Comparative Effectiveness of KarXT and Selective Second-Generation Antipsychotics for the Treatment of Schizophrenia: A Systematic Literature Review and Network Meta-Analysis

OBJECTIVES: To evaluate the comparative effectiveness of KarXT compared to three second-generation oral antipsychotics (aripiprazole, risperidone, and olanzapine) for the treatment of schizophrenia.

METHODS: We systematically identified randomized controlled trials of KarXT and three commonly used second generation antipsychotics that enrolled individuals for treatment of acute exacerbations of schizophrenia. We conducted random-effects Bayesian network meta-analyses (NMAs) and results are presented as relative risks (RR) or mean difference (MD). Our main outcomes were positive and negative syndrome scale (PANSS) total score, PANSS response [defined as >30% improvement PANSS score], weight gain, and all-cause discontinuation. All outcomes were evaluated between three and eight weeks. Long term comparative data was not available at the time of our review.

RESULTS: We identified 33 studies that met our criteria. All the antipsychotics had significant changes in PANSS total score and PANSS response compared to placebo. However, the NMA found no statistically significant differences between the active treatments for either outcome. At five weeks, the NMA results showed that KarXT had significantly less weight gain compared to olanzapine (MD: 2.49 kilograms; 95% credible interval [CrI]: 2.02, 3.0) and risperidone (MD: 1.69 kilograms; 95% CrI: 0.96, 2.43), though there was no statistically significant difference compared to placebo and aripiprazole. KarXT had numerically higher all-cause discontinuation than the three comparators and placebo, but the differences were only statistically significant compared with olanzapine (RR: 0.71; 95% CrI: 0.63, 0.81) and risperidone (RR: 0.75; 95% CrI: 0.65, 0.88).

CONCLUSIONS: KarXT provides similar clinical benefits to other second-generation antipsychotics with the potential for less weight gain. However, there is uncertainty around the long-term use of KarXT in an outpatient setting as only data from short-term inpatient trials are available. Results of the NMA may provide insight for patients and clinicians when comparing the efficacy and safety profiles of available treatment options.