Agomelatine: innovative pharmacological approach in depression

Currently available antidepressant agents such as tricyclic antidepressants (TCAs) act primarily through monoaminergic systems in the brain, and have proved to be suboptimal for the management of major depressive disorder (MDD). Such agents are also active at non-target receptor sites, contributing to the development of often serious adverse events. Even the newer selective serotonin reuptake inhibitors (SSRIs), which also act through monoaminergic systems, have suboptimal antidepressant efficacy, and the adverse events that do occur often negatively influence adherence. Although the pathophysiology of depression is not completely understood, it is increasingly recognized that monoamine deficiency/disruption is not the only pathway involved. Recognition that circadian rhythm desynchronization also plays a key role in mood disorders has led to the development of agomelatine, which is endowed with a novel mechanism of action distinct from that of currently available antidepressants. Agomelatine is an agonist of the melatonergic MT(1) and MT(2) receptors, as well as a 5-HT(2C) receptor antagonist. The antidepressant activity of agomelatine is proposed to stem from the synergy between these sets of receptors, which are key components of the circadian timing system. Agomelatine has shown antidepressant-like activity in a number of animal models of depression, such as the learned helplessness model, the chronic mild stress model, the forced swim test and the chronic psychosocial stress test. Moreover, agomelatine has been found to restore normal circadian rhythms in animal models of a disrupted circadian system, and has proved beneficial in an animal model of delayed sleep phase syndrome. Likewise, it has been shown to improve disturbed sleep-wake rhythms in depressed patients. Moreover, current pharmacological and clinical data strongly support the use of agomelatine in the management of MDD.