Rationale and Problems of Melatonergic Treatment

Melatonergic treatment can be successful under conditions of (i) decreased melatonin levels caused by aging and various diseases, (ii) circadian perturbations or dysfunction, including mood disorders with an etiology of circadian malfunction, (iii) sleep difficulties, and (iv) some metabolic disorders concerning energy metabolism and insulin resistance. In addition to melatonin, which is available as immediate- and prolonged-release formulations, several synthetic melatonergic drugs have been developed. Properties of melatonin are compared with those of β-methyl-6-chloromelatonin (TIK-301), piromelatine, agomelatine, ramelteon, GR 196429 and tasimelteon. The article emphasizes the necessity of distinguishing between promising approaches based on short but repeated actions and others aiming at a substitution therapy, which is not easily achieved. Short actions on sleep initiation and circadian phase shifting are already successful with low doses of melatonin. Such a chronobiotic approach may be also possible in bipolar and seasonal affective disorders. Longer actions are required for promoting sleep maintenance. Prolonged-release melatonin and agonists having a longer half-life in the circulation can be used, however, with a moderate outcome. Direct antidepressant actions are observed with compounds combining properties of melatonergic agonists and 5-HT2C serotonergic antagonists. Moreover, agonists that may be suitable for improving metabolic disorders including insulin resistance are discussed.