Melatonin agonists and insomnia

Centre for Sleep Research, University of South Australia, GPO Box 2471, Adelaide, SA 5001, Australia.
Expert Review of Neurotherapeutics (Impact Factor: 2.78). 02/2010; 10(2):305-18. DOI: 10.1586/ern.10.1
Source: PubMed


The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

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    • "and have fewer side effects [22]. Melatonin agonist drugs (eg, melatonin [31] [32] [33] [34] [35], ramelteon [36] [37] [38] [39] [40]) and antihistamine drugs (eg, diphenhydramine ) [27] [28] [29] [30] have also been studied extensively in recent years [41]. Although development and clinical trials for new medications are not popular for insomnia, a number of alternative remedies, especially over-the-counter products, have emerged on the market, including tryptophan, valerian, kava, Jamaican dogwood, hops, California poppy, St John's wort, alcohol-based preparations, muscle relaxants, and others [22]. "
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    ABSTRACT: Insomnia has been a rising public concern in recent years. As one example of a multidisciplinary topic, the theme of insomnia research has gradually shifted over time; however, there is very little quantitative characterization of the research trends in insomnia. The current study aims to quantitatively analyze trends in insomnia publications for the past 20 years. We retrospectively analyzed insomnia-related publications retrieved from PubMed and Google Scholar between 1994 and from a number of different perspectives. We investigated the major areas of research focus for insomnia, journal characteristics, as well as trends in clinical management and treatment modalities. The resulting 5841 publications presented an exponential growth trend over the past two decades, with mean annual growth rates at nearly 10% for each publication type. Analysis of major research focuses indicated that depression, hypnotics and sedatives, questionnaires, and polysomnography are the most common topics at present. Furthermore, we found that while studies on drug therapy and adverse effects decreased in the most recent five years, the greatest expansion of insomnia publications were in the areas of cognitive behavioral therapy for insomnia (CBT-I) and alternative therapies. Collectively, insomnia publications present a continuous trend of increase. While sedative and hypnotic drugs dominated the treatment of insomnia, non-pharmacological therapies may have great potential for advancement in future years. Future research effort is warranted for novel tools and clinical trials, especially on insomnia treatments with inadequate evidence or not-yet-clear efficacy and side effects. Copyright © 2014 Elsevier B.V. All rights reserved.
    Sleep Medicine 03/2015; 16(7). DOI:10.1016/j.sleep.2014.12.028 · 3.15 Impact Factor
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    • "However, benzodiazepine receptor agonists is limited by concerns regarding long-term efficacy and the potential for abuse, dependence, and adverse effects [12]. Clinical application of prolonged release melatonin was only recommended treatment of insomnia in the elderly for 3 weeks (1b) [9], and no consistent conclusion could be drawn so far [13]. "
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    ABSTRACT: Background Insomnia is a widespread human health problem, but there currently are the limitations of conventional therapies available. Suanzaoren decoction (SZRD) is a well known classic Chinese herbal prescription for insomnia and has been treating people’s insomnia for more than thousand years. The objective of this study was to evaluate the efficacy and safety of SZRD for insomnia. Methods A systematic literature search was performed for 6 databases up to July of 2012 to identify randomized control trials (RCTs) involving SZRD for insomniac patients. The methodological quality of RCTs was assessed independently using the Cochrane Handbook for Systematic Reviews of Interventions. Results Twelve RCTs with total of 1376 adult participants were identified. The methodological quality of all included trials are no more than 3/8 score. Majority of the RCTs concluded that SZRD was more significantly effective than benzodiazepines for treating insomnia. Despite these positive outcomes, there were many methodological shortcomings in the studies reviewed, including insufficient information about randomization generation and absence of allocation concealment, lack of blinding and no placebo control, absence of intention-to-treat analysis and lack of follow-ups, selective publishing and reporting, and small number of sample sizes. A number of clinical heterogeneity such as diagnosis, intervention, control, and outcome measures were also reviewed. Only 3 trials reported adverse events, whereas the other 9 trials did not provide the safety information. Conclusions Despite the apparent reported positive findings, there is insufficient evidence to support efficacy of SZRD for insomnia due to the poor methodological quality and the small number of trials of the included studies. SZRD seems generally safe, but is insufficient evidence to make conclusions on the safety because fewer studies reported the adverse events. Further large sample-size and well-designed RCTs are needed.
    BMC Complementary and Alternative Medicine 01/2013; 13(1):18. DOI:10.1186/1472-6882-13-18 · 2.02 Impact Factor
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    • "As melatonin is a short-lived molecule having a limited duration of action (half life = 0.54–0.67 h [33]), analogs with a high affinity for melatonin receptors and a longer duration of action have been synthesized with a potential therapeutic efficacy to treat insomnia and psychiatric disorders like depression and bipolar affective disorder [34]. Ramelteon was the first of these molecules approved by the U.S. Food and Drug Administration to be used in the treatment of insomnia [35] and its potential use in AD together with that of melatonin is discussed in this review article. "
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    ABSTRACT: Alzheimer's disease (AD) is an age-associated neurodegenerative disease characterized by the progressive loss of cognitive function, loss of memory and insomnia, and abnormal behavioral signs and symptoms. Among the various theories that have been put forth to explain the pathophysiology of AD, the oxidative stress induced by amyloid β-protein (Aβ) deposition has received great attention. Studies undertaken on postmortem brain samples of AD patients have consistently shown extensive lipid, protein, and DNA oxidation. Presence of abnormal tau protein, mitochondrial dysfunction, and protein hyperphosphorylation all have been demonstrated in neural tissues of AD patients. Moreover, AD patients exhibit severe sleep/wake disturbances and insomnia and these are associated with more rapid cognitive decline and memory impairment. On this basis, the successful management of AD patients requires an ideal drug that besides antagonizing Aβ-induced neurotoxicity could also correct the disturbed sleep-wake rhythm and improve sleep quality. Melatonin is an effective chronobiotic agent and has significant neuroprotective properties preventing Aβ-induced neurotoxic effects in a number of animal experimental models. Since melatonin levels in AD patients are greatly reduced, melatonin replacement has the potential value to be used as a therapeutic agent for treating AD, particularly at the early phases of the disease and especially in those in whom the relevant melatonin receptors are intact. As sleep deprivation has been shown to produce oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, and altered proteosomal processing with abnormal activation of enzymes, treatment of sleep disturbances may be a priority for arresting the progression of AD. In this context the newly introduced melatonin agonist ramelteon can be of much therapeutic value because of its highly selective action on melatonin MT(1)/MT(2) receptors in promoting sleep.
    International Journal of Alzheimer's Disease 12/2010; 2011:741974. DOI:10.4061/2011/741974
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