The Food and Drug Administration (FDA) has not approved any antidepressant for the treatment of bipolar depression. To date, the only antidepressant drug that showed evidence of efficacy in bipolar depression is fluoxetine but only when given combined with olanzapine, which allowed the FDA, but not the EMEA (European Medicines Agency), to approve a fixed dose olanzapine-fluoxetine combination for the treatment of acute bipolar I depression. Quetiapine monotherapy is at present the only both FDA- and EMEA-approved treatment for bipolar depression. In a recent metanalysis on treatment options for bipolar depression, quetiapine and the olanzapine-fluoxetine combination showed the greatest symptomatic improvements.

Aripiprazole showed a 6-week limited superiority compared to placebo, decreasing its effect size at endpoint. The very early onset of action of all tested atypical antipsychotics in the treatment of bipolar depression, even as monotherapy, may highlight an overlapping mechanism of action of these drugs as a potential class effect with independence of the monoaminergic pathways. Results suggest some atypical antipsychotics (quetiapine and olanzapine) may be considered as first line management option in acute bipolar I and/or II depression, even for poor responders subgruoups such as rapid cyclers and patients with psychotic feature.