Abstract
BACKGROUND: There is a need to provide up-to-date, clinically translatable data as it relates to the treatment of a major depressive episode (MDE) with mixed features. METHODS: PubMed and OVID were searched from inception to July 22, 2024. Randomized controlled trials (RCTs) investigating the efficacy of pharmacological agents for adults with bipolar disorder (BD) or major depressive disorder (MDD) in an MDE with mixed features were included. Risk of bias was assessed using the Cochrane Risk of Bias Tool for Randomized Studies (RoB2). RESULTS: A total of seven studies were included in this systematic review. The studies identified were all short-term acute studies ranging from 6 to 8 weeks. Treatment with lurasidone, olanzapine, cariprazine, lumateperone, quetiapine, and ziprasidone was associated with statistically significant reduction of depressive symptoms in MDEs with mixed features. Only lumateperone is studied in both BD subtypes [bipolar I disorder (BD-I), bipolar II disorder (BD-II)] and MDD, wherein efficacy in mixed features was the prespecified primary outcome. Lurasidone has a single study in MDD, while ziprasidone has data in a mixed sample of BD-II and MDD. Data for the other agents in mixed features is post hoc. Co-occurring hypomanic symptoms generally improved, and there was no significant difference between the above treatments and placebo with respect to hypomanic symptom severity intensification or treatment-emergent affective switching. CONCLUSION: Select atypical antipsychotics are effective in alleviating depressive symptoms in persons with mixed features; albeit, much of the data is obtained from post hoc analysis. Minimal evidence exists for the efficacy of lithium or valproate in the treatment of depressive episodes with mixed features. Antidepressant monotherapy has not been adequately evaluated in depressive episodes with mixed features. In addition, there is a pressing need for a consistent definition of mixed presentations to guide future interventional studies.