Xanomeline and Trospium Show Long-Term Efficacy and Safety in Schizophrenia Treatment

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CONFERENCE REPORTER

A 52-week open-label extension trial (EMERGENT-4) has confirmed that long-term treatment with xanomeline and trospium is both effective and well tolerated in individuals with schizophrenia.¹The new information was presented via poster session at the 30th Annual Nevada Psychiatric Association National Psychopharmacology Update.

Mechanism of Action

Xanomeline and trospium do not directly block dopamine D2 receptors. Instead, xanomeline acts as an M₁/M₄ preferring muscarinic receptor agonist, while trospium chloride, a peripherally restricted muscarinic receptor antagonist, helps reduce side effects.¹ This differentiates xanomeline and trospium from conventional schizophrenia treatments, offering an alternative approach to managing symptoms.

Trial Design and Participant Demographics

The study included participants who had previously completed either EMERGENT-2 or EMERGENT-3. Participants were required to be between 18 and 65 years old, with a primary diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score of 80 to 120 at the time of enrollment in the acute trials.¹ Overall, 122 of the 156 enrolled participants discontinued the trial, most due to withdrawal of consent, failure to adhere to treatment protocols, and lost to follow-up.

Sustained Symptom Improvement

Results showed that treatment with xanomeline and trospium led to continued, durable improvements in PANSS total scores, Clinical Global Impression–Severity scores, and both PANSS positive and negative subscale scores. By week 52, 68.6% of participants had achieved at least a 30% reduction in PANSS total scores from baseline, demonstrating long-term efficacy.¹

Manageable Safety Profile with Few Severe Adverse Events

Long-term treatment was generally well tolerated. The most common treatment-emergent adverse events were gastrointestinal-related, including nausea (9.2%), vomiting (7.9%), dyspepsia (5.9%), and dry mouth (5.3%).¹ Serious adverse effects were rare, with only 1.3% of participants experiencing treatment-related severe events, primarily associated with worsening schizophrenia rather than the medication itself.¹

Xanomeline and trospium did not lead to clinically meaningful weight gain. Instead, participants experienced an average weight reduction of 1.9 kg over 52 weeks. Additionally, there were no significant increases in prolactin levels, extrapyramidal symptoms, or tardive dyskinesia, further supporting the treatment’s favorable safety profile.

Potential for a New Standard in Schizophrenia Treatment

With the US Food and Drug Administration recently approving xanomeline and trospium for the treatment of schizophrenia in adults, the EMERGENT-4 trial adds valuable long-term data supporting its efficacy and safety. Xanomeline and trospium maintained symptom improvement without significant metabolic or movement-related adverse effects.

The findings from EMERGENT-4 reinforce xanomeline and trospium’s role as an effective long-term therapy, offering a new form of treatment for schizophrenia.

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Reference

1. Kaul I, Claxton A, Sauder C, et al. Long-term safety and efficacy of xanomeline and trospium chloride in schizophrenia: results from the 52-week, open-label EMERGENT-4 trial. Presented at: Nevada Psychiatric Association 30th Annual Psychopharmacology Update; February 13, 2025.