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: 8628877
• 负责人: ERIC A. STORCH
• 金额: $ 28.44万
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628877
• 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，在没有治疗的情况下进行慢性课程，并且与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）的药物治疗反应，但接受这些疗法后，大量青少年仍然有症状。 SRIS的药理学干预仅是适度有效的，很少产生缓解，可能伴有副作用，并且可能对某些父母来说是可以接受的干预措施。药物增强策略（例如非典型抗精神病药）经常用于部分反应的儿童，但具有代谢作用，并且没有系统的支持疗效或安全性数据。尽管CBT是小儿强迫症的黄金标准治疗方法，但并非所有患者都受益，并且熟练治疗师的可用性非常有限。因此，需要采取干预措施来改善小儿强迫症的治疗结果。重复CBT中的主要机制，并长时间暴露于恐惧的情况下，同时放弃强迫症仪式。这种治疗方法基于有条件恐惧的灭绝动物模型。关于恐惧灭绝的神经回路的基础研究导致对杏仁核NMDA受体的部分激动剂D-Cycloserine（DCS）的检查，作为能够增强灭绝学习的药物。在动物中成功验证了该策略后，成人人类的六次试验以及我们NIH资助的OCD青年试点研究 - 为DCS剂量提供了支持，作为促进基于暴露的心理治疗期间发生的灭绝学习。但是，包括FDA在内的美国负责调节药物适应症的专家和机构认识到，成人的安全性和疗效结果不应常规地推销给儿童。本研究进一步推进了我们在DCS上的飞行员工作，以增加CBT对强迫症儿童的影响。我们提出了一项在两个部位进行的双盲随机对照试验，以检查10个心理治疗课程的相对益处，其中4-10疗程将通过重量调整后的DC（25/50mg）进行增强，而cbt则与安慰剂相比。 OCD的150名青年（7-17岁）将被随机且均匀地分配给两个治疗条件之一。主要结果将是独立评估者评估的强迫症症状严重程度的变化。研究招聘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将提供药代动力学测定。我们的研究通过最终调查了一种创新的研究方法，该方法扩展了DCS增强焦虑症/强迫症青年的首次报告，该方法基于OCD神经生物学的翻译模型来操纵谷氨酸能途径，以调解基于暴露的心理疗法的改进结果。这项研究将产生临床上重要的数据，最终可以改善强迫症的青年治疗，并减少可能有害的药物。

项目成果

Irritability in Children and Adolescents With OCD.

• DOI: 10.1016/j.beth.2020.11.001
• 发表时间: 2021-07
• 期刊: Behavior therapy
• 影响因子: 3.7
• 作者: Guzick AG;Geller DA;Small BJ;Murphy TK;Wilhelm S;Storch EA
• 通讯作者: Storch EA

The moderating effect of age on the associations of cognitive and metacognitive beliefs with pediatric OCD symptoms.

• DOI: 10.1080/16506073.2020.1819866
• 发表时间: 2021-03
• 期刊: Cognitive behaviour therapy
• 影响因子: 4.7
• 作者: Rizvi M;Smilansky H;Porth R;Myers N;Geller D;Small BJ;McGuire JF;Wilhelm S;Storch EA
• 通讯作者: Storch EA

Living with tics: reduced impairment and improved quality of life for youth with chronic tic disorders.

• DOI: 10.1016/j.psychres.2014.11.045
• 发表时间: 2015-02-28
• 期刊: PSYCHIATRY RESEARCH
• 影响因子: 11.3
• 作者: McGuire, Joseph F.;Arnold, Elysse;Park, Jennifer M.;Nadeau, Joshua M.;Lewin, Adam B.;Murphy, Tanya K.;Storch, Eric A.
• 通讯作者: Storch, Eric A.

The Future of D-Cycloserine and Other Cognitive Modifiers in Obsessive-Compulsive and Related Disorders.

D-环丝氨酸和其他认知调节剂在强迫症及相关疾病中的未来。

• DOI: 10.2174/1573400510666140619224942
• 发表时间: 2014
• 期刊: Current psychiatry reviews
• 作者: Sulkowski,MichaelL;Geller,DanielA;Lewin,AdamB;Murphy,TanyaK;Mittelman,Andrew;Brown,Ashley;Storch,EricA
• 通讯作者: Storch,EricA

Cognitive Beliefs Across the Symptom Dimensions of Pediatric Obsessive-Compulsive Disorder: Type of Symptom Matters.

• DOI: 10.1016/j.beth.2021.08.001
• 发表时间: 2022-03
• 期刊: BEHAVIOR THERAPY
• 影响因子: 3.7
• 作者: Cervin, Matti;McNeel, Morgan M;Wilhelm, Sabine;McGuire, Joseph F;Murphy, Tanya K;Small, Brent J;Geller, Daniel A;Storch, Eric A
• 通讯作者: Storch, Eric A