A network meta-analysis of KarXT and commonly used pharmacological interventions for schizophrenia

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.