Aripiprazole, an oral quinolinone, is the first atypical antipsychotic agent to be approved in the US as adjunctive treatment in adult patients with major depressive disorder (MDD). In two large, well-designed trials in patients with MDD who had an inadequate response to standard antidepressant therapy, 6 weeks' adjunctive therapy with aripiprazole 2-20 mg/day improved mean Montgomery Asberg Depression Rating Scale (MADRS) total scores (primary endpoint) to a significantly greater extent than adjunctive placebo treatment. Improvements in mean MADRS total score during the double-blind phase favoured adjunctive aripiprazole treatment from 1-2 weeks onward, with per-protocol subgroup analyses showing that mean changes were not affected by the specific standard antidepressant therapy used, age or sex of the patient or the mean MADRS total scores at the start of double-blind adjunctive therapy. In general, secondary endpoint scores, including those for the Sheehan Disability Scale, Clinical Global Impression (CGI) Improvement scale and CGI Severity of Illness scale, improved to a significantly greater extent with adjunctive aripiprazole than with adjunctive placebo treatment, with significantly higher response and remission rates in the aripiprazole groups. In these two pivotal trials, adjunctive aripiprazole 2-20 mg/day was generally well tolerated, with most treatment-emergent adverse events being of mild to moderate severity.