Only 50% of depressed patients achieve remission of symptoms after 2 trials of antidepressants. Therefore one half of patients are considered treatment resistant. Studies have shown that with each failed antidepressant, chances of remission continue to decline. Untreated depressive symptoms lead to impaired social and occupational function, decline of physical health, suicidal thoughts, and increased health care utilization. Clinicians recognize there is an urgent need to find an efficacious treatment, but it becomes more difficult to decide on an appropriate therapy once a patient has failed 2 to 3 trials of antidepressants. An evidence-based review was performed to assess the efficacy and safety of several different antidepressant strategies to help the clinician decide which may be beneficial for specific patients.