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）：本申请涉及广泛的挑战领域“(04)：临床研究”和具体挑战主题“04-MH-103：针对儿童期发作的精神障碍症状维度的干预措施”。基于随机研究的荟萃分析，认知行为疗法 (CBT) 系列是实践指南中推荐的创伤后应激障碍 (PTSD) 干预措施。尽管针对儿童和青少年的研究较少，但这些研究都显示出 CBT 的类似效果。但完全治愈的情况很少见。大多数病情缓解到低于完全诊断水平的人仍然有持久的症状和损伤。因此，需要改进治疗。 D-环丝氨酸 (DCS) 是一种用于治疗结核病和尿路感染的抗生素，是 N-甲基-D-天冬氨酸 (NMDA) 受体甘氨酸调节位点的部分激动剂。研究发现 DCS 可以增强多种动物模型和阿尔茨海默病患者的学习和记忆能力。 DCS 还对大鼠恐惧增强惊吓的消除产生剂量依赖性的促进作用。然而，DCS 仅作为辅助手段产生消退效果，即与行为消退训练配合使用时，而不是简单地单独进行。目前已经进行了多项临床前和临床研究，一项荟萃分析得出的结论是，当与消退试验（动物）或基于暴露的心理治疗（人类）相结合时，辅助使用 DCS 可以增强恐惧消退。该提案将通过在 56 名 7-12 岁患有 PTSD 的青少年中进行 CBT 加 DCS (CBT+DCS) 与 CBT 加安慰剂 (CBT+P) 的随机临床试验来扩展该模型。这将是第二个已知的辅助 DCS 治疗 PTSD 的试验，也是第一个针对儿童的试验。具体目标 1：第一个目标是证明 CBT+DCS 与 CBT+P 相比，对于减少 7-12 岁 PTSD 儿童的 PTSD 症状更有效。两组都将接受手动 12 次 CBT。具体目标 2：第二个目标是通过在治疗早期减少主观痛苦单位 (SUDS) 来显示 CBT+DCS 比 CBT+P 更快速的有效性。辅助目标：这些目标是探索由 DCS 促进的变化机制和神经生物学相关性，通过显示可疑的潜在内表型（点探测任务中对威胁的注意偏差）和相关神经生物学测量（心率变异性和皮质醇）的并发变化规定）。该应用认识到潜在机制和症状表型表现之间复杂的相互作用。通过测量对威胁的注意力偏差，以及压力、心率变异性和皮质醇调节这两种众所周知的神经生物学测量方法，前瞻性地在干预前和干预后的设计中，这可能会提高我们对风险机制、可能的生物标志物和新的风险机制的理解。基于更客观和神经生物学测量的疾病分类方法。 D-环丝氨酸（DCS）代表了另一种治疗方式，可以更好、更快地缓解创伤后应激障碍。与传统药物相比，在认知行为疗法中添加 DCS 更容易实施，也更容易被患者接受，因为 DCS 在治疗期间只需要服用大约六次或更少，无需建立药物水平或维持维持剂量。 DCS 的安全性因其 50 多年用于治疗感染的历史而闻名，而且严重副作用的风险极小，尤其是像本研究中那样短期内低剂量服用时。