Exogenous melatonin has shown some positive treatment effects on the symptoms of depressive disorders, but its monotherapeutic effect in humans does not appear to be robust. However, augmentation strategies in which melatonin is added to antidepressants do show some promise.27 Agomelatine, an agent with effects on both the melatonergic (MT1, MT2) and serotonergic (serotonin-2C and to some degree serotonin-2B) systems, is a novel antidepressant that may address both circadian rhythm disruption and depressive symptom constellations. Theoretically, these effects make this agent a more tolerable and effective antidepressant.29 Unfortunately, it has not received FDA approval and is only available in Europe and Australia.
Numerous trials of agomelatine at doses of 25 to 50 mg have shown antidepressant effects superior to those of placebo and efficacy equal to or greater than that of currently effective antidepressants.30-34 Relapse prevention over 6 months has also been shown with agomelatine, although these results have been mixed.35,36 Agomelatine also appears to be safe and tolerable in the short term, with an overall adverse-effect profile that is comparable to that of placebo.30
Compared with placebo and venlafaxine, agomelatine has been found to promote beneficial changes in sleep architecture and overall sleep stability, with fewer problems of next day sedation.33,34,37-39 The improvement in sleep appears to precede the antidepressant effect, which suggests that the sleep improvement may be related to efficacy of the antidepressant. Agomelatine may also be beneficial in bipolar depression.40 In addition, agomelatine has demonstrated a circadian phase advance in healthy volunteers as well as correction of independent circadian rhythm disturbances in depressed patients and seasonally depressed patients, who are prone to circadian rhythm disruption.31,41,42
Overall, agomelatine is thought to have a balanced dual action. It promotes sleep at night with its melatonergic effects and alertness during the day with its serotonergic effects. Although data have been mixed, the number of positive results for agomelatine in the domains of antidepressant effect, sleep improvement, and regulation of the circadian rhythm speaks to the benefit of melatonin and its receptor agonists in sleep, circadian rhythm, and mood difficulties.
Melatonin and its receptor agonists have been shown to be safe in the short term.6 Trials up to 6 months showed no significant change in major safety parameters for controlled-release melatonin, ramelteon, and agomelatine.9,18,35 Controlled long-term data do not exist, but case reports indicate that numerous people have taken melatonin for years without any deleterious effects.43 Nonetheless, next day sedation and an increase in vivid dreams or nightmares are often seen clinically with melatonin.
It is possible that other hormone levels may also be disrupted. A rise in prolactin level and a decrease in follicle-stimulating hormone level have been seen, but there have been no changes in luteinizing hormone and thyroid-stimulating hormone levels and in orthostatic blood pressure.44 Although not formally recommended, melatonin is widely used clinically in children. Data show that it may have beneficial effects on insomnia in children with developmental delay, autism, and ADHD.26,42 The safety of melatonin in pregnancy is unknown.
No weight gain has been seen with melatonin treatment. In fact, melatonin appears to have significant cytoprotective properties that prevent metabolic syndrome sequelae in animal models as well as beneficial effects on thrombus growth, cholesterol levels, and blood pressure in humans. Given the well-known high rates of metabolic syndrome and its sequelae in major mental illness, this property of melatonin is one of its many intriguing benefits.
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