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

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 | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search 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 View ORCID Profile Jacob J. Crouse , View ORCID Profile Mirim Shin , View ORCID Profile Samuel J. Hockey , View ORCID Profile Elie Jeon , View ORCID Profile Nathan Bradshaw , View ORCID Profile Alissa Nichles , View ORCID Profile Natalia Zmicerevska , View ORCID Profile Min Chong , Hannah You , View ORCID Profile Naomi R. Wray , View ORCID Profile Jan Scott , View ORCID Profile Ronald R. Grunstein , View ORCID Profile Sharon L. Naismith , View ORCID Profile Kathleen R. Merikangas , View ORCID Profile Sean W. Cain , View ORCID Profile Sarah E. Medland , View ORCID Profile Frank Iorfino , View ORCID Profile Thomas D.A. Uebergang , View ORCID Profile Sarah McKenna , View ORCID Profile Joanne S Carpenter , View ORCID Profile Emiliana Tonini , Nayonika Bhattacharya , View ORCID Profile Blake A Hamilton , View ORCID Profile Leanne M Wallace , View ORCID Profile Anjali K Henders , View ORCID Profile Elizabeth M. Scott , View ORCID Profile Yun Ju (Christine) Song , Brain and Mind Centre Lived Experience Working Group , View ORCID Profile Ian B. Hickie doi: https://doi.org/10.1101/2025.09.08.25335055 Jacob J. Crouse 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jacob J. Crouse For correspondence: jacob.crouse{at}sydney.edu.au Mirim Shin 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Mirim Shin Samuel J. Hockey 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Samuel J. Hockey Elie Jeon 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Elie Jeon Nathan Bradshaw 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nathan Bradshaw Alissa Nichles 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Alissa Nichles Natalia Zmicerevska 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Natalia Zmicerevska Min Chong 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Min Chong Hannah You 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Naomi R. Wray 2 Department of Psychiatry, University of Oxford , Oxford, United Kingdom 3 Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford , Oxford, United Kingdom 4 Institute for Molecular Bioscience, The University of Queensland , QLD, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Naomi R. Wray Jan Scott 5 Academic Psychiatry, Institute of Neuroscience, University of Newcastle , Newcastle Upon Tyne, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jan Scott Ronald R. Grunstein 6 Woolcock Institute of Medical Research , NSW, Australia 7 Royal Prince Alfred Hospital , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ronald R. Grunstein Sharon L. Naismith 8 Charles Perkins Centre, The University of Sydney , NSW, Australia 9 Healthy Brain Ageing Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sharon L. Naismith Kathleen R. Merikangas 10 Genetic Epidemiology Branch, Intramural Research Program, National Institute of Mental Health , MD, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kathleen R. Merikangas Sean W. Cain 11 Flinders University , SA, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sean W. Cain Sarah E. Medland 12 Mental Health and Neuroscience Program, QIMR Berghofer Medical Research Institute , QLD, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sarah E. Medland Frank Iorfino 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Frank Iorfino Thomas D.A. Uebergang 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Thomas D.A. Uebergang Sarah McKenna 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sarah McKenna Joanne S Carpenter 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Joanne S Carpenter Emiliana Tonini 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Emiliana Tonini Nayonika Bhattacharya 13 Lived Experience Working Group, Brain and Mind Centre, University of Sydney Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Blake A Hamilton 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Blake A Hamilton Leanne M Wallace 4 Institute for Molecular Bioscience, The University of Queensland , QLD, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Leanne M Wallace Anjali K Henders 4 Institute for Molecular Bioscience, The University of Queensland , QLD, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Anjali K Henders Elizabeth M. Scott 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Elizabeth M. Scott Yun Ju (Christine) Song 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Yun Ju (Christine) Song Ian B. Hickie 1 Youth Mental Health and Technology Team, Brain and Mind Centre, The University of Sydney , NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ian B. Hickie Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Objectives Sleep 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 & analysis MELODY (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 Profiler TM ) 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 & dissemination 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 (LEWG) will contribute to dissemination of MELODY’s findings via youth-friendly methods (e.g., social media videos, explainers). Trial registration number ACTRN12624000017527 Strengths and limitations of the study MELODY 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. As 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. By 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. While 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. This 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). INTRODUCTION Improving the therapeutic landscape for young people with depressive and bipolar (mood) disorders is a global priority 1 – 7 . The peak phase of onset of mood disorders is during adolescence and early adulthood 5 , 8 , 9 . This is a time in which these conditions exert their most profound and enduring impacts on engagement with employment, education, and relationships 10 – 12 . Moreover, death by suicide 13 , 14 and the premature morbidity caused by comorbid physical illnesses 15 results in an average life expectancy 10-15 years lower than the general population 16 . Despite the magnitude of illness and disability caused by mood disorders, the average treatment outcomes for these conditions are sobering 17 , 18 . For example, in the case of depressive disorders, a meta-analysis of over 1M people estimated that globally only 35% of individuals receive treatment 19 . Among those who are treated, only 40% receive minimally adequate treatment 19 . Trials testing safe, affordable, and potentially scalable treatments are needed, particularly for young people 2 , who have been the focus of fewer trials compared to middle-aged and older populations. Sleep and circadian rhythm disturbances (SCRDs) have been proposed as targets for interventions for people with mood disorders 20 – 24 . There is compelling evidence from epidemiologic and interventional studies that sleep disturbances play a critical role in the onset and course of mental disorders 25 – 27 . There is suggestive (but nonconclusive) evidence of a critical role for circadian disturbances 23 , at least for a subgroup of people with mood disorders 21 , 28 – 31 . For example, in some studies, circadian disturbances are associated with the onset of mood disorders 32 , 33 , stage of illness (cross-sectionally) 34 , and progression to more severe stage of illness longitudinally 35 . If SCRDs are causative pathophysiological mechanisms of some types of mood disorders, then their correction may have therapeutic value. Two potential scalable interventions for SCRDs in young people with mood disorders are melatonin and digital cognitive behaviour therapy for insomnia. Melatonin is a hormone produced by the brain’s pineal gland. It plays a key role in the timing of the 24-hr circadian system as the chemical signal of darkness 36 . Exogenous melatonin has long been demonstrated to have an effect on the phase of the circadian rhythm of melatonin 37 , 38 . However clinical trials investigating the efficacy of adjunctive melatonin for depressive symptoms in the context of mood disorders have yielded mixed (but nonconclusive) results. We are aware of nine trials examining the effect of melatonin on depressive symptoms in people with mood disorders (including unipolar, bipolar, and seasonal mood disorders) 39 – 47 . The first trial, published ∼50 years ago, reported that melatonin worsened depressive symptoms in six people with moderate-to-severe depression 39 —this was the only trial to report a worsening in the depressive state. Since then, six trials have reported that melatonin (either alone or as an adjunct to buspirone 40 ) had no effect on depressive symptoms 41 – 44 , 47 , 48 . Three trials have reported that melatonin improved depressive symptoms 45 , 46 , 48 . A 2017 random-effects meta-analysis 49 of three trials (pooled N=113) reported a non-significant effect of melatonin on depressive symptoms in people with mood disorders (SMD=0.39; 95% CI [−0.05 to 0.78]; P=0.09). While non-significant, this point estimate of 0.39 SD is substantial and could imply low statistical power given that mood disorders are heterogeneous. A systematic review by the International Society for Bipolar Disorders (ISBD) Chronobiology and Chronotherapy Task Force concluded in 2019 that there was insufficient or conflicting data regarding melatonin or melatonergic agents for the acute or maintenance treatment of depression in bipolar disorders 20 . A Delphi expert consensus study by the same Task Force (led by the first-author of this paper) concluded this is still the state of the evidence 5 years later 50 . Each of these trials on exogenous melatonin contain methodological limitations that hamper the drawing of firm conclusions. The principal flaw is their small sample sizes, which range from 6-142 participants. Only one trial 40 was adequately-powered (80%) to detect a one-tailed Cohen’s d effect size of ≤0.5 (the upper end of which is likely to be an inflated average effect size 49 ). A second flaw is the common lack of selecting patients with significant SCRDs for whom it can be expected that melatonin would work for more effectively. To our knowledge, only three of the trials used such selection: one negative trial selected cases with major depressive disorder with concurrent early-morning wakening 43 , and two positive trials selected cases with a seasonal pattern of winter depression 45 , 46 . Altogether, we interpret this evidence base as non-conclusive. We conclude that a well-powered, randomised controlled trial is needed to definitively establish the efficacy of melatonin for the depressed phase of mood disorders in young people, and to examine whether it performs better in cases with significant sleep, sleep-wake, and/or circadian disturbances (or a specific profile). Comparison of circadian versus sleep targeted treatments may help identify treatment relevant subgroups for stratified treatment models. The sleep therapy with the strongest evidence base is cognitive behaviour therapy for insomnia (CBT-I), which is a first-line approach to treating insomnia. Its effectiveness is supported by dozens of clinical trials. Digital CBT-I (dCBT-I) programs have been developed to enhance its accessibility, and dCBT-I has also been shown to be highly effective for the treatment of insomnia. Given the identification of insomnia as a probable causal mechanism of some forms of depressive symptoms and disorders 25 , exploration of the effect of dCBT-I on depressive symptoms (acting via improvement in sleep) has been of great interest 51 – 53 . A recent meta-analysis of 14 studies across several health conditions reported a small-to-medium beneficial effect of fully automated dCBT-I (i.e., no therapist support) on depressive symptoms (SMD = −0.43; 95% CI [−0.61 to −0.26]; P<0.001) 54 . Another meta-analysis of seven trials of dCBT-I in people with comorbid insomnia and depression reported a medium-to-large effect of dCBT-I on depressive symptoms (SMD = −0.60; 95% CI [−0.79 to −0.40]; P<0.001) 55 . The mean age of many samples in these meta-analyses 55 are predominantly middle-aged (age 40-50) and only a handful of trials have been conducted in younger mood disorder populations 56 . Objectives of the study There is a need for definitive trials of scalable sleep and circadian therapies in young mood disorder samples 21 , 23 , 57 and head-to-head comparison of therapies with different mechanisms of action on SCRDs. The outcomes of such comparisons may be used to identify which therapies work best for whom 23 , 57 , particularly in the context of future stratified treatment models 21 for people with mood disorders. Accordingly, the main objective (primary planned analysis) of the MELODY trial is to investigate whether sleep and circadian targeted therapies (dCBT-I and melatonin) are more effective than placebo medicine at reducing depressive symptoms in young people with mood disorders. Other objectives include testing whether melatonin is more effective than dCBT-I at reducing depressive symptoms; whether improvements in sleep and circadian factors mediate reductions in depressive symptoms; and whether there are particular subgroups or profiles that respond preferentially to melatonin or dCBT-I. The outcomes of the MELODY trial will have significant implications for early intervention for young people with mood disorders, and for the causal status of SCRDs in these conditions (under the interventionist causal model 58 ). METHODS & ANALYSIS This protocol paper is written according to the 2013 SPIRIT guidelines 59 . Patient and public involvement Members of the Brain and Mind Centre Lived Experience Working Group (LEWG) 21 , 60 were consulted during the design and planning phases of the trial, and a Lived Experience Researcher is a Chief Investigator on the trial’s funding (227089/Z/23/Z). The LEWG consists of culturally and linguistically diverse adolescents and young adults aged 16-30 years. To date the LEWG have been engaged on the MELODY trial regarding eligibility criteria (e.g., decision to not exclude individuals who have taken melatonin previously); logo design; recruitment strategies; reimbursement rates; modes of communication with the study team; cultural considerations (e.g., timing study activities around periods such as Ramadan); and consent procedures (e.g., providing photographs of the overnight chronobiology suite). Throughout the lifetime of the trial, LEWG members will be engaged regularly to provide feedback on procedures, progress, and dissemination. Members are reimbursed in line with the Australian Paid Participation Policy , and consultation with the LEWG was approved by the University of Sydney’s Human Research Ethics Committee. Trial design, setting, and oversight The MELODY trial is an investigator-initiated, three-arm, randomised, placebo-controlled, phase 3, double-blinded, superiority trial. The MELODY trial is conducted at the Brain and Mind Centre, University of Sydney, NSW, Australia. A monitor that is independent from both the investigators and the trial sponsor has conducted a trial initiation visit and will conduct quarterly data monitoring audits, for-cause visits, and a trial close-out visit. The trial will be audited according to the Good Clinical Practice guidelines by the International Council for Harmonization. An independent Data Monitoring and Ethics Committee (DMEC) comprised of three psychiatrists and one statistician, and an independently-chaired and majority-independent Trial Steering Committee (TSC), are appointed to oversee the trial. Trial population and inclusion and exclusion criteria The trial is enrolling young adults in Sydney, Australia, who have a unipolar major depressive disorder or bipolar disorder type II (BD-II), and who report significant difficulties with their sleep and/or sleep-wake cycle. Potential participants can be referred by their clinician or they can self-refer to the study. Inclusion criteria Aged 18-30 (inclusive at the time of providing consent); and Current diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder type II (BD-II), confirmed via the Structured Clinical Interview for DSM-5 (SCID-5) 61 at the time of enrolment; and A score of ≥11 on the Quick Inventory of Depressive Symptomatology, Adolescent version, Clinician Rating (QIDS-A-CR) 62 , indicating a moderate-to-severe Major Depressive Episodes (MDE), assessed within 14 days prior to study entry; and Evidence of significant sleep or sleep-wake complaints, indicated by any of the following: o Moderate-to-severe sleep disturbance, indicated by a T-score ≥ 60 on the Patient-Reported Outcome Measurement Information System (PROMIS TM ) Sleep Disturbance 8-item short form 63 ; or o Sleep-related impairment, indicated by a T-score ≥ 60 on the Patient-Reported Outcome Measurement Information System (PROMIS TM ) Sleep-Related Impairment 8-item short form 63 ; or o Irregular sleep-wake timing, according to a response of “Never” or “Rarely” to the following modified item from the RU-SATED 64 scale, “Generally speaking, I go to bed and get out of bed at about the same time every day (within 2 hours), disregarding changes due to social occasions”; or o Delayed sleep phase, indicated by self-reported habitual sleep onset time ≥ 2 hours later than the desired or required bedtime; and Ability to provide written informed consent, including both adequate intellectual capacity and fluency in English Exclusion criteria Use of any form of melatonin or melatonin agonist within six weeks prior to study entry; or Initiation of new medication to treat a mental health condition within four weeks prior to study entry; or Current use of a wakefulness-promoting medication, such as Modafinil; or Current use of Warfarin Acute suicidal behaviour, indicated by a score of 6 or more on the Comprehensive Assessment of At-Risk Mental States (CAARMS) 65 item 7.3; or Self-reported diagnosis or treatment for a psychotic syndrome; or Self-reported diagnosis or treatment for an alcohol or substance use disorder; or Self-reported diagnosis or treatment for significantly impaired kidney or liver function; or Self-reported diagnosis or treatment for major sleep, respiratory or neurological disorders, or other medical condition causing significant sleep-wake dysfunction; or Self-reported allergy to melatonin or Microcrystalline Cellulose; or Self-reported pregnancy or breastfeeding; or Participation in another trial of a sleep or circadian therapy within four weeks prior to study entry; or Regular night shift work within two months prior to study entry; or Recent transmeridian travel, defined as crossing two or more time zones within four weeks prior to study entry; or Interventions Melatonin and placebo Participants allocated to a medication arm will receive a code-labelled bottle containing capsules of either melatonin (2mg) or placebo, to be taken each night, two hours before their desired bedtime. At week 4 (and subject to an assessment by the Study Doctor) the dose will be escalated to two capsules of melatonin (4mg) or placebo. Participants in the medication arms will be provided with a brief instructional video wherein the Principal Investigator (I.B.H.) discusses the rationale and procedure for taking melatonin, the importance of concurrently making relevant behavioural modifications (e.g., decreasing exposure to artificial light at night, increasing exposure to natural daylight), and instructions to try to align their sleep period within the dark period of the day (between ∼9pm-7am). Digital CBT for insomnia (dCBT-I) Participants allocated to the digital arm will be given access to ‘Sleep Healthy Using the Internet’ (SHUTi), an interactive, internet-based CBT-I intervention 66 . The program includes six sequential, interactive “core” modules, each of which take 45-60 minutes to complete; each new “core” module becomes available one week after completion of the previous core. Participants will be instructed by study staff to complete one module per week and to implement what they have learned during the remaining 12-week intervention period. They will be encouraged to return to previously completed modules as much as they would like to consolidate their learnings. The six “core” modules cover the definition of insomnia and its impact and risk factors; the rationale for dCBT-I in treating insomnia; sleep restriction and stimulus control strategies to strengthen the homeostatic sleep drive and increase sleep efficiency; education about good sleep and sleep hygiene practices (e.g., increasing exercise, avoiding meals and stimulants around bedtime); cognitive restructuring to challenge unhelpful beliefs and thoughts about sleep; and strategies to promote adherence to what has been learned through the program and strategies to prevent insomnia relapse. Participants in the trial will have access to a personalised home page showing their progress through SHUTi, and feedback and personalised tailoring of SHUTi is based on information provided by participants in an online daily sleep diary. Treatment as Usual (TAU) All participants will continue to receive any TAU from their treating clinician, which is not considered part of the trial activity. Adverse events (AEs) At baseline, a detailed self-report assessment of AEs common to melatonin and antidepressant medications (for the latter, using the Antidepressant Side-Effect Checklist 67 ) will be collected before the intervention. Thereafter, regular assessment of AEs will be conducted. Information about ancillary and post-trial care and withdrawal/discontinuation is in the Appendix. Adherence Participants in the medication arms will be asked to complete a medication diary, and the study team will remotely monitor adherence to SHUTi. Reimbursement Information about reimbursement is in the Appendix. Randomisation Participants are randomly assigned in a 1:1:1 ratio to receive melatonin, placebo medicine, or dCBT-I in variable block sizes, with stratification according to age (dichotomised as 18-24-years vs 25-30-years), sex assigned at birth (male vs female), and baseline severity of depressive symptoms ( Quick Inventory of Depressive Symptomatology Clinician Rated Adolescent Version [QIDS-A-CR] score dichotomised as 11-15 [moderate] vs 16+ [severe to very severe]). The randomisation sequence was generated electronically by a statistician not affiliated with the trial and transferred to the research team’s trial database (REDCap 68 ). The drug manufacturer created labels on pill bottles indicating the medication arm (melatonin vs placebo) which are torn off by an unblinded member of the trial team during dispensation. Trial participants and assessors are blinded to medication allocation (melatonin vs placebo) but not to allocation of medication vs dCBT-I. Information about unblinding is in the Appendix. Sample size calculation Meta-analyses report an effect size of 0.37 for melatonin (vs placebo) on depressive symptoms 49 and 0.35 for dCBT-I (vs various comparators) on depressive symptoms 69 . A minimum effect size of interest of 0.30 is clinically meaningful and a feasible target. Assuming an attrition rate of 20% based on RCTs in a similar population 70 (note: a lower attrition rate of 16% has been reported for academia-led pharmacological mental health trials 71 ), 660 participants (220 per arm) are needed to provide 80% power to detect differences in change from baseline (d=0.3) at α=0.05 (two tailed test). Study course and procedures All trial activities will be coordinated from the University of Sydney’s Brain and Mind Centre (BMC). A summary of the course and procedures of the trial is in Figure 1 and Table 1 , and the assessments are summarised in Table 2 . Advertisements for the trial will be distributed via social media, engagement with clinical contacts (e.g., headspace , Mind Plasticity ), and flyers given to clinics and distributed around local universities, with a QR code leading to the study website (hosted on REDCap 68 ). The study website contains a plain language summary about the study procedures and a copy of the consent form (PIS/CF). Upon completion of a brief online pre-screening form, potential participants will be contacted to schedule an in-person enrolment visit ( Table 1 ). Download figure Open in new tab Figure 1. MELODY trial schematic. View this table: View inline View popup Download powerpoint Table 1. Overview of study course and procedures. View this table: View inline View popup Table 2. Overview of research assessments. At the enrolment visit, participants will be given the opportunity to ask the Study Doctor and Clinical Research Manager (a nurse) any questions about the procedures and expectations of the trial. Subject to meeting eligibility criteria, participants will be asked to provide written informed consent (to the Study Doctor and/or Clinical Research Manager) and will then participate in a series of clinical, self-report, and medical history assessments. During the assessments, participants are offered comfort measures (e.g., tea, coffee), opportunities for breaks, and avenues for support in case of distress. They will be given an actigraphy watch (see “ Biological and behavioural measures”) and sleep diary to wear and complete, respectively, for ∼2 weeks. During this period, participants who meet all the eligibility criteria will be randomised. Participants will return ∼2 weeks later for the in-person baseline assessment ( Table 1 ) and will receive the Investigational Product (melatonin/placebo or log-in for SHUTi). A subset of participants will undergo a physiological assessment of sleep and circadian rhythms before starting the intervention (see “ Biological and behavioural measures”). During the 12-week intervention period, AEs and adherence will be monitored fortnightly and participants will complete follow-up assessments at Week 4 and 8 (via REDCap/MyCap for self-report and telephone for clinical assessments). To provide a safe and familiar participant experience, a member of the research team will be assigned to each participant to be a consistent contact and assessor throughout the trial. Subject to the Study Doctor’s discretion based on information gathered at the Week 4 assessment, participants in the medication arm will start taking an escalated dose (from 2mg to 4mg) starting at Week 5. Around the end of the 12-week intervention period, the trial team will schedule the end of treatment assessment visit (primary endpoint) and ∼6 months later, the team will schedule a post-discontinuation assessment. Primary and secondary outcomes Primary efficacy endpoint Change in depressive symptoms from baseline to 12 weeks, as assessed by the QIDS-A-CR 62 Secondary endpoints ( Note : *common metric mandated by funder, **common metric recommended by consortium of teams with a 2023 Wellcome Mental Health Award): Partial remission of major depressive episode (MDE) at 12 weeks according to SCID-5 61 . Change in depressive symptoms from baseline to 12 weeks, assessed by the PHQ-9* 72 and QIDS-A-SR 62 Change in anxiety symptoms from baseline to 12 weeks, assessed by the GAD-7* 73 and the OASIS 74 Change in anxiety/depressive symptoms from baseline to 12 weeks, assessed by the RCADS* 75 (18-year-olds only) Change in insomnia symptoms from baseline to 12 weeks, assessed by the ISI** 76 Change in general sleep-related impairment from baseline to 12 weeks, assessed by the PROMIS Sleep-Related Impairment short form 8a 63 Change in general sleep disturbance from baseline to 12 weeks, assessed by the PROMIS Sleep Disturbance short form 63 Change in chronotype from baseline to 12 weeks, assessed by the MEQ** 77 Change in quality of life from baseline to 12 weeks, assessed by the ReQoL 78 Change in social and occupational functioning from baseline to 12 weeks, assessed by the SOFAS 79 Change in disability from baseline to 12 weeks, assessed by the WHODAS 2.0* 80 Change in suicidal thoughts and behaviours from baseline to 12 weeks, assessed by the SIDAS 81 Change in hypo/manic symptoms from baseline to 12 weeks, as assessed by the ASRM 82 Change in alcohol, cannabis, and tobacco use from baseline to 12 weeks, assessed by the WHO-ASSIST 83 Change in sleep-waking timing from baseline to 12 weeks, assessed by the Consensus Sleep Diary* 84 Change in sleep-wake cycles from baseline to 12 weeks, assessed by actigraphy Change in dim-light melatonin onset (DLMO) time from baseline to 12 weeks, as measured by salivary melatonin sampling (20% subset of cases; see “Biological and behavioural measures” below) Change in sleep physiology (exploratory) from baseline to 12 weeks, assessed by Sleep Profiler TM EEG Sleep Monitor (20% subset of cases; see “Biological and behavioural measures” below) Biological and behavioural measures Genetics All participants will be asked to provide a saliva sample for the purpose of investigating genetic predictors of treatment response (e.g., polygenic risk scores for sleep and circadian traits such as chronotype 86 ). Samples will be analysed at the University of Queensland’s Human Studies Unit. The authors have experience collecting saliva for DNA from 500+ young people with mental disorders at the BMC 87 – 89 and thousands of cases in other studies (e.g., Australian Genetics of Depression Study 90 , 91 , Australian Genetics of Bipolar Disorder Study 92 ). Actigraphy All participants will be asked to wear a wrist-worn passive-sensing device (GENEActiv, Activinsights, UK) for 10-14 days (including two weekends) for the purpose of tracking whether the interventions cause changes in sleep-wake cycles and circadian rhythms. Actigraphy data will be collected before the intervention and near its completion ( Table 1 ). Participants will be instructed to wear the device continuously on their non-dominant wrist, removing it only when showering, bathing, or swimming. The authors have experience collecting actigraphy data from 500+ young people with mental disorders at the BMC 87 , 93 – 95 and ∼500 community-residing adolescents in Australia 96 , 97 . Dim-light melatonin onset (DLMO) A subset of participants (∼20%) will undergo melatonin sampling during chronobiology studies at the Woolcock Institute for Medical Research at Macquarie University for the purpose of testing whether the interventions cause changes to circadian rhythmicity of melatonin. This circadian assessment will be done before the intervention and near its completion ( Table 1 ). Sampling will be performed according to established DLMO protocols 98 . Under dim-light (<5 lux) conditions and in a semi-recumbent position, hourly saliva samples will be collected from participants using passive drool kit, starting 6 hours before, and ending 2 hours after, their habitual bedtime (during which they are kept awake). Participants will be provided with non-electronic entertainment options while awake (e.g., music, audiobooks). Saliva samples will be analysed at the Adelaide Research Assay Facility. The authors have experience collecting overnight salivary melatonin samples in 70+ young people with mental disorders recruited at the BMC 99 , 100 . Sleep physiology The same subset (∼20%) of participants will undergo home-based assessments of sleep physiology. The Sleep Profiler TM EEG Sleep Monitor (Advanced Brain Monitoring, Inc., USA) is a research-grade, wireless, multichannel forehead electroencephalography device that also records electrooculography, electromyography, pulse rate, head position, head movement, and snoring, and auto-stages several physiologic measures (e.g., sleep latency, sleep spindles, arousals). This assessment will be done before the intervention and near its completion ( Table 1 ). The automated sleep staging of the Sleep Profiler TM agrees strongly with human-scored polysomnography in clinical and nonclinical samples 101 , 102 . The device was chosen given its portability, ability to be self-applied, and therefore its feasibility in this large trial. The acceptability of the Sleep Profiler TM in our population is not yet known. Pupillometry All participants will undergo an assessment to examine the pupil’s response to light (pupillary light reflex [PLR]), given the observation that the PLR can discriminate circadian from non-circadian forms of delayed sleep phase disorder 103 . The PLR will be measured by a PLR-3000 monocular pupillometer (NeurOptics, USA) in a windowless room (∼1-2 lux), using a protocol of 10-min of dark adaptation and two 1-sec light pulses (∼10 lux followed by ∼1500 lux). The authors have used this protocol in 100+ young people with mental disorders at the BMC 87 . Data management and security Data collected for the purposes of the trial will be linked to unique study ID codes and will not contain identifiable information. Data collection will be conducted only by authorised members of the trial team, to whom this duty has been allocated, and who are named on the HREC application and Governance approvals for the trial. Research data will be stored in REDCap 68 and on the University of Sydney’s hosted Research Data Store (RDS). The PI (IBH) and team (JJC, Clinical Research Manager [EJ]) will have access to the final trial dataset. Publications or reports based on this trial will include only pooled results. Routine internal audits of data files will ensure completeness of data collection. Data for which hardcopies are generated will be stored securely in both original hardcopy and electronic form. Hardcopies will be retained so that comparison between electronic and original data is possible, to ensure accuracy of data entry and to resolve issues concerning any spurious data in the electronic file. These data will be kept under (1) lock and key at the trial site (BMC, University of Sydney) or (2) electronic file that is password-protected and accessible only by the trial team responsible for data entry or monitoring. Statistical Analysis Plan The primary planned contrast on which the study is powered is the active intervention group (melatonin and dCBT-I arms) vs placebo. The secondary planned contrasts are melatonin vs dCBT-I; melatonin vs placebo; and dCBT-I vs placebo. A comprehensive data validation of the trial database will be performed before commencing analyses. A detailed final Statistical Analysis Plan (SAP) will be developed before database lock and unblinding, which will include prespecified estimands, sensitivity analyses, exact statistical models (e.g., covariance structure, adjustment for degrees of freedom), mock tables, etc, compliant within the R1 addendum to ICH E9 104 . The primary outcome (QIDS-A-CR total) will be analysed using a linear mixed model for repeated measures (MMRM) including all available QIDS-A-CR scores (intention-to-treat) measured at weeks 4, 8, and 12 (end of treatment). Fixed effects will include the randomisation group, time point as a categorical variable, and the interaction between randomisation group and time point. The baseline QIDS-A-CR score will be included as a covariate alongside age and sex. The MMRM model will be used to estimate the effect of the intervention(s) at week 12 (end of treatment), expressed as the adjusted mean difference and its 95% confidence interval. Secondary outcomes will be analysed using a similar approach. For binary outcomes (e.g., MDE partial remission), logistic regression (binomial regression with logit link) will be used. Given that linear MMRMs use all data available and make valid inference under the assumption that data are Missing at Random, the primary analysis will not impute missing data. Broadly, sensitivity analyses will be conducted to assess the robustness of the results under different assumptions of the missing data mechanism (e.g., Missing Not at Random); these will be prespecified in the final SAP according to the R1 addendum to ICH E9 104 prior to database lock and unblinding. Exploratory mediation analyses will be undertaken to examine whether changes in circadian rhythms (e.g., phase-advance of DLMO) mediate clinical changes (e.g., improvement in depressive symptoms). An interim analysis is not yet planned. CONCLUSION The MELODY trial launched recruitment in August 2025. The trial aims to provide new knowledge about the value of melatonin and dCBT-I for improving the depressed phase of mood disorders in young people, and according to the interventionist model of causality 58 , the trial’s results may shed light on the nature of SCRDs as pathophysiological mechanisms of some types of mood disorders 31 . ETHICS AND DISSEMINATION The MELODY trial will be performed according to the Declaration of Helsinki (2008) and the International Conference on Harmonisation–Good Clinical Practice (ICH-GCP) and 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 trial has been registered in the Australian New Zealand Clinical Trial Registry (ACTRN12624000017527). Any modifications will be submitted to the HREC for review prior to implementation as per HREC guidelines. The findings of the trial will be disseminated into the scientific and clinical communities via peer-reviewed publications, talks, and clinician-facing outlets. LEWG will contribute to dissemination of the trial’s findings to the general public via relevant streams (e.g., social media, explainers, infographics). For each paper, all authors will satisfy the Vancouver criteria for authorship. There is no planned use of a professional writer. Funding This work was supported by the Wellcome Trust [227089/Z/23/Z]. The funder has no role in collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. The funder mandated the use of some assessments as part of their common metrics scheme. Barring this mandate, the funder has no ultimate authority in any of the other activities. Trial sponsor University of Sydney (within Australia: 1800 793 864; outside Australia: +61 2 8627 1444). The sponsor had no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. The sponsor has no ultimate authority of any of these activities. Author contributions JJC, SJH, NRW, JS, RRG, SLN, FI, KRM, SWC, SEM, YJCS, and IBH obtained funding for the trial. JJC wrote the first draft of the manuscript with input from MS and IBH. All authors contributed to subsequent drafts of the manuscript. Declarations of interest The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organisations, agencies, or US government. EMS is a Principal Research Fellow at the Brain and Mind Centre, The University of Sydney. She is Discipline Leader of Adult Mental Health, School of Medicine, University of Notre Dame, and a Consultant Psychiatrist. She was the Medical Director, Young Adult Mental Health Unit, St Vincent’s Hospital Darlinghurst until January 2021. She has received honoraria for educational seminars related to the clinical management of depressive disorders supported by Servier, Janssen and Eli-Lilly Pharmaceuticals. She has participated in a national advisory board for the antidepressant compound Pristiq, manufactured by Pfizer. She was the national coordinator of an antidepressant trial sponsored by Servier. IBH is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney, Australia. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) projects focused on the identification and better management of anxiety and depression and investigator-initiated studies of agomelatine. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to lead transformation of mental health services internationally through the use of innovative technologies. Data statement The datasets generated and/or analysed during this study will be accessible upon request to Prof Ian Hickie ( ian.hickie{at}sydney.edu.au ). The data provided will be fully anonymised, with all participant-identifiable information removed. Access to the full dataset will be granted only after the formal reporting of study findings in a peer-reviewed scientific journal. Datasets will be available exclusively to bona fide scientific researchers. Requests must be submitted in writing to the Principal Investigator, including details about the investigator’s background and the intended purpose of the data. Each request will be evaluated based on the proposed analyses, with potential uses likely to include meta-analyses, for example. The study’s Participant Information Sheet and consent forms explicitly mentioned the availability of anonymised data, a process approved by the Sydney Local Health District HREC. Acknowledgements We are grateful to members of the Brain and Mind Centre Lived Experience Working Group for their help designing, planning, and conducting the trial. JJC is supported by a National Health and Medical Research Council (NHMRC) Emerging Leadership Fellowship (2008196). NRW is supported by a NHMRC L3 Leadership Fellowship (1173790). IBH is supported by a NHMRC L3 Leadership Fellowship (2016346). REFERENCES 1. ↵ Hickie IB , Scott EM , Cross SP , et al. Right care, first time: a highly personalised and measurement-based care model to manage youth mental health . Medical Journal of Australia 2019 ; 211 ( S9 ): S3 – S46 . OpenUrl 2. ↵ McGorry PD , Mei C , Dalal N , et al. The Lancet Psychiatry Commission on youth mental health . The Lancet Psychiatry 2024 ; 11 ( 9 ): 731 – 74 . OpenUrl PubMed 3. Ratheesh A , Hett D , Ramain J , et al. A systematic review of interventions in the early course of bipolar disorder I or II: a report of the International Society for Bipolar Disorders Taskforce on early intervention . International Journal of Bipolar Disorders 2023 ; 11 ( 1 ). 4. Davey CG , McGorry PD . Early intervention for depression in young people: a blind spot in mental health care . The Lancet Psychiatry 2019 ; 6 ( 3 ): 267 – 72 . OpenUrl CrossRef PubMed 5. ↵ Uhlhaas PJ , Davey CG , Mehta UM , et al. Towards a youth mental health paradigm: a perspective and roadmap . Molecular Psychiatry 2023 ; 28 ( 8 ): 3171 – 81 . OpenUrl CrossRef PubMed 6. Cotton SM , Jain V , Ratheesh A , et al. Views of international experts on challenges to early intervention for bipolar disorder . World psychiatry : official journal of the World Psychiatric Association (WPA) 2025 ; 24 ( 2 ): 275 – 7 . OpenUrl PubMed 7. ↵ Thapar A , Eyre O , Patel V , Brent D . Depression in young people. Lancet (London , England) 2022 ; 400 ( 10352 ): 617 – 31 . OpenUrl 8. ↵ Avenevoli S , Swendsen J , He JP , Burstein M , Merikangas KR . Major depression in the national comorbidity survey-adolescent supplement: prevalence, correlates, and treatment . J Am Acad Child Adolesc Psychiatry 2015 ; 54 ( 1 ): 37 – 44 .e2. OpenUrl CrossRef PubMed 9. ↵ Merikangas KR , Jin R , He JP , et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative . Arch Gen Psychiatry 2011 ; 68 ( 3 ): 241 – 51 . OpenUrl CrossRef PubMed Web of Science 10. ↵ Kieling C , Buchweitz C , Caye A , et al. Worldwide Prevalence and Disability From Mental Disorders Across Childhood and Adolescence: Evidence From the Global Burden of Disease Study . JAMA psychiatry 2024 ; 81 ( 4 ): 347 – 56 . OpenUrl PubMed 11. Scott J , Fowler D , McGorry P , et al. Adolescents and young adults who are not in employment, education, or training . Bmj 2013 ; 347 : f5270 . OpenUrl FREE Full Text 12. ↵ Iorfino F , Carpenter JS , Cross SP , et al. Social and occupational outcomes for young people who attend early intervention mental health services: a longitudinal study . The Medical journal of Australia 2022 ; 216 ( 2 ): 87 – 93 . OpenUrl PubMed 13. ↵ Ferrari AJ , Norman RE , Freedman G , et al. The burden attributable to mental and substance use disorders as risk factors for suicide: findings from the Global Burden of Disease Study 2010 . PLoS One 2014 ; 9 ( 4 ): e91936 . OpenUrl CrossRef PubMed 14. ↵ Chesney E , Goodwin GM , Fazel S . Risks of all-cause and suicide mortality in mental disorders: a meta-review . World psychiatry : official journal of the World Psychiatric Association (WPA) 2014 ; 13 ( 2 ): 153 – 60 . OpenUrl PubMed 15. ↵ Momen NC , Plana-Ripoll O , Agerbo E , et al. Association between Mental Disorders and Subsequent Medical Conditions . New England Journal of Medicine 2020 ; 382 ( 18 ): 1721 – 31 . OpenUrl CrossRef PubMed 16. ↵ Laursen TM , Musliner KL , Benros ME , Vestergaard M , Munk-Olsen T . Mortality and life expectancy in persons with severe unipolar depression . Journal of affective disorders 2016 ; 193 : 203 – 7 . OpenUrl CrossRef PubMed 17. ↵ Ormel J , Hollon SD , Kessler RC , Cuijpers P , Monroe SM . More treatment but no less depression: The treatment-prevalence paradox . Clinical Psychology Review 2022 ; 91 : 102111 . OpenUrl CrossRef PubMed 18. ↵ Leichsenring F , Steinert C , Rabung S , Ioannidis JPA . The efficacy of psychotherapies and pharmacotherapies for mental disorders in adults: an umbrella review and meta-analytic evaluation of recent meta-analyses . World psychiatry : official journal of the World Psychiatric Association (WPA) 2022 ; 21 ( 1 ): 133 – 45 . OpenUrl PubMed 19. ↵ Mekonen T , Chan GCK , Connor JP , Hides L , Leung J . Estimating the global treatment rates for depression: A systematic review and meta-analysis . J Affect Disord 2021 ; 295 : 1234 – 42 . OpenUrl PubMed 20. ↵ Gottlieb JF , Benedetti F , Geoffroy PA , et al. The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology . Bipolar Disorders 2019 ; 21 ( 8 ): 741 – 73 . OpenUrl PubMed 21. ↵ Crouse JJ , Carpenter JS , Song YJC , et al. Circadian rhythm sleep–wake disturbances and depression in young people: implications for prevention and early intervention . The Lancet Psychiatry 2021 ; 8 ( 9 ): 813 – 23 . OpenUrl CrossRef PubMed 22. Carpenter JS , Crouse JJ , Scott EM , et al. Circadian depression: A mood disorder phenotype . Neuroscience & Biobehavioral Reviews 2021 ; 126 : 79 – 101 . OpenUrl PubMed 23. ↵ Wellcome Trust . Sleep, circadian rhythms and mental health: Advances, gaps, challenges and opportunities , 2022 . 24. ↵ Robillard R , Carpenter JS , Rogers NL , et al. Circadian rhythms and psychiatric profiles in young adults with unipolar depressive disorders . Translational Psychiatry 2018 ; 8 ( 1 ): 213 . OpenUrl PubMed 25. ↵ Freeman D , Sheaves B , Waite F , Harvey AG , Harrison PJ . Sleep disturbance and psychiatric disorders . The Lancet Psychiatry 2020 ; 7 ( 7 ): 628 – 37 . OpenUrl CrossRef PubMed 26. Hill ED , Kashyap P , Raffanello E , et al. Prediction of mental health risk in adolescents . Nat Med 2025 . 27. ↵ Crouse JJ , Ho N , Scott J , et al. Dynamic networks of psychological symptoms, impairment, substance use, and social support: The evolution of psychopathology among emerging adults . Eur Psychiatry 2022 ; 65 ( 1 ): e32 . OpenUrl PubMed 28. ↵ Edgar N , McClung CA . Major depressive disorder: a loss of circadian synchrony? BioEssays : news and reviews in molecular, cellular and developmental biology 2013 ; 35 ( 11 ): 940 – 4 . OpenUrl 29. Glozier N , O’Dea B , McGorry PD , et al. Delayed sleep onset in depressed young people . BMC Psychiatry 2014 ; 14 ( 1 ): 33 . OpenUrl CrossRef PubMed 30. Hickie IB , Merikangas KR , Carpenter JS , et al. Does circadian dysrhythmia drive the switch into high- or low-activation states in bipolar I disorder? Bipolar Disord 2023 ; 25 ( 3 ): 191 – 9 . OpenUrl CrossRef PubMed 31. ↵ Hickie IB , Crouse JJ . Sleep and circadian rhythm disturbances: plausible pathways to major mental disorders? World psychiatry : official journal of the World Psychiatric Association (WPA) 2024 ; 23 ( 1 ): 150 – 1 . OpenUrl PubMed 32. ↵ Byrne EM , Timmerman A , Wray NR , Agerbo E . Sleep Disorders and Risk of Incident Depression: A Population Case-Control Study . Twin research and human genetics : the official journal of the International Society for Twin Studies 2019 ; 22 ( 3 ): 140 – 6 . OpenUrl 33. ↵ Scott J , Etain B , Miklowitz D , et al. A systematic review and meta-analysis of sleep and circadian rhythms disturbances in individuals at high-risk of developing or with early onset of bipolar disorders . Neurosci Biobehav Rev 2022 ; 135 : 104585 . OpenUrl PubMed 34. ↵ Scott J , Etain B , Grierson A , Naismith S , Scott E , Hickie I . A network analysis of rest-activity rhythms in young people with emerging bipolar disorders . Journal of Affective Disorders 2022 ; 305 : 220 – 6 . OpenUrl PubMed 35. ↵ Iorfino F , Scott EM , Carpenter JS , et al. Clinical Stage Transitions in Persons Aged 12 to 25 Years Presenting to Early Intervention Mental Health Services With Anxiety, Mood, and Psychotic Disorders . JAMA psychiatry 2019 ; 28 . 36. ↵ Tan DX , Hardeland R , Manchester LC , et al. The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness . Biol Rev Camb Philos Soc 2010 ; 85 ( 3 ): 607 – 23 . OpenUrl CrossRef PubMed 37. ↵ Arendt J , Bojkowski C , Folkard S , et al. Some effects of melatonin and the control of its secretion in humans . Ciba Found Symp 1985 ; 117 : 266 – 83 . OpenUrl PubMed 38. ↵ Hickie IB , Rogers NL . Novel melatonin-based therapies: potential advances in the treatment of major depression . Lancet (London, England) 2011 ; 378 ( 9791 ): 621 – 31 . OpenUrl PubMed 39. ↵ Carman JS , Post RM , Buswell R , Goodwin FK . Negative effects of melatonin on depression . The American journal of psychiatry 1976 ; 133 ( 10 ): 1181 – 6 . OpenUrl CrossRef PubMed Web of Science 40. ↵ Fava M , Targum SD , Nierenberg AA , et al. An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery . J Psychiatr Res 2012 ; 46 ( 12 ): 1553 – 63 . OpenUrl CrossRef PubMed 41. ↵ Leibenluft E , Feldman-Naim S , Turner EH , Wehr TA , Rosenthal NE . Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder . The Journal of clinical psychiatry 1997 ; 58 ( 9 ): 383 – 8 . OpenUrl CrossRef PubMed Web of Science 42. Dolberg OT , Hirschmann S , Grunhaus L . Melatonin for the treatment of sleep disturbances in major depressive disorder . The American journal of psychiatry 1998 ; 155 ( 8 ): 1119 – 21 . OpenUrl CrossRef PubMed Web of Science 43. ↵ Serfaty MA , Osborne D , Buszewicz MJ , Blizard R , Raven PW . A randomized double-blind placebo-controlled trial of treatment as usual plus exogenous slow-release melatonin (6 mg) or placebo for sleep disturbance and depressed mood . Int Clin Psychopharmacol 2010 ; 25 ( 3 ): 132 – 42 . OpenUrl CrossRef PubMed 44. ↵ Danilenko KV , Putilov AA . Melatonin treatment of winter depression following total sleep deprivation: waking EEG and mood correlates . Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2005 ; 30 ( 7 ): 1345 – 52 . OpenUrl PubMed 45. ↵ Lewy AJ , Bauer VK , Cutler NL , Sack RL . Melatonin treatment of winter depression: a pilot study . Psychiatry research 1998 ; 77 ( 1 ): 57 – 61 . OpenUrl CrossRef PubMed Web of Science 46. ↵ Lewy AJ , Lefler BJ , Emens JS , Bauer VK . The circadian basis of winter depression . Proc Natl Acad Sci U S A 2006 ; 103 ( 19 ): 7414 – 9 . OpenUrl Abstract / FREE Full Text 47. ↵ Sherer MA , Weingartner H , James SP , Rosenthal NE . Effects of melatonin on performance testing in patients with seasonal affective disorder . Neuroscience Letters 1985 ; 58 ( 3 ): 277 – 82 . OpenUrl CrossRef PubMed Web of Science 48. ↵ Targum SD , Wedel PC , Fava M . Changes in cognitive symptoms after a buspirone-melatonin combination treatment for Major Depressive Disorder . J Psychiatr Res 2015 ; 68 : 392 – 6 . OpenUrl CrossRef PubMed 49. ↵ De Crescenzo F , Lennox A , Gibson J , et al. Melatonin as a treatment for mood disorders: a systematic review . Acta psychiatrica Scandinavica 2017 ; 136 ( 6 ): 549 – 58 . OpenUrl PubMed 50. ↵ Crouse JJ , Loblay V , Jorm A , et al. Essential information about chronobiology and chronotherapy for the optimal care of people with bipolar disorders: an international expert consensus . medRxiv 2025 : 2025.06.17.25329750. 51. ↵ van der Zweerde T , van Straten A , Effting M , Kyle SD , Lancee J . Does online insomnia treatment reduce depressive symptoms? A randomized controlled trial in individuals with both insomnia and depressive symptoms . Psychological medicine 2019 ; 49 ( 3 ): 501 – 9 . OpenUrl PubMed 52. Henry AL , Miller CB , Emsley R , et al. Insomnia as a mediating therapeutic target for depressive symptoms: A sub-analysis of participant data from two large randomized controlled trials of a digital sleep intervention . Journal of Sleep Research 2021 ; 30 ( 1 ): e13140 . OpenUrl PubMed 53. ↵ Cheng P , Kalmbach DA , Tallent G , Joseph CL , Espie CA , Drake CL . Depression prevention via digital cognitive behavioral therapy for insomnia: a randomized controlled trial . Sleep 2019 ; 42 ( 10 ). 54. ↵ Lee S , Oh JW , Park KM , Lee S , Lee E. Digital cognitive behavioral therapy for insomnia on depression and anxiety: a systematic review and meta-analysis . NPJ Digit Med 2023 ; 6 ( 1 ): 52 . OpenUrl PubMed 55. ↵ Bai N , Cao J , Zhang H , Liu X , Yin M . Digital cognitive behavioural therapy for patients with insomnia and depression: A systematic review and meta-analysis . J Psychiatr Ment Health Nurs 2024 ; 31 ( 4 ): 654 – 67 . OpenUrl PubMed 56. ↵ Chan CS , Wong CYF , Yu BYM , Hui VKY , Ho FYY , Cuijpers P . Treating depression with a smartphone-delivered self-help cognitive behavioral therapy for insomnia: a parallel-group randomized controlled trial . Psychological medicine 2023 ; 53 ( 5 ): 1799 – 813 . OpenUrl PubMed 57. ↵ Wellcome Trust . What science has shown can help young people with anxiety and depression ., 2022 . 58. ↵ Kendler KS , Campbell J . Interventionist causal models in psychiatry: repositioning the mind-body problem . Psychological medicine 2009 ; 39 ( 6 ): 881 – 7 . OpenUrl CrossRef PubMed Web of Science 59. ↵ Chan A-W , Tetzlaff JM , Altman DG , et al. SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials . Annals of Internal Medicine 2013 ; 158 ( 3 ): 200 – 7 . OpenUrl CrossRef PubMed Web of Science 60. ↵ Lee GY , McKenna S , Song YJC , et al. Strengthening mental health research outcomes through genuine partnerships with young people with lived or living experience: A pilot evaluation study . Health Expectations 2023 ; 26 ( 4 ): 1703 – 15 . OpenUrl PubMed 61. ↵ First MB . Structured Clinical Interview for the (SCID) . The Encyclopedia of Clinical Psychology : 1 – 6 . 62. ↵ Haley CL , Kennard BD , Morris DW , et al. The Quick Inventory of Depressive Symptomatology, Adolescent Version (QIDS-A(17)): A Psychometric Evaluation . Neuropsychiatr Dis Treat 2023 ; 19 : 1085 – 102 . OpenUrl PubMed 63. ↵ Yu L , Buysse DJ , Germain A , et al. Development of short forms from the PROMIS™ sleep disturbance and Sleep-Related Impairment item banks . Behav Sleep Med 2011 ; 10 ( 1 ): 6 – 24 . OpenUrl CrossRef PubMed Web of Science 64. ↵ Buysse DJ . Sleep health: can we define it? Does it matter? Sleep 2014 ; 37 ( 1 ): 9 – 17 . OpenUrl CrossRef PubMed 65. ↵ Yung AR , Yuen HP , McGorry PD , et al. Mapping the onset of psychosis: the Comprehensive Assessment of At-Risk Mental States . Aust N Z J Psychiatry 2005 ; 39 ( 11-12 ): 964 – 71 . OpenUrl CrossRef PubMed Web of Science 66. ↵ Ritterband LM , Thorndike FP , Gonder-Frederick LA , et al. Efficacy of an Internet-based behavioral intervention for adults with insomnia . Arch Gen Psychiatry 2009 ; 66 ( 7 ): 692 – 8 . OpenUrl CrossRef PubMed Web of Science 67. ↵ Uher R , Farmer A , Henigsberg N , et al. Adverse reactions to antidepressants . The British journal of psychiatry : the journal of mental science 2009 ; 195 ( 3 ): 202 – 10 . OpenUrl Abstract / FREE Full Text 68. ↵ Harris PA , Taylor R , Minor BL , et al. The REDCap consortium: Building an international community of software platform partners . J Biomed Inform 2019 ; 95 : 103208 . OpenUrl CrossRef PubMed 69. ↵ Ho FY-Y , Chan CS , Lo W-Y , Leung JC-Y . The effect of self-help cognitive behavioral therapy for insomnia on depressive symptoms: An updated meta-analysis of randomized controlled trials . Journal of Affective Disorders 2020 ; 265 : 287 – 304 . OpenUrl PubMed 70. ↵ Davey CG , Chanen AM , Hetrick SE , et al. The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): a randomised, double-blind, placebo-controlled, multicentre clinical trial . Lancet Psychiatry 2019 ; 6 ( 9 ): 735 – 44 . OpenUrl CrossRef PubMed 71. ↵ Trust TW. Improving recruitment and retention in mental health clinical trials: The role of digital tools . Wellcome Open Res 2025 ; 10 ( 155 ). 72. ↵ Kroenke K , Spitzer RL , Williams JB . The PHQ-9: validity of a brief depression severity measure . Journal of general internal medicine 2001 ; 16 ( 9 ): 606 – 13 . OpenUrl CrossRef PubMed Web of Science 73. ↵ Spitzer RL , Kroenke K , Williams JB , Lowe B . A brief measure for assessing generalized anxiety disorder: the GAD-7 . Archives of internal medicine 2006 ; 166 ( 10 ): 1092 – 7 . OpenUrl CrossRef PubMed Web of Science 74. ↵ Norman SB , Cissell SH , Means-Christensen AJ , Stein MB . Development and validation of an Overall Anxiety Severity And Impairment Scale (OASIS) . Depress Anxiety 2006 ; 23 ( 4 ): 245 – 9 . OpenUrl CrossRef PubMed Web of Science 75. ↵ Chorpita BF , Moffitt CE , Gray J . Psychometric properties of the Revised Child Anxiety and Depression Scale in a clinical sample . Behav Res Ther 2005 ; 43 ( 3 ): 309 – 22 . OpenUrl CrossRef PubMed Web of Science 76. ↵ Morin CM , Belleville G , Bélanger L , Ivers H . The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response . Sleep 2011 ; 34 ( 5 ): 601 – 8 . OpenUrl CrossRef PubMed Web of Science 77. ↵ Horne JA , Östberg O . A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms . International Journal of Chronobiology 1976 ; 4 : 97 – 110 . OpenUrl CrossRef PubMed 78. ↵ Keetharuth AD , Brazier J , Connell J , et al. Recovering Quality of Life (ReQoL): a new generic self-reported outcome measure for use with people experiencing mental health difficulties . The British journal of psychiatry : the journal of mental science 2018 ; 212 ( 1 ): 42 – 9 . OpenUrl CrossRef PubMed 79. ↵ Morosini PL , Magliano L , Brambilla L , Ugolini S , Pioli R . Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social funtioning . Acta psychiatrica Scandinavica 2000 ; 101 ( 4 ): 323 – 9 . OpenUrl CrossRef PubMed Web of Science 80. ↵ Ustun TB , Chatterji S , Kostanjsek N , et al. Developing the World Health Organization Disability Assessment Schedule 2.0 . Bulletin of the World Health Organization 2010 ; 88 ( 11 ): 815 – 23 . OpenUrl CrossRef PubMed Web of Science 81. ↵ van Spijker BA , Batterham PJ , Calear AL , et al. The suicidal ideation attributes scale (SIDAS): Community-based validation study of a new scale for the measurement of suicidal ideation . Suicide & life-threatening behavior 2014 ; 44 ( 4 ): 408 – 19 . OpenUrl 82. ↵ Altman EG , Hedeker D , Peterson JL , Davis JM . The Altman Self-Rating Mania Scale . Biol Psychiatry 1997 ; 42 ( 10 ): 948 – 55 . OpenUrl CrossRef PubMed Web of Science 83. ↵ Humeniuk R , Ali R , Babor TF , et al. Validation of the Alcohol, Smoking And Substance Involvement Screening Test (ASSIST). Addiction (Abingdon , England) 2008 ; 103 ( 6 ): 1039 – 47 . OpenUrl 84. ↵ Carney CE , Buysse DJ , Ancoli-Israel S , et al. The consensus sleep diary: standardizing prospective sleep self-monitoring . Sleep 2012 ; 35 ( 2 ): 287 – 302 . OpenUrl CrossRef PubMed Web of Science 85. Shah JL , Scott J , McGorry PD , et al. Transdiagnostic clinical staging in youth mental health: a first international consensus statement . World psychiatry : official journal of the World Psychiatric Association (WPA) 2020 ; 19 ( 2 ): 233 – 42 . OpenUrl PubMed 86. ↵ Crouse JJ , Park SH , Byrne EM , et al. Evening Chronotypes With Depression Report Poorer Outcomes of Selective Serotonin Reuptake Inhibitors: A Survey-Based Study of Self-Ratings . Biol Psychiatry 2024 ; 96 ( 1 ): 4 – 14 . OpenUrl PubMed 87. ↵ Nichles A , Zmicerevska N , Song YJC , et al. Neurobiology Youth Follow-up Study: protocol to establish a longitudinal and prospective research database using multimodal assessments for current and past mental health treatment-seeking young people within an early intervention service . BMJ Open 2021 ; 11 ( 6 ): e044731 . OpenUrl Abstract / FREE Full Text 88. Murray GK , Lin T , Austin J , McGrath JJ , Hickie IB , Wray NR . Could Polygenic Risk Scores Be Useful in Psychiatry?: A Review . JAMA psychiatry 2021 ; 78 ( 2 ): 210 – 9 . OpenUrl PubMed 89. ↵ Crouse JJ , Carpenter JS , Iorfino F , et al. Schizophrenia polygenic risk scores in youth mental health: preliminary associations with diagnosis, clinical stage and functioning . BJPsych open 2021 ; 7 ( 2 ): e58 . OpenUrl 90. ↵ Byrne EM , Kirk KM , Medland SE , et al. Cohort profile: the Australian genetics of depression study . BMJ Open 2020 ; 10 ( 5 ): e032580 . OpenUrl Abstract / FREE Full Text 91. ↵ Crouse JJ , Park SH , Byrne EM , et al. Patterns of stressful life events and polygenic scores for five mental disorders and neuroticism among adults with depression . Mol Psychiatry 2024 ; 29 ( 9 ): 2765 – 73 . OpenUrl PubMed 92. ↵ Lind PA , Siskind DJ , Hickie IB , et al. Preliminary results from the Australian Genetics of Bipolar Disorder Study: A nation-wide cohort . Aust N Z J Psychiatry 2023 ; 57 ( 11 ): 1428 – 42 . OpenUrl PubMed 93. ↵ Carpenter JS , Crouse JJ , Park SH , et al. Actigraphy-derived circadian rhythms, sleep-wake patterns, and physical activity across clinical stages and pathophysiological subgroups in young people presenting for mental health care . Journal of Psychiatric Research 2025 ; 186 : 396 – 406 . OpenUrl PubMed 94. Shin M , Carpenter JS , Park SH , et al. Twenty-four-hour Skin Temperature Rhythms in Young People With Emerging Mood Disorders: Relationships With Illness Subtypes and Clinical Stage . J Biol Rhythms 2025 ; 40 ( 3 ): 262 – 74 . OpenUrl PubMed 95. ↵ Carpenter JS , Crouse JJ , Shin M , et al. Evidence for Internal Misalignment of Circadian Rhythms in Youth With Emerging Mood Disorders . J Biol Rhythms 2025 : 7487304251349408 . 96. ↵ O’Callaghan VS , Hansell NK , Guo W , et al. Genetic and environmental influences on sleep-wake behaviors in adolescence . Sleep Adv 2021 ; 2 ( 1 ): zpab018 . OpenUrl 97. ↵ Sletten TL , Rajaratnam SM , Wright MJ , et al. Genetic and environmental contributions to sleep-wake behavior in 12-year-old twins . Sleep 2013 ; 36 ( 11 ): 1715 – 22 . OpenUrl CrossRef PubMed 98. ↵ St Hilaire MA , Lockley SW . Measuring Dim Light Melatonin Onset in Humans . Methods Mol Biol 2022 ; 2550 : 13 – 20 . OpenUrl PubMed 99. ↵ Carpenter JS , Robillard R , Hermens DF , et al. Sleep-wake profiles and circadian rhythms of core temperature and melatonin in young people with affective disorders . J Psychiatr Res 2017 ; 94 : 131 – 8 . OpenUrl PubMed 100. ↵ Robillard R , Carpenter JS , Feilds K , et al. Parallel Changes in Mood and Melatonin Rhythm Following an Adjunctive Multimodal Chronobiological Intervention With Agomelatine in People With Depression: A Proof of Concept Open Label Study . Frontiers in Psychiatry 2018 ; 9 ( 624 ). 101. ↵ Levendowski DJ , Ferini-Strambi L , Gamaldo C , Cetel M , Rosenberg R , Westbrook PR. The Accuracy, Night-to-Night Variability, and Stability of Frontopolar Sleep Electroencephalography Biomarkers . J Clin Sleep Med 2017 ; 13 ( 6 ): 791 – 803 . OpenUrl PubMed 102. ↵ Finan PH , Richards JM , Gamaldo CE , et al. Validation of a Wireless, Self-Application, Ambulatory Electroencephalographic Sleep Monitoring Device in Healthy Volunteers . J Clin Sleep Med 2016 ; 12 ( 11 ): 1443 – 51 . OpenUrl PubMed 103. ↵ McGlashan EM , Burns AC , Murray JM , et al. The pupillary light reflex distinguishes between circadian and non-circadian delayed sleep phase disorder (DSPD) phenotypes in young adults . PLoS One 2018 ; 13 ( 9 ): e0204621 . OpenUrl PubMed 104. ↵ Agency EM. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials , 2020 . View the discussion thread. Back to top Previous Next Posted September 09, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following 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 Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share 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 Jacob J. Crouse , Mirim Shin , Samuel J. Hockey , Elie Jeon , Nathan Bradshaw , Alissa Nichles , Natalia Zmicerevska , Min Chong , Hannah You , Naomi R. Wray , Jan Scott , Ronald R. Grunstein , Sharon L. Naismith , Kathleen R. Merikangas , Sean W. Cain , Sarah E. Medland , Frank Iorfino , Thomas D.A. Uebergang , Sarah McKenna , Joanne S Carpenter , Emiliana Tonini , Nayonika Bhattacharya , Blake A Hamilton , Leanne M Wallace , Anjali K Henders , Elizabeth M. Scott , Yun Ju (Christine) Song , Brain and Mind Centre Lived Experience Working Group , Ian B. Hickie medRxiv 2025.09.08.25335055; doi: https://doi.org/10.1101/2025.09.08.25335055 Share This Article: Copy Citation Tools 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 Jacob J. Crouse , Mirim Shin , Samuel J. Hockey , Elie Jeon , Nathan Bradshaw , Alissa Nichles , Natalia Zmicerevska , Min Chong , Hannah You , Naomi R. Wray , Jan Scott , Ronald R. Grunstein , Sharon L. Naismith , Kathleen R. Merikangas , Sean W. Cain , Sarah E. Medland , Frank Iorfino , Thomas D.A. Uebergang , Sarah McKenna , Joanne S Carpenter , Emiliana Tonini , Nayonika Bhattacharya , Blake A Hamilton , Leanne M Wallace , Anjali K Henders , Elizabeth M. Scott , Yun Ju (Christine) Song , Brain and Mind Centre Lived Experience Working Group , Ian B. Hickie medRxiv 2025.09.08.25335055; doi: https://doi.org/10.1101/2025.09.08.25335055 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Psychiatry and Clinical Psychology Subject Areas All Articles Addiction Medicine (569) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4442) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (609) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1511) Epidemiology (15230) Forensic Medicine (30) Gastroenterology (1126) Genetic and Genomic Medicine (6610) Geriatric Medicine (668) Health Economics (998) Health Informatics (4542) Health Policy (1370) Health Systems and Quality Improvement (1613) Hematology (543) HIV/AIDS (1266) Infectious Diseases (except HIV/AIDS) (15923) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (147) Nephrology (668) Neurology (6607) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1146) Occupational and Environmental Health (957) Oncology (3337) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (664) Pediatrics (1693) Pharmacology and Therapeutics (692) Primary Care Research (712) Psychiatry and Clinical Psychology (5448) Public and Global Health (9238) Radiology and Imaging (2202) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (596) Sexual and Reproductive Health (714) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a01c6c4d0ea758d3',t:'MTc3OTc5NDc2Ng=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();