Drug Insight: The use of melatonergic agonists for the treatment of insomnia - Focus on ramelteon

Comprehensive Center for Sleep Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Nature Clinical Practice Neurology (Impact Factor: 7.64). 05/2007; 3(4):221-8. DOI: 10.1038/ncpneuro0467
Source: PubMed


Melatonin, a chronobiotic that participates in the control of the circadian system, is known for its sleep-promoting effects, which include shortening of sleep latency and lengthening of sleep duration. As a result of its short half-life, melatonin does not exhibit undesirable side effects, and its broad applicability for a variety of sleep problems has been the focus of numerous scientific studies. Melatonin has not, however, received regulatory approval from the US FDA as a drug, because it can be sold freely as a food supplement. Consequently, there has been an active search for patentable melatonin receptor ligands in recent years. Ramelteon, an agonist that acts solely on melatonin MT(1) and MT(2) receptors, is of particular interest, and preliminary research indicates that it holds considerable promise for clinical applications. Ramelteon has been shown to induce sleep initiation and maintenance in various animal models and in clinical trials. In chronic insomnia, ramelteon decreases sleep latency and increases total sleep time and sleep efficiency, without causing hangover, addiction or withdrawal effects. Ramelteon is thought to promote sleep by influencing homeostatic sleep signaling mediated by the suprachiasmatic nucleus. Although ramelteon's metabolism and pharmacokinetics differ from those of melatonin, its safety seems to be sufficient for short-term application. Its long-term effects remain to be determined.

6 Reads
  • Source
    • "Melatonin promotes and synchronizes sleep by acting on SCN-expressing melatonin MT1 and MT2 receptors, respectively. Synthesized melatonin receptor agonists exhibiting an increased duration of action are expected to provide significant clinical value for treatment of insomnia patients [93]. The onset of melatonin secretion begins 14-16 hours after waking, usually around dusk [94]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Circadian disruptions are common in modern society, and there is an urgent need for effective treatment strategies. According to standard diagnostic criteria, most adolescents showing both insomnia and daytime sleepiness are diagnosed as having behavioral-induced sleep efficiency syndrome resulting from insomnia due to inadequate sleep hygiene. However, a simple intervention of adequate sleep hygiene often fails to treat them. As a solution to this clinical problem, the present review first overviews the basic neurochemical and neuropharmachological aspects of sleep and circadian rhythm regulation, then explains several circadian disruptions from similar viewpoints, and finally introduces the clinical notion of asynchronization. Asynchronization is designated to explain the pathophysiology/pathogenesis of exhibition of both insomnia and hypersomnia in adolescents, which comprises disturbances in various aspects of biological rhythms. The major triggers for asynchronization are considered to be a combination of light exposure during the night, which disturbs the biological clock and decreases melatonin secretion, as well as a lack of light exposure in the morning, which prohibits normal synchronization of the biological clock to the 24-hour cycle of the earth and decreases the activity of serotonin. In the chronic phase of asynchronization, involvement of both wake- and sleep-promoting systems is suggested. Both conventional and alternative therapeutic approaches for potential treatment of asynchronization are suggested.
    DNA research: an international journal for rapid publication of reports on genes and genomes 06/2011; 9(2):330-41. DOI:10.2174/157015911795596522 · 3.05 Impact Factor
  • Source
    • "Ramelteon (Rozerem™) is a MT 1 /MT 2 melatonin receptor agonist, synthesized by Takeda Chemical Industries with a half-life much longer (1-2 h) than that of melatonin. Ramelteon acts on both MT 1 and MT 2 melatonergic receptors present in the SCN (for ref. see [191] [192]). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Normal circadian rhythms are synchronized to a regular 24 hr environmental light/dark cycle. Both the su-prachiasmatic nucleus (SCN) and melatonin are essential for this adaptation. Melatonin exerts its chronophysiological action in part by acting through specific receptors (MT 1 , MT 2) which have been identified in the plasma membrane of SCN as well as in several neural and non-neural tissues. Both receptors have been cloned and share general features with other G protein linked receptors. Melatonin also exerts direct effects on intracellular proteins such as calmodulin or tubu-lin and has strong free radical scavenger properties which are non-receptor mediated. Within the SCN, melatonin reduces neuronal activity in a time-dependent manner. SCN MT 1 and MT 2 receptors appear to be insensitive during the day, but sensitive at dusk and dawn (MT 2 ; causes phase shifts) or during early night period (MT 1 ; decreases neuronal firing rate). Melatonin secreted during nighttime provides enough inertia to resist minor perturbations of the circadian timing system. The disruption of these circadian mechanisms cause a number of sleep disorders named according to the International Classification of Sleep Disorders as circadian rhythm sleep disorders (CRSDs). CRSDs include delayed or advanced sleep phase syndromes, non 24 hr sleep/wake rhythm disorder, time zone change syndrome ("jet lag") and shift work sleep dis-order. Disturbances in the circadian phase position of plasma melatonin levels have been found in all these disorders. In addition, co-morbility of severe circadian alterations with neurodegenerative diseases like Alzheimer´disease (AD) has been documented. Although further research involving larger number of patients suffering CRSDs is required, currently there is sufficient evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology. Mela-tonin and its analogs can constitute useful therapeutic tools to treat disturbed sleep-wake rhythms in CRSDs. Melatonin secretion decreases in AD patients and its administration improves sleep efficiency, sundowning and cognitive function. This effect can be particularly important in mild cognitive impairment, an etiologically heterogeneous syndrome charac-terized by cognitive impairment preceding dementia.
  • Source
    • "In the context of its chronobiotic actions, melatonin is involved in sleep initiation and phasing [15] [335] [336] [337]. These effects, which are mediated through mechanisms involving the SCN and the hypothalamic sleep switch, are working in humans and diurnally active vertebrates, but not in the nocturnal animals, in which sleep is associated with photophase. "

    The Open Physiology Journal 04/2008; 1(1):1-22. DOI:10.2174/1874360900801010001
Show more