Treatment resistance is frequently encountered during the long-term care of patients with major depression. A number of 'next step' therapeutic options exist in such cases, including switching to an alternative antidepressant, combining antidepressants from different pharmacological classes, adding evidence-supported psychotherapies to ongoing antidepressant treatment and augmentation with a nonantidepressant drug. Augmenting antidepressants with atypical antipsychotic drugs has generated considerable clinical interest. Three atypical antipsychotics (aripiprazole, quetiapine and olanzapine) have received regulatory approval for adjunctive use with antidepressants for treatment-resistant major depression (TRD) in adults. Symbyax® (olanzapine-fluoxetine combination or OFC), the combination of olanzapine and the selective serotonin-reuptake inhibitor fluoxetine, is also approved for this indication. The short-term effectiveness of OFC for TRD is supported by results of five published randomized, controlled, acute-phase studies of generally similar design. In each study, OFC was associated with rapid reduction in depressive symptoms. In two studies, significantly greater improvement in depressive symptoms occurred in OFC-treated patients at study end point compared with those who received antidepressant monotherapy. These effects appeared to be strongest in cases where antidepressant failure was established during the current depressive episode. Although OFC was well-tolerated, increases in body weight and prolactin concentration were greater with OFC than antidepressant monotherapy, and were similar to olanzapine monotherapy. Increases in random total cholesterol levels were greatest for OFC, and were significantly greater than those of olanzapine and antidepressant monotherapy. The long-term efficacy and tolerability of OFC for TRD has not been investigated, and the comparative effectiveness of OFC versus other next-step options is unknown. As such, the exact place of OFC among the available therapeutic options for TRD is not fully understood at this time. © 2010 Expert Reviews Ltd.