<p><b>Objective.</b> To study the efficacy and safety of Cortexin as an additional therapy in patients with depressive disorder. <b>Materials and methods.</b> The study involved 98 patients (56 women and 42 men, mean age 44.0 (36.0; 52.0) years), who were divided into two groups: Group 1 (<i>n</i> = 48) received basic antidepressant treatment along with i.m. Cortexin at a dose of 10 mg once a day (in the morning) for 10 days; Group 2 (<i>n</i> = 50) received basic antidepressant treatment alone. Over the course of three visits (baseline and days 14 and 28), the severity of depression and changes in severity during therapy were analyzed on the Montgomery–Åsberg Depression Rating Scale (MADRS), social functioning was assessed on the Social Adjustment Scale (SASS), treatment efficacy was followed on the CGI scale with assessment of changes in condition at treatment weeks 2 and 4, and adverse events were recorded using the Udvalg for Kliniske Undersøgelser (UKU) scale. <b>Results.</b> At visit 2, there was a significant decrease in the severity of depression (MADRS scale), along with an improvement in the quality of life of patients with depressive disorder (SASS scale) and a decrease in adverse events (UKU scale), with significant between-group differences (<i>p</i> = 0.001). At the end of the study, a significantly higher proportion of patients in the study group rated the improvement from therapy as “significant” or “substantial” (<i>p</i> = 0.001). <b>Conclusions.</b> The use of Cortexin as an adjunctive therapy in patients with depressive disorder was effective and safe. Combination therapy with antidepressants and Cortexin was superior to antidepressant monotherapy in terms of therapeutic response and health-related quality of life. A more favorable safety profile was also demonstrated with the combined use of antidepressants and Cortexin.</p>