RecruitingPhase 3ACTRN12624000017527

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

Sponsor

The University of Sydney

Enrollment

660 participants

Start Date

Aug 7, 2025

Study Type

Interventional

Conditions

Bipolar Disorder Type II Depression Sleep Disturbance

Summary

Melatonin is considered safe, cost-effective, and scalable, thus, a justifiable intervention for circadian mood disorders. To counter the previous clinical trials design flaws, the present study will employ a larger sample size allowing for high statistical power of analyses. Additionally, in the proposed target treatment approach, patients will be stratified based on SCRDs (Sleep and Circadian Rhythm Disturbance) to enhance the potential effectiveness of the intervention. In a recent proof-of-concept study utilizing agomelatine, a melatonin agonist and serotonin antagonist, for the treatment of major depressive disorder, adults with depression had significantly reduced symptoms after the intervention (Robillard et al., 2018). Moreover, sleep disturbances were significantly reduced, and a strong correlation between relative improvements in depression severity and some components of circadian rhythm disturbances was reported (Robillard et al., 2018). The overall aim of the study is to examine whether melatonin is a more effective early intervention for youth with depression and SCRDs compared to dCBT-I alone. Additionally, the study aims to investigate whether improvements in SCRDs causally mediate changes in depressive symptoms. The outcomes of this clinical trial will hold significant implications for early intervention in mood disorders. The findings have the potential to validate and strengthen the hypothesis that individuals with circadian depression may respond more favourably to sleep and circadian-based interventions, such as melatonin. This, in turn, could have transformative implications for personalised interventions in the treatment of mood disorders.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 30 Yearss

Inclusion Criteria10

Aged between 18 and 30 years (inclusive) at the time of providing informed consent
Current diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder Type II, confirmed via the Structured Clinical Interview for DSM-5 (SCID-5) at the time of enrolment
A score of >= 11 on the Quick Inventory of Depressive Symptomatology - Adolescent version, Clinician Rating (QIDS-A-CR), indicating moderate-to-severe Major Depressive Episodes (MDE), assessed within 14 days prior to study entry
Evidence of significant sleep or sleep-wake complaints, indicated by any of the following:
o PROMIS T-score indicating moderate or severe sleep disturbance
o PROMIS T-score indicating sleep-related impairment
o Irregular sleep-wake cycles, as assessed by RU-SATED
o Self-reported delayed sleep phase, defined as habitual sleep onset time
>= 2 hours later than the desired or required sleep onset time
Ability to provide written informed consent, including adequate intellectual capacity and fluency in English

Exclusion Criteria14

Use of any form of melatonin or melatonin agonist within six weeks prior to study entry
Initiation of new medication to treat a mental health condition within four weeks prior to study entry
Current use of a wakefulness-promoting medication, such as modafinil
Current use of Warfarin
Acute suicidal behaviour, indicated by a score of 6 or more on CAARMS Item 7.3
Self-reported diagnosis or treatment for a psychotic syndrome
Self-reported diagnosis or treatment for an alcohol or substance use disorder
Self-reported diagnosis or treatment for significantly impaired kidney or liver function
Self-reported diagnosis or treatment for major sleep, respiratory or neurological disorders, or other medical conditions causing significant sleep-wake dysfunction
Self-reported allergy to melatonin or Microcrystalline Cellulose
Self-reported pregnancy or breastfeeding
Participation in another trial of a sleep or circadian therapy within four weeks prior to study entry
Regular night shift work within two months prior to study entry
Recent transmeridian travel, defined as crossing two or more time zones within four weeks prior to study entry

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Interventions

Eligible participants who meet all inclusion criteria will be randomly assigned to one of three study arms: Melatonin, Placebo, or Digital Cognitive Behavioural Therapy for Insomnia (dCBT-i). The intervention period for all groups is 12 weeks, with a follow-up assessment conducted at Week 26. Participants in the Melatonin and Placebo arms will be instructed to take a 2 mg capsule (instant-release melatonin or placebo) nightly, approximately two hours before their desired bedtime. Following a safety assessment at Week 5, the dose will be increased to 4 mg (two capsules per night). Participants assigned to the dCBT-i arm will receive access to the online program, Sleep Healthy Using the Internet (SHUTi), and will be instructed to complete six modules over the 12-week intervention period. All participants will continue to receive Treatment As Usual (TAU) from their treating clinician throughout the study. Study-related activities—including self-report questionnaires and clinical assessments—will be completed at baseline, Week 4, Week 8, end of treatment (Week 12), and follow-up (Week 26). These assessments may be conducted either in-person or online, depending on participant preference and availability. To ensure participant safety and monitor progress, the study team will conduct fortnightly check-ins throughout the intervention period.