What are the clinical implications of mixed features in major depressive disorder? A VAST-D report

Mixed manic/hypomanic symptoms commonly occur in major depressive disorder (MDD), yet their prognostic and therapeutic significance following inadequate response to monoaminergic treatment remains uncertain. This secondary analysis of the Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) trial examined the prevalence, clinical correlates, and treatment implications of mixed features in 1522 nonbipolar outpatients with insufficient benefit from at least one prior monoaminergic agent.

To explore the prevalence, clinical correlates, and potential treatment implications of mixed features among patients with antidepressant-nonresponsive MDD.

Participants were randomized to switching to bupropion sustained release (S-BUP), combining their current monoaminergic agent with bupropion sustained release (C-BUP), or augmenting treatment with aripiprazole (A-ARI). Mixed features were categorized into five exploratory, non-Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) levels based on the number and intensity of manic/hypomanic symptoms.

Overall, 76.5% of participants endorsed at least one manic/hypomanic symptom occurring "a little" or "a lot," and 10.2% endorsed more than two symptoms occurring "a lot." Higher mixed-feature levels were associated with greater depressive severity, functional impairment, and recurrent depressive episodes. Mixed features were not associated with treatment retention, response, or suicidal ideation. However, remission rates declined progressively across mixed-feature levels in the S-BUP group, a pattern not observed in the C-BUP or A-ARI groups.

Mixed features were highly prevalent and associated with greater clinical burden. Assessment of mixed features may provide clinically relevant information when selecting next-step pharmacologic strategies, particularly when considering a switch to bupropion sustained release.