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Less than half of those suffering major depressive episodes achieve remission with the first antidepressant provided and one-third of all patients suffering depression have a chronic condition. Clinical experience indicates that a substantial proportion of patients suffer treatment-resistant depression (TRD). Our aim is to explore the literature reporting the drug treatment of TRD, and to present such information as would be of interest to clinical psychiatrists. Literature searches were conducted using PubMed and entering the words antidepressant, augmentation, combined antidepressants, treatment resistant depression and the names of individual antidepressant medications. Most authors recommended that TRD should be first approached by reassessing the diagnosis, adding psychotherapy and attending to psychosocial factors. Details of the following pharmacological options were identified: (i) augmentation of the currently employed antidepressant with a medication which is not an antidepressant; (ii) change of antidepressant; and (iii) addition of a second antidepressant to the current antidepressant, or commencement of a combination of two antidepressants. When monotherapy provided at the maximum manufacturer-recommended doses for 3−4 weeks has failed to provide remission in depression, the diagnosis should be confirmed, psychotherapy added and psychosocial factors should receive attention. In the sustained absence of remission, a better outcome may be obtained by augmenting the antidepressant, changing from a single-action to a double- or multiple-action drug, or by combining antidepressants. [ABSTRACT FROM AUTHOR]