Successful management of major depressive disorder (MDD) requires antidepressant efficacy at each stage of treatment: rapid improvement of the symptoms in the acute phase, good quality remission in the continuation phase, leading to complete recovery in the maintenance phase. The early improvement of symptoms during the acute phase is predictive of chances of remission, as well as better long-term compliance and reduced risk of suicide.

Agomelatine is the first melatonergic antidepressant acting as a melatonergic MT1 and MT2 receptor agonist and as a 5-HT2C receptor antagonist. Its efficacy in the acute phase of treatment was examined in 4 short-term studies: 1) two 6-week, randomized, double-blind studies comparing agomelatine (25-50 mg/d) with venlafaxine (75-150 mg/d), (2) a 6-week comparison study of agomelatine (25-50 mg/d) with sertraline (50-100 mg/d), and (3) an 8-week comparison with fluoxetine (20-40 mg/d) in patients with severe depression.

After 1 week of treatment, agomelatine was significantly more effective than venlafaxine on the following parameters: CGI-I (total score and response rate), daytime alertness, feeling good, getting to sleep, and quality of sleep. After 2 weeks, using HAM-D, there were twice as many responders to agomelatine as to sertraline. After 6 weeks of treatment, these differences in favor of agomelatine were maintained. After 8 weeks, agomelatine showed superior antidepressant efficacy on HAM-D total score and CGI-I over fluoxetine in treating patients with severe episodes. These convergent results make agomelatine a promising antidepressant for improving all stages of MDD and ultimately helping more patients to achieve complete and sustained remission.