The clinical properties of the first antidepressant, imipramine, were described already 50 years ago. Almost all antidepressants are noradrenergic, serotonergic and/or dopaminergic. Pharmaceutical companies experience difficulties in the development of drugs, of which the mecanism of action is related to other neuronal systems. Recently, the dual reuptake inhibitor duloxetine, the atypical antipsychotic quetiapine, desvenlafaxine (the main metabolite of venlafaxine) were developed for the treatment of depression. The noradrenergic and dopaminergic bupropion, in combination with other antidepressants, is a promising drug for the treatment of resistant depression. Finally, agomelatine, by its effects on the receptors of melatonin and on the 5-HT2c receptor, presents a unique pharmacological profile.