<p>The search for potential biomarkers to improve differential diagnosis and improve its accuracy is one of the primary tasks of modern psychiatry. In actual clinical practice, distinguishing bipolar affective disorder (BAD) from unipolar (clinical) depression is often difficult. There are a large number of animal models imitating depression-like behavior, while the study of the BAD pathogenesis mechanisms is complicated by the almost complete absence of experimental models that adequately mimic both the manic and depressive phases of this disorder. Today, there is no doubt about the involvement of the monoamine serotonin (5-HT) system in the pathophysiology of both unipolar and bipolar depression. The similarity of the clinical picture of the depressive episode of BAD and unipolar depression suggests common mechanisms, while the presence of the manic episode of BAD, on the contrary, implies opposite changes, including in the level of central 5‑HT signal transduction. However, given the sufficient study of the 5-HT system role in the pathogenesis of clinical depression and its successful correction by selective serotonin reuptake inhibitors (SSRIs), the significance of its involvement in the processes of BAD manifestation, as well as in the mechanisms of “phase switches”, remains a debatable issue. The aim of this review was to compare the pathogenesis of uni- and bipolar depression (including depressive and manic episodes) and the diversity of their experimental models, as well as to analyze the contribution of key elements of the 5-HT system (5-HT, its precursors and main metabolites, 5-HT1A autoreceptor, 5-HT transporter, 5-HTT/SERT) into the pathophysiology of disorders.</p>