The mainstay of treatment for major depressive disorder has been antidepressant monotherapy or, preferably, the combination of psychotherapy and antidepressants. However, combining antidepressant agents as a first-line treatment is an emerging area of research that is not yet widely practiced. Factors for choosing an antidepressant include indication, efficacy, tolerability, and safety. Patient preference and treatment history should also be considered when deciding which initial treatment approach is appropriate.