The EMERGENT-3 trial evaluated the efficacy and safety of xanomeline-tropsium chloride (KarXT) in adults with schizophrenia experiencing acute psychosis. Xanomeline is a dual M1/M4 muscarinic receptor agonist, and KarXT combines it with the peripheral muscarinic receptor antagonist tropsium chloride to reduce adverse events. The trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled study conducted at 30 inpatient sites in the US and Ukraine from April 1, 2021, to December 7, 2022. Participants were randomized 1:1 to receive xanomeline-tropsium or placebo for 5 weeks. The primary endpoint was the change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 5. Secondary outcomes included changes in PANSS positive and negative subscale scores, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and the proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also assessed. A total of 256 participants were randomized, with a mean age of 43 years. At week 5, xanomeline-tropsium significantly reduced the PANSS total score compared to placebo (-20.6 vs -12.2, respectively; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events were similar between the xanomeline-tropsium and placebo groups. Common TEAEs included nausea, dyspepsia, vomiting, and constipation. The results suggest that xanomeline-tropsium is effective and well-tolerated in adults with schizophrenia experiencing acute psychosis. These findings, along with those from previous trials, support the potential of xanomeline-tropsium as a new class of antipsychotic medications without D2 dopamine receptor blocking activity.The EMERGENT-3 trial evaluated the efficacy and safety of xanomeline-tropsium chloride (KarXT) in adults with schizophrenia experiencing acute psychosis. Xanomeline is a dual M1/M4 muscarinic receptor agonist, and KarXT combines it with the peripheral muscarinic receptor antagonist tropsium chloride to reduce adverse events. The trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled study conducted at 30 inpatient sites in the US and Ukraine from April 1, 2021, to December 7, 2022. Participants were randomized 1:1 to receive xanomeline-tropsium or placebo for 5 weeks. The primary endpoint was the change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 5. Secondary outcomes included changes in PANSS positive and negative subscale scores, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and the proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also assessed. A total of 256 participants were randomized, with a mean age of 43 years. At week 5, xanomeline-tropsium significantly reduced the PANSS total score compared to placebo (-20.6 vs -12.2, respectively; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events were similar between the xanomeline-tropsium and placebo groups. Common TEAEs included nausea, dyspepsia, vomiting, and constipation. The results suggest that xanomeline-tropsium is effective and well-tolerated in adults with schizophrenia experiencing acute psychosis. These findings, along with those from previous trials, support the potential of xanomeline-tropsium as a new class of antipsychotic medications without D2 dopamine receptor blocking activity.