Journal of affective disorders · 2026
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.
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Fornaro Michele, Di Lorenzo Chiara, Nunez Nicolas, Singh Balwinder, Veldic Marin, Sambataro Fabio, McIntyre Roger S, Frye Mark A, Miola Alessandro
Аннотация
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.
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.