Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomised clinical trial
- PMID: 29912983
- PMCID: PMC6005466
- DOI: 10.1371/journal.pmed.1002587
Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomised clinical trial
Abstract
Background: Delayed Sleep-Wake Phase Disorder (DSWPD) is characterised by sleep initiation insomnia when attempting sleep at conventional times and difficulty waking at the required time for daytime commitments. Although there are published therapeutic guidelines for the administration of melatonin for DSWPD, to our knowledge, randomised controlled trials are lacking. This trial tested the efficacy of 0.5 mg melatonin, combined with behavioural sleep-wake scheduling, for improving sleep initiation in clinically diagnosed DSWPD patients with a delayed endogenous melatonin rhythm relative to patient-desired (or -required) bedtime (DBT).
Methods: This randomised, placebo-controlled, double-blind clinical trial was conducted in an Australian outpatient DSWPD population. Following 1-wk baseline, clinically diagnosed DSWPD patients with delayed melatonin rhythm relative to DBT (salivary dim light melatonin onset [DLMO] after or within 30 min before DBT) were randomised to 4-wk treatment with 0.5 mg fast-release melatonin or placebo 1 h before DBT for at least 5 consecutive nights per week. All patients received behavioural sleep-wake scheduling, consisting of bedtime scheduled at DBT. The primary outcome was actigraphic sleep onset time. Secondary outcomes were sleep efficiency in the first third of time in bed (SE T1) on treatment nights, subjective sleep-related daytime impairment (Patient Reported Outcomes Measurement Information System [PROMIS]), PROMIS sleep disturbance, measures of daytime sleepiness, clinician-rated change in illness severity, and DLMO time.
Findings: Between September 13, 2012 and September 1, 2014, 307 participants were registered; 116 were randomised to treatment (intention-to-treat n = 116; n = 62 males; mean age, 29.0 y). Relative to baseline and compared to placebo, sleep onset occurred 34 min earlier (95% confidence interval [CI] -60 to -8) in the melatonin group. SE T1 increased; PROMIS sleep-related impairment, PROMIS sleep disturbance, insomnia severity, and functional disability decreased; and a greater proportion of patients showed more than minimal clinician-rated improvement following melatonin treatment (52.8%) compared to placebo (24.0%) (P < 0.05). The groups did not differ in the number of nights treatment was taken per protocol. Post-treatment DLMO assessed in a subset of patients (n = 43) was not significantly different between groups. Adverse events included light-headedness, daytime sleepiness, and decreased libido, although rates were similar between treatment groups. The clinical benefits or safety of melatonin with long-term treatment were not assessed, and it remains unknown whether the same treatment regime would benefit patients experiencing DSWPD sleep symptomology without a delay in the endogenous melatonin rhythm.
Conclusions: In this study, melatonin treatment 1 h prior to DBT combined with behavioural sleep-wake scheduling was efficacious for improving objective and subjective measures of sleep disturbances and sleep-related impairments in DSWPD patients with delayed circadian phase relative to DBT. Improvements were achieved largely through the sleep-promoting effects of melatonin, combined with behavioural sleep-wake scheduling.
Trial registration: This trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000425897.
Conflict of interest statement
I have read the journal’s policy and the authors of this manuscript have the following competing interests: TLS reports her institution has received equipment donations or other support from Philips Lighting and Philips Respironics. DJK reports he and his institution receive royalties under a licence agreement with Buhlmann Laboratories to supply reagents for melatonin analysis. LCL is a shareholder in Re-Time Pty Ltd. RRG has provided advisory board services for Merck and Teva and has been a medico-legal expert witness for Queensland Health, NSW Nurses Federation, NSW Health, and NSW Director of Public Prosecutions. SWL declares no conflicts of interest related to the published work. In the past 5 years, he has held consulting contracts and received reimbursement from Akili Interactive; Consumer Sleep Solutions; Delos Living LLC; Headwaters Inc.; Hintsa Performance AG; Light Cognitive; Lighting Science Group Corporation; Mental Workout; Pegasus Capital Advisors LP; PlanLED; Six Senses; and Wyle Integrated Science and Engineering. He has also received one-off consulting fees from Carbon Limiting Technologies and OpTerra Energy Services Inc. in relation to lighting; from several sports teams in relation to jetlag; and from 15 investment firms for short briefings on non-24-hour sleep-wake disorder. Through Brigham & Women’s Hospital, he has received unrestricted equipment gifts from Bioilluminations LLC, Bionetics Corporation, F. Lux Software LLC, and Philips Lighting; service agreements from Rio Tinto Iron Ore and Vanda Pharmaceuticals Inc.; three completed sponsored initiated clinical research contracts with Vanda Pharmaceuticals Inc.; investigator-initiated research grants from Biological Illumination LLC, F. Lux Software, LLC and Vanda Pharmaceuticals Inc.; and a patent for a method for determining and/or controlling sleep quality. SWL has also served as a paid expert witness in an arbitration related to work hours, and in legal proceedings related to light, sleep, and health. SMWR reports that he has served as a consultant through his institution to Vanda Pharmaceuticals, Philips Respironics, and Teva Pharma Australia and has, through his institution, received research grants and/or unrestricted educational grants from Vanda Pharmaceuticals, Takeda Pharmaceuticals North America, Philips Lighting, Philips Respironics, Cephalon, and ResMed Foundation as well as reimbursements for conference travel expenses from Vanda Pharmaceuticals. TLS, JMM, and CJG serve as Project Leaders, and RRG, SWL, and SMWR serve as Program Leaders in the Cooperative Research Centre for Alertness, Safety and Productivity. The other authors declare no conflicts of interest.
Figures
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