Happy Birthday, Cobenfy: Peter Weiden, MD, Reflects on a Year’s Progress for Cobenfy

Peter Weiden, MD, reflected on the first year of clinical experience with Cobenfy following its approval for the treatment of schizophrenia, emphasizing its significance for practicing psychiatrists. He highlighted that 2024 marked the first time in over 50 years that a schizophrenia treatment with no direct dopamine receptor activity had been approved.¹ Instead, Cobenfy acts through muscarinic receptor stimulation, representing a fundamentally new mechanism of action and a regulatory acknowledgment that schizophrenia treatments were no longer limited to variations on dopamine antagonism.

Weiden noted that initial enthusiasm surrounding Cobenfy stemmed from its robust efficacy to treat positive symptoms, with clinical trial data demonstrating effects comparable to established antipsychotics such as risperidone, despite the absence of dopamine blockade.² Importantly, postapproval clinical experience over the subsequent year appeared consistent with trial findings. Clinicians reported meaningful symptomatic improvement in patients who had not responded adequately to other antipsychotics, supporting the view that Cobenfy had largely lived up to its therapeutic promise.

From a safety perspective, Weiden observed that no unexpected or serious adverse effects had emerged during broader clinical use. Gastrointestinal side effects, including nausea and vomiting, posed challenges to tolerability but were anticipated based on trial data. He emphasized that the absence of new, unforeseen risks was reassuring for a first-in-class agent.

Weiden also discussed challenges related to clinician and patient perceptions of risk, noting that unfamiliar adverse effects were often viewed as more threatening than well-known metabolic, neurologic, and endocrine risks associated with dopamine-based antipsychotics. He argued that this “novel risk aversion” underscored the need for improved education and anticipatory guidance.

Finally, Weiden expressed concern that many clinicians remained unaware of Cobenfy or its mechanism of action. While acknowledging that cautious adoption was reasonable, he stressed that lack of awareness represented a disservice to patients continuing to struggle with schizophrenia. He concluded that learning about and thoughtfully considering new mechanisms is essential as the field continues to evolve.

Dr Weiden is a clinical professor of psychiatry at the Renaissance School of Medicine at Stony Brook University in New York. He is Psychiatric Times’ Schizophrenia and Psychosis Section Editor. Dr Weiden was involved in initial research on this agent.

References

1. FDA approves drug with new mechanism of action for treatment of schizophrenia. US Food and Drug Administration. September 26, 2204. Accessed January 14, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia

2. Hasan AH, Abid MA. Cobenfy (xanomeline-trospium chloride): a new frontier in schizophrenia management. Cureus. 2024;16(10):e71131.