Depression and the complications of its pharmacotherapy remain relevant issues in modern medicine. Since the advent of the first antidepressants, more than 60 years ago, to the present, their arsenal has expanded significantly. On the one hand, the emergence of new antidepressants is a great achievement in psychopharmacology, and on the other hand, due to their specificity, antidepressants cause many complications. In addition, in recent years, the list of diseases in which off label (outside the instructions) use these drugs has expanded significantly, and given the fact that for these diseases, anti-depressants are prescribed in combination with other drugs, so the risk of developing side effects increases significantly . This article analyzes the frequently encountered side effects of antidepressants, the mechanisms of their occurrence when using both first-generation antidepressants (three and tetracyclic antidepressants, monoamine oxidase inhibitors) and newer drugs from the group of selective serotonin reuptake inhibitors. The conditions for the rational use of antidepressants are also presented, which allows to optimize their use and the safety of pharmacotherapy for depression. Thus, today it is necessary to create new safer antidepressants that selectively inhibit the reuptake of one of monoamines (for example, serotonin) and third-generation drugs with a “double” effect, i. e. selectively and equipotentially inhibiting the reuptake of serotonin and norepinephrine.