Pharmacology of a New Antidepressant: Benefit of the Implication of the Melatonergic System

The limitations of current antidepressant medications merit the exploration of alternative agents with novel antidepressant mechanisms of action. The established clinical finding that desynchronization of internal rhythms plays an important role in the pathophysiology of depressive disorders has stimulated the idea that resetting normal circadian rhythms may have antidepressant potential. Recent experiments using the novel melatonin receptor agonist and serotonin 2 (5-HT2c) receptor antagonist agomelatine (S20098; N[2-(7-methoxy-1-naphthyl)ethyl]- acetamide) revealed a notable chronobiotic activity and clear antidepressant-like effects in a variety of preclinical models. Binding studies performed in vitro proved that agomelatine is a high-affinity agonist at both the melatonin MT1 and MT2 receptor types. In addition, these studies revealed that agomelatine, in contrast to melatonin, blocks 5-HT2c receptors with significant affinity. Antagonism of 5-HT2c receptors is reported for various established antidepressant compounds. The antidepressant properties of agomelatine are thus based on its melatonergic actions and 5-HT2c receptor antagonism.