Most antidepressants acting through monoaminergic systems have limitations in efficacy and tolerability and this has led to other approaches to provide patients with adequate treatment.

Agomelatine is an innovative approach to depression as it resynchronizes circadian rhythms, which are disturbed in depressed patients, thanks to its action on the melatonergic MT1 and MT2 receptors, and the 5-HT2C receptors.

The efficacy of agomelatine in depressed patients has been shown in several multicenter, randomized, double-blind parallel-group studies either in comparison with placebo or in 4 head-to-head studies vs an SSRI (sertraline, escitalopram, or fluoxetine in patients with more severe depression) or vs an SNRI (venlafaxine) after 6-8 weeks of treatment.

Agomelatine produced a continuous improvement by significantly reducing all core symptoms of depression. Agomelatine significantly reduced the incidence of relapse in acute responders over a 6-month period (21.7% for agomelatine versus 46.6% for placebo, P = 0.0001), even in the severely depressed patients. Agomelatine was well tolerated in the short and long term.

The pooled analysis of 4 head-to-head comparison studies showed after 6-8 weeks a significant difference in favor of agomelatine vs SSRIs/SNRIs in the HAM-D total score 1.37 (P < 0.001) and for responders (7.21%, P = 0.005). In addition, fewer patients withdrew due to emergent adverse events with agomelatine (6.3%) than with SSRIs/SNRIs (10.5%, P = 0.0058).

Taken together these data indicate that agomelatine is an effective treatment of depression in the short and long term, with a distinctive efficacy and better tolerability than the main current treatments.