OBJECTIVE: Xanomeline and trospium chloride (formerly known as KarXT), a novel M METHODS: Data were pooled from two 5-week inpatient trials of xanomeline/trospium monotherapy in patients with acute schizophrenia. The statistical analysis plan prespecified comparisons of cognitive composite score changes between xanomeline/trospium and placebo in the full sample and the cognitively impaired (≤1 SD below norms at baseline) subgroup. RESULTS: There was no significant xanomeline/trospium effect in the full sample (N=357)
however, in the impaired subgroup, xanomeline/trospium (N=71) had a significantly greater benefit for cognition compared with placebo (N=66
least squares mean difference=0.31, SE=0.10
d=0.54). The xanomeline/trospium effect size increased significantly with a more stringent baseline impairment threshold (≤-1.5 SD
d=0.80). Improvements in cognition were minimally correlated with concurrent changes in total, positive, and negative symptoms in both treatment groups. CONCLUSIONS: Participants with acute schizophrenia with prespecified impairments demonstrated significant cognitive improvement with xanomeline/trospium compared with placebo. This result directly confirms earlier findings. This benefit is not attributable to changes in symptoms, despite substantial evidence of efficacy for psychosis. Evaluation of xanomeline/trospium's potential for cognitive enhancement in a well-controlled trial of stable patients with cognitive impairment is warranted.