Dose Timing of D-cycloserine to Augment CBT for Social Anxiety Disorder

描述（由申请人提供）：本申请是对PAR-12-071：精神疾病创新治疗初步研究的协作R34（协作R34）的回应。D-环丝氨酸（DCS）是一种部分N-甲基-D-天冬氨酸谷氨酸激动剂，已被证明可增强焦虑症的暴露疗法。这种方法基于最近在理解恐惧消退背后的神经回路方面的研究进展，并且基于转化研究的惊人成功之一。迄今为止，所有人体临床研究均在暴露前至少1小时给予DCS。这种剂量定时策略限制了这种非常有前途的增强策略的临床效用，特别是累积研究表明DCS增强暴露治疗结局的疗效可能取决于暴露会话的成功。临床前和初始临床数据表明，当在成功的暴露期后进行消退试验后立即给予DCS时，也可以获得DCS的增强效果。拟议的研究建立在现有研究的基础上，通过测试定制的会话后DCS管理的功效（即，仅在成功的暴露会话之后）用于增强暴露疗法。为了在这项R34研究中保持较高的内部效度，我们将在先前验证的5次CBT方案中招募社交焦虑障碍（SAD）患者，并将其随机分配至：（1）定制的会议后DCS管理;（2）会议前DCS管理;（3）安慰剂管理;或（4）非定制的会议后DCS管理。主要结局将是社交焦虑严重程度的短期和长期改善：我们预计，在治疗后、1个月和3个月随访时，定制的会话后DCS给药条件将分别优于会话前DCS给药、安慰剂给药和非定制的会话后DCS给药条件。此外，我们将探讨定制的会话后DCS管理的疗效的潜在调节剂，以加强暴露治疗。这种应用是DCS研究的逻辑下一步。它为实现个性化医疗提供了重要的创新举措，为最终开发用于在CBT中管理DCS的算法提供了第一步，其目标是最大限度地提高焦虑症治疗的疗效和成本效益，这是一些最普遍的精神疾病，使其成为具有潜在高度公共卫生意义的项目。

DESCRIPTION (provided by applicant): This application is in response to PAR-12-071: Collaborative R34s for Pilot Studies of Innovative Treatments in Mental Disorders (Collaborative R34). D-cycloserine (DCS) is a partial N-methyl-D-aspartate glutamate agonist that has been shown to enhance exposure therapies for anxiety disorders. This approach is grounded in recent research advances in understanding the neural circuitry underlying fear extinction and is based upon one of the striking successes of translational research. All human clinical studies to date have administered DCS at least 1 hour prior to the exposure sessions. This dose-timing strategy limits the clinical utility of this highly promising augmentation strategy, especially sine accumulating research suggest that the efficacy of DCS for enhancing exposure therapy outcomes may depend on the success of exposure sessions. Pre-clinical and initial clinical data suggest that the DCS exposure-augmentation effect can also be obtained when DCS is administered immediately after an extinction trial when it follows successful exposure sessions. The proposed study builds upon this extant research by testing the efficacy of tailored post-session DCS administration (i.e., only following successful exposure sessions) for augmenting exposure therapy. In order to maintain high internal validity in this R34 study, we will enroll patients with social anxiety disorder (SAD) in a previously validated 5-session CBT protocol and randomize them to: (1) tailored post-session DCS administration; (2) pre-session DCS administration; (3) placebo administration; or (4) non-tailored post-session DCS administration. The primary outcomes will be short- and long-term improvements in social anxiety severity: We expect that the tailored post-session DCS administration condition will outperform the pre-session DCS administration, placebo administration, and non-tailored post-session DCS administration conditions, respectively, at posttreatment, 1-month and 3-month follow-up. In addition, we will explore potential moderators of the efficacy of tailored post-session DCS administration for augmenting exposure therapy. This application is the logical next step in the study of DCS. It provides an important innovative move toward the realization of personalized medicine by providing the first step in the eventual development of an algorithm for administering DCS in CBT with the goal of maximizing the efficacy and cost-effectiveness of therapy for anxiety disorders, which are some of the most prevalent mental conditions, making this a project of potentially high public health significance.