COBENFY (Xanomeline–Trospium): A Cholinergic Shift in the Schizophrenia Narrative

In 2023, the FDA approved COBENFY—a fixed-dose combination of xanomeline (a centrally acting muscarinic receptor agonist) and trospium chloride (a peripheral muscarinic antagonist)—marking a paradigm shift in antipsychotic pharmacology. For the first time in decades, we have an approved antipsychotic that doesn’t work through dopamine blockade.

This article explores what COBENFY is, how it works, its clinical data, its potential, and the controversies surrounding its use—all through the lens of brain science and clinical psychiatry.

What is COBENFY?

• Approved for: Treatment of schizophrenia in adults (FDA, 2023)

• Composition:

  
  

  • Xanomeline: A muscarinic M1/M4 receptor agonist

  • Trospium: A non-selective peripheral muscarinic antagonist to reduce side effects like nausea, sweating, and GI discomfort

  
  

• Brand name: COBENFY

• Development name in trials: KarXT

• Manufacturer: Bristol Myers Squibb (originally developed by Karuna Therapeutics)

Why is it different?

Unlike all other antipsychotics which modulate dopamine (D2) receptors, COBENFY works via the cholinergic system. This is significant because:

• Cholinergic deficits (especially in M1/M4 receptors) have been implicated in schizophrenia’s cognitive and negative symptoms.

• Avoiding dopamine blockade reduces risk of extrapyramidal symptoms, tardive dyskinesia, and prolactin elevation.

This fits into a broader trend of looking beyond dopamine—similar to how research on glutamate, GABA, and gut-brain communication is reshaping our understanding of psychiatric disorders.

Clinical Trial Data

Key studies:

• EMERGENT-2 (Lancet, 2024)

• EMERGENT-3 (JAMA Psychiatry, 2024)

Design: 5-week, double-blind, placebo-controlled trials involving adults with acute schizophrenia.

Primary outcome: Change in PANSS total score

Findings:

• PANSS reduction:

  
  

  • EMERGENT-2: 21.2 points (COBENFY) vs 11.6 (placebo)

  • EMERGENT-3: 20.6 points (COBENFY) vs 12.2 (placebo)

  
  

• Improved CGI-Severity and PANSS Negative Subscale scores

  
  

• Lower risk of:

  
  

  • Weight gain

  • Extrapyramidal symptoms

  • Sedation

  
  

Common side effects:

Nausea, vomiting, constipation, dyspepsia, dry mouth, dizziness

Neuroscience Behind It

Muscarinic receptors—especially M1 and M4 subtypes—are involved in:

• Cognitive processing (M1)

• Regulation of dopaminergic activity (M4)

• Inflammatory modulation via vagus nerve pathways

This ties in with growing evidence that cholinergic dysfunction may contribute to schizophrenia, especially cognitive symptoms and treatment resistance.

Interestingly, xanomeline was originally tested in Alzheimer’s disease, but the side effects limited its use—until trospium was added to reduce the peripheral burden.

Controversies and Concerns

1. Short Trial Durations

Only 5-week data is available. Long-term effects on cognition, relapse, and functional outcomes are unknown.

2.Anticholinergic Side Effects

Despite trospium, peripheral cholinergic effects remain—especially in elderly or those with GI, bladder, or ocular comorbidities.

3.Cognitive Trade-offs?

Anticholinergic agents are often linked to cognitive decline. Though xanomeline is central and trospium is peripheral, the long-term net cognitive effect remains unclear.

4.Cost and Accessibility

Pricing may limit its use in low- and middle-income settings unless access programs expand. No generics exist yet.

Future Directions

• Ongoing studies: Use in psychosis in Alzheimer’s disease (KarXT-AD) and bipolar disorder

• Formulation changes: Extended-release versions are in the pipeline

• Real-world trials needed to assess effectiveness, side effects, and long-term functional outcomes

Final Thoughts

COBENFY represents an exciting shift—a novel mechanism, strong early data, and fewer traditional side effects. But excitement must be balanced with caution. The field needs:

• Long-term data

• Biomarker research to identify responders

• Guidelines for responsible use, especially in treatment-resistant schizophrenia

Much like the gut-brain axis opened new perspectives in anxiety and mood disorders, COBENFY may open doors in psychosis—if guided by science and ethics, not just marketing.

References

1. Hasan AH, Abid MA. Cobenfy (Xanomeline-Trospium Chloride): A New Frontier in Schizophrenia Management. Cureus. 2024;16(10):e71131. doi:10.7759/cureus.71131

2. Kaul I, et al. Lancet. 2024;403:160–70. doi:10.1016/S0140-6736(23)02190-6

3. Kaul I, et al. JAMA Psychiatry. 2024;81:749-56. doi:10.1001/jamapsychiatry.2024.0785

4. COBENFY Prescribing Information – BMS

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