Muscarinic Mechanisms Continue a New Chapter in Schizophrenia Treatment

The muscarinic receptor agonist xanomeline represents a mechanistically distinct approach to treating schizophrenia, diverging from the dopamine- and serotonin-based mechanisms of atypical antipsychotics.¹ Steve Brannan, MD, shared his experience developing xanomeline-trospium (Cobenfy) from the Precision Therapeutics in Schizophrenia symposium.

Unlike D2-blocking agents, xanomeline was not associated with extrapyramidal symptoms, weight gain, metabolic syndrome, or prolactin elevation, effects historically linked to off-target dopaminergic activity.¹ Additional muscarinic compounds and other novel mechanisms are in development, a shift Brannan said would move schizophrenia treatment toward the mechanistic diversity long available for depression, similar to the choice among monoamine oxidase inhibitors, tricyclics, and selective serotonin reuptake inhibitors.

Cognitive effects, though not an FDA-approved indication for Cobenfy, has emerged as a notable area of investigation. M1 receptor activity had shown procognitive effects in animal studies, and xanomeline was originally developed by Eli Lilly for Alzheimer disease based on this property. In an exploratory phase 2 post hoc analysis, patients divided by a median split at approximately 1 standard deviation below the mean on baseline cognitive testing showed benefit that strengthened with greater baseline impairment, an effect that grew stronger by tertile.² In the phase 3 program, using a different cognitive battery, investigators prospectively evaluated patients 1 standard deviation below the mean and again found a strong cognitive effect that increased further at 1.5 standard deviations below the mean.²

"Schizophrenia patients in general are 1 to 2 standard deviations below the mean compared to the normal human population, and this is right around 1, and the people who are 1 standard deviation or below when they came in, so we had a baseline measurement, actually did pretty well on cognition," Brannan said.

Brannan added: "There's likely going to be more muscarinics coming out, and people are working on compounds with even another different mechanism of action, so I look forward to that inflection point and seeing schizophrenia as a place where patients can try out different medications."

Dr Brannan is a psychiatrist and former chief medical officer of Karuna Therapeutics.

References

1. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-170.

2. Sauder C, Allen LA, Baker E, et al. Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. Transl Psychiatry. 2022;12(1):491.