1/2-D-Cycloserine Augmentation of CBT for Pediatric OCD

描述（由申请人提供）：强迫症（OCD）影响1-2%的儿童，在没有治疗的情况下进行慢性病程，并与相当大的功能障碍和生活质量差有关。虽然大多数强迫症患者对认知行为疗法（CBT）或5-羟色胺再摄取抑制剂（SRI）的药物治疗有反应，但相当数量的年轻人在接受这些治疗后仍有症状。SRI的药物干预仅具有中等有效性，很少产生缓解，可能伴有副作用，并且可能不是一些父母可接受的干预。非典型抗精神病药等药物强化策略常用于部分缓解的儿童，但存在代谢影响，且无系统性支持疗效或安全性数据。虽然CBT是儿童强迫症的金标准治疗，但并非所有患者都受益，并且熟练的治疗师的可用性非常有限。因此，迫切需要干预措施来改善儿童强迫症的治疗结果。CBT的主要机制是重复和长期暴露于恐惧的情况下，同时放弃强迫症仪式。这种治疗是基于消除条件性恐惧的动物模型。对恐惧消退背后的神经回路的基础研究导致了对d-环丝氨酸（DCS）的研究，DCS是杏仁核中NMDA受体的部分激动剂，作为能够增强消退学习的药剂。在动物中成功验证了这一策略之后，在成年人中进行的六项试验-以及我们在患有强迫症的青年中进行的NIH资助的试点研究-为DCS剂量提供了支持，以促进在基于焦虑的心理治疗期间发生的消退学习。然而，美国负责监管药物适应症的专家和机构（包括FDA）认识到，成人的安全性和有效性研究结果不应常规外推至儿童。本研究进一步扩大了我们在DCS上的试点工作，以增强CBT对强迫症儿童的影响。我们提出了一项双盲随机对照试验，在两个地点进行，以检查10个心理治疗疗程的相对益处，其中第4-10个疗程将增加体重调整剂量的DCS（25/50 mg），与CBT增加安慰剂相比。150名患有强迫症的青少年（7-17岁）将被随机平均分配到两种治疗条件之一。主要结果将是由独立评估者评估的强迫症症状严重程度的变化。研究招募中心为南佛罗里达大学（USF）和马萨诸塞州总医院/哈佛医学院（MGH）。USF将提供数据管理服务，而MGH将提供药代动力学试验。我们的研究扩展了第一份关于焦虑症/强迫症青少年DCS增强的报告，最终调查了一种创新的研究方法，该方法基于强迫症神经生物学的转化模型，操纵神经元通路，以介导基于焦虑的心理治疗的改善结果。这项研究将产生临床上重要的数据，最终可以改善对患有强迫症的青少年的治疗，并减少对潜在有害药物的暴露。

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) affects 1-2% of children, runs a chronic course without treatment, and is associated with considerable functional impairment and poor quality of life. Although most patients with OCD respond to cognitive-behavioral therapy (CBT) or pharmacotherapy with a serotonin reuptake inhibitor (SRI), a substantial number of youth remain symptomatic after receiving these therapies. Pharmacological interventions with SRIs are only moderately efficacious, rarely produce remission, may be accompanied by side effects, and may not be an acceptable intervention to some parents. Medication augmentation strategies such as atypical antipsychotics are often used in children with partial response but have concerning metabolic effects and no systematic supporting efficacy or safety data. Although CBT is the gold standard treatment for pediatric OCD, not all patients benefit and the availability of skilled therapists is quite limited. Thus, there is a critical need for interventions to improve treatment outcome in pediatric OCD. The primary mechanism in CBT is repeated and prolonged exposure to feared situations while abstaining from OCD rituals. This treatment is based on animal models of extinction of conditioned fears. Basic research on the neural circuitry underlying fear extinction led to the examination of d-cycloserine (DCS), a partial agonist at the NMDA receptor in the amygdala, as an agent capable of enhancing extinction learning. Following successful validation of this strategy in animals, six trials in adult humans - and our NIH-funded pilot study in youth with OCD - provide support for DCS dosing as facilitating extinction learning that occurs during exposure-based psychotherapy. However, experts and agencies responsible for regulating drug indications in the US, including the FDA, recognize that safety and efficacy findings in adults should not be routinely extrapolated to children. The present study furthers our pilot work on DCS to augment the effects of CBT in children with OCD. We propose a double-blind randomized controlled trial, conducted at two sites, to examine the relative benefit of 10 psychotherapy sessions of which sessions 4-10 will be augmented with weight-adjusted doses of DCS (25/50mg) compared to CBT augmented with placebo. 150 youth (ages 7-17) with OCD will be randomly and evenly assigned to one of the two treatment conditions. The primary outcome will be change in OCD symptom severity assessed by independent evaluators. The study recruitment sites are the University of South Florida (USF) and Massachusetts General Hospital/Harvard Medical School (MGH). USF will provide data management services while MGH will provide pharmacokinetic assays. Our study extends the first report of DCS augmentation in youth with anxiety disorder/OCD by conclusively investigating an innovative research approach that manipulates glutamatergic pathways to mediate improved outcomes of exposure-based psychotherapy based upon a translational model of the neurobiology of OCD. This study will yield clinically important data, which could ultimately improve the treatment of youth with OCD and reduce exposure to potentially harmful medications.