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.

Abstract

In this randomized trial, Tracey L Sletten demonstrate sleep-promoting effects of melatonin combined with behavioral sleep-wake scheduling in participants with Delayed Sleep-Wake Phase Disorder.

Author summary

Why was this study done?

• Circadian disruption—and Delayed Sleep-Wake Phase Disorder (DSWPD) specifically—is associated with significant morbidity, including depression, poor academic and work performance, and adverse social and economic outcomes.

• Previous studies examining treatments for DSWPD have typically diagnosed the disorder based on sleep symptomology, not circadian timing, which may result in misdiagnosis of sleep initiation insomnia as DSWPD and thus inappropriate treatment.

• Although exogenous melatonin has been widely advocated as a treatment for DSWPD, the therapeutic potential of the sleep-promoting effects of melatonin have not been evaluated rigorously in a randomised controlled trial in well-characterised DSWPD patients.

What did the researchers do and find?

• DSWPD patients ( n = 116) with a delayed melatonin rhythm relative to patient desired bedtime (DBT) completed a 4-wk trial of melatonin (0.5 mg) or placebo administered 1 h prior to DBT, combined with a behavioural sleep-wake intervention consisting of attempting sleep at the patient DBT for at least 5 nights per week.

• Relative to baseline, sleep onset time was 34 min earlier, sleep efficiency during the first tertile of sleep (SE T1) was greater, and sleep-related functional impairment was lower in the melatonin group compared to placebo.

• Sleep disturbance, insomnia severity, and functional disability decreased, and a greater proportion of patients showed clinician-rated improvement following melatonin treatment (52.8%) compared to placebo (24.0%).

• The observed improvements in sleep were clinically significant according to clinical practice guidelines for the treatment of circadian rhythm sleep disorders and compared to other established therapeutic approaches.

What do the findings mean?

• Melatonin treatment, when combined with behavioural sleep-wake scheduling, is efficacious for improving sleep disturbances and sleep-related impairments in DSWPD patients and potentially in other patients who show abnormal circadian timing relative to sleep.

• Current melatonin treatment protocols for DSWPD vary in patient diagnostic criteria; vary in the dose, formulation, and timing of melatonin; and may result in low compliance due to the requirement for strict adherence every day.

• These findings contribute to the evidence base to improve the diagnosis of DSWPD and the development of a standardised treatment protocol.