanism (PA-11-261), we investigate the role of DCS in enhancing declarative memory in depressed individuals, as evaluated by standardized tests and the retention of cognitive therapy session material. In seeking to extend the therapeutic targets for DCS augmentation, we are also proposing to study an active comparison agent. This agent, modafinil, appears to offer cognitive enhancing effects among both sleep deprived and non-sleep deprived individuals, but also appears to have drug-state (e.g., mood and side) effects that are not characteristic of DCS augmentation. For this reason, drug-context effects may affect memory retention over time. Hence, we will evaluate memory enhancement effects both during the period of drug action as well as one week later when no drug is taken. Overall, we propose to examine cognitive function and memory performance over 4 study sessions in 96 men and women with major depression, who, in a double-blind fashion, will be randomly assigned to either: (1) 50mg DCS, (2) 250mg DCS, (3) 100mg modafinil, or (4) placebo administered on Study Weeks 2 and 3. The memory tests include both items unique to a given study week (i.e., item categorization, the HVLT, and digits backward), and memory tasks that are repeated over time (logical memory tasks and the cognitive therapy content), that allow assessment of memory and retention effects across one-week periods (i.e., from Week 2 to Week 3 and from Week 3 to Week 4). We believe this study is the next logical step toward the goal of extending CBT augmentation effects for depression. If study aims are achieved in this R21 study, we will proceed with a R01 application at the conclusion of the funding period, working to show whether augmentation of therapeutic learning leads to an earlier and/or more robust treatment response for depressed patients undergoing CBT.