D-Cycloserine Augmentation of Therapy for Pediatric Obsessive-Compulsive Disorder

描述(申请人提供)：暴露和反应预防疗法(E/RP)已被证明对治疗儿童强迫症(OCD)有效。然而，E/RP并不能帮助所有的儿童，那些受益的人在治疗完成后往往仍然有症状。作为E/RP基础的行为理论基于两个组成部分，即恐惧条件作用和消退。在神经层面上，E/RP结合了与恐惧条件作用机制类似的机制。参与学习和记忆的N-甲基-D-天冬氨酸(NMDA)谷氨酸能受体的拮抗剂可以阻止恐惧学习和灭绝。有证据表明，D-环丝氨酸(DC)是NMDA谷氨酸受体的部分激动剂，可以增强动物和人类的联想学习和作为一种学习形式的消亡。最近在患有其他焦虑症(恐高症和社交恐惧症)的成年人中进行的临床试验支持了DCS剂量，因为它促进了基于暴露的心理治疗期间发生的联想学习。鉴于E/RP是基于灭绝的原则，在患有强迫症的青少年中，DC可能会增加E/RP，这是一种在概念上类似于恐高症和社交恐惧症的焦虑症。考虑到这一点，我建议进行一项随机、双盲、安慰剂对照的DC试点研究，以确定它对患有强迫症的青年患者的E/RP是否有任何短期的临床益处。20名初步诊断为强迫症的儿童和青少年(8-17岁)将被随机分配到两种治疗方案中的一种：(1)E/RP+DCs(25或50 mg，视体重而定)，或(2)E/RP+安慰剂。所有患者都将接受基于简化POTS(2004)方案的10个疗程的E/RP。参与者将在第4-10疗程前4小时服用DCs或安慰剂(第1-3疗程不涉及暴露，因此DCs不会有假设的效果)。一名盲目的独立评估员将在三个时间点对参与者进行评估。其中两项评估(基线评估、治疗后评估)将是综合性的(例如诊断性访谈、自我报告、CYBOCS、实验室测试)，而第四周的评估将仅涉及执行CYBOCS、CGI、CGI-S和不良症状检查表。这项研究的结果可能具有强大的临床意义，因为它为增强标准E/RP有效性的药理学药物提供了初步支持。这类药物可能在改善结果、减少过早终止治疗以及针对治疗难治的患者方面具有实用价值。

DESCRIPTION (provided by applicant): Exposure and response prevention therapy (E/RP) has proven efficacy for treatment of pediatric obsessive-compulsive disorder (OCD). Yet, E/RP does not help all children and those who benefit often remain symptomatic upon treatment completion. The behavioral theory that underlies E/RP is based on two components, namely fear conditioning and extinction. On a neural level, E/RP incorporates similar mechanisms to those involved in fear conditioning. Antagonists at the N-methyl-D-aspartate (NMDA) glutamatergic receptor, which is involved in learning and memory, block both fear learning and extinction. Evidence suggests that D-Cycloserine (DCS), a partial agonist at the NMDA glutamate receptor, augments associative learning and extinction as a form of learning in animals and humans. Recent clinical trials in adults with other anxiety disorders (acrophobia and social phobia) provided support for DCS dosing as facilitating associative learning that occurs during exposure-based psychotherapy. Given that E/RP is based on the principles of extinction, DCS may augment E/RP in youth with OCD, an anxiety disorder that is conceptually similar to acrophobia and social phobia. With this in mind, I propose to undertake a randomized, double-blind placebo controlled pilot study of DCS to determine whether it had any short-term clinical benefits on E/RP in youth with OCD. Twenty children and adolescents (ages 8-17) with a primary diagnosis of OCD will be randomly assigned to one of two treatment conditions: (1) E/RP plus DCS (25 or 50mg depending on weight), or (2) E/RP plus placebo. All patients will receive 10 sessions of E/RP based on an abbreviated POTS (2004) protocol. Participants will take DCS or placebo 4 hours prior to therapy sessions 4-10 (sessions 1-3 do not involve exposure, thus DCS would have no hypothesized effect). A blinded, independent evaluator will assess participants at three time points. Two of the assessments (Baseline, Post-treatment) will be comprehensive in nature (e.g., diagnostic interview, self-reports, CYBOCS, laboratory tests), whereas the week four assessment will involve administration of the CYBOCS, CGI, CGI-S, and Adverse Symptom Checklist only. Results from this study may have powerful clinical implications by providing preliminary support for pharmacological agents that enhance the effectiveness of standard E/RP. Such agents may have utility in improving outcome, reducing premature therapy termination, and targeting patients who have been treatment refractory.