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This column is the third in a series that began in January, 2009 on the improved understanding of and ability to treat patients with major depression. This column focuses on options for the patient who has not benefitted from one or more adequate trials of currently available antidepressants. It begins with a summary of the results of the switching and augmentation strategies studied in the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, funded by the National Institute of Mental Health (NIMH). The column then discusses options not included in the STAR*D study, including aripiprazole, which is now the first medication approved by the U.S. Food and Drug Administration (FDA) as adjunctive therapy for the treatment of patients with clinical depression, and vagus nerve stimulation, delivered by the first implantable device approved by the FDA for the treatment of patients with treatment-resistant depression (TRD). The goal of this column to summarize the data supporting various options for the busy clinician who treats such patients.