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

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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.