Melatonin sleep

Melatonin levels increase from evening to night and then decrease as morning approaches. People with high levels of melatonin sleep longer and more soundly than those with low levels. The concentration of the hormone in the blood varies with age—6-year-olds have more than five times the concentration that 80-year-olds have—which is one of the reasons why young people have less trouble sleeping than older people. Melatonin supplements are used to treat insomnia, jet lag, and seasonal affective disorder. 

Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms rationale for development of specific melatonin agonists. Sleep Med 2004 5 523-532. 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Figure 22.1 Pathways projecting to and from the suprachiasmatic nucleus (SCN). Inputs from photoreceptors in the retina help to reset the circadian clock in response to changes in the light cycle. Other inputs derive from the lateral geniculate complex and the serotonergic, Raphe nuclei and help to reset the SCN in response to non-photic stimuli. Neurons in the SCN project to the hypothalamus, which has a key role in the regulation of the reproductive cycle, mood and the sleep-waking cycle. These neurons also project to the pineal gland which shows rhythmic changes in the rate of synthesis and release of the hormone, melatonin...

The precise role of melatonin in sleep and waking is uncertain but it seems to act as a go-between for the light and biological cycles and evidence suggests that it has a reciprocal relationship with the SCN (Fig. 22.3). Its actions are mediated by (MLi) receptors which are found predominantly in the SCN as well as thalamic nuclei and the anterior pituitary. These are G protein-coupled receptors, with seven transmembrane domains, that inhibit adenylyl cyclase. Their activation by melatonin, or an MLi agonist such as 2-iodomelatonin, restores the impaired circadian cycle in aged rats. 

In humans, poor sleep correlates with low plasma melatonin and can be improved by melatonin administration. This therapeutic approach has been tried especially in individuals whose sleep rhythms are disrupted by shift-work, blindness or jet-lag but its benefits are as yet unconfirmed and, in any case, the mechanisms by which it might reset sleep patterns are unclear. Of course, it must be remembered that other body... 

Figure 22.9 Summary of the influence of varying factors on sleep and waking. The EEG is shown diagramatically in the typical arousal (awake) state and in both non-REM (slow wave) and REM sleep. Appropriate activity levels, high or low, are shown for the different factors such as light input, melatonin secretion or ACh, NA, and 5-HT function in the different phases...

Arendt, J, Middleton, B, Stone, B and Skene, D (1999) Complex effects of melatonin Evidence for photoperiodic responses in humans Sleep 22 625-635. 

Antihistamines such as diphenhydramine are known for their sedating properties and are frequently used over-the-counter medications (usual doses 25-50 mg) for difficulty sleeping. Diphenhydramine is approved by the FDA for the treatment of insomnia and can be effective at reducing sleep latency and increasing sleep time.43 However, diphenhydramine produces undesirable anticholinergic effects and carryover sedation that limit its use. As with TCAs and BZDRAs, diphenhydramine should be used with caution in the elderly. Valerian root is an herbal sleep remedy that has inconsistent effects on sleep but may reduce sleep latency and efficiency at commonly used doses of 400 to 900 mg valerian extract. Ramelteon, a new melatonin receptor agonist, is indicated for insomnia characterized by difficulty with sleep onset. The recommended dose is 8 mg at bedtime. Ramelteon is not a controlled substance and thus may be a viable option for patients with a history of substance abuse. 

Non-REM parasomnias usually do not require treatment. If needed, low-dose benzodiazepines such as clonazepam can be prescribed for bothersome episodes. Clonazepam reduces the amount of sleep time spent in stages 3 and 4 of non-REM sleep, where most non-REM parasomnias occur. For treating RBD, clonazepam 0.5 to 2 mg at bedtime is the drug of choice, although melatonin 3 to 12 mg at bedtime also may be effective. Patients with RBD also should have dangerous objects removed from the bedroom and cushions placed on the floor to reduce the chance of injury from breakthrough episodes. 

Melatonin at doses of 0.5 to 5 mg taken at appropriate target bedtimes for east or west travel is becoming the drug of choice for jet lag. Melatonin significantly reduces jet lag and shortens sleep latency in travelers.50 Hypnotic agents with relatively short durations of action (3 to 5 hours) also may be used to sustain sleep during the initial adaptation to the new time zone. 

Melatonin and its receptors biological function in circadian sleep-wake regulation... 

Melatonin secretion is synchronized to the light/dark (LD) cycle, with a nocturnal maximum (in young humans, about 200 pg/ml plasma) and low diurnal baseline levels (about 10 pg/ml plasma). Studies have supported the value of the exogenous administration of melatonin in circadian rhythm sleep disorders, insomnia, cancer, neurodegenerative diseases, disorders of the immune function, and oxidative damage (Karasek et al. 2002 Pandi-Perumal et al. 2005, 2006 Srinivasan et al. 2005a,b, 2006 Hardeland et al. 2006). 

Effects of exogenous melatonin administration on human sleep... 

A reduced endogenous melatonin production seems to be a prerequisite for effective exogenous melatonin treatment of sleep disorders. A recent metaanalysis of the effects of melatonin in sleep disturbances, including all age... 

In contrast, another meta-analysis undertaken by Brzezinski et al., using 17 different studies involving 284 subjects, most of whom were older, concluded that melatonin is effective in increasing sleep efficiency and reducing sleep onset time (Brzezinski et al. 2005). Based on this meta-analysis the use of melatonin in the treatment of insomnia, particularly in aged individuals with nocturnal melatonin deficiency, was proposed. 

One of us examined the timely use of three factors (melatonin treatment, exposure to light, physical exercise) to hasten the resynchronization of the sleep-wake cycle in a group of elite sports competitors after a transmeridian flight across 12 time zones (Cardinali et al. 2002). Outdoor light exposure and physical exercise were used to cover symmetrically the phase delay and the phase advance portions of the phase-response curve. Melatonin taken at local bedtime helped to resynchronize the circadian oscillator to the new time. Individual actograms taken from sleep log data showed that all subjects became synchronized in their sleep to the local time in 24-48 h, well in advance of what would be expected in the absence of any treatment (Cardinali et al. 2002). More recently, a retrospective analysis of the data obtained from 134 normal volunteers flying the Buenos Aires - Sydney transpolar route in the past 9 years was published this further supports such a role for exogenous melatonin in resynchronization of sleep cycles (Cardinal et al. 2006). 

A number of clinical studies have now made use of the phase advancing property of melatonin for treating delayed sleep phase syndrome (DSPS). Melatonin, at a 5 mg dose, has been found beneficial in advancing the sleep onset time and wake time in DSPS subjects (Dahlitz et al. 1991 Nagtegaal et al. 1998 Kayumov et al. 2001). Melatonin was found to be effective when given five hours before its endogenous onset or seven hours before sleep onset. 

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