NEI Congress 2025 | Colorado Springs, CO
Long-Term Evaluation of a Muscarinic-Based Approach in Schizophrenia
Xanomeline–trospium (X/T) was approved by the U.S. Food and Drug Administration in 2024 for the treatment of schizophrenia in adults. Unlike currently available antipsychotics, X/T acts through muscarinic receptor modulation rather than dopamine receptor blockade. The combination pairs xanomeline, a dual M1/M4-preferring agonist that engages central muscarinic receptors, with trospium chloride, a peripherally restricted antagonist designed to mitigate peripheral cholinergic side effects.
The EMERGENT clinical program has established the short-term efficacy and safety of X/T in adults experiencing acute exacerbations of schizophrenia. An analysis presented by Lara Shirikjian, MD, and colleagues at the 2025 NEI Congress, examined whether the symptomatic benefits observed in the acute trials were sustained over one year and whether improvement extended across the full spectrum of schizophrenia symptom domains.
Methods
EMERGENT-4 (NCT04659174) was a 52-week, phase 3 multicenter, open-label study enrolling adults who had completed treatment in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-2 or EMERGENT-3 trials.
Participants (aged 18–65 years) began X/T 50 mg/20 mg twice daily, titrated to a maximum dose of 125 mg/30 mg twice daily based on tolerability. The modified intention-to-treat (mITT) population included 111 participants, of whom 49 had received X/T and 62 had received placebo during their respective acute trials.
Efficacy was assessed by change in PANSS total and Marder factor scores from the acute study baseline (ASB) through Week 52. The five Marder factors, positive, negative, uncontrolled hostility, disorganized thought, and depression/anxiety, were examined to capture distinct symptom dimensions.
Results
Demographic and clinical characteristics were comparable between groups at the acute trial baseline (mean age 44 years; 77% male; mean PANSS total 98).
PANSS total score:
- Sustained improvements were observed across both groups.
- Mean change from baseline to Week 52 was –33.8 in participants who received X/T throughout (X/T→X/T) and –31.3 among those switching from placebo to X/T (placebo→X/T).
- Participants previously on placebo demonstrated rapid symptom improvement after initiating X/T, reaching comparable PANSS scores by Week 4 of the extension phase.
PANSS Marder factors:
Long-term reductions were evident across all five domains. Improvements were similar between treatment arms for the positive, negative, disorganized thought, and depression/anxiety factors. The uncontrolled hostility factor showed numerically greater reduction in the X/T→X/T group (–4.6) than in the placebo→X/T group (–1.9).
Analyses of individual PANSS items within each factor indicated consistent score decreases, suggesting broad symptomatic benefit across psychotic, cognitive, and affective dimensions.
Conclusions
Over 52 weeks of continuous treatment, xanomeline–trospium was associated with sustained symptom reduction across all major domains of schizophrenia, including both positive and negative symptoms. Participants switching from placebo experienced rapid and durable improvement after X/T initiation, indicating stability of effect over extended treatment.
These results add to prior evidence from the acute EMERGENT trials, supporting the long-term clinical utility of muscarinic receptor modulation in schizophrenia management. As an agent with a mechanism distinct from dopamine receptor antagonism, X/T provides additional insight into how targeting alternative neural pathways may contribute to broad, durable symptom control.
