Pharmacotherapy and psychotherapy, separately or in combination, have been used successfully in the treatment of depression. Recent studies have compared the two modes of treatment and their combination with respect to relative efficacy and have found psychotherapy, alone or combined with medication, to be the preferential treatment approach for depressive disorders. However, the adequacy of pharmacotherapy administered in these trials remains in question. The last decade's major comparative studies are systematically reviewed in order to evaluate the nature and specifics of pharmacotherapy. Special emphasis is placed on essential requirements of pharmacotherapy, methods of treating refractory cases, and details of treatment provision. Most of the studies used inadequate antidepressant doses, did not measure tricyclic plasma concentrations systematically, neglected the use of accepted strategies for response enhancement in refractory cases, and at times provided pharmacotherapy in nonspecialized settings or by inexperienced physicians. Findings indicate that pharmacotherapy administered in these studies does not fulfill requirements for adequacy and thereby precludes any definite conclusions regarding relative efficacy. The authors propose the term "optimization" of treatment to reflect maximized pharmacotherapy, discuss its essential requirements, and submit that such optimization be assured in future comparative trials.