NEI Congress 2025 | Colorado Springs, CO
Evaluating EPS Risk During Long-Term Treatment
Extrapyramidal symptoms (EPS) such as akathisia, dystonia, and tardive dyskinesia remain an important consideration in the treatment of schizophrenia. These motor side effects are commonly linked to dopaminergic blockade, the primary mechanism of action of available antipsychotic medications.
Xanomeline–trospium (X/T), approved by the U.S. Food and Drug Administration in 2024, offers a different pharmacologic approach through muscarinic receptor modulation. The combination of xanomeline, a centrally active dual M1/M4-preferring muscarinic receptor agonist, and trospium chloride, a peripherally restricted antagonist, was designed to achieve central receptor engagement while minimizing peripheral cholinergic effects.
Short-term (5-week) EMERGENT trials established the efficacy and general tolerability of X/T, including a low incidence of EPS. The analysis presented by Inder Kaul, PhD, and colleagues at the 2025 NEI Congress extended this evaluation to long-term treatment, examining EPS outcomes over 52 weeks in two open-label studies.
Methods
Data were pooled from the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, which included adults aged 18–65 years with a DSM-5 diagnosis of schizophrenia.
- EMERGENT-4 was a long-term open label extension of the acute EMERGENT-2 and EMERGENT-3 trials which enrolled participants with acute exacerbations who had recently been hospitalized and discontinued prior antipsychotic therapy.
- EMERGENT-5 enrolled adults with stable schizophrenia and no prior X/T exposure.
All participants received X/T 50 mg/20 mg twice daily, titrated to a target dose of 125 mg/30 mg twice daily for up to one year. The pooled safety population included 718 participants from sites in the United States and Ukraine.
EPS were identified both through investigator-assessed treatment-emergent adverse events (TEAEs) with preferred terms of dystonia, dyskinesia, akathisia, or extrapyramidal disorder, and through serial assessments using the Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), and Abnormal Involuntary Movement Scale (AIMS).
Results
Among 718 participants (mean age 46.9 years; 68% male), 76.5% experienced at least one TEAE, most commonly gastrointestinal in nature (nausea 20%, vomiting 18%, constipation 15%). TEAEs generally did not lead to discontinuation.
EPS-related events were infrequent. Only 6 participants (0.8%) experienced an EPS TEAE considered related to treatment, most often akathisia (0.7%). No cases of dystonia or extrapyramidal disorder were reported, and no participants discontinued treatment because of EPS.
Mean changes on movement-disorder scales were small and not clinically meaningful over 52 weeks:
- SAS: −0.3 ± 0.06
- BARS: −0.2 ± 0.06
- AIMS: −0.1 ± 0.04
Overall, the safety and tolerability profile of X/T in these long-term studies was consistent with earlier 5-week data from the acute EMERGENT program, with no new safety signals observed over one year of treatment.
Conclusions
Pooled long-term data from the EMERGENT-4 and EMERGENT-5 studies demonstrate that xanomeline–trospium was not associated with extrapyramidal symptoms or clinically significant changes on movement-disorder scales through 52 weeks of treatment.
These findings add to the growing body of evidence supporting the sustained tolerability of X/T and its differentiation from antipsychotics that act directly at D2 dopamine receptors which are associated with EPS risk. Continued evaluation in broader clinical settings may help further define its long-term safety profile and clinical role in schizophrenia management.
