Research Article: Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomised clinical trial

Date Published: June 18, 2018

Publisher: Public Library of Science

Author(s): Tracey L. Sletten, Michelle Magee, Jade M. Murray, Christopher J. Gordon, Nicole Lovato, David J. Kennaway, Stella M. Gwini, Delwyn J. Bartlett, Steven W. Lockley, Leon C. Lack, Ronald R. Grunstein, Shantha M. W. Rajaratnam, David Peiris

Abstract: BackgroundDelayed 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).MethodsThis 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.FindingsBetween 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.ConclusionsIn 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 registrationThis trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000425897.

Partial Text: 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 such as work or school [1,2]. DSWPD is often associated with chronic sleep restriction [3] and adverse academic, occupational, financial, mental health, and social outcomes [4–6].

Preliminary online screening was completed by 3,522 individuals, of whom 307 were enrolled in the study, 187 attended the laboratory-based circadian phase assessment, and 116 were randomised to treatment (Fig 1). Of the 186 who completed the circadian phase assessment, 62 (33.3%) did not have circadian misalignment between DLMO and DBT (defined as DLMO <30 min before or any time after DBT) and were excluded from the trial. Comparison of sleep-wake and mood characteristics of patients with and without circadian misalignment from this trial are presented elsewhere [8]. In a sample of DSWPD patients with confirmed circadian misalignment, compared to placebo, 0.5 mg melatonin taken 1 h prior to patient-DBT in a pragmatic treatment protocol resulted in earlier timing of sleep onset, improved sleep quality, and reduced sleep-related impairments. Melatonin treatment reduced patient-reported sleep disturbance, insomnia severity, and daytime functional disability and was associated with larger clinician-rated improvements in symptoms. This is the largest placebo-controlled trial to assess the clinical efficacy of melatonin to improve sleep initiation and sleep quality in DSWPD. The trial has assessed the effects of melatonin when sleep is attempted at the patient-DBT in DSWPD patients with confirmed circadian misalignment, using patient-reported (PROMIS, PSQI, ISI, SDS, PGI-C), clinician-assessed (CGI-Global Improvement and Efficacy), and objective (actigraphic sleep onset time, SOL, SE) assessments of sleep quality and daytime function. Source:


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