https://www.gwern.net/docs/melatonin/2005-brzezinski.pdf

Effects of exogenous melatonin on sleep: a meta-analysis

Importance Sleep disturbances are recognized as a common nonmotor complaint in Parkinson disease but their etiology is poorly understood. Objective To define the sleep and circadian phenotype of patients with early-stage Parkinson disease. Design, Setting, and Participants Initial assessment of sleep characteristics in a large population-representative incident Parkinson disease cohort (N=239) at the University of Cambridge, England, followed by further comprehensive case-control sleep assessments in a subgroup of these patients (n=30) and matched controls (n=15). Main Outcomes and Measures Sleep diagnoses and sleep architecture based on polysomnography studies, actigraphy assessment, and 24-hour analyses of serum cortisol, melatonin, and peripheral clock gene expression ( Bmal1 , Per2 , and Rev-Erbα ). Results Subjective sleep complaints were present in almost half of newly diagnosed patients and correlated significantly with poorer quality of life. Patients with Parkinson disease exhibited increased sleep latency ( P  = .04), reduced sleep efficiency ( P  = .008), and reduced rapid eye movement sleep ( P  = .02). In addition, there was a sustained elevation of serum cortisol levels, reduced circulating melatonin levels, and altered Bmal1 expression in patients with Parkinson disease compared with controls. Conclusions and Relevance Sleep dysfunction seen in early Parkinson disease may reflect a more fundamental pathology in the molecular clock underlying circadian rhythms.

/pdf/sleep-and-circadian-rhythm-regulation-in-early-parkinson-39xg12u5zn.pdf

Sleep and Circadian Rhythm Regulation in Early Parkinson Disease

Melatonin receptors: Role on sleep and circadian rhythm regulation

Rapid eye movement (REM) sleep behaviour disorder (RBD) has been suggested to predict the development of neurodegenerative disorders. Patients with RBD are acting out dream behaviour associated with loss of normal muscle atonia of REM sleep. The aim of the present study was to confirm that exogenous melatonin improves RBD. Eight consecutively recruited males (mean age 54 years) with a polysomnographically (PSG) confirmed diagnosis of RBD were included in a two-part, randomized, double-blind, placebo-controlled cross-over study. Patients received placebo and 3 mg of melatonin daily in a cross-over design, administered between 22:00 h and 23:00 h over a period of 4 weeks. PSG recordings were performed in all patients at baseline, at the end of Part I of the trial and at the end of Part II of the trial. Compared to baseline, melatonin significantly reduced the number of 30-s REM sleep epochs without muscle atonia (39% versus 27%; P = 0.012), and led to a significant improvement in clinical global impression (CGI: 6.1 versus 4.6; P = 0.024). Interestingly, the number of REM sleep epochs without muscle atonia remained lower in patients who took placebo during Part II after having received melatonin in Part I (-16% compared to baseline; P = 0.043). In contrast, patients who took placebo during Part I showed improvements in REM sleep muscle atonia only during Part II (i.e. during melatonin treatment). The data suggest that melatonin might be a second useful agent besides clonazepam in the treatment of RBD.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2869.2010.00848.x

A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder.

Objective To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders. Design 12 week double masked randomised placebo controlled phase III trial. Setting 19 hospitals across England and Wales. Participants 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours’ continuous sleep. Interventions Immediate release melatonin or matching placebo capsules administered 45 minutes before the child’s bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment. Main outcome measures Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy. Results Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (−15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (−37.5 minutes, −55.3 to −19.7 minutes) and actigraphy (−45.3 minutes, −68.8 to −21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups. Conclusions Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required. Trial registration ISRCT No 05534585.

https://www.bmj.com/content/bmj/345/bmj.e6664.full.pdf

Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial.

Recent data suggest that melatonin may influence human physiology, including the sleep-wake cycle, in a time-dependent manner via the body's internal clock. Rapid-eye-movement (REM) sleep expression is strongly circadian modulated, and the impact of REM sleep on primary brain functions, metabolic processes, and immune system function has become increasingly clear over the past decade. In our study, we evaluated the effects of exogenous melatonin on disturbed REM sleep in humans. Fourteen consecutive outpatients (five women, nine men; mean age, 50 yr) with unselected neuropsychiatric sleep disorders and reduced REM sleep duration (25% or more below age norm according to diagnostic polysomnography) were included in two consecutive, randomized, double-blind, placebo-controlled, parallel design clinical trials. Patients received 3 mg melatonin daily, administered between 2200 and 2300 h for 4 wk. The results of the study show that melatonin was significantly more effective than placebo: patients on melatonin experienced significant increases in REM sleep percentage (baseline/melatonin, 14.7/17.8 vs. baseline/placebo, 14.3/12.0) and improvements in subjective measures of daytime dysfunction as well as clinical global impression score. Melatonin did not shift circadian phase or suppress temperature but did increase REM sleep continuity and promote decline in rectal temperature during sleep. These results were confirmed in patients who received melatonin in the second study (REM sleep percentage baseline/placebo/melatonin, 14.3/12.0/17.9). In patients who received melatonin in the first study and placebo in the second, the above mentioned effects outlasted the period of melatonin administration and diminished only slowly over time (REM sleep percentage baseline/melatonin/placebo, 14.7/17.8/16.2). Our findings show that exogenous melatonin, when administered at the appropriate time, seems to normalize circadian variation in human physiology. It may, therefore, have a strong impact on general health, especially in the elderly and in shift workers.

/pdf/melatonin-in-patients-with-reduced-rem-sleep-duration-two-gw060clx8c.pdf

Melatonin in Patients with Reduced REM Sleep Duration: Two Randomized Controlled Trials

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Melatonin in Patients with Reduced REM Sleep Duration: Two Randomized Controlled Trials