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.

项目摘要 青春期的重度抑郁症（MDD）与严重的心理社会障碍有关， 健康问题，学业失败，自杀倾向。许多年轻人尽管接受了治疗， 目前的一线治疗，强调需要新的，可修改的目标，以改善抑郁症 治疗结果。60-81%患有MDD的青少年有晚上的昼夜节律偏好 (ECP)被定义为对较晚的睡眠和唤醒时间的行为偏好。ECP与增加 MDD严重程度、抗抑郁反应差、MDD复发和自杀倾向增加。在初始 在42名患有MDD和ECP的年轻人中进行的疗效研究，一种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（transdiagnosis Sleep and Circadian Intervention，transS-C）改善了抑郁症患者的抑郁轨迹。 与主动控制相比，一年。TransS-C对MDD的治疗作用是通过以下途径介导的： 增加从受试者在晚上昏暗的光线（昏暗的光线）下开始褪黑激素释放的时间 褪黑激素起效[DLMO]，生物昼夜节律定时的金标准客观测量）和 平均唤醒时间这种对生物钟和行为之间的时间一致性的测量是 通常用于昼夜节律研究，称为相位角差（PAD） 在DLMO和唤醒时间（PADDLMO WAKETIME）之间。初步疗效研究数据表明，90%的青少年与 ECP和MDD的PADDLMO WAKETIME较短，将被Trans-C延长。基于我们最初的功效 研究中，我们提出了一个充分的功效验证性试验，以确认Trans-C将延长 PADDLMO WAKETIME，从而改善ECP，MDD和短PADDLMO WAKETIME青少年的抑郁症。 根据实验治疗方法，我们提出了一项盲法随机对照试验， 在200例MDD、ECP和短PADDLMO唤醒时间青少年中使用TransS-C，以确认目标参与 （延长PADDLMO WAKETIME）以及是否参与该靶点对MDD具有治疗效果。青少年 将接受8周的TransS-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、数据驱动的精准医学方法，以改善青少年的MDD 患有MDD、ECP和短PADDLMO WAKETIME的患者，是一个庞大、服务不足和脆弱的亚组。它还将 建立短PADDLMO唤醒时间作为开发其他新型抗抑郁治疗的新目标。