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

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 circad...

Systems approach reveals photosensitivity and PER 2 level as determinants of clock‐modulator efficacy

“…therapeutic effect than a non-circadian-based regimen. This may explain why the current circadian-based treatment can alleviate sleep disorders (Zhu & Zee, 2012;Sletten et al, 2018). However, our model predicts that even if the circadian phase of patients is similar, their response to CK1i can be considerably different depending on the molecular cause and the environmental lighting condition (Fig 4A-D).…”

“…Our systems chronopharmacology model based on experimental data from NHPs and humans predicts that a regimen reflecting a patient's individual circadian phase can achieve a more precise therapeutic effect than a non‐circadian‐based regimen. This may explain why the current circadian‐based treatment can alleviate sleep disorders (Zhu & Zee, ; Sletten et al , ). However, our model predicts that even if the circadian phase of patients is similar, their response to CK1i can be considerably different depending on the molecular cause and the environmental lighting condition (Fig A–D).…”

A PERIOD3 variable number tandem repeat polymorphism modulates melatonin treatment response in delayed sleep‐wake phase disorder

“…10 While these results contribute to the growing evidence for the use of melatonin as a treatment for DSWPD, [11][12][13][14][15][16] treatment efficacy can vary between patients; for example, 22.2% of individuals who received melatonin demonstrated no change or worsening of symptoms. 10 Inter-individual factors that modulate melatonin treatment efficacy should therefore be examined.…”

“…MAGEE Et Al controlled trial (Australian and New Zealand Clinical Trials Registry number ACTRN12612000425897). 10,37 This study was conducted at three sites in Australia: Monash University (Melbourne), Woolcock Institute of Medical Research (Sydney) and Flinders University (Adelaide). Data collection occurred between September 2012 and September 2014.…”

Sleep Physiology, Circadian Rhythms, Waking Performance and the Development of Sleep-Wake Therapeutics

“…Evidence for melatonin's effectiveness in delaying endogenous circadian rhythms is more limited. The phase-advancing effects of melatonin have been successfully exploited in several disorders such as DSPS (Sletten et al 2018). Melatonin is also used to treat sleep disturbances in developmental disorders such as autism (Gringras et al 2017).…”