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

描述(申请人提供)：本申请是对PAR-12-071：精神疾病创新治疗先导研究协作R34(协作R34)的响应。D-环丝氨酸(DC)是一种部分N-甲基-D-天冬氨酸谷氨酸激动剂，已被证明可加强焦虑症的暴露治疗。这一方法的基础是最近在理解恐惧消退背后的神经回路方面的研究进展，并基于翻译研究的一项显著成功。到目前为止，所有的人类临床研究都在暴露前至少1小时给药。这种剂量-时间策略限制了这一极具前景的增强策略的临床应用，特别是Sine累积研究表明，DC在增强暴露治疗结果方面的有效性可能取决于暴露治疗的成功。临床前和最初的临床数据表明，如果在消光试验结束后立即给药，并在成功接触之后立即给药，也可以获得DCS暴露增加的效果。这项拟议的研究建立在现有研究的基础上，通过测试量身定制的会议后给药(即，仅在成功的暴露会议之后)加强暴露治疗的有效性。为了在这项R34研究中保持高的内部有效性，我们将社交焦虑症(SAD)患者纳入先前验证的5次CBT方案，并将他们随机分为：(1)量身定制的会后给药；(2)会前给药；(3)安慰剂给药；或(4)非量身定制的会后给药。主要结果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个月的随访中，量身定制的会后给药条件将分别优于会前给药、安慰剂给药和非定制的会后给药条件。此外，我们还将探索为加强暴露治疗量身定做的会议后给药的疗效的潜在调节因素。这一应用是研究集散控制系统的合乎逻辑的下一步。它为实现个性化医疗提供了重要的创新举措，为最终开发在CBT中管理DC的算法提供了第一步，目标是最大化焦虑症的治疗效果和成本效益，焦虑症是一些最普遍的精神疾病，使这一项目具有潜在的高公共卫生意义。

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.