Long-term antidepressant treatment success should be viewed as the result of the cumulative effects of treatment at each stage of major depressive disorder (MDD), and as a balance between efficacy and tolerability/safety. Depression is a heterogeneous disorder and different mechanisms of action of different antidepressants probably capitalize on this response heterogeneity. Results from clinical trials with agomelatine, a melatonergic receptor agonist (MT(1)/MT(2)) and 5HT(2C) receptor antagonist, have shown that it is efficacious in both the acute phase and the continuation phase of treatment of depression. Agomelatine's efficacy is observed in different depressive symptom clusters (core depression symptoms, sleep symptoms, anxiety, retardation, somatic symptoms, and work and activities). Active comparator trials show at least comparable efficacy with other antidepressants (paroxetine, venlafaxine, sertraline, fluoxetine) and efficacy has also been demonstrated in severe depression and in treating anxiety symptoms associated with major depression. The tolerability profile shows some clinically significant advantages especially in the lower incidence of treatment emergent sexual dysfunction and of weight gain, two adverse events experienced by patients as most bothersome. Transient aminotransferase elevations without clinical signs of liver damage have been observed more frequently than with placebo (1.1% versus 0.7%), and a hepatic monitoring schedule is therefore recommended.
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