Treatment of depressive episodes with mixed features: A systematic review and meta-analysis

Depressive episodes with concurrent manic or hypomanic symptoms-i.e., depressive episodes with mixed features-are common in bipolar disorder and are associated with greater chronicity, functional impairment, and suicide risk. However, treatment guidance remains limited and inconsistent.

To systematically review and perform a stratified meta-analysis of pharmacological and non-pharmacological interventions for depressive episodes with mixed features, distinguishing randomized controlled trials (RCTs) from non-RCTs and assessing risk of bias.

A systematic review was conducted in accordance with the PRISMA 2020 guidelines. MEDLINE, CINAHL Complete, Epistemonikos, and ClinicalTrials.gov were systematically searched between July and November 2024 without language restrictions (PROSPERO CRD42025644083). Eligible studies included adults with bipolar depression and mixed features. Two reviewers independently screened, extracted data, and assessed bias. Standardized mean differences (SMD, Hedges' g) were pooled using random-effects models with Hartung-Knapp adjustment. RCTs were not combined with non-RCTs.

Twenty-two studies (n = 3525) met inclusion: five parallel RCTs, one crossover RCT, five pooled analyses, nine post-hoc studies, and two quasi-experimental designs. Among RCTs, antipsychotic treatments demonstrated efficacy with low heterogeneity (pooled SMD -0.70; I² = 0.0 %). Single RCTs of lurasidone (SMD -0.80) and ziprasidone (SMD -0.70) showed improvement versus placebo; lumateperone yielded a moderate effect (SMD -0.64). Celecoxib and theta-burst stimulation were not superior to placebo. Non-RCTs of antipsychotics showed smaller effects with substantial heterogeneity (SMD -0.55; I² = 81.7 %).

Limited but consistent RCT evidence supports lurasidone and ziprasidone for mixed-feature depression, while other interventions showed no clear benefit. Standardized diagnostic definitions and additional high-quality trials are essential to refine therapeutic recommendations and reduce heterogeneity.