Beyond the monoaminergic hypothesis: Agomelatine, a new antidepressant with an innovative mechanism of action

There are many potentials for the development of more effective, better tolerated, and more rapidly acting antidepressants. As there is large prevalence of circadian dysfunction in various affective disorders, including depression, one of the approaches is the development of antidepressant drugs with melatonergic agonist properties. Agomelatine, with its melatonergic agonistic (at both MT1 an MT2 receptors) and 5-HT2C antagonistic properties, represents a new concept for the treatment of depression. The antidepressant action of agomelatine has been initially demonstrated in animal models of depression, such as the forced swim - the learned helplessness - and the chronic mild stress paradigms. Subsequent studies demonstrated that the antidepressant activity of agomelatine does not solely depend on its agonistic action at melatonergic receptors, but also on its antagonistic activity at 5-HT2C receptors. Agomelatine also exhibits anxiolytic properties that bear a striking resemblance to those of selective 5-HT2C receptor antagonists. In patients with major depressive disorder, agomelatine had efficacy at least comparable to that seen with available antidepressants. Interestingly, agomelatine demonstrated antidepressant efficacy not only in patients with a moderate depressive episode but also in a more severe depressed subpopulation of patients. The treatment effect increased with the severity of the disease. Agomelatine also rapidly regulates the sleep-wake cycle without causing sedation and improves daytime condition. Agomelatine has an excellent safety profile, is weight neutral, does not affect sexual functioning and does not cause discontinuation syndrome. Collectively, its efficacy, together with its excellent tolerability, makes agomelatine an especially promising antidepressant for the near future.