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In this article, we review the literature defining treatment-resistant depression and pharmacological strategies to manage these difficult and challenging clinical cases. Augmentation strategies reviewed in this paper are limited and include the classic and very well-established antidepressant-augmenters such as lithium and thyroid, in addition to the newer use of pindolol and tryptophan. We also present possible clinical variables which may be complicating the choice, administration and monitoring safely and effectively during switching and augmenting antidepressant drugs.