A Confirmatory Efficacy Trial of Engaging a Novel Sleep/Circadian Rhythm Target as Treatment for Depression in Adolescents

采用新型睡眠/昼夜节律目标治疗青少年抑郁症的验证疗效试验

• 批准号: 10581357
• 负责人: Lauren Asarnow
• 金额: $ 76.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581357
• 关键词: Accidents; Address; Adolescence; Adolescent; Aftercare; Antidepressive Agents; Behavior; Behavioral; Biological; Blinded; Chronic; Circadian Rhythms; Cognitive; Data; Development; Diagnostic; Diet; Dose; Exercise; Failure; Funding; Future; Health; Impairment; Individual; Intervention; Investigational Therapies; Light; Major Depressive Disorder; Measurement; Measures; Mediating; Melatonin; Mental Depression; Moods; Outcome; Patients; Phase; Public Health; ROC Curve; Randomized, Controlled Trials; Recurrence; Research; Schools; Severities; Sleep; Stress; Subgroup; Testing; Therapeutic Effect; Time; Treatment outcome; United States National Institutes of Health; Work; Youth; active control; child depression; children' s depression rating scale; circadian; circadian biology; clinically significant; confirmatory trial; depressive symptoms; design; efficacy study; evidence base; experience; follow-up; improved; novel; precision medicine; preference; psychoeducation; psychoeducational; psychosocial; response; social stigma; suicidal; treatment optimization

Project Summary Major Depressive Disorder (MDD) in adolescence is associated with significant psychosocial impairment, health problems, school failure, and suicidality. Many youth remain substantially symptomatic despite receiving current first-line treatments, underscoring the need for novel, modifiable targets to improve depression treatment outcomes. Between 60-81% of adolescents suffering from MDD have evening circadian preference (ECP), defined as the behavioral predilection for later sleep and wake timing. ECP is associated with increased MDD severity, poor antidepressant response, recurrent MDD episodes, and increased suicidality. In an initial efficacy study among 42 youth with MDD and ECP, an evidence based cognitive-behavioral sleep therapy, the Transdiagnostic Sleep and Circadian Intervention (TranS-C), resulted in improved depression trajectories for one year compared to an active control. The therapeutic effect of TranS-C on MDD was mediated by increasing the time from when subjects have onset of melatonin release in dim light in the evening (dim light melatonin onset [DLMO], the gold standard objective measurement of biological circadian rhythm timing) and average wake time. This measure of the alignment between the timing of circadian biology and behavior is commonly employed in circadian rhythm research and referred to as the phase angle difference (PAD) between DLMO and waketime (PADDLMO WAKETIME). Initial efficacy study data suggests that 90% of youth with ECP and MDD have a short PADDLMO WAKETIME that will be lengthened by TranS-C. Building on our initial efficacy study, we propose a sufficiently powered confirmatory efficacy trial to confirm that TranS-C will lengthen PADDLMO WAKETIME and thereby improve depression in adolescents with ECP, MDD and short PADDLMO WAKETIME. Following the Experimental Therapeutics Approach, we propose a blinded randomized controlled trial of TranS-C in 200 adolescents with MDD, ECP, and short PADDLMO WAKETIME to confirm target engagement (lengthening PADDLMO WAKETIME) and whether engaging this target has a therapeutic effect on MDD. Adolescents will receive 8 weeks of TranS-C or a credible comparator condition (Psychoeducation). If successful this study will provide a low stigma, safe, data driven precision medicine approach, for improving MDD for adolescents with MDD, ECP and short PADDLMO WAKETIME, a large, underserved, and vulnerable sub-group. It will also establish short PADDLMO WAKETIME as a new target for the development of other novel antidepressant therapies.

项目概要 青春期的重度抑郁症（MDD）与严重的社会心理障碍有关， 健康问题、学业失败和自杀倾向。尽管接受了治疗，许多青少年仍然存在严重症状 当前的一线治疗，强调需要新的、可修改的目标来改善抑郁症 治疗结果。 60-81% 患有 MDD 的青少年偏好晚间昼夜节律 （ECP），定义为较晚睡眠和醒来时间的行为偏好。 ECP 与增加有关 MDD 严重程度、抗抑郁反应不佳、MDD 反复发作以及自杀倾向增加。在最初的 对 42 名患有 MDD 和 ECP 的青少年进行的疗效研究，这是一项基于证据的认知行为睡眠疗法， 跨诊断睡眠和昼夜节律干预 (TranS-C) 改善了抑郁症轨迹 与主动对照相比一年。 TranS-C 对 MDD 的治疗作用是通过 增加受试者在晚上昏暗的灯光下褪黑激素开始释放的时间（昏暗的灯光 褪黑激素开始[DLMO]，生物昼夜节律计时的金标准客观测量）和 平均醒来时间。这种昼夜节律生物学和行为时间之间一致性的衡量标准是 常用于昼夜节律研究，称为相位角差 (PAD) DLMO 和唤醒时间 (PADDLMO WAKETIME) 之间。初步疗效研究数据表明，90% 的青少年患有 ECP 和 MDD 的 PADDLMO WAKETIME 很短，TranS-C 会延长该 WAKETIME。以我们最初的功效为基础 研究中，我们提出了一项足够有力的验证性疗效试验，以确认 TranS-C 会延长 PADDLMO WAKETIME，从而改善患有 ECP、MDD 和 PADDLMO WAKETIME 较短的青少年的抑郁症。 按照实验治疗方法，我们提出了一项盲法随机对照试验 对 200 名患有 MDD、ECP 和短 PADDLMO WAKETIME 的青少年进行 TranS-C 以确认目标参与度 （延长 PADDLMO WAKETIME）以及参与该目标是否对 MDD 有治疗作用。青少年 将接受 8 周的 TranS-C 或可信的比较条件（心理教育）。如果这项研究成功 将提供一种低耻辱、安全、数据驱动的精准医疗方法，以改善青少年的 MDD MDD、ECP 和 PADDLMO WAKETIME 较短，这是一个大型、服务不足且脆弱的子群体。它还将 将短 PADDLMO WAKETIME 作为开发其他新型抗抑郁疗法的新目标。