Dopaminergic antipsychotics for schizophrenia have modest effects on symptoms and can cause important side effects. KarXT is an investigational drug for schizophrenia with a novel mechanism targeting muscarinic receptors that may limit these side effects. We conducted a systematic review and Bayesian random-effects network meta-analyses of short-term RCTs (3–8 weeks) that enrolled adults with schizophrenia. We compared KarXT to aripiprazole, risperidone, and olanzapine. We sought evidence for symptoms (Positive and Negative Symptoms Scale [PANSS]), weight gain, and all-cause discontinuation. We included 33 trials with 7193 participants. For total, positive, and negative symptoms, KarXT and the three antipsychotics were significantly more efficacious than placebo (mean difference [MD] vs placebo range for total symptoms: −10.67 to −8.05; positive symptoms: −3.46 to −2.53; negative symptoms: −1.99 to −1.44) but not significantly different from each other. KarXT was ranked as least likely to lead to weight gain. This was significant versus risperidone (−2.06 kg; 95 % CrI: −3.28, −0.87) and olanzapine (−2.86 kg; 95 % CrI: −3.97, −1.82). However, KarXT was ranked highest for all-cause discontinuation. This was significant versus risperidone (RR: 0.64; 95 % CrI: 0.46, 0.89) and olanzapine (RR: 0.6; 95 % CrI: 0.44, 0.83). KarXT and commonly used antipsychotics were more efficacious than placebo at reducing symptoms, but there were no clear differences in short-term efficacy among the active interventions. KarXT was less likely to cause weight gain, an important outcome for those with schizophrenia; short-term data do not permit evaluation of the risk for tardive dyskinesia. Long-term data are needed.
