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Clinical Trial
. 2025 Mar 1;182(3):297-306.
doi: 10.1176/appi.ajp.20240076. Epub 2024 Dec 11.

The Impact of Xanomeline and Trospium Chloride on Cognitive Impairment in Acute Schizophrenia: Replication in Pooled Data From Two Phase 3 Trials

William P Horan  1 , Colin Sauder  1 , Philip D Harvey  1 , Ian S Ramsay  1 , Samantha E Yohn  1 , Richard S E Keefe  1 , Vicki G Davis  1 , Steven M Paul  1 , Stephen K Brannan  1
Affiliations
Clinical Trial

The Impact of Xanomeline and Trospium Chloride on Cognitive Impairment in Acute Schizophrenia: Replication in Pooled Data From Two Phase 3 Trials

William P Horan et al. Am J Psychiatry. .

Abstract

Objective: Xanomeline and trospium chloride (formerly known as KarXT), a novel M1/M4 muscarinic receptor agonist, demonstrated efficacy across phase 2 and 3 trials as monotherapy for the treatment of inpatients with acute schizophrenia on the Positive and Negative Syndrome Scale total score primary endpoint. In the phase 2 trial, xanomeline/trospium improved performance on a cognitive outcome measure in the subgroup of participants with clinically significant baseline cognitive impairment. The authors sought to confirm this finding using data from two phase 3 trials.

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.

Keywords: Cognition/Learning/Memory; Schizophrenia Spectrum and Other Psychotic Disorders.

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Conflict of interest statement

Dr. Horan, Dr. Sauder, Dr. Ramsay, and Dr. Yohn are employees of Bristol Myers Squibb. Dr. Harvey has received consulting fees or travel reimbursement from Alkermes, Boehringer-Ingelheim, Bristol Myers Squibb, Karuna Therapeutics, Merck, Minerva Neuroscience, and Sunovion/DSP; he has received royalties for the Brief Assessment of Cognition in Schizophrenia (owned by WCG); and he is chief scientific officer of i-Function, Inc., and a scientific consultant for EMA Wellness, Inc. Dr. Ramsay holds and is owed restricted stock units at Bristol Myers Squibb. Dr. Keefe has served as a consultant for Biogen, Boehringer-Ingelheim, Bristol Myers Squibb, Gedeon Richter, Neurocrine Pangea, Recognify, Sirtsei, Vandria, and WCG; he has received royalties for the BACS, SCoRS, and VRFCAT; he has received support from Boehringer Ingelheim for attending meetings and/or travel; and he has participated in data safety monitoring boards or advisory boards for Boehringer-Ingelheim, Karuna, Merck, and Neurocrine. Dr. Davis has served as a consultant for Abyrx, Arkana Laboratories, Boehringer Ingelheim, Bristol Myers Squibb, Eikonoklastes Therapeutics, Harm Reduction Therapeutics, LyGenesis, Renerva, University of North Carolina School of Medicine, Division of Nephropathology, and VeraSci. Dr. Paul was an employee of and had a leadership/fiduciary role at Karuna Therapeutics at the time this research was conducted, and he has a leadership/fiduciary role at Sage Therapeutics and Voyager Therapeutics; he holds equity in Eli Lilly, NeuMarker, Rapport Therapeutics, Sage Therapeutics, Seaport Therapeutics, and Voyager Therapeutics. Dr. Brannan was an employee of Karuna Therapeutics at the time this research was conducted and is currently a consultant for Bristol Myers Squibb.

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