Larger Response in Prominent Negative Symptoms, but No Evidence of Superiority

Negative Symptoms Have Historically Been Less Responsive to Antipsychotic Treatment

Negative symptoms, including avolition, anhedonia, and reduced emotional expression, have historically been less responsive to antipsychotics than positive symptoms.¹ Most antipsychotics act through dopamine D₂ receptor antagonism or partial agonism, and their efficacy for negative symptoms has generally been limited.² Xanomeline-trospium acts through agonism at M₁ and M₄ muscarinic receptors rather than direct D₂ receptor antagonism; its efficacy in acute schizophrenia was demonstrated in a pooled analysis of the EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials.³ What that same dataset shows for negative symptoms depends on which patients are counted and how negative-symptom burden is defined. One post hoc analysis restricted the sample to 64 of 640 participants who had prominent negative symptoms without predominant positive symptoms at baseline. Using the Positive and Negative Syndrome Scale (PANSS) Marder Negative Factor Score, the effect size in that subgroup was 1.18 versus 0.42 in the full pooled sample; the authors considered the finding preliminary because the subgroup was small.¹ A subsequent post hoc analysis took the opposite approach, keeping the full pooled population and applying two different definitions of prominent negative symptoms to examine whether response varied by baseline severity.⁴

Response Was Larger, Not Smaller, With Greater Negative-Symptom Severity

The analysis performed by Halassa et al.⁴ included the full pooled population of 640 participants. Response was defined as ≥30% improvement in PANSS total score at week 5, under two negative-symptom definitions.⁴ Under EPA-5 (≥2 of 7 PANSS negative items rated moderately severe or higher), 44.8% of patients with prominent negative symptoms responded on xanomeline-trospium versus 15.7% on placebo; non-prominent patients responded at 40.6% versus 22.3%. EPA-4 (≥3 items rated moderate or higher) showed a smaller treatment-placebo difference: prominent patients responded at 43.5% on xanomeline-trospium versus 20.5% on placebo, and non-prominent patients responded at 38.3% versus 21.3%.⁴ The treatment-placebo difference was larger for the prominent than non-prominent subgroup under both definitions; however, no treatment-by-severity interaction was tested statistically, so this pattern is descriptive rather than evidence of effect modification. Much of the widened gap under EPA-5 came from a lower placebo response in the prominent subgroup (15.7% vs 22.3%) rather than a higher response on xanomeline-trospium (44.8% vs 40.6%).⁴

Across the four subgroups, 66.9% to 68.8% of patients on xanomeline-trospium and 44.3% to 53.1% on placebo had ≥1 treatment-emergent adverse event, with no treatment-emergent adverse event leading to death.⁴ In the pooled population, gastrointestinal events were the most common treatment-related adverse events, led by nausea (17.1% vs 3.2% on placebo).² Across the severity definitions examined, greater negative-symptom burden was associated with a larger, not smaller, treatment-placebo difference.

Network Meta-Analyses Do Not Show an Advantage Over Other Antipsychotics

Two network meta-analyses have indirectly compared xanomeline-trospium with other antipsychotics on negative-symptom outcomes. A Bayesian network meta-analysis incorporating eight oral antipsychotics found no credible evidence that the effect of xanomeline-trospium on negative symptoms differed from any comparator, though point estimates were numerically favorable for several.⁵ A frequentist analysis of 23 antipsychotics found its effect against placebo within the range reported for the other antipsychotics, without evidence of superiority.⁶ Both analyses draw on the same three EMERGENT trials for the xanomeline-trospium data, so their concordant findings do not constitute independent replication.

The Evidence Supports Activity, Not Superiority

A larger effect in patients with prominent negative symptoms is not the same as an advantage over other antipsychotics, and the available evidence does not establish superiority. The pooled EMERGENT trials were placebo-controlled with no active antipsychotic comparator, so they cannot directly test superiority over another antipsychotic; the absence of a comparison is not evidence of no difference.³ Separately, neither network meta-analysis found a credible difference from other agents on negative-symptom outcomes. Within the prominent negative-symptom subgroup, the treatment effect held at weeks 4 and 5 after changes in positive symptoms, disorganization, depression/anxiety, and hostility were entered as covariates, so negative-symptom improvement was not fully explained by improvement in those domains.¹ A prospective study with an active comparator and a prespecified negative-symptom outcome, in patients selected for stable, prominent negative symptoms, would be needed to test whether its negative-symptom effect exceeds that of other antipsychotics.

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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

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

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

Whether this mechanistic difference is associated with a different motor safety profile has been a key clinical question.

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.
Financial support was provided by Bristol Myers Squibb. Psychiatrist.com independently developed the content and maintained final editorial control.

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).

Table 1. Eight-week outcomes by taper arm

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

The study also examined whether outcomes differed according to the antipsychotic participants were taking before the switch

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

Financial support was provided by Bristol Myers Squibb. Psychiatrist.com independently developed the content and maintained final editorial control.