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

项目摘要 青春期的严重抑郁障碍(MDD)与严重的心理社会障碍有关， 健康问题、学业失败和自杀。许多年轻人在接受治疗后仍然有很大的症状 目前的一线治疗，强调了需要新的、可修改的目标来改善抑郁症 治疗结果。60%-81%患有MDD的青少年有夜间昼夜节律偏好 (ECP)，定义为较晚睡眠和起床时间的行为倾向。ECP与增加的 MDD严重，抗抑郁反应差，MDD反复发作，自杀率增加。在首字母中 对42名患有MDD和ECP的青年的疗效研究，这是一种循证认知-行为睡眠疗法， 跨诊断性睡眠和昼夜节律干预(TRANS-C)，改善了患者的抑郁轨迹 一年，而不是主动控制。反式-C对MDD的治疗作用是通过 增加从受试者在晚上昏暗的灯光(昏暗的灯光)中开始释放褪黑素的时间 褪黑素起病[DLMO]，生物昼夜节律计时的黄金标准客观测量)和 平均唤醒时间。生物昼夜节律的时间和行为之间的一致性的这种衡量标准是 常用于昼夜节律研究，称为相角差(PAD)。 在DLMO和唤醒时间(PADDLMO唤醒时间)之间。初步疗效研究数据显示，90%的年轻人患有 ECP和MDD具有较短的PADDLMO唤醒时间，该唤醒时间将被反式-C延长。以我们最初的功效为基础 研究中，我们提出了一项足够强大的验证性疗效试验，以证实反式-C将延长 PADDLMO唤醒时间，从而改善患有ECP、MDD和PADDLMO觉醒时间较短的青少年的抑郁。 遵循实验治疗学的方法，我们提出了一项盲法随机对照试验 200名患有MDD、ECP且PADDLMO觉醒时间短以确认目标参与的青少年中的反式-C (延长PADDLMO觉醒时间)以及使用该靶点是否对MDD有治疗效果。青少年 将接受8周的反式-C或可信的对照条件(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 有MDD、ECP和较短的PADDLMO唤醒时间，这是一个庞大、服务不足且易受攻击的亚群。它还将 建立较短的PADDLMO觉醒时间作为开发其他新型抗抑郁药物治疗的新目标。

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.