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

描述(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疗程，并与相当大的功能障碍和较低的生活质量有关。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)药物疗法有反应，但相当数量的年轻人在接受这些疗法后仍有症状。使用SRIs的药物干预只是中等有效，很少产生缓解，可能伴随副作用，可能不是一些父母可以接受的干预措施。药物强化策略，如非典型抗精神病药物，经常用于部分反应的儿童，但涉及代谢影响，没有系统的支持疗效或安全性数据。虽然CBT是治疗儿童强迫症的黄金标准，但并不是所有的患者都能受益，熟练的治疗师的可获得性也相当有限。因此，迫切需要干预措施来改善儿童强迫症的治疗结果。CBT的主要机制是反复和长期暴露在令人恐惧的情况下，同时戒除强迫症仪式。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，d-环丝氨酸是杏仁核中nmda受体的部分激动剂，能够促进消退学习。在动物身上成功验证了这一策略后，在成年人身上进行的六项试验-以及我们由美国国立卫生研究院资助的针对患有强迫症的青年的试点研究-为DC剂量提供了支持，因为它促进了基于暴露的心理治疗期间发生的灭绝学习。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例行公事地推断到儿童。这项研究进一步推进了我们在分布式控制系统方面的试点工作，以增强CBT在强迫症儿童中的效果。我们提出了一项在两个地点进行的双盲随机对照试验，以检验10个心理治疗疗程的相对益处，其中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中的一种。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。研究招募地点是南佛罗里达大学(USF)和马萨诸塞州综合医院/哈佛医学院(MGH)。USF将提供数据管理服务，而MGH将提供药代动力学分析。我们的研究扩展了第一份关于患有焦虑症/强迫症的年轻人的DC增强的报告，最终调查了一种创新的研究方法，该方法操纵谷氨酸能通路，以基于强迫症神经生物学的翻译模型为基础，调节暴露为基础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，最终可能会改善患有强迫症的青少年的治疗，并减少潜在有害药物的暴露。 公共卫生相关性：我们建议进行一项随机、双盲、安慰剂对照研究，以评估认知行为疗法的d-环丝氨酸强化治疗儿童强迫症的疗效。这项研究代表了一种创新的方法，将实验室研究结果转化为临床研究，并测试了一种新的方法，以安全的非精神药物药物加强有效的心理治疗。

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. PUBLIC HEALTH RELEVANCE: We are proposing a randomized double-blind placebo-controlled study to assess the efficacy of d-cycloserine augmentation of cognitive-behavioral therapy for the treatment of pediatric obsessive compulsive disorder. This study represents an innovative approach in translating bench research findings into clinical research and testing a new approach for augmenting an effective psychotherapy with a safe non-psychotropic medication.