Efficacy and safety of pharmacological interventions for the maintenance of bipolar disorder: A systematic review and dose-related network meta-analysis across different age groups

Background Bipolar disorder (BD) is a chronic mental illness that requires lifelong treatment. We investigated the comparative efficacy and safety of pharmacological interventions for bipolar maintenance, considering dose effects across different age groups. Methods We conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing pharmacological interventions against each other or placebo for the maintenance of BD, searching for records indexed in PubMed/MEDLINE, Embase, Web of Science, and Scopus (from inception through 2026.1.12). Co-primary outcomes were the relapse rate (into an acute episode of any mood polarity) and tolerability (discontinuation due to side effects). Relapse into episodes of specific mood polarities (namely, depressive/manic/mixed polarity), acceptability (discontinuation due to any cause), and rate of specific adverse events were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. Results Forty-four RCTs involving 23 distinct treatment combinations encompassed 10,867 participants. Sensitivity analysis retaining only low-risk-of-bias studies and excluding outliers for possible effect modifiers indicated that asenapine 20 mg/day, aripiprazole 20 mg/day, 30 mg/day, quetiapine 300 mg/day, 600 mg/day and 550 mg/day, lithium 800 mg/day, lurasidone 80 mg/day, carbamazepine 400 mg/day and 650 mg/day, valproate 71–125 μg/mL, olanzapine 20 mg/day, long-acting aripiprazole 400 mg/4 weeks, long-acting risperidone 25 mg/2 weeks, aripiprazole 30 mg/day+lamotrigine 200 mg/day outperformed placebo. Several additional drugs might be efficacious, although they either emerged as outliers for the mean age of participants/proportion of females/proportion of BD-I/II patients, baseline severity of mania/depression, and trial duration. Conclusions Our findings are consistent with previous NMAs and current guidelines, yet they expand current knowledge by concurrently appraising different drugs, doses, and age groups.