Does KarXT (xanomeline-trospium) represent a novel approach to schizophrenia management? A GRADE-assessed systematic review and meta-analysis of randomized controlled clinical trials

Abstract

Background: Schizophrenia is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms. KarXT, a novel combination of xanomeline and trospium, offers potential therapeutic benefits for schizophrenia treatment by targeting muscarinic receptors and avoiding dopamine receptor blockade. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of KarXT.

Methods: PubMed, Scopus, Web of Science, and Cochrane databases were systematically searched for relevant randomized controlled trials (RCTs) up to October 2024. Studies involving adult patients with schizophrenia treated with KarXT were included. Furthermore, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to assess evidence quality, and the risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool.

Results: Four studies with 690 participants were included. KarXT significantly reduced Positive and Negative Syndrome Scale (PANSS) total scores compared to placebo (mean difference (MD): -13.77, 95% confidence interval (CI) [-22.33 to -5.20], P-value = 0.002), with significant improvements in positive and negative subscale scores. It significantly increased the incidence of achieving ≥ 30% PANSS score reduction (risk ratio: 2.15, 95% CI [1.64 to 2.84], P < 0.00001). Moreover, KarXT demonstrated a favorable safety profile, with side effects such as nausea and constipation being mild and transient. Notably, it was not significantly associated with weight gain or extrapyramidal symptoms, which are common with traditional antipsychotics.

Conclusions: KarXT's distinct mechanism and tolerability highlight its potential to address unmet needs in schizophrenia treatment. Future studies should explore its long-term efficacy, delayed adverse effects, and comparative effectiveness against existing therapies.

Clinical trial number: Not applicable.

Keywords: KarXT; Meta-analysis; Schizophrenia; Systematic review; Trospium; Xanomeline; Xanomeline-trospium.

Fig. 1

PRISMA flow diagram

Fig. 2

Risk of bias summary and graph

Fig. 3

Comparison of KarXT versus Placebo in terms of A) PANSS total score, B) PANSS positive subscale, C) PANSS negative subscale, D) ≥ 30% reduction in PANSS total score, E) PANSS Marder negative factor score, F) CGI-S score

Fig. 4

Comparison of KarXT versus Placebo in terms of A) Discontinuations due to adverse events, B) Constipation, C) Dyspepsia, D) Nausea, E) Vomiting, F) Hypertension

Fig. 5

Comparison of KarXT versus Placebo in terms of A) Weight change, B) Barnes Akathisia Rating Scale, C) Abnormal Involuntary Movement Scale, D) Simpson-Angus Scale