It has been just over a year since xanomeline/trospium (Cobenfy) became a commercially available treatment for schizophrenia. Its approval in September 2024 was a major event, with headlines describing it as a “first new treatment for schizophrenia in decades” and the “first...new mechanism of action since the 1950s.”1,2 This kind of attention is highly unusual for a new approval to treat schizophrenia and was due to 2 disruptive features: (1) It is the first time an investigational treatment that is devoid of direct dopamine receptor activity received FDA approval, and (2) it is also the first—but by no means that last—of a new class of psychiatric medications that work by activation of central muscarinic receptors. But has it made a difference?
Looking Back: Good News
It is important to remember that this is only the beginning of what might be a new era of treatment. The first year is the beginning of a longer journey that may take years to fully understand.
Real-world use demonstrates excellent positive symptom efficacy. Xanomeline/trospium performed very well in phase 2 and 3 studies,3 but its real test happened this year. The good news is that it passed with flying colors in clinical practice.
The reliability and consistency of its positive symptom efficacy are remarkable. The feedback from clinicians and patients that I have heard has been very favorable for remarkable benefits in positive symptom response in patients who struggled with years of persistent psychosis (Sidebar).
Sidebar. Real-World Data Provide Insights
Now 1 year past the xanomeline/trospium (Cobenfy) approval, early real-world reports are beginning to offer insights into how the agent is being implemented in clinical practice.
As discussed in the accompanying commentary by Peter Weiden, MD, preliminary case reports have indicated that xanomeline/trospium can make a meaningful difference in patient care. Such a case study was published in Frontiers in Psychiatry and documented positive outcomes for patients with comorbidities (ie, tic disorder, autism spectrum disorder , tardive dyskinesia, obesity, Alzheimer dementia and aggression, and obsessive compulsive disorder).1 The authors reported on 3 cases that highlighted common real-world considerations related to tolerability, dosing, and patient selection.
One illustrative case involved an 18-year-old man who presented with auditory hallucinations with paranoia and a history of autism spectrum disorder and eye blinking tics. The patient had been treated with other antipsychotics (ie, a trial of risperidone followed by a trial of aripiprazole), both of which showed some efficacy but were discontinued due to adverse events. Xanomeline/trospium 50 mg/20 mg was initiated, with the dose eventually increased to the maximum dose of 125 mg/30 mg. The patient required treatment guidance (eg, take 1 hour before breakfast and dinner) to support tolerability and address gastrointestinal upset. Subsequently, the patient was able to return to college, “with good concentration, psychosis free, tics resolved, solid eye contact, and improved social-emotional communication and insight, even exceeding his premorbid schizophrenia baseline functioning.” His parents shared with gratitude, “We have our son back, and he’s better than ever!”1
Additional early real-world data have begun to emerge in inpatient settings. In a post hoc analysis of medical records for 24 patients who received xanomeline/trospium as add-on administration. Results indicated that approximately 40% of patients demonstrated clinically meaningful improvement, although outcome measures and responses varied across individuals.2
As case reports and postapproval efficacy and safety information continue to be reported, experts are working to explore and define best practices for its clinical use. In July 2025, a consensus panel convened to discuss practical tips and guidance for clinicians. The panel, which consisted of Ilan Melnick, MD; Erin C. Crown, MHS, PA-C; Manish Zinzuvadia, MD; Michael M. Halassa, MD, PhD, shared several key insights3:
- For appropriate patients, consider leveraging xanomeline-trospium
early on.
- Individualization is necessary and important when considering initiating and titrating the agent, balancing efficacy in addressing symptoms and tolerability issues.
- Proactively manage anticholinergic adverse events for best success.
- Leveraging cross-tritration strategies with existing antipsychotics is often necessary.
Meanwhile, as Weiden noted in the accompanying article, clinician (and patient) response to xanomeline/trospium has reflected a mixture of enthusiasm and caution. Early reports suggested that there were about 1000 filled prescriptions by the end of January 2025, with a majority of Medicaid and Medicare programs providing coverage. At the time, Adam Lenkowsky, executive vice president and chief commercialization at Bristol Myers Squibb, told investors that the “launch is really off to a strong start” and was making “very good progress achieving our access goals.”4 By March 2025, analysts were reporting a 17% growth week over week (earnest) of prescriptions. More recently, third quarter sales for the agent were reported at $43 million.5 For historical context, fluoxetine (Prozac) was estimated to generate approximately $100 million in US retail sales during its first year following approval, underscoring the different market environments and expectations surrounding first-in-class psychiatric therapies across eras.6
3. Melnick I, Crown EC, Zinzuvadia M, Halassa MM. Real-world implementation of xanomeline-trospium in schizophrenia: a consensus panel report. J Clin Psychiatry. 2025;86(4):hxtachi2509.
4. Bell J. Bristol Myers gives first peek at closely watched launch of schizophrenia drug. Biopharma Dive. February 5, 2026. Accessed December 8, 2025. https://www.biopharmadive.com/news/cobenfy-bristol-myers-sales-schizophrenia-drug-launch/739410/
6. Lilly’s Prozac U.S. Retail Sales Annualizing Ner $100 Mil. The Pink Sheet. September 19, 1988. Accessed December 17, 2025. https://insights.citeline.com/PS014299/LILLYs-PROZAC-US-RETAIL-SALES-ANNUALIZING-NEAR--100-MIL/
There is a growing consensus that many patients report better efficacy from xanomeline/trospium than prior treatments.4 There are, however, a few important caveats. For example, xanomeline/trospium is not shown to be effective for treatment-resistant schizophrenia, there are no head-to-head comparative studies, and of course there will be a range of individual therapeutic responses, just as there are for all available treatments.
There were no new safety problems during the first year. When a new drug is approved, the number of individuals exposed quickly expands and, as such, there is always the possibility that a serious safety issue will emerge that was not observed (or fully recognized) in the clinical development program. To the best of my knowledge, no new safety signals have yet emerged.5
Lessons Learned
Despite the impressive performance of the agent itself, its first-year success has been weighed down by implementation problems, in my opinion.
Sometimes xanomeline/trospium was prescribed too quickly, with anecdotal reports of high rates of early discontinuation. The initial wave of treatment initiation went to patients who were eager to get started. This makes sense, as a new mechanism offers hope for patients who have endured the shortcomings of dopamine receptor–based therapies. Likewise, many prescribers were eager to provide a new opportunity for patients, many of whom may have exhausted the pharmacologic playbook of available treatment options.
But what seems to have been forgotten are switching principles. Switching skills can make or break the outcome of a new medication, and it involves a skill set that combines technical knowledge with situational awareness. The technical knowledge pertains to pharmacodynamics and pharmacokinetics of the old medication that is being jettisoned and the new one being added to the treatment plan. Situational awareness pertains to anticipating how psychological, interpersonal, and systems factors influence results.
In the excitement surrounding the new mechanism of action, we forgot to spend time and attention on implementing switching strategies.
The bad news is actually good news for the future. It might be helpful to review basic switching principles as well as muscarinic pharmacology. The Table covers some of the key learnings and best practices.6-9
Although many of the principles remain the same for xanomeline/trospium, the new medication has a fundamentally different pharmacologic profile and will require attention. This includes education that reviews the muscarinic receptor pharmacology and the specific pharmacokinetics of this treatment, which covers 2 separate medications that need to be released in harmony. Fortunately, we have many resources.
We are OK with familiar medication risks but hate unfamiliar risks. Our brains respond very differently to known, familiar risks than to unknown, unfamiliar risks. The classic example is when our brains are much more fearful of a terrorist event than of dying in an automobile accident, despite the knowledge that the risk of dying in a car accident far exceeds the odds of a plane crash.10,11
The first-year experience with xanomeline/trospium is a great example of how these different fear and risk categorizations can factor into prescriber hesitancy to recommend a new agent or prematurely discontinue it when a patient experiences a sudden and unfamiliar adverse effect.
Let me explain. Antipsychotics, for all their faults, have been around for many years, and we know what to expect from them. We have gotten used to accommodating some really terrible events: severe akathisia, tardive dyskinesia, and medical risks from weight gain or dyslipidemia, etc. This can be desensitizing. On the other hand, xanomeline/trospium has an unfamiliar adverse effect profile based on its muscarinic affinity.
If we did a thought experiment in which a clinician without prior experience had to compare safety and tolerability profile of xanomeline/trospium and an atypical antipsychotic, it is likely that xanomeline/trospium would be the winner. Yet because these safety and tolerability issues associated with the muscarinic receptor are new and unfamiliar to us, they seem more daunting.
In addition, some clinicians who were overly enthusiastic may have jumped in without an adequate understanding of the agent’s unique pharmacology, resulting in a desire to return the more familiar issues. Likewise, patients may panic in part because dyspepsia, for example, is a new problem, whereas antipsychotic-induced parkinsonism is distressing but not as frightful because of its familiarity.
Fear of Change and Status Quo Bias
I have saved my biggest concern for last: the status quo bias. Evolution has made fear of changing a part of normal brain functioning.12 Similarly, there may be resistance to changing strongly held beliefs. We have lived with dopamine hypothesis for so long maybe we underestimated the fear of recommending anything that is not related to dopamine antagonism.
Clinicians are not alone in this bias. In my experience, patients are often frightened of change. Attempts at changing medications have led to disappointment.13,14
At the very least, I encourage all clinicians to learn more about the agent, how it works, and when it might benefit their patients.15
Concluding Thoughts
When it was approved, xanomeline/trospium was heralded as a game-changing medication, with great expectations for success. Yet adoption and growth are not as fast and vast as anticipated and warranted as a first-in-class agent.
In my opinion, what makes xanomeline/trospium remarkable is that a nondopamine muscarinic agonist seems to provide the same heft and robustness of positive symptom control without the baggage of direct dopamine blockade and all the collateral damage from this class of medication. It provides the theoretical alternative of an effective medicine to potentially help individuals who do not fully respond to the previous class of medication.
This year has shown that breaking up with the dopamine receptor does not compromise full antipsychotic efficacy. But it also demonstrates the challenges of adapting to changes in treatment practices and the need for increased education.
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. Torjesen I. Schizophrenia: US approves first new treatment in decades. BMJ. 2024; 386:q2133.
2. Kingwell K. FDA approves first schizophrenia drug with new mechanism of action since 1950s. Nat Rev Drug Discov. 2024;23(11):803.
3. U.S. Food and Drug Administration approves Bristol Myers Squibb’s Cobenfy (xanomeline and trospium chloride), a first-in-class muscarinic agonist for the treatment of schizophrenia in adults. News release. Bristol Myers Squibb. September 26, 2024. Accessed December 8, 2025. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx
4. Price MZ, Price RL. Early outpatient clinical experience with xanomeline and trospium chloride for schizophrenia: a case report. Front Psychiatry. 2025;16:1630574.
5. Correll CU, Angelov AS, Miller AC, et al. Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia. Schizophrenia (Heidelb). 2022;8(1):109.
6. Weiden PJ, Buckley PF. Reducing the burden of side effects during long-term antipsychotic therapy: the role of “switching” medications.
J Clin Psychiatry. 2007;68(suppl 6):14-23.
7. Scheifler PL, Weiden PJ. Beyond psychopharmacology: psychosocial strategies for getting the best results when switching antipsychotic medications. Postgrad Med. 2006;spec no:45-53.
8. Fabiano N, Zhou C, Wong S, et al. Switching to a muscarinic agonist to alleviate antipsychotic-induced metabolic and neuromotor adverse effects in a person living with schizophrenia. J Psychiatry Neurosci. 2025;50(4):E200-E201.
9. Weiden PJ. Switching in the era of atypical antipsychotics. an updated review. Postgrad Med. 2006;spec no:27-44.
10. Persson E, Erlandsson A, Slovic P, et al. The prominence effect in health-care priority setting. Judgm Decis Mak. 2022;17(6):1379-1391.
11. Slovic P. Perception of risk. Science. 1987;236(4799):280-285.
12. Fleming SM, Thomas CL, Dolan RJ. Overcoming status quo bias in the human brain. Proc Natl Acad Sci U S A. 2010;107(13):6005-6009.
13. Kahneman D, Knetsch JL, Thaler RH. Anomalies: the endowment effect, loss aversion, and status quo bias. J Econ Perspect. 1991;5(1):193-206.
14. Redelmeier DA, Rozin P, Kahneman D. Understanding patients’ decisions. Cognitive and emotional perspectives. JAMA. 1993;270(1):72-76.
15. Frank RG, Zeckhauser RJ. Custom-made versus ready-to-wear treatments: behavioral propensities in physicians’ choices. J Health Econ. 2007;26(6):1101-1127.
