Effect of D-cycloserine on treatment of PTSD in youth

D-环丝氨酸治疗青少年PTSD的效果

• 批准号: 7938687
• 负责人: MICHAEL S SCHEERINGA
• 金额: $ 46.58万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938687
• 关键词: 12 year old; Address; Adolescent; Adverse effects; Agonist; Alzheimer' s Disease; Animal Model; Animals; Antibiotics; Area; Behavior; Behavioral; Biological Markers; Biological Markers; Child; Childhood; Clinical; Clinical Research; Cognition; Cognitive Therapy; Complex; Coupled; Cycloserine; Diagnosis; Dimensions; Disease; Disease remission; Distress; Dose; Effectiveness; Extinction (Psychology); Family; Fright; Glycine; Heart; Human; Hydrocortisone; Impairment; Infection; Institutes; Intervention; Intervention Studies; Learning; Maintenance; Measures; Memory; Mental disorders; Meta-Analysis; Modality; Modeling; N-Methylaspartate; National Institute of Mental Health; Neurobiology; Patients; Persons; Pharmaceutical Preparations; Placebos; Post-Traumatic Stress Disorders; Practice Guidelines; Process; Psychotherapy; Randomized; Randomized Clinical Trials; Rattus; Regulation; Research; Risk; Risk Factors; Safety; Site; Strategic Planning; Stress; Symptoms; Time; Training; Translating; Translations; Tuberculosis; Urinary tract infection; Veterans; Walkers; Youth; aspartate receptor; base; cognitive function; design; endophenotype; health administration; improved; innovation; post intervention; pre-clinical; preclinical study; therapy design

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area "(04): Clinical Research" and Specific Challenge Topic "04-MH-103: Interventions That Target Symptom Dimensions of Childhood-Onset Mental Disorders." The family of cognitive-behavioral therapies (CBT) is a recommended intervention for posttraumatic stress disorder (PTSD) in practice guidelines based on meta-analyses of randomized studies. Although there are fewer studies in children and adolescents, these have shown similar effectiveness for CBT. But complete cure is rare. Most persons who remit below the level of full diagnosis still have enduring symptoms and impairment. Accordingly, there is a need for treatment advances. D-cycloserine (DCS), an antibiotic used to treat tuberculosis and urinary tract infections, is a partial agonist at the glycine modulatory site of the N-methyl- D-aspartic acid (NMDA) receptor. DCS was found to enhance learning and memory in several animal models and in human patients with Alzheimer's disease. DCS also produces a dose-dependent facilitation of extinction of fear-potentiated startle in the rat. However, DCS only produces an extinction effect as an adjunct, i.e., when paired with behavioral extinction training, not when simply given alone. Multiple preclinical and clinical studies have now been conducted, and a meta-analysis concluded that adjunctive use of DCS enhanced fear extinction when coupled with extinction trials (animals) or exposure-based psychotherapy (humans). This proposal will extend this model by conducting a randomized clinical trial of CBT plus DCS (CBT+DCS) versus CBT plus placebo (CBT+P) in 56 7-12 years-old youth with PTSD. This will be the second known trial of adjunctive DCS to treat PTSD and the first in children. Specific Aim 1: The first aim is to show a greater effectiveness of CBT+DCS versus CBT+P for reducing PTSD symptoms in 7-12 years-old children with PTSD. Both groups will receive manualized 12-session CBT. Specific Aim 2: The second aim is to show more rapid effectiveness of CBT+DCS versus CBT+P by reduction of subjective units of distress (SUDS) earlier in treatment. Ancillary Aims: These aims are to explore the mechanism of change and neurobiological correlates that are facilitated by DCS by showing concurrent changes in a suspected underlying endophenotype (attentional bias to threat on a dot probe task) and correlated neurobiological measures (heart period variability and cortisol regulation). This application recognizes the complex interplay between underlying mechanisms and phenotypic manifestation of symptoms. By measuring attentional bias to threat, and two well-known neurobiological measures of stress, heart period variability and cortisol regulation, prospectively in a design of pre- and post- intervention, this may improve our understanding of risk mechanisms, possible biomarkers, and new ways of classifying disorders based on more objective and neurobiological measures. D-cycloserine (DCS) represents an additional treatment modality that would provide greater and more rapid remission of posttraumatic stress disorder. The addition of DCS to cognitive behavioral therapy would be easier to implement and more acceptable to patients than traditional medication because DCS only needs to be taken about half a dozen times or less during therapy with no need to build drug levels or stay on a maintenance dose. The safety profile of DCS is well-known from its use for over 50 years to treat infections, and the risk of serious side effects would be minimal, especially when taken at low doses over short periods as in this study.

描述（由申请人提供）：此申请解决广泛的挑战领域“（04）：临床研究”和特定的挑战主题“ 04-MH-103：针对儿童期精神障碍的症状维度的干预措施。”认知行为疗法（CBT）家族是根据随机研究的荟萃分析的实践指南中的创伤后应激障碍（PTSD）的建议干预措施。尽管对儿童和青少年的研究较少，但这些研究对CBT显示出相似的有效性。但是完全治愈是罕见的。大多数低于完全诊断水平的人仍然具有持久的症状和障碍。因此，需要治疗进展。 D-Cycloserine（DCS）是一种用于治疗结核病和尿路感染的抗生素，是N-甲基 - 天冬氨酸（NMDA）受体的甘氨酸调节位点的部分激动剂。发现DC可以增强多种动物模型和阿尔茨海默氏病的人类的学习和记忆。 DC还产生剂量依赖性的促进，以促进大鼠恐惧的惊吓。但是，DC仅作为辅助作用产生灭绝效果，即与行为灭绝训练配对时，而不是单独给出时。现在已经进行了多项临床前研究和临床研究，一项荟萃分析得出结论，与灭绝试验（动物）或基于暴露的心理治疗（人类）相结合时，辅助使用DC会增强恐惧灭绝。该提案将通过在56 7 - 2岁的PTSD青年中进行CBT Plus DC（CBT+DC）与CBT Plus Plus Plus Plus Plus Plus（CBT+P）进行随机临床试验来扩展该模型。这将是对治疗PTSD的辅助DC的第二次已知试验，也是第一次在儿童中进行的试验。具体目的1：第一个目的是显示CBT+DC与CBT+P的更大有效性，以减少7-12岁儿童PTSD儿童的PTSD症状。两组将获得手动的12条CBT。具体目的2：第二个目的是通过减少治疗中的主观遇险单位（SUD）来显示CBT+DC与CBT+P的更快有效性。辅助目的：这些目的是探索DC的变化机制和神经生物学相关的机制，通过在可疑的潜在的内类型型（注意点探测任务的威胁）中显示同时发生变化，并进行了神经生物学测量（心脏周期可变性和Cortisolisol法规）。该应用认识到潜在机制与症状的表型表现之间的复杂相互作用。通过测量对威胁的注意力偏见，以及两种众所周知的神经生物学测量，对压力，心脏周期可变性和皮质醇调节的调节，前瞻性地在干预前和干预后设计中，这可能会提高我们对基于更多客观和神经生物学测量方法对疾病的风险机制，可能的生物标志物，可能的生物标志物以及新的方法进行分类的理解。 D-胞克氨酸（DCS）代表了一种额外的治疗方式，可提供创伤后应激障碍的更快缓解。与传统药物相比，在认知行为疗法中添加DC将更容易实施，并且对患者更容易接受，因为在治疗期间只需要服用大约六次或更少的时间，而无需建立药物水平或保持维持剂量。 DCS的安全性概况是从50多年来用于治疗感染的50多年来众所周知的，严重副作用的风险将很小，尤其是在短期内低剂量服用时，如本研究中时。