MELODY trial: Study protocol for a 12-week randomised controlled trial of adjunctive melatonin, digital cognitive behaviour therapy for insomnia, or pill placebo to improve depressive symptoms in young adults with mood disorders

ObjectivesSleep and circadian rhythm disturbances (SCRDs) are proposed to be pathophysiological mechanisms underlying some cases of depressive and bipolar (mood) disorders. An unresolved clinical question is whether sleep and circadian based therapies are effective antidepressants for young adults (18-30-years) with a mood disorder. Method & analysisMELODY (Melatonin for Depression in Youth) is an investigator-initiated, single-centre, randomised, placebo-controlled, phase 3 clinical trial. The trial is testing whether 12 weeks of adjunctive melatonin or digital cognitive behavioural therapy for insomnia (dCBT-I) are more effective than pill placebo at reducing depressive symptoms in 660 young people aged 18-30-years with a Structured Clinical Interview for DSM-5 (SCID-5) diagnosis of Major Depressive Disorder or Bipolar Disorder type II, moderate-to-severe depressive symptoms, and significant sleep or sleep-wake complaints. The week 12 primary outcome is depressive symptoms (Quick Inventory of Depressive Symptomatology, Adolescent version). Secondary outcomes include partial remission of the Major Depressive Episode (SCID-5) and change in other mental health symptoms, sleep, functioning, or quality of life. A subset of participants will undergo in-home assessment of sleep physiology (Sleep ProfilerTM) and in-lab assessment of circadian rhythms (dim-light melatonin onset) to examine biological changes. A 6-month follow-up will explore durability of treatment effects. Mediation analyses will test whether sleep or circadian rhythm changes play a causal role in antidepressant effects. Ethics & disseminationMELODY has been reviewed and approved by the Human Research Ethics Committee (HREC) of the Sydney Local Health District (HREC Approval Number: X23-0450, Protocol version: 1.4, 7/7/25). The findings of the MELODY trial will be disseminated into the scientific and clinical communities via refereed publications, talks, and other professional and media outlets. The Brain and Mind Centres Lived Experience Working Group (LEWG) will contribute to dissemination of MELODYs findings via youth-friendly methods (e.g., social media videos, explainers). Trial registration numberACTRN12624000017527 Strengths and limitations of the studyO_LIMELODY is the first trial to be well-powered (>80%) to detect the summary effect size reported in the only meta-analysis on the effect of melatonin on depressive symptoms in people with mood disorders (standardised mean difference=0.37); MELODY will therefore be the first definitive trial on the topic. C_LIO_LIAs melatonin and digital cognitive behavioural therapy for insomnia (dCBT-I) are scalable treatments, the success of either arm compared to placebo is likely to lead to real-world clinical impacts. C_LIO_LIBy recruiting a sample with a spectrum of sleep and sleep-wake complaints, post-hoc analyses may be able to identify profiles or subgroups that can guide stratified trials or guidelines for melatonin and dCBT-I in young people with mood disorders. C_LIO_LIWhile we expect participants in the dCBT-I arm will learn sustainable skills to improve their sleep, sleep-wake cycles, and circadian rhythms, the likelihood of durable gains from melatonin is unclear; this will be explored at 6-month follow-up. C_LIO_LIThis study adopts a primarily biomedical and clinical approach to the understanding and treatment of mood disorders and therefore does not encompass all perspectives on mood disorders (e.g., social, cultural). C_LI