Clinical Pearls · 2026

Switching From Oral Atypical Antipsychotics to Xanomeline-Trospium in Schizophrenia

Switch Evaluation of Xanomeline and Trospium Chloride

Phase 4, randomized, multicenter, open-label, 8-week trial; N=105.

N = 105

patients
clinically stable

weeks randomized
open-label

n = 52

2-wk taper
faster arm

n = 53

4-wk taper
slower arm

86%

hit target dose
125/30 mg BID, n=90

discontinuations recorded
for lack of efficacy

The question:Does the pace of withdrawing the old antipsychotic matter when moving a clinically stable outpatient to xanomeline-trospium (XT) monotherapy? Reported outcome: all-cause XT discontinuation at 8 weeks. LAI users were excluded.

The Switch, Week by Week

XT dosing begins during the same visit the taper starts

XT doseBoth arms, identical

50/20

100/20

Titrate toward 125/30 mg BID as tolerated

Prior AP2-week arm (n=52)

100→50%

50→0%

XT monotherapy from week 2

Prior AP4-week arm (n=53)

100→75%

75→50%

50→25%

25→0%

XT monotherapy from week 4

Week 01234567Week 8

Doses as xanomeline/trospium mg/mg.

Trial Findings

All analyses descriptive

Adverse Events

39.0% mild

9.5%

51.4% no TEAE

Mild 39.0% · 41 Moderate 9.5% · 10 Severe 0% · 0 No TEAE 51.4% · 54

48.6% had ≥1 TEAE, none serious. Mainly nausea 13.3%, vomiting 11.4%, dry mouth 8.6%. 2.9% (n=3) stopped XT for an adverse event.

Symptom Change

PANSS change from baseline−3.1 vs −4.2Observed means; P=.40, not significant

All-Cause Discontinuation, 8 Weeks

15.4%

2-week taper arm
(8/52)

26.4%

4-week taper arm
(14/53)

Both arms combined: 21.0% (22/105); the difference between arms was not significant (P=NS). Reasons: unknown completion status 7, nonadherence 5, withdrawal 4, adverse event 3, physician decision 1, alcohol abuse 1, illegal drug use 1. Six of the 7 unknown-status cases were in the 4-week arm. The trial does not establish that one taper speed is superior to the other.

Stability held on both schedules

Similar PANSS improvement, minimal weight change (−0.3 kg vs −0.1 kg), and none recorded as discontinuing for lack of efficacy.

None recorded for worsening psychosis

No participant in either arm was recorded as discontinuing for worsening psychosis.

All TEAEs were mild or moderate

48.6% had ≥1 TEAE. No TEAE was serious, and none was severe, on either source poster.

Clinical Pearls · 2026

Practical Switching Considerations from an Expert Panel

Based on the article titled, Real World Implementation of Xanomeline-Trospium in Clinical Practice: A Consensus Report, published by The Journal of Clinical Psychiatry.

The recommendations reflect the panelists’ early clinical experience rather than study data.

Taper Duration by Prior Antipsychotic Class

Expert consensus

Bars on a common 0–21 day scale

Prior antipsychotic

Taper duration

How the panel starts XT

"-dones"High-potency D2 antagonists · Risperidone, paliperidone

2–5 days

071421 d

XT begins at 50/20 mg BID concurrently with the taper.

"-pines"Strong histaminergic / anticholinergic · Olanzapine, quetiapine, clozapine

1–3 weeks

071421 d

XT begins at 50/20 mg BID, though the panel suggests morning-only dosing at first. The dose holds until roughly 50% of the taper is done, and the PM dose is added once the "-pine" is down to a low dose.

"-azoles"D2 partial agonists, long half-lives · Aripiprazole, brexpiprazole, cariprazine

May stop rapidly

071421 d

Long half-lives cover the gap. XT begins at 50/20 mg BID without overlap.

Expert consensus, not tested in the SWITCH trial

This class-tiered schedule reflects expert-opinion consensus and was not evaluated in the SWITCH protocol, which used fixed 2- or 4-week tapers regardless of prior-antipsychotic class. SWITCH enrolled 63% (n=66) on a "-pine" and 37% (n=38) on a non-pine agent (1 not recorded), with similar outcomes across subgroups, though samples were small. The panel describes its recommendations as early clinical experience to be interpreted with appropriate caution, noting the absence of randomized head-to-head comparisons, the lack of long-term safety and functional outcome data, and the potential for practice patterns to evolve as familiarity with XT grows.

Cautions From the Trial and the Panel

Cautions

Prior quetiapine exposure

SWITCH trial

All three participants who stopped XT for an adverse event had previously received quetiapine. Interpretation is limited by the small number.

Males over 50 with BPH

Expert consensus

XT may not be an appropriate option, given the risk of urinary retention.

Clinical Pearls · 2026

Practical Switching Considerations from an Expert Panel (continued)

Four Points the Panel Watches

Expert consensus

Tolerability and monitoring

Same-visit start · four early checks

The panel recommends the prescription be filled promptly so the first dose can be taken that evening. Early monitoring: GI tolerability · symptom stability · adherence · anticholinergic burden.

Fasting administration

Trospium absorption drops with food, attenuating its peripheral anticholinergic effect.

Antiemetic on hand

Ondansetron 4 mg PRN, 14-day supply; repeat at 30 min if needed. Dopamine-antagonist antiemetics are avoided.

Anticholinergic burden

The panel reconciles Rx, OTC and supplements, swapping diphenhydramine for a non-anticholinergic sleep aid such as suvorexant, an orexin-receptor antagonist. Urinary retention, dry mouth and constipation are monitored.

Fallback plan

If decompensation occurs, the prior antipsychotic is reintroduced, with clinician-guided down-titration preferred over abrupt stopping.

Sources and Disclosures

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

Phase 4 Switch Trial analysis. All Switch analyses were descriptive; data are summarized descriptively and reported P values reflect those analyses. Safety observations are limited to 8 weeks in clinically stable outpatients. Both source posters report the same discontinuation figures; a sponsor press release for this trial reports a lower total, which traces to a completion-rate misstatement rather than to a separate analysis, so the poster figures are used here. The trial has not been published or peer-reviewed, and findings should be interpreted accordingly.

Sources: Walling D, Marbot N, Shirikjian L, et al. Poster SIRS S254, Schizophrenia International Research Society; March 25–29, 2026; Florence, Italy (NCT06924255): design, discontinuation, efficacy and safety. Walling D, et al. Same trial, ASCP Annual Meeting; May 26–29, 2026; Miami, FL: discontinuation reasons, arm-level dose attainment, and the quetiapine finding. Melnick I, Crown EC, Zinzuvadia M, et al. J Clin Psychiatry. 2025;86(4):hxtachi2509: expert consensus. Review the original sources for full detail.