Asenapine (Saphris) surprised in this analysis
A third of bipolar depressions carry mixed features, and a few antipsychotics have the best evidence
STUDY: Fornaro M et al, Journal of Affective Disorders 2026
STUDY TYPE: Systematic review and network meta-analysis
FUNDING: Independent
Background
Mixed features show up in about 18% of major depressive episodes and 33% of bipolar depressions. They bring more suicidality, substance use, and switching on antidepressants. Guidelines favor second-generation antipsychotics, and this network analysis estimates their relative efficacy.
The Study
- 35 randomized trials: 22 in bipolar depression (5,241 patients) and 13 in major depressive disorder (about 1,800 patients), including 3 pediatric trials.
Results
In bipolar depression with mixed features, these beat placebo on depression scores:
- Lurasidone 60 to 80 mg (effect size 0.4)
- Asenapine 15 mg (effect size 0.5)
Cariprazine 1.5 to 3 mg, lurasidone 80 mg, olanzapine 12.5 mg, and olanzapine-fluoxetine raised response rates. Lurasidone also helped children and adolescents.
Quetiapine led to more dropouts.
In major depressive disorder with mixed features, lurasidone 40 mg showed a large effect (0.8), and lumateperone 42 mg raised response by 61%.
Limitations
Network meta-analyses assume that all trials are similar, so this study highlights effective meds but can barely estimate their differences.
Lower-quality trials reported bigger effects. The bipolar results varied widely from trial to trial, and most major depression data came from post hoc analyses of trials not designed for mixed features.
Practice Implications
- Lurasidone has the most consistent evidence across both diagnoses and ages, with cariprazine and lumateperone close behind.
- Lithium can also work here, but most trials on mixed features launched after DSM5 (2013), in the antipsychotic funded era.
- Mixed features can look like many other psych disorders. Learn how to recognize them.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
