Xanomeline-Trospium and EPS: Low Rates Across EMERGENT, Limited Evidence

A mechanism that bypasses dopamine blockade

Xanomeline-trospium acts through M1/M4 muscarinic agonism without direct D2 dopamine-receptor activity, unlike other approved antipsychotics.¹  The addition of trospium, a peripherally restricted muscarinic receptor antagonist, is intended to reduce peripheral muscarinic adverse effects while preserving the centrally mediated activity of xanomeline.¹ Because dystonia, parkinsonism, and tardive dyskinesia are largely linked to D2 receptor blockade, this distinct mechanism provides a biologically plausible rationale for a different motor safety profile. Whether this mechanistic difference is associated with a different motor safety profile has been a key clinical question.

The controlled-trial baseline

Across the pooled EMERGENT-1, EMERGENT-2, and EMERGENT-3 safety population (n=683), extrapyramidal symptom (EPS) treatment-emergent adverse events (TEAEs) occurred in 3.2% of participants receiving xanomeline-trospium and 0.9% receiving placebo (Table 1).¹ The treatment-related EPS events occurred in 1.5% of participants receiving xanomeline-trospium and 0.3% receiving placebo.  All events were nonserious and mild or moderate in intensity, and no TEAE reports of tardive dyskinesia occurred during the 5-week controlled period.^1,5 Eight participants receiving xanomeline-trospium (2.3%) and 5 receiving placebo (1.5%) discontinued treatment because of EPS.⁵ Mean changes on the Simpson-Angus, Barnes Akathisia, and Abnormal Involuntary Movement scales were near zero in both arms; none were tested statistically. Six of 11 akathisia reports came from a single EMERGENT-3 site, including 4 of 14 participants receiving xanomeline-trospium and 2 of 14 receiving placebo; none occurred among the other 225 participants. In discussion, the authors of both reports raise the possibility that some of these cases were misdiagnoses of acute psychosis-related agitation rather than true akathisia.^1,5 The site investigator did not consider any of the akathisia reports study-drug related.⁵

Reanalyzing the same three trials

A separate systematic review and meta-analysis of the EMERGENT trials found no significant difference from placebo in standardized mean differences for akathisia on the Barnes Akathisia Scale (0.00; 95% confidence interval [CI], −0.16, 0.16; 3 trials), dyskinesia on the Abnormal Involuntary Movement Scale (0.00; −0.19, 0.19; 2 trials), or parkinsonism on the Simpson-Angus Scale (0.05; −0.11, 0.20; 3 trials).² GRADE certainty was low for all three.²  Because it analyzes the same patients, it does not provide independent replication.^1,2

Long-term safety across two studies

In the open-label extension of EMERGENT-2/3 completers, 152 participants received at least one dose; no TEAEs of akathisia or tardive dyskinesia were reported.³ That zero comes from a cohort in which only 34 of 156 enrolled participants (21.8%) completed the 52-week treatment period, and the study does not report a mean exposure duration.³ A separate 52-week study (EMERGENT-5) enrolled 566 psychiatrically stable outpatients who received at least one dose, with 48.9% completion and 228 days’ mean exposure, and recorded akathisia in 7 (1.2%), tardive dyskinesia in 2 (0.4%), and dyskinesia in 1 (0.2%).⁴  The studies enrolled different patient populations, and the EMERGENT-2/3 extension had substantial attrition, limiting interpretation of the zero-event finding.³ In EMERGENT-5, the reported motor events occurred during a longer follow-up period than in the controlled trials.⁴

Clinical Considerations

In the double-blind studies, no statistically significant difference in EPS incidence was observed versus placebo, though the report gives no test statistic and used a broader EPS definition than Table 1.^1,5 A post-hoc exploratory analysis without inferential statistics found that movement-scale scores improved in 13 of 15 participants on the Simpson-Angus scale, 12 of 13 on the Barnes Akathisia scale, and 10 of 20 on the AIMS, with 1 participant showing worsening on the AIMS.⁵ Prior antipsychotics were withdrawn at study initiation, and the authors did not have a complete record of pre-existing EPS medication so these changes cannot be attributed specifically to xanomeline-trospium.⁵ The available evidence remains limited by the small number of randomized trials and relatively limited long-term follow-up. No comparator trial exists in the program, so a motor safety profile distinct from dopamine-antagonist antipsychotics is not established, and monitoring past the first year remains warranted.

Table 1. Movement-related outcomes, pooled 5-week EMERGENT-1, EMERGENT-2, and EMERGENT-3 safety population

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Two taper schedules, similar results

An 8-week, open-label, multicenter randomized outpatient study (NCT06924255) assigned 105 clinically stable adults with schizophrenia to a 2- or 4-week taper of their prior oral atypical antipsychotic. Both groups followed the same xanomeline-trospium titration, starting at 50/20 mg twice daily, followed by 100/20 mg twice daily, with a target of 125/30 mg twice daily if tolerated.^1,3 Entry required a Positive and Negative Syndrome Scale (PANSS) total of 80 or less and a Clinical Global Impression-Severity (CGI-S) score of 4 or less; patients with treatment resistance, prior clozapine, or current long-acting injectable use were excluded.¹ All-cause discontinuation over 8 weeks was the primary endpoint.  Discontinuation occurred in 8 of 52 participants (15.4%) in the 2-week group and 14 of 53 (26.4%) in the 4-week group, 22 participants (21.0%) overall.^1,2 The investigators described the 2-week group as having numerically lower discontinuation rates, with the difference not significant.^1,2 All analyses were descriptive in nature (Table 1).

Where the 22 discontinuations came from

Of the 22 discontinuations, 3 were due to adverse events, 7 had unknown treatment-completion status, 5 were due to protocol nonadherence, and 4 followed participant withdrawal. Six of the 7 participants with unknown treatment-completion status were in the 4-week group.¹ Physician decision, alcohol abuse, and illegal drug use accounted for 1 discontinuation each.¹ None was attributed to lack of efficacy or worsening psychosis.^1,2

Outcomes by prior antipsychotics

The study also examined whether outcomes differed according to the antipsychotic participants were taking before the switch. Participants were taking olanzapine or quetiapine (66 participants, 63%); or aripiprazole, lurasidone, or risperidone (38 participants, 37%). The prior antipsychotic was not recorded for one participant.¹ Taper length was fixed by randomized assignment rather than chosen according to the prior antipsychotic.¹  Discontinuation rates, PANSS changes, and adverse event rates were generally similar between the two prior-antipsychotic groups. All 3 participants who discontinued study drug because of an adverse event had been taking quetiapine. Small subgroup sizes limited these comparisons.¹

Symptom and function scores through week 8

The PANSS findings were similar between groups. Mean PANSS total change to week 8 was −3.6 (SE 0.6) overall, with a least-squares mean difference between arms of 1.0 (P=.40).^1,2 CGI-S and Personal and Social Performance scores improved in both groups,¹ as did Medication Satisfaction Questionnaire scores (Table 1).¹  Overall, 86% (n=90) reached the 125/30 mg target without de-escalation.¹

Tolerability during the transition

Treatment-emergent adverse events occurred in 48.6% of participants, with 39.0% experiencing mild events and 9.5% moderate events; none were severe or serious.^1,2 Nausea (13.3%), vomiting (11.4%), dry mouth (8.6%), and constipation (6.7%) were the most common events.^1,2 An antinausea medication was used by 9.5% of participants (n=10): calcium carbonate (n=8) and ondansetron (n=2).^1,2 Mean weight change was −0.3 kg in the 2-week group and −0.1 kg in the 4-week group; no statistical comparison was reported.¹  Both schedules were studied over 8 weeks with no active comparator, and the investigators concluded that additional studies of switching to xanomeline-trospium are needed.¹

Consensus recommendations for switching

A consensus panel of clinicians recommended tapering risperidone or paliperidone over several days and quetiapine, olanzapine, or clozapine over 1 to 3 weeks; these recommendations reflect expert consensus rather than trial evidence and rest on early clinical experience the panel says should be interpreted with caution.⁴ The panel also noted that some long-half-life partial agonists may not require formal tapering.⁴ The panel also recommended prophylactic ondansetron at initiation.⁴

Table 1. Eight-week outcomes by taper arm

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