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: 8278496
• 负责人: ERIC A. STORCH
• 金额: $ 28.19万
• 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/8278496
• 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 1-2% 的儿童，未经治疗会形成慢性病程，并与严重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）或血清素再摄取抑制剂（SRI）药物疗法有反应，但相当多的青少年在接受这些疗法后仍然有症状。 SRI 的药物干预效果有限，很少产生缓解，可能伴有副作用，并且可能不是一些家长可接受的干预措施。非典型抗精神病药等药物增强策略通常用于有部分反应的儿童，但具有代谢效应，并且没有系统支持的功效或安全性数据。尽管 CBT 是儿童强迫症的黄金标准治疗方法，但并非所有患者都能受益，而且熟练治疗师的数量也相当有限。因此，迫切需要采取干预措施来改善儿科强迫症的治疗结果。 CBT 的主要机制是重复且长时间地暴露于恐惧的情境中，同时避免强迫症仪式。这种治疗基于条件性恐惧消失的动物模型。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，它是杏仁核 NMDA 受体的部分激动剂，作为一种能够增强消退学习的药物。在动物身上成功验证了这一策略后，六项针对成年人的试验以及我们在患有强迫症的青少年中进行的由 NIH 资助的试点研究为 DCS 剂量提供了支持，以促进基于暴露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到儿童。本研究进一步推进了我们的 DCS 试点工作，以增强 CBT 对强迫症儿童的效果。我们建议在两个地点进行一项双盲随机对照试验，以检验 10 次心理治疗的相对益处，其中第 4-10 次心理治疗将增加体重调整剂量的 DCS（25/50 毫克），而 CBT 则增加安慰剂。 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 将提供药代动力学测定。我们的研究通过最终研究一种创新的研究方法，基于强迫症的神经生物学转化模型，操纵谷氨酸通路来介导基于暴露的心理治疗的改善结果，从而扩展了第一份关于患有焦虑症/强迫症的青少年的 DCS 增强的报告。这项研究将产生临床上重要的数据，最终可以改善患有强迫症的青少年的治疗并减少接触潜在有害药物的机会。