Unmet needs in Major depression reflect the properties of a complex and multidimensional disease, where long-term outcome appears unsatisfying. The relapse rate within 12 months is about 35%; about 20% of depressed patients is affected by chronic depression and only 25-30% of patients achieve complete remission. Despite second generation antidepressants were found to be effective, the latency to therapeutic effect, the adverse effects, the management of treatment resistant depression, the poor efficacy on cognitive deficits and somatic symptoms, are critical points in depression treatment. Agomelatine represents an innovative approach to depression treatment, that involves a non-monoaminergic system. The synergism between melatoninergic agonism and 5HT2c antagonism results in a faster onset of therapeutic effect, a specific action on several symptoms (circadian rhythm alterations), a good tolerability, which define the best compliance to treatment, less relapse rates, therefore a better course of disease.