The World Health Organization estimates that depression is the fourth leading cause of disability worldwide with a lifetime prevalence of ∼15% to 20%. While the antidepressants currently on the market will be effective in most patients, a significant number of patients will experience residual symptoms, treatment-resistance, and relapse. The recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study has shed some light on the reality of antidepressant treatment. At first, only one-third of patients on citalopram monotherapy remitted. The other two-thirds who failed to remit saw their likelihood of remission decrease with each successive trial of another antidepressant monotherapy. Thus, after four successive monotherapies were tried over the course of one year, (ie, after four treatments each lasting 12 weeks), only two-thirds of patients achieved remission (Figure 1). Besides this poor prognosis, the patients who required more treatment cycles to get better also had a higher likelihood of relapsing. Once patients reach that point, they are considered treatment-resistant.