Real-World and Long-Term Trial Data Show Xanomeline/Trospium Cuts Hospitalizations, Antipsychotic Burden in Schizophrenia

New data presented at the American Psychiatric Association (APA) Annual Meeting, held May 16-20, 2026, in San Francisco, California, provide the first real-world look at xanomeline and trospium chloride (KarXT; Cobenfy) since its US Food and Drug Administration (FDA) approval, alongside pooled long-term safety findings from 2 phase 3 open-label trials. Together, the 3 posters describe how the drug is being used in practice, its effect on health care utilization and costs, and its cardiometabolic and urinary safety profile over 52 weeks of continuous treatment.

Xanomeline and trospium chloride combines the dual M1/M4-preferring muscarinic receptor agonist xanomeline with the peripherally restricted pan-muscarinic receptor antagonist trospium chloride. The combination was approved by the FDA in 2024 for the treatment of schizophrenia in adults, representing a mechanism distinct from the D2 dopamine receptor antagonism that has anchored antipsychotic treatment for decades and that carries well-documented risks of cardiometabolic disturbance and extrapyramidal or other movement disorders.

Real-World Treatment Patterns and Outcomes

The first analysis, led by Jose M. Rubio, MD, of Northwell Health, used administrative claims from the Komodo Research Database (January 1, 2016-August 31, 2025) to characterize adults with schizophrenia who initiated KarXT in the months following its approval. The final cohort included 2613 adults with a mean age of 43.4 years; 62% were male. Insurance coverage skewed toward public payers, with 48% covered by Medicare and 37% by Medicaid.

Baseline comorbidity burden was substantial. Anxiety disorders were present in 54% of patients, depressive disorders in 45%, and substance-related and addictive disorders in 38%. Cardiometabolic conditions were also common at baseline, including dyslipidemia (44%), hypertension (42%), obesity (34%), and type 2 diabetes (28%). Prior antipsychotic use was extensive: 95% had used an oral antipsychotic and 41% a long-acting injectable in the 12 months before KarXT initiation, and 49% were on 3 or more distinct antipsychotic agents at the time of KarXT initiation.

Adherence and persistence were moderate to high over an average observation period of 150.1±71.4 days. Proportion of days covered (PDC) was 0.77±0.26 overall, with 59% of patients achieving PDC of 0.8 or greater. Kaplan-Meier analysis showed 65.5% of patients remained persistent on KarXT through month 5.

Initiation of KarXT was associated with statistically significant reductions in use of other antipsychotics and select mental health medications. Rates of oral antipsychotic use fell (rate ratio [RR], 0.77; 95% CI, 0.74-0.79; P<.001), as did long-acting injectable antipsychotic use (RR, 0.80; 95% CI, 0.76-0.84; P <.001), mood stabilizer use (RR, 0.94; 95% CI, 0.90-0.99; P =.009), and anticholinergic use (RR, 0.85; 95% CI, 0.81-0.90; P <.001). Rates of antidepressants, anxiolytics, anticonvulsants, and opioids did not differ significantly pre- vs post-initiation.

Health care resource utilization also declined. All-cause hospitalizations fell significantly post-initiation (RR, 0.92; 95% CI, 0.89-0.95; P <.001), as did mental health-related (RR, 0.91; 95% CI, 0.87-0.95; P <.001) and schizophrenia-related hospitalizations (RR, 0.92; 95% CI, 0.86-0.97; P =.003). Emergency department and outpatient visit rates showed similar reductions across all-cause, mental health-related, and schizophrenia-related categories. Total medical costs decreased significantly for mental health-related (mean difference, -$2563; 95% CI, -$4588 to -$537; P =.013) and schizophrenia-related care (mean difference, -$2140; 95% CI, -$3973 to -$307; P =.022), though the all-cause total medical cost reduction did not reach significance (mean difference, -$1488; 95% CI, -$3143 to $167; P =.078). Pharmacy costs excluding KarXT itself decreased significantly (mean difference, -$2188; 95% CI, -$3396 to -$981; P <.001).

The authors noted limitations inherent to claims-based analysis, including limited post-initiation follow-up given the drug's recent approval and the inability to confirm medication was taken as dispensed or to capture clinical reasons for discontinuation.

Long-Term Metabolic and Cardiovascular Safety

A second poster, led by James Appio of Bristol Myers Squibb, pooled safety data from the 52-week, open-label phase 3 EMERGENT-4 and EMERGENT-5 trials to characterize long-term metabolic and cardiovascular tolerability. The pooled safety population included 718 participants with a mean baseline body mass index of 29.5 kg/m2 and hemoglobin A1c (HbA1c) of 5.8%, indicating some baseline cardiometabolic risk. By last dose, 71.4% of participants were on the highest KarXT dose (125 mg/30 mg twice daily).

Body weight decreased over the 52-week treatment period, with a mean change from baseline of -2.13±6.1 kg; 17.6% of participants lost 7% or more of body weight, compared with 4.1% who gained 7% or more. Cholesterol and triglyceride levels trended favorably, with fewer participants above the upper limit of normal at last assessment than at baseline (cholesterol, 28.3% vs 33.7%; triglycerides, 11.8% vs 16.2%). HbA1c remained essentially stable (55.4% abnormal at last assessment vs 54.7% at baseline), and prolactin levels decreased by a mean of 3.1±15.0 μg/L.

Cardiovascular changes were small and transient. Mean supine heart rate increased 2.3 beats per minute from baseline to week 52, peaking at week 2 before partially attenuating. Supine systolic and diastolic blood pressure increased by a mean of 1.7 mmHg and 1.3 mmHg, respectively, peaking at day 8 before also partially resolving with continued treatment. Hypertension-related treatment-emergent adverse events (TEAEs) occurred in 10.2% of participants (73/718) and tachycardia-related TEAEs in 4.2% (30/718). One cardiovascular TEAE was classified as serious: a 36-year-old man experienced grade 3 angina pectoris on day 46 requiring hospitalization, judged unrelated to study treatment, with recovery after a 1-day treatment interruption. Nine participants discontinued due to cardiometabolic TEAEs, including 4 for hypertension and 1 each for syncope, prolonged QT interval, increased heart rate, and atrioventricular block.

Urinary Retention and Related Adverse Events

Because trospium chloride's peripheral antimuscarinic activity carries a labeled contraindication in patients with urinary retention, a third poster, led by Scott Vuocolo of Bristol Myers Squibb, conducted a post hoc analysis of urinary-related TEAEs specifically within the 566-participant EMERGENT-5 safety population, with subgroup analysis by sex and age (younger than 55 years vs 55 years or older).

Urinary retention TEAEs occurred in 2.8% of participants (16/566) and treatment-related adverse events (TRAEs) in 2.5% (14/566). Rates were similar between men and women (TEAEs, 2.9% vs 2.6%; TRAEs, 2.4% vs 2.6%) but higher among participants 55 years or older than younger participants (TEAEs, 4.6% vs 1.9%; TRAEs, 3.6% vs 1.9%). Urinary tract infection (UTI) TEAEs occurred in 3.2% of participants (18/566) overall and were more common in women than men (5.8% vs 1.9%), although TRAE rates for UTI were identical between sexes (0.5% each). Most urinary TEAEs of interest were mild or moderate in severity, and median duration ranged from 7 days for dysuria to 38 days for urinary hesitation.

What This Means in Practice

Taken together, the 3 analyses suggest that early real-world adopters of KarXT, who by the claims analysis carried a heavy prior burden of antipsychotic polypharmacy and cardiometabolic comorbidity, experienced meaningful reductions in concomitant antipsychotic and anticholinergic use alongside fewer hospitalizations and outpatient visits after starting treatment. The pooled trial data reinforce that these utilization gains occurred without the cardiometabolic tradeoffs historically associated with D2-antagonist antipsychotics: weight, cholesterol, and triglycerides trended favorably or remained stable over a full year of treatment, and the small increases observed in heart rate and blood pressure were transient. The urinary safety data indicate that, consistent with trospium's known pharmacology, clinicians should anticipate a modestly elevated risk of urinary retention in older patients specifically, while reassuring most patients that urinary adverse events, when they occur, are typically mild and time-limited.

The real-world analysis's authors cautioned that the observation period remains short given KarXT's recent approval, and that future studies with longer follow-up are needed to confirm whether the adherence, persistence, and cost patterns observed in the first several months after launch hold up over time. The EMERGENT-4/EMERGENT-5 pooled safety analysis and the EMERGENT-5 urinary retention analysis both draw on data collected before FDA approval, providing a longer-term safety window that real-world claims data cannot yet match, and together the 3 posters offer clinicians converging evidence, from both practice and trials, on how KarXT performs outside the original 5-week acute registration studies.

References

1. Rubio JM, Zhong Y, Gillard K, Gao C, Laliberté F. Real-World Use of Xanomeline and Trospium Chloride in Schizophrenia: Patient Characteristics, Treatment Patterns, and Outcomes. Poster APA 4683. Presented at: American Psychiatric Association Annual Meeting; May 16-20, 2026; San Francisco, CA.

2. Vuocolo S, Radhakrishnan R, Nicolas P, Elias M, Thorpe A. Occurrence of Urinary Retention-Related Adverse Events With Xanomeline and Trospium Chloride: Results From the 52-Week Open-Label EMERGENT-5 Trial. Poster APA 4493. Presented at: American Psychiatric Association Annual Meeting; May 16-20, 2026; San Francisco, CA.

3. Appio J, Radhakrishnan R, Nicolas P, Vuocolo S, Kramer K. Long-term Metabolic and Cardiovascular Safety and Tolerability With Xanomeline and Trospium Chloride: Pooled Results From EMERGENT-4 and EMERGENT-5. Poster APA 4653. Presented at: American Psychiatric Association Annual Meeting; May 16-20, 2026; San Francisco, CA.

4. Cobenfy [package insert]. Princeton, NJ: Bristol Myers Squibb; 2026.