Melatonin, insomnia and the use of melatonergic drugs

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT1 and MT2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon’s use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders

Melatonergic Drugs for Therapeutic Use in Insomnia and Sleep Disturbances of Mood Disorders

Insomnia is common among elderly people and nearly 30 to 40% of the adult population also suffer from insomnia. Pharmacological treatment of insomnia include the use of benzodiazepine and non-benzodiazepine drugs like zolpidem, zaleplon,Zopiclone. Although these drugs improve sleep ,their usage is also associated with number of adverse effects, Melatonin ,the hormone secreted by the pineal gland of all animals and human beings has been used for treatment of insomnias,since the timing of its secretion in humans as well as in most of the animals coincides with the increase of nocturnal sleep propensity.Because of its short half life,melatonin slow release preparations were introduced for treatment of insomnia. Recently ramelteon ,a selective MT1,MT2 receptor agonist with greater efficacy of action in treating insomnia has been used clinically and has been found effective in improving sleep quality ,sleep efficacy and also in reducing the sleep onset time when compared to melatonin or slow melatonin preparations.The mechanism of action of ramelteon in improving sleep is discussed in the paper. Another melatonergic drug agomelatine besides acting on MT1/MT2 receptors also displays 5-HT2c antagonism and this drug has been found effective as a novel antidepressant for treating major depressive disorders.Agomelatine besides causing remission of depressive symptoms also improves sleep quality and efficiency. Other antidepressants depressants that are in clinical use today do not improve sleep. There are other melatonergic drugs like tasimelteon ,6-chloromelatonin.But ramelteon and agomelatine deserve special attention for treatment of insomnia and sleep disturbances associated with depressive disorders and have promising role for treatment of sleep disorders

Melatonin, insomnia and the use of melatonergic drugs

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on thedevelopment of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT1 and MT2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon’s use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders

Melatonin in Mitochondrial Dysfunction and Related Disorders

Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R), septic shock, and neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R

Sleep, mood disorders and antidepressants: the melatonergic antidepressant agomelatine offers a new strategy for treatment

Insomnia often precedes the appearance of mood changes. While the presence of disturbed sleep prior to the onset of depressed mood is useful prognostically, the ultimate co-occurrence of these symptoms can pose a considerable challenge for pharmaceutical therapy. Most currently used antidepressants (tricyclics, monoamine oxidase inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin receptor-2 antagonist/serotonin reuptake inhibitors, selective serotonin reuptake inhibitors) are effective antidepressants but they have the disadvantage that often aggravate sleep disturbances. An ideal antidepressant should address both problems: such an antidepressant should exert a rapid onset of action both on depressive symptomatology as well on sleep problems. The recently introduced novel antidepressant agomelatine has melatonergic agonist and 5-HT2C antagonistic properties, and has been found effective in improving both depressive mood and sleep disturbances. Its mechanism of action differs from the currently used antidepressants. It thus represents a possible first line drug for treatment of mood disorders such as major depressive disorder, bipolar disorder and seasonal affective disorder. This review summarises what is known about the clinical efficacy and mechanism of action of agomelatine and compares these findings with those of currently available antidepressants.Fil: Srinivasan, Venkatramanujam. No especifíca;Fil: Brzezinski, Amnon. No especifíca;Fil: Spence Warren, D.. No especifíca;Fil: Pandi Perumal, Seithikurippu R.. No especifíca;Fil: Hardeland, Rüdiger. No especifíca;Fil: Brown, Gregory M.. No especifíca;Fil: Cardinali, Daniel Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Pharmacotherapy of Insomnia with Ramelteon: Safety, Efficacy and Clinical Applications

Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT1 and MT2 melatonin receptors. Ramelteon is the first melatonin receptor agonist approved by the Food and Drug Administration (FDA) for the treatment of insomnia characterized by sleep onset difficulties. Ramelteon is both a chronobiotic and a hypnotic that has been shown to promote sleep initiation and maintenance in various preclinical and in clinical trials. The efficacy and safety of ramelteon in patients with chronic insomnia was initially confirmed in short-term placebo-controlled trials. These showed little evidence of next-day residual effects, withdrawal symptoms or rebound insomnia. Other studies indicated that ramelteon lacked abuse potential and had a minimal risk of producing dependence or adverse effects on cognitive or psychomotor performance. A 6-month placebo-controlled international study and a 1-year open-label study in the USA demonstrated that ramelteon was effective and well tolerated. Other potential off-label uses of ramelteon include circadian rhythm sleep disorders such as shift-work and jet lag. At the present time the drug should be cautiously prescribed for short-term treatment only

Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection

Sleep disorders constitute major nonmotor features of Parkinson’s disease (PD) that have a substantial effect on patients’ quality of life and can be related to the progression of the neurodegenerative disease. They can also serve as preclinical markers for PD, as it is the case for rapid eye movement (REM)-associated sleep behavior disorder (RBD). Although the etiology of sleep disorders in PD remains undefined, the assessment of the components of the circadian system, including melatonin secretion, could give therapeutically valuable insight on their pathophysiopathology. Melatonin is a regulator of the sleep/wake cycle and also acts as an effective antioxidant and mitochondrial function protector. A reduction in the expression of melatonin MT1 and MT2 receptors has been documented in the substantia nigra of PD patients. The efficacy of melatonin for preventing neuronal cell death and for ameliorating PD symptoms has been demonstrated in animal models of PD employing neurotoxins. A small number of controlled trials indicate that melatonin is useful in treating disturbed sleep in PD, in particular RBD. Whether melatonin and the recently developed melatonergic agents (ramelteon, tasimelteon, agomelatine) have therapeutic potential in PD is also discussed