Chelsie Monroe, APN

On September 26, 2024, the US Food and Drug Administration (FDA) approved xanomeline and trospium chloride capsules (Cobenfy), a muscarinic agent, for 

10 months later, the future of muscarinic agents was discussed at the 2025 Southern California Psychiatry Conference (So Cal Psych) in Huntington Beach, CA, from July 11 – 12, 2025.

In this interview at So Cal Psych, Chelsie Monroe, APN, PMHNP-BC, a psychiatric nurse practitioner and founder of a group private practice, Balanced Mental Wellness in Colorado, talked about muscarinic agents—why they are exciting, their robust efficacy data, and when to consider xanomeline trospium chloride (Cobenfy) over clozapine.

 What is exciting about muscarinic agents?

This is really exciting because it's a whole new mechanism of action to use in treating schizophrenia. We're really working off of a whole new pathway, so this is cholinergic pathways to modulate dopamine, which doesn't have the same baggage as our D2 antagonists.

If a clinician is considering trying this with a patient, what should they be thinking about?

We should be thinking about a whole conglomerate of symptoms that we're wanting to improve, and so this particular medication has the opportunity to change both positive, negative, and cognitive symptoms in schizophrenia. We want to be mindful, though, that if they're on current medications for antipsychotics with their schizophrenia, that if there is an anticholinergic on board…combining that with this muscarinic agonist [can lead to] some potential changes that you need to be aware of in the muscarinic system. It's a little bit different, as this medication is typically used as monotherapy, but in reality, we're all trying to figure out how to treat schizophrenia really well, and so we need to be mindful of what other medications are on board.

What does the data show that really makes people think this is what we want to be trying?

The effect sizes of the first 3 trials that were done for Cobenfy, for this muscarinic agonist…are pretty robust. We're looking at in comparison to other antipsychotics; we see that the effect sizes are pretty up there, point 5, 6. If you look at other antipsychotics, the only outlier that's much higher than that is clozapine, which we know is really used well for treatment-resistant schizophrenia, but this has the efficacy that we're looking for in a robust antipsychotic without the baggage of metabolic syndrome, tardive dyskinesia, motor movements.

You mentioned treatment-resistant schizophrenia. What are the thoughts on using Cobenfy treatment?

I have some mixed thoughts. We always think as clinicians, ‘Oh, a new drug is out there. I'm going to use this for my most difficult client, that nothing will work for them, and now this is a new thing, let me try it.’

I want to provide some caution around that we know that about 30% of clients with schizophrenia may be treatment resistant, and that may not be solely due to a dopaminergic problem. So, there is a dopaminergic dysfunction in most patients with schizophrenia, but in those treatment-resistant cases, it may not just be dopamine; it may also be other things like glutamate. And so, there is a reason why we should provide some caution for something like clozapine.

I would definitely not rip clozapine off and try this new medication, because those folks who have met the criteria for clozapine generally can be destabilized very easily. We want to exercise some caution if you're going to use it… with clozapine…. because clozapine is highly anticholinergic, and if you're adding in an anticholinergic with this medication, you want to be really cautious that we're not causing more anticholinergic effects for the client.

Persistently around Clozapine. I'm worried about constipation and ileus, those sorts of things. And so, there's a way to potentially manage both, but I would not switch one for the other.

What advice would you give a clinician to talk to their patient who is nervous about adverse events?

I would give them reassurance that we actually have been managing schizophrenia all along with all this baggage of side effects that you have to follow for that patient's life, right? Every 6 months to a year, we're really managing metabolics. We're constantly looking for tardive dyskinesia. The long haul of this medication, you don't have some of those same concerns that I've been dealing with for the entirety of schizophrenia in my career. All I have to worry about is the first 2 weeks to a month, and that's just getting past the hump of someone potentially having cholinergic side effects that's very different than what they're used to for other antipsychotics.

I would encourage the clinician to actually have some hope and excitement and encourage the client, the patient, that this is a whole new mechanism of action. This is not your typical antipsychotic. It's not just another med that I'm giving you, that you have some predictive value of what you've been experiencing in the past. It's a whole new mechanism. Now, there may be some side effects early on, but if we can mitigate those and get you through the first couple of weeks, we may be in the clear and have the efficacy that we've been looking for all along without all the downsides.

Any other thoughts or tips that you want to share with people?

I would say have openness. You know that you really have to think critically when using these new muscarinic agonists, and it's not necessarily just an easy drug to throw at your patient. You have to think through a little bit in the beginning how to start them on the medication…our patients really do deserve the highest level of care, and getting past some of these residual positive symptoms that many of them experience, let alone the cognitive and the negative symptoms, I think that this really has the opportunity to change psychiatry, and this is the first of several that will be in the line thereafter. We really need to challenge ourselves to get used to using these agents and learning about the muscarinic system.

What else is in the pipeline, and what we might be can you talk about that?

They're looking at really isolating the different muscarinic receptors. Right now, we have an M1 M4 agonist, but there's some things in the pipeline where they're really looking at M1 specifically, M4 specifically, positive allosteric modulators…and so really there's an expansion around muscarinics right now.

There may be several molecules out there in the future that can modulate these muscarinics and dopamine pre-synaptically. That's really what we're getting to; instead of blocking everything after the fact, like a leaky basement, you've got this flood going on in your basement with dopamine. Instead of taking a bucket and throwing out that water 1 by 1 with our normal antipsychotics, we now can shut the water off at the faucet. It's exciting times be looking out there for all of the other muscarinic agents that should be coming in the future.

Derman, C. FDA Approves Xanomeline and Trospium Chloride (Cobenfy) for Schizophrenia. HCPLive. September 26, 2024. 

https://www.hcplive.com/view/fda-approves-xanomeline-and-trospium-chloride-cobenfy-for-schizophrenia

Articles

The FDA approved xanomeline and trospium chloride (Cobenfy) for schizophrenia, marking a significant advancement in treatment options. Muscarinic agents offer a novel mechanism by modulating cholinergic pathways to influence dopamine, potentially improving positive, negative, and cognitive symptoms without the side effects associated with traditional antipsychotics. While promising, caution is advised when considering Cobenfy for treatment-resistant schizophrenia, especially in patients on clozapine due to potential anticholinergic interactions. Future developments in muscarinic agents focus on targeting specific receptors, offering hope for more precise and effective treatments.

At So Cal Psych 2025, Monroe discusses the promise of xanomeline-trospium (Cobenfy) and its novel mechanism.