Nava Zisapel

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.

Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways

Melatonin, an endogenous signal of darkness, is an important component of the bodys internal time-keeping system. As such it regulates major physiological processes including the sleep wake cycle, pubertal development and seasonal adaptation. In addition to its relevant antioxidant activity, melatonin exerts many of its physiological actions by interacting with membrane MT1 and MT2 receptors and intracellular proteins such as quinone reductase 2, calmodulin, calreticulin and tubulin. Here we review the current knowledge about the properties and signaling of melatonin receptors as well as their potential role in health and some diseases. Melatonin MT1 and MT2 receptors are G protein coupled receptors which are expressed in various parts of the CNS (suprachiasmatic nuclei, hippocampus, cerebellar cortex, prefrontal cortex, basal ganglia, substantia nigra, ventral tegmental area, nucleus accumbens and retinal horizontal, amacrine and ganglion cells) and in peripheral organs (blood vessels, mammary gland, gastrointestinal tract, liver, kidney and bladder, ovary, testis, prostate, skin and the immune system). Melatonin receptors mediate a plethora of intracellular effects depending on the cellular milieu. These effects comprise changes in intracellular cyclic nucleotides (cAMP, cGMP) and calcium levels, activation of certain protein kinase C subtypes, intracellular localization of steroid hormone receptors and regulation of G protein signaling proteins. There are circadian variations in melatonin receptors and responses. Alterations in melatonin receptor expression as well as changes in endogenous melatonin production have been shown in circadian rhythm sleep disorders, Alzheimers and Parkinsons diseases, glaucoma, depressive disorder, breast and prostate cancer, hepatoma and melanoma. This paper reviews the evidence concerning melatonin receptors and signal transduction pathways in various organs. It further considers their relevance to circadian physiology and pathogenesis of certain human diseases, with a focus on the brain, the cardiovascular and immune systems, and cancer.

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 …

Circadian Rhythm Sleep Disorders Pathophysiology and Potential Approaches to Management

An intrinsic body clock residing in the suprachiasmatic nucleus (SCN) within the brain regulates a complex series of rhythms in humans, including sleep/wakefulness. The individual period of the endogenous clock is usually >24 hours and is normally entrained to match the environmental rhythm.Misalignment of the circadian clock with the environmental cycle may result in sleep disorders. Among these are chronic insomnias associated with an endogenous clock which runs slower or faster than the norm [delayed (DSPS) or advanced (ASPS) sleep phase syndrome, or irregular sleep-wake cycle], periodic insomnias due to disturbances in light perception (non-24-hour sleep-wake syndrome and sleep disturbances in blind individuals) and temporary insomnias due to social circumstances (jet lag and shift-work sleep disorder).Synthesis of melatonin (N-acetyl-5-methoxytryptamine) within the pineal gland is induced at night, directly regulated by the SCN. Melatonin can relay time-of-day information (signal of darkness) to various organs, including the SCN itself. The phase-shifting effects of melatonin are essentially opposite to those of light. In addition, melatonin facilitates sleep in humans. In the absence of a light-dark cycle, the timing of the circadian clock, including the timing of melatonin production in the pineal gland, may to some extent be adjusted with properly timed physical exercise.Bright light exposure has been demonstrated as an effective treatment for circadian rhythm sleep disorders. Under conditions of entrainment to the 24-hour cycle, bright light in the early morning and avoidance of light in the evening should produce a phase advance (for treatment of DSPS), whereas bright light in the evening may be effective in delaying the clock (ASPS).Melatonin, given several hours before its endogenous peak at night, effectively advances sleep time in DSPS and adjusts the sleep-wake cycle to 24 hours in blind individuals. In some blind individuals, melatonin appears to fully entrain the clock. Melatonin and light, when properly timed, may also alleviate jet lag. Because of its sleep-promoting effect, melatonin may improve sleep in night-shift workers trying to sleep during the daytime. Melatonin replacement therapy may also provide a rational approach to the treatment of age-related insomnia in the elderly.However, there is currently no melatonin formulation approved for clinical use, neither are there consensus protocols for light or melatonin therapies. The use of bright light or melatonin for circadian rhythm sleep disorders is thus considered exploratory at this stage.

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.

Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting.

To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin–dopamine interactions in mammals. Melatonin, the hormone produced by the pineal gland atnight, influences circadian and seasonal rhythms, most notably the sleep–wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears tobe effective in the treatment of tardive dyskinesia, a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D2 receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.

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.

Sleep and sleep disturbances: biological basis and clinical implications

Abstract.Sleep is a neurochemical process involving sleep promoting and arousal centers in the brain. Sleep performs an essential restorative function and facilitates memory consolidation in humans. The remarkably standardized bouts of consolidated sleep at night and daytime wakefulness reflect an interaction between the homeostatic sleep need that is manifested by increase in sleep propensity after sleep deprivation and decrease during sleep and the circadian pacemaker. Melatonin, the hormone produced nocturnally by the pineal gland, serves as a time cue and sleep-anticipating signal. A close interaction exists between the sleep-wake, melatonin, core temperature, blood pressure, immune and hormonal rhythms leading to optimization of the internal temporal order. With age the robustness of the circadian system decreases and the prevalence of sleep disorders, particularly insomnia, increases. Deviant sleep patterns are associated with increased risks of morbidity, poor quality of life and mortality. Current sleep pharmacotherapies treat insufficient sleep quantity, but fail to improve daytime functioning. New treatment modalities for sleep disorders that will also improve daytime functioning remain a scientific and medical challenge.

Phorbol ester and calcium act synergistically to enhance neurotransmitter release by brain neurons in culture.

Phorbol ester Calcium Brain neuron Neurotransmitter