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

Abstract

Sleep and circadian rhythm disturbances 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. MELODY (Melatonin for Depression in Youth) is an investigator-initiated, single-centre, phase 3, randomised controlled trial with two blinded pharmacological arms (melatonin vs placebo) and one open-label digital intervention arm (digital cognitive behavioural therapy for insomnia (dCBT-I)). The trial is testing whether 12 weeks of adjunctive melatonin or 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 (Diagnostic and Statistical Manual of Mental Disorders, fifth edition; 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 Profiler) 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. MELODY 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 Centre's Lived Experience Working Group will contribute to dissemination of MELODY's findings via youth-friendly methods (eg, social media videos, explainers). ACTRN12624000017527.