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

1/2-D-环丝氨酸强化 CBT 治疗儿童强迫症

• 批准号: 8425105
• 负责人: ERIC A. STORCH
• 金额: $ 29.65万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-08 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425105
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Adverse effects; Affect; Aftercare; Age; Agonist; Amygdaloid structure; Animal Experimentation; Animal Model; Animals; Anxiety; Anxiety Disorders; Applications Grants; Basic Science; Biological Assay; Blood specimen; Budgets; Cell Extracts; Cell Line; Child; Childhood; Chronic; Clinical; Clinical Services; Clinical Trials; Cognitive Therapy; Collaborations; Combined Modality Therapy; Comorbidity; Cycloserine; DNA; Data; Data Analyses; Dimensions; Disease remission; Dose; Double-Blind Method; Drug Kinetics; Effect Modifiers (Epidemiology); Exhibits; Exposure to; Extinction (Psychology); Florida; Fright; Funding; Future; General Hospitals; Genes; Genetic Research; Genomics; Glutamates; Gold; Hour; Impairment; Individual; Intervention; Massachusetts; Mediating; Medical; Mental disorders; Metabolic; Modeling; Monitor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Obsessive-Compulsive Disorder; Outcome; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Placebos; Plasma; Population; Procedures; Process; Psychotherapy; Quality of life; Randomized; Randomized Controlled Trials; Recording of previous events; Recruitment Activity; Relative (related person); Reporting; Research; Research Personnel; Resources; Ritual compulsion; Role; Running; Safety; Sampling; Selective Serotonin Reuptake Inhibitor; Services; Severities; Site; Specific qualifier value; Supervision; Symptoms; Training; Translating; Treatment Efficacy; Treatment outcome; Typology; United States National Institutes of Health; Universities; Validation; Vulnerable Populations; Weight; Work; Youth; alcohol use disorder; atypical antipsychotic; base; conditioned fear; cost; data management; depressive symptoms; experience; follow-up; functional disability; genome wide association study; improved; innovation; learning extinction; medical schools; multi-site trial; neural circuit; novel; novel strategies; partial response; placebo controlled study; primary outcome; prototype; research clinical testing; response; standard care; therapy adherence

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.

描述（由申请人提供）：强迫症（OCD）影响了1-2%的儿童，是一个没有治疗的慢性过程，并与相当大的功能障碍和生活质量差有关。尽管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，但相当多的年轻人在接受这些疗法后仍有症状。SRIs的药物干预只有中等效果，很少产生缓解，可能伴有副作用，对一些家长来说可能不是一种可接受的干预。非典型抗精神病药物等药物增强策略通常用于部分缓解的儿童，但其代谢影响有关，且没有系统的有效性或安全性数据支持。虽然CBT是儿童强迫症的黄金标准治疗方法，但并不是所有的患者都能从中受益，而且熟练的治疗师的可用性也相当有限。因此，迫切需要干预措施来改善儿童强迫症的治疗效果。CBT的主要机制是反复和长时间地暴露于恐惧情境中，同时戒除强迫症的仪式。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，能够增强消退学习。这一策略在动物身上成功验证后，在成人身上进行的六项试验——以及美国国立卫生研究院资助的青少年强迫症试点研究——为DCS剂量促进暴露型心理治疗中发生的消退学习提供了支持。然而，在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地推断到儿童。本研究进一步推进了DCS的试点工作，以增强CBT对强迫症儿童的影响。我们建议在两个地点进行一项双盲随机对照试验，以检查10个心理治疗阶段的相对益处，其中4-10个阶段将增加体重调整剂量的DCS (25/50mg)，与CBT增加安慰剂相比。150名患有强迫症的青少年（7-17岁）将被随机均匀地分配到两种治疗条件中的一种。主要结局将是由独立评估者评估的强迫症症状严重程度的改变。研究招募地点是南佛罗里达大学（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将提供药代动力学分析。我们的研究扩展了第一篇关于焦虑障碍/强迫症青少年DCS增强的报道，最终研究了一种创新的研究方法，即基于强迫症神经生物学的翻译模型，通过操纵谷氨酸能途径来调节基于暴露的心理治疗的改善结果。这项研究将产生重要的临床数据，最终可以改善青少年强迫症的治疗，减少潜在有害药物的暴露。