Pharmacological interventions for acute major depression and bipolar depression with mixed features: A systematic review and dose-related network meta-analysis across different age groups

Background Acute mixed bipolar/major depression is relatively frequent, yet quantitative information about its pharmacological management is relatively scant, warranting network meta-analysis (NMA) of comparative efficacy/response/acceptability of pharmacological interventions accounting for dose effects across different age groups.Methods We searched PubMed/MEDLINE/Embase/Web of Science/Scopus (from database inception to 2026.05.25) for randomized controlled trials (RCTs) comparing pharmacological interventions with each other or placebo in patients with acute major depression/bipolar depression with mixed features. Co-primary outcomes were the change in depressive symptoms and response. Tolerability, acceptability, and change in manic symptoms were secondary outcomes. Confidence-In-Network-Meta-Analysis was appraised.Results 22 studies assessed 5241 acute mixed bipolar depressed participants, whereas 13 studies encompassed 1852 acute mixed major depression patients. Sensitivity analyses, including those retaining low-risk-of-bias studies only, and excluding outliers for possible effect modifiers, indicated that asenapine-15 mg/day (SMD = -0.54; 95%C.I. = -1.06; -0.02), lurasidone-60 mg/day (SMD = -0.43; 95%C.I. = -0.72, -0.14), lurasidone-80 mg/day (SMD = -0.39; 95%C.I. = -0.55, -0.23) outperformed placebo for depressive symptoms reduction in bipolar patients. Lurasidone-60 mg/day (SMD = -0.43; 95%C.I. = -0.72, -0.14), lurasidone-80 mg/day (SMD = -0.38; 95%C.I. = -0.59, -0.17) outperformed placebo for bipolar children and adolescents. Lurasidone-40 mg/day (SMD = -0.80; 95% C.I. = -0.95, -0.65) outperformed placebo for major depression. Cariprazine-1.5 mg/day (RR = 1.23; 95%C.I. = 1.01, 1.51), cariprazine-3 mg/day (RR = 1.32; 95%C.I. = 1.08, 1.60), lurasidone-80 mg/day (RR = 1.36; 95%C.I. = 1.14, 1.63), olanzapine-12.5 mg/day (RR = 1.63; 95%C.I. = 1.07, 2.51), olanzapine-6 mg/day+fluoxetine-50 mg/day (RR = 2.61; 95%C.I. = 1.60, 4.39) outperformed placebo response in bipolar samples. Lumateperone-42 mg/day (RR = 1.61; 95%C.I. = 1.20; 2.18) outperformed placebo for major depression response. Quetiapine-530 mg/day in augmentation to mood stabilizers led to a significantly higher number of dropouts in bipolar patients than placebo. Meta-regression of the AMSTAR-Plus content score against efficacy and response measures showed that larger effect sizes (SMDs/logRRs) were associated with lower AMSTAR scores, reflecting lower study quality.Conclusions Our findings are consistent with previous NMAs and current guidelines, yet they expand knowledge by concurrently appraising different drugs, doses, and age groups, and the quality of the evidence.