Moshe Laudon

Improvement of sleep quality in elderly people by controlled-release melatonin

Melatonin, produced by the pineal gland at night, has a role in regulation of the sleep-wake cycle. Among elderly people, even those who are healthy, the frequency of sleep disorders is high and there is an association with impairment of melatonin production. We investigated the effect of a controlled-release formulation of melatonin on sleep quality in 12 elderly subjects (aged 76 [SD 8] years) who were receiving various medications for chronic illnesses and who complained of insomnia. In all 12 subjects the peak excretion of the main melatonin metabolite 6-sulphatoxymelatonin during the night was lower than normal and/or delayed in comparison with non-insomniac elderly people. In a randomised, double-blind, crossover study the subjects were treated for 3 weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo, with a weeks washout period. Sleep quality was objectively monitored by wrist actigraphy. Sleep efficiency was significantly greater after melatonin than after placebo (83 [SE 4] vs 75 [3]%, p < 0.001) and wake time after sleep onset was significantly shorter (49 [14] vs 73 [13] min, p < 0.001). Sleep latency decreased, but not significantly (19 [5] vs 33 [7] min, p = 0.088). Total sleep time was not affected. The only adverse effects reported were two cases of pruritus, one during melatonin and one during placebo treatment; both resolved spontaneously. Melatonin deficiency may have an important role in the high frequency of insomnia among elderly people. Controlled-release melatonin replacement therapy effectively improves sleep quality in this population.

Sleep disorders and melatonin rhythms in elderly people.

Biological aging is often associated with problems with sleep and daytime napping.1 There is considerable evidence linking melatonin, produced by the pineal gland, with the sleep-wake cycle. When administered orally to humans or animals it enhances sleep2 and has a synchronising effect on circadian rhythms. Circulating melatonin concentrations decrease in old age, and its time of secretion is delayed.3 We examined whether sleep disorders in old age were associated with changes in concentration of 6-sulphatoxymelatonin, the major urinary measure of melatonin. The study population comprised four groups: (a) eight independently living patients with insomnia (four men, four women, mean age 73.1 (SD 3.9)); (b) 15 patients with insomnia (five men, 10 women, mean age 82.1 (8.8)) who had lived a minimum of six months in a nursing home; (c) 25 elderly patients without sleep disorders (19 …

Prolonged‐release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects

Melatonin, secreted nocturnally by the pineal gland, is an endogenous sleep regulator. Impaired melatonin production and complaints on poor quality of sleep are common among the elderly. Non‐restorative sleep (perceived poor quality of sleep) and subsequently poor daytime functioning are increasingly recognized as a leading syndrome in the diagnostic and therapeutic process of insomnia complaints. The effects of 3‐weeks prolonged‐release melatonin 2 mg (PR‐melatonin) versus placebo treatment were assessed in a multi‐center randomized placebo‐controlled study in 170 primary insomnia outpatients aged ≥55 years. Improvements in quality of sleep (QOS) the night before and morning alertness (BFW) were assessed using the Leeds Sleep Evaluation Questionnaire and changes in sleep quality (QON) reported on five categorical unit scales. Rebound insomnia and withdrawal effects following discontinuation were also evaluated. PR‐melatonin significantly improved QOS (−22.5 versus −16.5 mm, P = 0.047), QON (0.89 versus 0.46 units; P = 0.003) and BFW (−15.7 versus −6.8 mm; P = 0.002) compared with placebo. The improvements in QOS and BFW were strongly correlated (Rval = 0.77, P < 0.001) suggesting a beneficial treatment effect on the restorative value of sleep. These results were confirmed in a subgroup of patients with a greater symptom severity. There was no evidence of rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was low and most side‐effects were judged to be of minor severity. PR‐melatonin is the first drug shown to significantly improve quality of sleep and morning alertness in primary insomnia patients aged 55 years and older‐suggesting more restorative sleep, and without withdrawal symptoms upon discontinuation.

Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes.

ABSTRACT Objective: Melatonin, the hormone produced nocturnally by the pineal gland, serves as a circadian time cue and sleep-anticipating signal in humans. With age, melatonin production declines and the prevalence of sleep disorders, particularly insomnia, increases. The efficacy and safety of a prolonged release melatonin formulation (PR-melatonin; Circadin* 2 mg) were examined in insomnia patients aged 55 years and older. Design: Randomised, double blind, placebo-controlled. Setting: Primary care. Methodology: From 1248 patients pre-screened and 523 attending visit 1, 354 males and females aged 55–80 years were admitted to the study, 177 to active medication and 177 to placebo. The study was conducted by primary care physicians in the West of Scotland and consisted of a 2‐week, single blind, placebo run-in period followed by a 3‐week double blind treatment period with PR-melatonin or placebo, one tablet per day at 2 hours before bedtime. Main outcome measures: Responder rate (concomitant improvement in sleep quality and morning alertness on Leeds Sleep Evaluation Questionnaire [LSEQ]), other LSEQ assessments, Pittsburgh Sleep Quality Index (PSQI) global score, other PSQI assessments, Quality of Night and Quality of Day derived from a diary, Clinical Global Improvement scale (CGI) score and quality of life (WHO‐5 well being index). Results: Of the 354 patients entering the active phase of the study, 20 failed to complete visit 3 (eight PR-melatonin; 12 Placebo). The principal reasons for drop-out were patient decision and lost to follow-up. Significant differences in favour of PR-melatonin vs. placebo treatment were found in concomitant and clinically relevant improvements in quality of sleep and morning alertness, demonstrated by responder analysis (26% vs. 15%; p = 0.014) as well as on each of these parameters separately. A significant and clinically relevant shortening of sleep latency to the same extent as most frequently used sleep medications was also found (–24.3 vs.–12.9 minutes; p = 0.028). Quality of life also improved significantly ( p = 0.034). Conclusions: PR-melatonin results in significant and clinically meaningful improvements in sleep quality, morning alertness, sleep onset latency and quality of life in primary insomnia patients aged 55 years and over. Trial registration: The trial was conducted prior to registration being introduced.

Inhibition of dopamine release by melatonin: regional distribution in the rat brain

Dopamine release evoked by electrical field stimulation of slices from various regions of rat brain was assessed in the presence of 10-10-10-5 M melatonin. Inhibition of dopamine release by melatonin was observed in the ventral hippocampus, medulla pons, preoptic area and median and posterior hypothalamus. No inhibitory effect of melatonin on dopamine release was observed in the cerebral cortex, cerebellum, dorsal hippocampus and striatum. Equal concentrations of melatonin were needed to produce half-maximal inhibition in all the regions affected. The results indicate that the brain sites for inhibitory effect of melatonin on dopamine neurosecretion overlap the sites reportedly involved in its modulation of neuroendocrine functions.

Clinical trials of controlled-release melatonin in children with sleep–wake cycle disorders

This is the first study to examine effective doses of controlled‐release (CR) melatonin in children with chronic sleep–wake cycle disorders. All 42 subjects had severe neurodevelopmental difficulties. Initially, a randomized double‐blinded cross‐over design was used in 16 children, comparing the effectiveness of fast‐release (FR) and CR melatonin. In the remainder of the patients, the CR melatonin was studied on a clinical basis. The effectiveness of treatment was assessed by sleep charts and clinical follow‐up. Emphasis was placed on the judgement of the parents, who had guidance from the physicians. The average final CR melatonin dose in the 42 patients was 5.7 mg (2–12 mg). The studies showed that the FR melatonin was most effective when there was only delayed sleep onset, but CR formulations were more useful for sleep maintenance. Children appeared to require higher doses than adults.

Melatonin Receptors in Discrete Brain Areas of the Male Rat

The distribution of melatonin receptors in six discrete brain areas of mature (3-4 months old) and aged (greater than 24 months old) male rats was recorded every 4 h during a 24-hour light: dark cycle (L:D 14:10h). 125I-melatonin was used as a melatonin receptor probe. In the mature animals, specific binding of 125I-melatonin was found in all brain areas investigated, i.e. hypothalamus, medulla pons, hippocampus, cerebellum, parietal cortex and striatum. The density of 125I-melatonin-binding sites in the hypothalamus, medulla pons and hippocampus exhibited clear diurnal rhythms with different patterns and phases. No such rhythm was evident in the cerebellum, parietal cortex and striatum. The apparent affinity of the binding sites was similar in all the brain regions and did not change at any of the times recorded. In the old male rats, the density of 125I-melatonin binding sites in the hypothalamus was only 10% of that in the mature animals at 13 h after the onset of light and was vanishingly small throughout the 24-hour period. The 24-hour mean of the binding site density in the parietal cortex, hippocampus and medulla pons was significantly lower than in mature rats with no apparent diurnal variations. The age-related decrease in the density of melatonin-binding sites was less pronounced in the cerebellum and striatum. In all brain areas tested, apart from the hypothalamus, the decrease in receptor densities was not accompanied by changes in the apparent affinity towards the ligand.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition by melatonin of dopamine release from rat hypothalamus: regulation of calcium entry

The [Ca2+] dependency of dopamine release evoked by electrical field stimulation of hypothalamic tissue from female rats at the estrous stage was assessed in the presence of melatonin. At concentrations of 10(-9)-10(-6) M, melatonin inhibited the [Ca2+]-dependent dopamine release. Melatonin reduced tissue uptake of 45Ca2+ during stimulation either by an electrical field or by elevated K+ concentration. About 90% of this inhibition by melatonin of 45Ca2+ uptake, as well as of dopamine release, was not observed in the presence of the calcium ionophore A23187. Hence, the inhibitory effect on dopamine release by melatonin may stem from the reduction of calcium entry into the presynaptic nerve endings.

Dopamine release induced by electrical field stimulation of rat hypothalamus invitro: Inhibition by melatonin

Abstract Microdissected slices of rat hypothalamus were incubated with 3 H -dopamine and then subjected to two successive sets of electrical field stimulation in a superfusion chamber. Neurotransmitter release was found to be calcium dependent and the amount of release was determined by scintillation counting of the effluent buffer. The release obtained following the first train of stimuli served as an internal reference. The samples were exposed to drugs during the interval between the two sets of stimuli. Using this technique, as well as K + -evoked depolarization, we were able to show that subnanomolar concentrations of melatonin, the hormone secreted from the pineal gland, inhibits dopamine release from hypothalamic slices. The possibility that melatonin modulates neurotransmission in the brain is therefore indicated.

Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety.

BackgroundMelatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.MethodsAdult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.ResultsOn the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] ≤8 μg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.ConclusionsThe results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.