Efficacy and Safety of Cariprazine, Asenapine, Xanomeline-Trospium, and Lumateperone for Acute Exacerbations of Schizophrenia in Adults: A Network Meta-Analysis

Alaaeddin Abusalameh; Celina R Andonie; Mahmoud Ladadweh; Tamer Hodrob; Ibrahim Ismail; Hazem Ayesh

doi:10.1093/schizbullopen/sgaf024

Efficacy and Safety of Cariprazine, Asenapine, Xanomeline-Trospium, and Lumateperone for Acute Exacerbations of Schizophrenia in Adults: A Network Meta-Analysis

Schizophr Bull Open. 2025 Oct 16;6(1):sgaf024. doi: 10.1093/schizbullopen/sgaf024. eCollection 2025 Jan.

Authors

Alaaeddin Abusalameh¹, Celina R Andonie¹, Mahmoud Ladadweh¹, Tamer Hodrob¹, Ibrahim Ismail¹, Hazem Ayesh²

Affiliations

¹ Faculty of Medicine, Al-Quds University, East Jerusalem, 91105, Palestine.
² Deaconess Clinic Endocrinology, Deaconess Health System, Evansville, IN 47708, United States.

Abstract

Objective: This network meta-analysis evaluated the efficacy and safety of cariprazine, asenapine, xanomeline-trospium chloride, and lumateperone in treating acute exacerbations of schizophrenia in adults, compared with placebo.

Methods: A systematic search of PubMed, Scopus, Cochrane Central, and ClinicalTrials.gov identified 12 randomized controlled trials (RCTs; n = 4584 patients). Efficacy was assessed using changes in Positive and Negative Syndrome Scale (PANSS) total scores; safety outcomes included adverse events (AEs), treatment discontinuation, and specific side effects.

Results: Asenapine (MD = -9.83; 95% CI, -13.49 to -6.18), xanomeline-trospium (MD = -9.80; 95% CI, -13.00 to -6.60), and cariprazine (MD = -8.41; 95% CI, -11.33 to -5.50) showed statistically significant PANSS score reductions. Lumateperone, however, did not reach statistical significance (MD = -2.79; 95% CI, -6.60 to 1.01). Safety profiles varied: cariprazine had the lowest risk of serious AEs (RR = 0.52), while xanomeline-trospium was associated with gastrointestinal AEs (RR = 3.86), and asenapine with weight gain (RR = 3.12).

Conclusions: This network meta-analysis found that among asenapine, xanomeline-trospium, lumateperone and cariprazine, asenapine, xanomeline-trospium, and cariprazine were effective in reducing PANSS total score compared with placebo, whereas lumateperone did not show statistically significant reduction compared with placebo. These findings offer important insights into efficacy and safety of these 4 medications in the treatment of acute exacerbation of schizophrenia. However, further head-to-head comparisons with standard treatments are needed to guide a more evidence-based selection. Future trials with longer durations and more diverse populations are warranted to confirm and extend these findings.

Keywords: PANSS total score; asenapine; cariprazine; lumateperone; schizophrenia; xanomeline–trospium.