Considerations for Incorporating Muscarinic Agonists Into Schizophrenia Treatment

While dopamine-blocking antipsychotics have long been used for the treatment of schizophrenia, the 2024 Food and Drug Administration (FDA) approval of xanomeline-trospium brought attention to the promise of muscarinic receptor-based options. In this video, Psych Congress Elevate Co-Chair and Scientific Director Craig Chepke, MD, DFAPA, shares an overview of some of the most promising clinical findings regarding muscarinic receptor activators. With a focus on treatment-resistant patients, Dr Chepke also flags potential challenges or considerations clinicians should be aware of as they integrate these newer treatment options into their practice.

For more expert insights, visit the Schizophrenia Excellence Forum right here on Psych Congress Network. 

Hear more from Dr Chepke at the 2025 Psych Congress on September 17-21 in San Diego, CA. 

Read the Transcript

Craig Chepke, MD, DFAPA: Hi, my name's Craig Chepke. I'm the medical director of Excel Psychiatric Associates in Huntersville, North Carolina. I'm also an adjunct associate professor of psychiatry for Atrium Health in Charlotte, North Carolina, and I'm also the scientific director of the Psych Congress event portfolio.

Psych Congress Network: What have been some of the most promising clinical findings regarding muscarinic receptor activators, and how do they compare to traditional antipsychotic treatments in addressing both positive and negative symptoms of schizophrenia? 

Chepke: Understanding the proposed mechanism of the muscarinic activators, along with the clinical trial data, is very interesting, because we see some differences and some potential differences that we may not be able to discern from the trials. Now, in terms of positive symptoms and overall symptoms in the Positive and Negative Syndrome Scale (PANSS), we do see robust reductions in the overall PANSS score on par with some of the largest that we've seen with other antipsychotics historically. 

That is actually really important because in the past decade or two, there's been a rising tide of the placebo response which has shrunk the difference between the medication and placebo, whereas for the muscarinic activator, the muscarinic agonist M1, M4 of xanomeline-trospium, there was a very large effect size in the range of 0.6, which is on par with the best antipsychotics back in the heyday in the 1980s and ’90s. Not only that, if you break down into the different scales—the positive subscale, negative subscale, general psychopathology subscale—there are robust reductions in all of them, but particularly impressive are the negative symptom reductions. Now, these trials were not designed to look at people with prominent negative symptoms, so we can't really say that there is a differential effect, but this is some hypothesis generating data that could lead us to believe it could be beneficial there. 

Given the fact that this is a mechanism that doesn't reduce dopamine release in the frontal cortex, which does happen with the dopamine blocking antipsychotics, that could cause negative symptoms that are secondary to that dopamine blockade. You don't have that with muscarinic agonists. On top of that, xanomeline was initially studied for improvements in cognition in Alzheimer disease before it was put on the shelf for many years and then resurrected to become the xanomeline-trospium combination. Therefore, we would think it could have cognitive benefits in schizophrenia. 

If you stratify the results—which was done by the company that developed it in a post hoc analysis—by those who have a greater than average reduction in cognitive performance versus those who have a more normal level of cognitive dysfunction, those with greater cognitive dysfunction had a much bigger improvement in their cognitive functioning. So, that leads us to believe that there could be some cognitive benefits, which again is congruent with the potential MOA. And that's really exciting. A full 25% of people with schizophrenia have what we call the Muscarinic Receptor Deficit Syndrome, where that 25% has 75% less muscarinic receptors than the average individual. That would be a great subtype to look at for treatment with this new medication, because if you have someone with schizophrenia who you know has prominent consistent cognitive deficits, I would really want to try this medication with those individuals as a first step before some other individuals.

PCN: What challenges or considerations should clinicians be aware of when incorporating muscarinic receptor-based treatments into their practice, particularly in patients with treatment-resistant schizophrenia? 

Chepke: Despite the promise of the muscarinic agonists and other activators, there are some challenges that we're going to have to face in order to utilize these well in our practice. We're going to have to learn a different set of side effects that we have to look at. The first medication, xanomeline-trospium, is a twice daily medication, and there are food restrictions: there shouldn't be food eaten 1 hour before or 2 hours after [taking the medication]. That's really important because food intake within that time frame will severely decrease the availability of the trospium component, almost 90% or so, and that's what balances out a lot of the pro-cholinergic side effects of it. So, eating with this medication could increase the GI side effects dramatically. 

Another important factor is that because we're trying to get pro-cholinergic effects centrally to have that M1/M4 agonism, if the individual is taking something that is anticholinergic, we don't have data, but logically it makes sense that it would block or at least severely attenuate the potential efficacy of the medication. Unfortunately, individuals with schizophrenia very commonly are on anticholinergic medications, whether that's something like benztropine for a movement disorder or prophylactic use to prevent a movement disorder with an antipsychotic and then they just never got taken off of it. Or it could be that they're on a current antipsychotic medication that does have anticholinergic effects—olanzapine would be one of those. But also, a population in which we may be using the xanomeline-trospium a lot initially, because this is what we do with all medications, is the people who have had the least success. 

For treatment resistance schizophrenia, there's one medication that's approved, and that is clozapine. Clozapine is also very strongly anticholinergic as well. We can't do a traditional cross-taper where we start the new medication while the old medication is still on board if it has anticholinergic effects, like an olanzapine, like a clozapine, because that's going to block the efficacy, we believe, of these xanomeline-trospium combination. We're going to have to get them entirely off of those medications before we start the new xanomeline -trospium combination and any other subsequent pro-muscarinic acetylcholine receptor activators.

So that's going to take some knowledge of deprescribing. That’s very important because too quick of a taper of an anticholinergic medication can lead to some muscarinic-cholinergic rebound, and that's very unpleasant. It's not life-threatening like a GABA withdrawal or alcohol withdrawal, but it's very, very unpleasant, similar to flu-like symptoms. It has to be done very slowly, cautiously over time. It's going to take some skill in the deprescribing of those medications. 

That's not even to mention over-the-counter medications such as cough and cold medications—diphenhydramine, for example—and a lot of allergy medications, even though many of them are antihistamines, they have anticholinergic effects, too. Many patients don't even tell us about over-the-counter medications they're taking because they consider it to be not a “real” medication. We're going to have to be really careful in our interviewing and making sure that we know all the medications that the individual is on and that we have a plan on how to appropriately and safely deprescribe them from those in order to have good success with the muscarinic activating medications in schizophrenia. 

Thanks so much for joining me today. I hope you check back with Psych Congress Network regularly, as we frequently update our content for schizophrenia as well as every other psychiatric disease state.

Craig Chepke, MD, DFAPA, is a board-certified psychiatrist in clinical practice as the medical director of Excel Psychiatric Associates in Huntersville, NC, and is an Adjunct Associate Professor of Psychiatry for the Sandra and Leon Levine Psychiatry Residency Program at Atrium Health. Dr Chepke is the scientific director for the Psych Congress portfolio of CME conferences, and he has been recognized as a Distinguished Fellow of the American Psychiatric Association.

© 2025 HMP Global. All Rights Reserved.

Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of Psych Congress Network or HMP Global, their employees, and affiliates.