Pharmacological profile of antidepressants: a likely basis for their efficacy and side effects?

SummaryMost antidepressant drugs act not only on molecular targets directly responsible for their expected therapeutic action (monoamine transporters, monoamine oxidase A, presynaptic inhibitory auto and hetero-receptors), but also on secondary targets at the origin of side effects. In particular, tricyclic antidepressants, which inhibit serotonin and/or noradrenaline reuptake, are most often endowed with antagonist properties at histamine H1, muscarinic and α1-adrenergic receptors, thereby causing sedation, body weight gain, constipation, memory disorders, orthostatic hypotension, etc. The selective monoamine reuptake inhibitors are better tolerated because they are generally devoid of such secondary effects. However, through the indirect promotion of serotonin action at specific receptors, they unavoidably produce some gastrointestinal, sleep and sexual disorders. Agomelatine markedly differs from other classes of antidepressant drugs: its primary molecular targets in vivo are the melatonin MT1 and MT2 receptors, where it acts as a potent agonist, and the 5-HT2c receptors, where it exerts clear-cut antagonist properties. The unique pharmacological profile of agomelatine explains its antidepressant efficacy and good tolerability.