Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia
ABSTRACT 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.
- SourceAvailable from: Jun Kohyama[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 · 2.35 Impact Factor
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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 · 4.03 Impact Factor
Article: Sleep health and asynchronization[Show abstract] [Hide abstract]
ABSTRACT: Recent surveys in Japan reported that more than half of children interviewed complained of daytime sleepiness, approximately one quarter reported insomnia, and some complained of both nocturnal insomnia and daytime sleepiness. To explain the pathophysiology of this type of sleep disturbance, a novel clinical concept of asynchronization has been proposed. Asynchronization involves disturbances in various aspects of biological rhythms that normally exhibit circadian oscillations. The putative major triggers for asynchronization include a combination of nighttime light exposure, which can disturb the biological clock and decrease melatonin secretion, and a lack of morning light exposure, which can prohibit normal synchronization of the biological clock to a 24-h cycle and decrease activity in the serotonergic system. The early phase of asynchronization may be caused by inadequate sleep hygiene, is likely to be functional, and to be relatively easily resolved by establishing a regular sleep-wakefulness cycle. However, without adequate intervention, these disturbances may gradually worsen, resulting into the chronic phase. No single symptom appears to be specific for the clinical phases, and the chronic phase is defined in terms of the response to interventions. The factors causing the transition from the early to chronic phase of asynchronization and those producing the difficulties of recovering patients with the chronic phase of asynchronization are currently unclear.Brain & development 10/2010; 33(3):252-9. DOI:10.1016/j.braindev.2010.09.006 · 1.54 Impact Factor