Cobenfy in Practice: Hope, Hurdles, and the Next Chapter in Schizophrenia Care

The treatment landscape for schizophrenia, a discipline that has seen relatively limited therapeutic advancements, is currently undergoing a profound transformation. The introduction of xanomeline-trospium chloride, which is marketed as Cobenfy, has been celebrated as a significant breakthrough and the first significant treatment innovation in 35 years. However, clinical integration of Cobenfy is characterized by considerable uncertainty, according to a recent publication from Psychiatry Online.

Yaara Zisman-Ilani, Ph.D., from the Department of Social and Behavioral Sciences, College of Public Health at Temple University in Philadelphia, and her team drew a cautionary parallel to the introduction of previous antipsychotic medications, where significant side effects were not immediately appreciated. They cited clozapine’s approval and the subsequent case reports of tardive dyskinesia emerging later in the decade. Finally, they observed that the full extent of metabolic side effects was not initially comprehended with the approval of second-generation antipsychotics. They contend that this historical context emphasizes the necessity of exercising caution and vigilance when administering any new medication, including Cobenfy.

Cobenfy is a critical therapeutic due to its departure from conventional antipsychotic medications, which are predominantly based on dopamine receptor antagonisms. Trospium, a peripheral anticholinergic agent that alleviates peripheral cholinergic adverse effects, is combined with xanomeline, which modulates the dopaminergic system through agonism of cholinergic muscarinic M1 and M4 receptors. This mechanism is a unique feature of the drug.

During clinical trials, patients taking Cobenfy demonstrated significant improvements in positive symptoms and the total Positive and Negative Syndrome Scale score. Preliminary data also suggests potential benefits for negative symptoms. Common antipsychotic adverse effects, such as considerable weight gain, movement disorders, and drowsiness, did not differ from placebo. Because of the lack of metabolic side effects, Cobenfy may be a good option for people who cannot tolerate those side effects associated with dopamine D2 blockade.

Zisman-Ilani and team pointed out that as promising as these initial results are, the arrival of Cobenfy presents a critical challenge: integrating a groundbreaking solution when much about its long-term impact remains unknown. Available data are limited to the short, five-week trial duration, which is insufficient for fully assessing long-term efficacy or sustained adverse effects for chronic conditions like schizophrenia. Additionally, the trials excluded patients with a history of treatment resistance, those with a first episode of psychosis, and those with co-occurring medical conditions, concentrating on a specific subset of the schizophrenia population.

The efficacy of the drug was also compared with that of a placebo, which left open concerns regarding its performance in comparison to older antipsychotic medications. According to the authors, this history is a reminder to prescribers of the initial optimism that surrounded the introduction of past drugs, such as chlorpromazine in the 1950s or the introduction of second-generation agents whose metabolic side effects were not initially appreciated. Consequently, caution is necessary.

The authors suggest that schizophrenia care should prioritize choice and person-centered care in order to navigate the uncertainties surrounding Cobenfy. The personal values and preferences of patients, in conjunction with the input of providers and families, must serve as the foundation for treatment decisions.

The cornerstone of this approach is Shared Decision Making (SDM), a health communication technique that is especially effective in situations characterized by uncertainty, such as the initial prescribing of Cobenfy. The authors propose that it is imperative to incorporate patient-centered tools, particularly decision aids and decision support tools. The process is structured by these interventions, which offer patients and families comprehensive information, including information regarding what is not yet known.

Health plans should consider how their coverage policies facilitate this shift toward patient-centered care. Cobenfy’s status as a breakthrough means its coverage will be essential for patients who cannot tolerate D2 blockade-related side effects.

Cobenfy was approved in September 2024. It was developed by Karuna Therapeutics, and Bristol Myers Squibb acquired Karuna in December 2023 for about $14 billion. Cobenfy has a list price of $1,850 for a month’s supply or $22,500 annually. For the first half of 2025, BMS reported $62 million in sales for Cobenfy.