The pharmacotherapeutic approach to the treatment of major depression consists in giving an optimal dose of an antidepressant medication for a sufficient time. Using this conventional strategy in standard medication trials, approximately half the patients present a response, defined as a 50% improvement, but only about 30-40% generally achieves remission. This is a poor treatment outcome and these numbers have been questioned the patient population tested may be different from those in regular ambulatory conditions. The STAR*D project addressed the latter concern by treating patients all comers, including patients with physical and psychiatric co-morbidities, first with a SSRI and then with switch and combination approaches. Not covered in STAR*D was the strategy of adding an atypical antipsychotic in SSRI-resistant patients. Finally, a novel strategy consists in using two antidepressant medications from treatment initiation.