OBJECTIVES: While several clinical trials have been conducted to assess atypical antipsychotics for the treatment of patients with bipolar depression, head-to-head data comparing these treatments are lacking. This study aimed to assess the relative clinical efficacy and tolerability of lurasidone monotherapy compared to other atypical antipsychotics for the management of bipolar depression. METHODS: An update of a systematic literature review performed by the National Institute for Health and Care Excellence was conducted to identify relevant randomized controlled trials. Outcomes included response, remission, change in Montgomery–Åsberg Depression Rating Scale (MADRS) total score from baseline, change in Clinical Global Impressions–Bipolar Disorder–Severity (CGI-BP-S) score from baseline, change in weight from baseline, somnolence, extrapyramidal symptoms, and all-cause discontinuation. Outcomes were analyzed using Bayesian network meta-analysis (NMA) adopting a random-effects model to incorporate between-trial heterogeneity. RESULTS: Fourteen trials met the inclusion criteria for evidence synthesis. NMA results suggested that lurasidone was associated with better efficacy compared to aripiprazole (mean odds ratio [mOR] for response: 2.40, 95% credible interval [CrI]: 1.36, 3.96, mOR for remission: 2.28, 95% CrI: 1.22, 3.90, mean ΔMADRS: -3.62, 95% Crl: -7.04, -0.20, mean ΔCGI-BP-S: -0.42, 95% Crl: -0.78, -0.07) and ziprasidone (mOR for response: 2.45, 95% CrI: 1.38, 4.05, mOR for remission: 2.18, 95% CrI: 1.21, 3.65, mean ΔMADRS: -3.38, 95% Crl: -6.68, -0.11, mean ΔCGI-BP-S: -0.59, 95% Crl: -0.94, -0.24). Compared to quetiapine, lurasidone had similar efficacy but was associated with less weight gain (mean Δweight: -0.83kg, 95% CrI: -1.59, -0.08) and a lower probability of somnolence (mOR: 0.33, 95% CrI: 0.11, 0.82). Results for other outcomes were not statistically meaningful. CONCLUSIONS: This network meta-analysis suggests that lurasidone is more efficacious than aripiprazole and ziprasidone and has similar efficacy compared to quetiapine (with fewer effects on weight and somnolence than quetiapine) for the management of bipolar depression.