Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia

Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, CFP-3, Detroit, MI 48202, USA.
Sleep Medicine (Impact Factor: 3.15). 07/2006; 7(4):312-8. DOI: 10.1016/j.sleep.2006.01.003
Source: PubMed


To assess the efficacy and safety of ramelteon, a selective MT(1)/MT(2) receptor agonist, for chronic insomnia treatment.
Randomized, double-blind, placebo-controlled 35-night outpatient trial with weekly clinic visits at multiple centers. Patients include older adults (>or=65 years; N=829) with chronic insomnia. Placebo, ramelteon 4mg, or ramelteon 8mg were taken nightly for five weeks, and patient-reported sleep data were collected using sleep diaries. Primary efficacy was sleep latency at week 1. Sustained efficacy was examined at weeks 3 and 5. Rebound insomnia and withdrawal effects were evaluated during a 7-day placebo run-out.
Both doses of ramelteon produced statistically significant reductions in sleep latency vs. placebo at week 1 (ramelteon 4mg: 70.2 vs. 78.5min, P=.008; ramelteon 8mg: 70.2 vs. 78.5 min, P=.008). Patients continued to report reduced sleep latency at week 3 with ramelteon 8mg (60.3 vs. 69.3min, P=.003), and at week 5 with ramelteon 4 mg (63.4 vs. 70.6 min, P=.028) and ramelteon 8 mg (57.7 vs. 70.6 min; P<.001). Statistically significant increases in total sleep time were observed with ramelteon 4 mg at week 1 (324.6 vs. 313.9 min, P=.004) and week 3 (336.0 vs. 324.3min, P=.007) compared with placebo. There was no evidence of significant rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was similar among all treatment groups; most were mild or moderate.
In older adults with chronic insomnia, ramelteon significantly reduced patient reports of sleep latency over five weeks of treatment with no significant rebound insomnia or withdrawal effects.

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    • "Of the synthesized ligands of melatonin receptors [100], agomelatine for the treatment of depression [101], ramelteon for the treatment of primary chronic insomnia characterized by difficulty with sleep onset [102], and tasimelteon for transient insomnia in circadian rhythm sleep disorders [103] are the three clinically important agents. Agomelatine especially represents a new concept for the treatment of depression [104]. "
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    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
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    • "In addition ramelteon did not produce any memory, cognitive (Erman et al. 2006; Roth et al. 2007) or psychomotor impairment (Erman et al. 2006; Roth et al. 2005; Roth et al. 2007; Zammit 2007) and in general did not differ from placebo. Furthermore, it did not produce any next day hangover effects or discontinuation related rebound insomnia or withdrawal symptoms (Johnson et al. 2006; Roth et al. 2006; Mayer et al. 2009). "
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    ABSTRACT: Current pharmacological treatment of insomnia involves the use of sedative-hypnotic benzodiazepine and non-benzodiazepine drugs. Although benzodiazepines improve sleep, their multiple adverse effects hamper their application. Adverse effects include impairment of memory and cognitive functions, next-day hangover and dependence. Non-benzodiazepines are effective for initiating sleep but are not as effective as benzodiazepines for improving sleep quality or efficiency. Furthermore, their prolonged use produces adverse effects similar to those observed with benzodiazepines. Inasmuch as insomnia may be associated with decreased nocturnal melatonin, administration of melatonin is a strategy that has been increasingly used for treating insomnia. Melatonin can be effective for improving sleep quality without the adverse effects associated with hypnotic-sedatives. Ramelteon, a synthetic analog of melatonin which has a longer half life and a stronger affinity for MT1 and MT2 melatonergic receptors, has been reportedly effective for initiating and improving sleep in both adult and elderly insomniacs without showing hangover, dependence, or cognitive impairment. Insomnia is also a major complaint among patients suffering from depressive disorders and is often aggravated by conventional antidepressants especially the specific serotonin reuptake inhibitors. The novel antidepressant agomelatine, a dual action agent with affinity for melatonin MT1 and MT2 receptors and 5-HT2c antagonistic properties, constitutes a new approach to the treatment of major depressive disorders. Agomelatine ameliorates the symptoms of depression and improves the quality and efficiency of sleep. Taken together, the evidence indicates that MT1/MT2 receptor agonists like ramelteon or agomelatine may be valuable pharmacological tools for insomnia and for depression-associated insomnia.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2011; 35(4):913-23. DOI:10.1016/j.pnpbp.2011.03.013 · 3.69 Impact Factor
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    • "Concerning the safety and adverse effects with ramelteon, in a double blind placebo controlled study of rebound insomnia (sleep latency after treatment discontinuation) Roth and co-workers [143] evaluated each of the 7 nights of placebo run-out period. It was noted that during each of the 7 nights, patients in both ramelteon treatment groups (4 mg/day and 8 mg/day) maintained a similar or greater reduction in sleep latency from baseline as compared to those receiving placebo [143]. Withdrawal effects, as assessed by a BZP withdrawal symptom questionnaire, did not differ from the placebo group [143]. "
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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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