What information is available regarding the new antipsychotic xanomeline/trospium?

Background
Schizophrenia is a severe, chronic mental disorder that typically manifests in late adolescence or early adulthood.1,2 Manifestations of schizophrenia can generally be categorized as positive symptoms, negative symptoms, or cognitive symptoms.3 Positive symptoms include hallucinations, delusions, and disorganized thinking. Negative symptoms include loss of motivation, loss of interest and enjoyment in daily activities, social withdrawal, difficulty showing emotions, and low energy or catatonia. Cognitive symptoms may include problems with attention, concentration, or memory; these symptoms may make it difficult for patients to make decisions or learn new things. A diagnosis of schizophrenia requires the presence of at least 2 of 5 key symptoms (delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms), with at least one of those symptoms being delusions, hallucinations, or disorganized speech.4 Symptoms must persist for at least 6 months.

Although the pathogenesis of schizophrenia remains unknown, the dopamine hypothesis is the most prominent theory; according to this hypothesis, schizophrenia is caused by reduced dopaminergic activity in the prefrontal cerebral region (leading to negative symptoms) and heightened dopaminergic activity in the limbic system (leading to positive symptoms).1,5 In line with this hypothesis, most of the currently available antipsychotic medications exert their therapeutic effects by acting as dopamine D2 receptor antagonists.6 However, limitations to the dopamine hypothesis have been noted, and despite the availability of numerous antipsychotic medications, approximately one-third of patients are resistant to conventional treatments.2,5 These factors have prompted investigation into the potential role of other neurotransmitter systems in the pathophysiology of schizophrenia.

Acetylcholine has been identified as a potential target for schizophrenia drug development.7 Acetylcholine regulates dopaminergic, glutamatergic, and gamma-aminobutyric acid (GABA)-ergic signaling in the central nervous system.5 In particular, the muscarinic acetylcholine receptors (M1 through M5) play essential roles in regulating cognition and the development of psychosis and addiction. Interest in acetylcholine as a drug target was spurred in part by the distinctive actions of clozapine, an existing drug that is known to be effective in treatment-resistant schizophrenia.1,7 Clozapine has minimal D2 antagonist activity, but it is a potent anticholinergic; it was therefore hypothesized that targeting cholinergic receptors may be an alternative method to treat symptoms associated with schizophrenia.

Xanomeline/Trospium for Schizophrenia
In September 2024, xanomeline/trospium was approved for the treatment of schizophrenia in adults.8 Xanomeline/trospium is the first antipsychotic that targets cholinergic receptors as opposed to dopamine receptors. Xanomeline is a muscarinic receptor agonist, specifically acting on M1 and M4 muscarinic receptors in the brain.9 Actions at the M1 receptor lead to increased dopamine release in the hippocampus and prefrontal cortex, resulting in decreased cognitive and negative symptoms.5,7 Actions at the M4 receptor inhibit dopamine release in the substantia nigra, nucleus accumbens, and ventral striatum, leading to reductions in positive symptoms. Trospium is a nonselective anticholinergic drug that cannot pass the blood-brain barrier; it does not interfere with the action of xanomeline in the brain, but prevents the action of xanomeline in the periphery and thereby decreases the incidence of cholinergic side effects.9

The efficacy of xanomeline/trospium is supported by data from 3 randomized, double-blind, placebo-controlled inpatient trials (EMERGENT-1, EMERGENT-2, and EMERGENT-3).10-12 Results of these trials are summarized in the Table below. Briefly, all 3 studies found that xanomeline/trospium was more effective than placebo for reducing the total Positive and Negative Syndrome Scale (PANSS) score in patients with schizophrenia. The PANSS score ranges from 30 to 210, with higher numbers indicating greater symptom severity; a score of 90 to 120 is typical for a patient with an acute psychotic episode, and a reduction in PANSS total score of at least 20% is typically considered clinically significant.13 Subscores specifically assessing the severity of positive or negative symptoms were also examined in the EMERGENT trials as secondary endpoints.10-12 Xanomeline/trospium was generally found to improve both positive and negative symptoms more effectively than placebo (although EMERGENT-3 did not find a significant difference in change in PANSS negative symptom subscore for xanomeline/trospium versus placebo). The most common adverse effects observed with xanomeline/trospium were gastrointestinal (eg, nausea, vomiting, dyspepsia, constipation). Although these trials have demonstrated promising results, they were only 5 weeks in length, and were conducted in an inpatient setting; therefore, additional studies are needed to verify the efficacy and safety of xanomeline/trospium in the long-term treatment of schizophrenia.

Comparisons of xanomeline/trospium to other antipsychotic agents are limited. A network meta-analysis compared xanomeline/trospium to aripiprazole, risperidone, and olanzapine for the short-term treatment of adults with schizophrenia.14 The analysis included 33 trials enrolling 7193 patients; the mean patient ages ranged from 34 to 46 years, and baseline PANSS scores ranged from 63 to 108. In this analysis, all 4 active drugs were more effective than placebo for symptom improvement, but no significant differences were found among active treatments. For the adverse effect of weight gain, only risperidone and olanzapine were associated with significantly increased weight gain compared to placebo; these agents were also associated with significantly greater weight gain than xanomeline/trospium. All-cause discontinuation rates were highest with xanomeline/trospium, and significantly greater with xanomeline/trospium than with olanzapine or risperidone.

Table. Overview of randomized controlled trials for xanomeline/trospium in schizophrenia.10-12
Study design and durationSubjectsInterventionsResultsConclusions
Kaul 2024a10

EMERGENT-3

Phase 3, MC, DB, PC, RCT

5 weeks		N=256 adult inpatients aged 18 to 65 years with schizophrenia

Mean age: 43.6 years (xanomeline/ trospium), 42.6 years (placebo)

Mean PANSS total score at baseline: 97.3 (xanomeline/ trospium), 96.7 (placebo)		Xanomeline/trospium, flexible dose (100/20 mg twice daily to 125/30 mg twice daily) (n=125)

Placebo (n=131)		Primary:
LSM change from baseline in PANSS total score at week 5: -20.6 for xanomeline/trospium vs. -12.2 for placebo (difference, -8.4; 95% CI, -12.4 to -4.3; p<0.0001)

Secondary:
LSM change from baseline in PANSS positive symptom subscore at week 5: -7.1 for xanomeline/trospium vs. -3.6 for placebo (difference, -3.5; 95% CI, -4.7 to -2.2; p<0.0001)

Change from baseline in PANSS negative symptom subscore at week 5: -2.7 for xanomeline/trospium vs. -1.8 for placebo (difference, -0.8; 95% CI, -1.9 to 0.2; p=NS)

Change from baseline in CGI-S score at week 5: ‑1.1 for xanomeline/trospium vs. -0.6 for placebo (difference, -0.5; 95% CI, -0.8 to -0.3; p<0.0001)

PANSS response (≥30% reduction from baseline in PANSS total score) at week 5: 50.6% for xanomeline/trospium vs. 25.3% for placebo (difference, 25.4%; 95% CI, 10.8 to 38.6; p=0.0056)

Safety:
AEs occurred in 70.4% of patients who received xanomeline/trospium and 50% of patients who received placebo

The most common AEs in the xanomeline/ trospium group were nausea (19.2%), dyspepsia (16%), vomiting (16%), constipation (12.8%), hypertension (6.4%), and diarrhea (5.6%)

Rates of discontinuation due to AEs were similar between groups

Weight gain and EPS were similar between groups		Xanomeline/ trospium was more effective than placebo for reducing schizophrenia symptoms.
Kaul 2024b11

EMERGENT-2

Phase 3, MC, DB, PC, RCT

5 weeks		N=252 adult inpatients aged 18 to 65 years with schizophrenia

Mean age: 45.6 years (xanomeline/ trospium), 46.2 years (placebo)

Mean PANSS total score at baseline: 98.3 (xanomeline/ trospium), 97.9 (placebo)		Xanomeline/trospium, flexible dose (100/20 mg twice daily to 125/30 mg twice daily) (n=126)

Placebo (n=126)		Primary:
LSM change from baseline in PANSS total score at week 5: -21.2 for xanomeline/trospium vs. -11.6 for placebo (difference, -9.6; 95% CI, -13.9 to -5.2; p<0.0001)

Secondary:
LSM change from baseline in PANSS positive symptom subscore at week 5: -6.8 for xanomeline/trospium vs. -3.9 for placebo (difference, -2.9; 95% CI, -4.3 to -1.5; p<0.0001)

Change from baseline in PANSS negative symptom subscore at week 5: -3.4 for xanomeline/trospium vs. -1.6 for placebo (difference, -1.8; 95% CI, -3.1 to -0.5; p=0.0055)

Change from baseline in CGI-S score at week 5: ‑1.2 for xanomeline/trospium vs. -0.7 for placebo (difference, -0.6; 95% CI, -0.9 to -0.3; p<0.0001)

PANSS response (≥30% reduction from baseline in PANSS total score) at week 5: 55% for xanomeline/trospium vs. 28% for placebo (difference, 27%; 95% CI, 13 to 39; p<0.0001)

Safety:
AEs occurred in 75% of patients who received xanomeline/trospium and 58% of patients who received placebo

The most common AEs in the xanomeline/ trospium group were constipation (21%), dyspepsia (19%), nausea (19%), vomiting (14%), hypertension (10%), dizziness (9%), and GERD (6%)

Rates of discontinuation due to AEs were similar between groups

Weight gain and EPS were similar between groups		Xanomeline/ trospium was more effective than placebo for reducing positive and negative schizophrenia symptoms.
Brannan 202112

EMERGENT-1

Phase 2, MC, DB, PC, RCT

5 weeks		N=182 adult inpatients aged 18 to 60 years with schizophrenia

Mean age: 43.4 years (xanomeline/ trospium), 41.6 years (placebo)

Mean PANSS total score at baseline: 97.7 (xanomeline/ trospium), 96.6 (placebo)		Xanomeline/trospium, flexible dose (100/20 mg twice daily to 125/30 mg twice daily) (n=90)

Placebo (n=92)		Primary:
LSM change from baseline in PANSS total score at week 5: -17.4 for xanomeline/trospium vs. -5.9 for placebo (difference, -11.6; 95% CI, -16.1 to -7.1; p<0.001)

Secondary:
LSM change from baseline in PANSS positive symptom subscore at week 5: -5.6 for xanomeline/trospium vs. -2.4 for placebo (difference, -3.2; 95% CI, -4.8 to -1.7; p<0.001)

Change from baseline in PANSS negative symptom subscore at week 5: -3.2 for xanomeline/trospium vs. -0.9 for placebo (difference, -2.3; 95% CI, -3.5 to -1.1; p<0.001)

The distribution of CGI-S scores at week 5 favored xanomeline/ trospium (p<0.001), but the proportion of patients with a CGI-S response (CGI-S score of 1 or 2) was not significantly different between groups

Safety:
AEs occurred in 54% of patients who received xanomeline/trospium and 43% of patients who received placebo

The most common AEs in the xanomeline/ trospium group were constipation (17%), nausea (17%), dry mouth (9%), dyspepsia (9%), and vomiting (9%); these AEs did not result in treatment discontinuation

Changes in weight were similar between groups		Xanomeline/ trospium was more effective than placebo for reducing schizophrenia symptoms.
Abbreviations: AE=adverse event; CGI-S=Clinical Global Impression-Severity; CI=confidence interval; DB=double-blind; EPS=extrapyramidal symptoms; GERD=gastroesophageal reflux disease; LSM=least squares mean; MC=multicenter; NS=not significant; PANSS=Positive and Negative Syndrome Scale; PC=placebo-controlled; RCT=randomized controlled trial.

Current Standards of Care
According to current guidelines, antipsychotic medications are the first-line treatment for patients with schizophrenia.6,15 In general, the choice of antipsychotic medication should be individualized based on factors such as patient preference, previous response to treatment (if known), comorbidities, and medication-specific factors (eg, side effect profile, available formulations, drug interaction potential, receptor binding profile, pharmacokinetic considerations).15 Although an individual patient may respond differently to different antipsychotic medications, evidence is insufficient to state that one medication is consistently more effective than others. If a patient does not respond to or tolerate an adequate trial of one antipsychotic medication, another antipsychotic medication should be tried.6 As previously mentioned, most available antipsychotic medications are classified as dopamine D2 receptor antagonists. Adverse effects with these agents can include extrapyramidal symptoms (eg, pseudoparkinsonian symptoms, akathisia, dystonia, tardive dyskinesia, neuroleptic malignant syndrome), sedation, anticholinergic effects, weight gain, metabolic abnormalities (eg, hyperlipidemia, diabetes), prolactin elevation, cardiovascular effects (eg, dysrhythmia, QT prolongation), and seizures.6,15 Different antipsychotic medications may be more or less likely to cause a given adverse effect; for example, first-generation antipsychotics are more likely to cause extrapyramidal symptoms, while second-generation antipsychotics are associated with weight gain and metabolic effects.

Options for patients with treatment-resistant schizophrenia (which is typically defined as moderate symptoms/impairments despite at least 2 adequate courses of treatment with different antipsychotic medications) are limited.6,15 Current guidelines recommend clozapine for patients with treatment-resistant schizophrenia; if clozapine alone is insufficient, augmentation with another second-generation antipsychotic can be tried.

Conclusion
Xanomeline/trospium represents a promising new option for the treatment of schizophrenia. Although its long-term efficacy and specific place in therapy remain to be established, it is effective for improving the symptoms of schizophrenia and it avoids the weight gain that commonly accompanies other antipsychotic medications. Its unique mechanism of action may make it a useful option for patients who do not respond adequately to dopamine D2 receptor antagonists. The gastrointestinal adverse effects may be bothersome to some patients; as mentioned in current guidelines, selection of an antipsychotic medication should be individualized based on patient preferences and other factors.

References

  1. Kidambi N, Elsayed OH, El-Mallakh RS. Xanomeline-trospium and muscarinic involvement in schizophrenia. Neuropsychiatr Dis Treat. 2023;19:1145-1151. doi: 10.2147/NDT.S406371
  2. Dudzik P, Lustyk K, Pytka K. Beyond dopamine: novel strategies for schizophrenia treatment. Med Res Rev. 2024;44(5):2307-2330. doi: 10.1002/med.22042
  3. Schizophrenia. National Institute of Mental Health. Updated December 2024. Accessed December 13, 2024. https://www.nimh.nih.gov/health/topics/schizophrenia
  4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013. Accessed December 13, 2024. https://psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596
  5. Vasiliu O, Budeanu B, Cătănescu MȘ. The new horizon of antipsychotics beyond the classic dopaminergic hypothesis-the case of the xanomeline-trospium combination: a systematic review. Pharmaceuticals (Basel). 2024;17(5):610. doi: 10.3390/ph17050610
  6. U.S. Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for management of first-episode psychosis and schizophrenia, version 2.0. U.S. Department of Veterans Affairs. Updated 2023. Accessed December 19, 2024. https://www.healthquality.va.gov/guidelines/MH/scz/VA-DOD-CPG-Schizophrenia-CPG_Finalv231924.pdf
  7. Azargoonjahromi A. Current findings and potential mechanisms of KarXT (xanomeline-trospium) in schizophrenia treatment. Clin Drug Investig. 2024;44(7):471-493. doi: 10.1007/s40261-024-01377-9
  8. FDA approves drug with new mechanism of action for treatment of schizophrenia. U.S. Food and Drug Administration. Updated September 26, 2024. Accessed December 19, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia
  9. Mills J. A new antipsychotic for schizophrenia: xanomeline and trospium (Cobenfy). Issues Ment Health Nurs. 2024:1-4. doi: 10.1080/01612840.2024.2427561
  10. Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2024;81(8):749-756. doi: 10.1001/jamapsychiatry.2024.0785
  11. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-170. doi: 10.1016/S0140-6736(23)02190-6
  12. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021 Feb 25;384(8):717-726. doi: 10.1056/NEJMoa2017015
  13. Caley CF. Schizophrenia MTM Data Set. In: Whalen K, Hardin HC. eds. Medication Therapy Management: A Comprehensive Approach. 2nd ed. McGraw-Hill Education; 2018. Accessed December 18, 2024. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2319§ionid=180053799
  14. Wright AC, McKenna A, Tice JA, Rind DM, Agboola F. A network meta-analysis of KarXT and commonly used pharmacological interventions for schizophrenia. Schizophr Res. 2024;274:212-219. doi: 10.1016/j.schres.2024.09.023
  15. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Schizophrenia. 3rd ed. American Psychiatric Association; 2021. Accessed December 19, 2024. https://psychiatryonline.org/doi/book/10.1176/appi.books.9780890424841

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

January 2025

The information presented is current as of December 12, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.