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Muscarinic in Schizophrenia PC
Beyond the Podium: Continuing the Q&A on Schizophrenia  

Released: January 13, 2026

Jonathan M. Meyer
Jonathan M. Meyer, MD, DLFAPA
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In this podcast episode, Dr Jonathan Meyer answers additional questions from learners at our Psychopharmacology Update conference. Questions explore other disease states where psychosis can occur, practical considerations around special populations, tolerability, drug combinations, and the potential future of muscarinic-based therapies. For additional activities in this program including a ClinicalThought commentary, a CME/CE/CPE certified on-demand webcast and a downloadable slideset, go to: https://deceraclinical.com/education/program/psychiatry/understanding-muscarinic-acetylcholine-receptors/52399

 

Lisa Phipps:
Welcome to the Decera Clinical Education Psychiatry and Neurology Podcast. I'm Lisa Phipps, Director of Scientific Services for Neuroscience here at Decera Clinical Education, serving as your host today. I'm pleased to be here with Dr. Jonathan Meyer, Voluntary Clinical Professor at the University of California, San Diego, and Senior Academic Advisor of the California Department of State Hospitals. Today's podcast is part of our larger program on schizophrenia, titled Decoding Dual Action: Understanding Muscarinic Acetylcholine Receptors in Schizophrenia Management, and is supported by an independent educational grant from Bristol-Myers Squibb. Hi, Jonathan, thanks for being here with us today to impart some additional wisdom.

Jonathan Meyer:
Hi, Lisa, and it's wonderful to be here.

Lisa Phipps:
At our recent Psychopharmacology Update Conference, you did a marvelous talk on schizophrenia called Dopamine Detours: New Paths for Positive, Negative, and Cognitive Symptoms. This topic is so hot right now, we could have done an entire hour just on the things people wonder about it. That being said, we're following up the talk with this podcast to continue the conversation, answering some of those additional questions and themes that continued to pop up. Let’s dive right in. Naturally, we had a lot of questions about other disease states where this medication might be used, particularly others where psychosis or schizophrenia-like symptoms can occur. We were asked about schizoaffective, schizotypal, schizophreniform, and delusional disorders, as well as psychosis associated with substance use, Parkinson’s disease, and Alzheimer’s disease. Let’s briefly differentiate these conditions and talk about treatments.

Jonathan Meyer:
Real quickly—schizotypal is a personality disorder, not a psychotic disorder, and there really aren’t medications typically used for that. Schizophreniform disorder, on the other hand, looks very much like schizophrenia; patients simply haven’t met the six-month time point. Delusional disorder resembles schizophrenia only in the sense that patients have positive symptoms in the form of delusions. If they had hallucinations, they would meet criteria for schizophrenia. What we don’t see in delusional disorder are negative symptoms or cognitive deficits, which helps distinguish it. There are no FDA-approved treatments for delusional disorder, but we approach it as a chronic psychotic disorder. When I trained, we were taught antipsychotics weren’t very effective, but we now know second-generation antipsychotics provide benefit at similar rates to schizophrenia—about two-thirds of patients.

Substance-induced psychosis should be transient and typically doesn’t warrant chronic antipsychotic therapy. Parkinson’s disease psychosis and dementia-related psychosis, such as Alzheimer’s disease, are different. We do need antipsychotic therapy there, and it’s helpful to have agents without dopamine D2 blockade. For Parkinson’s disease, the FDA-approved agent is pimavanserin, which has no D2 binding. Clozapine also has strong evidence. Quetiapine was once thought effective, but most studies failed, and it’s no longer strongly recommended.

Schizoaffective disorder is essentially schizophrenia plus an independent mood component—sometimes depression, sometimes bipolar disorder. Although few treatments are specifically approved, we treat the psychotic component just like schizophrenia. The differentiator is that patients with bipolar diathesis typically require mood stabilization, with lithium being the preferred option. Valproate is increasingly avoided due to reproductive risks.

Regarding xanomeline/trospium, it could certainly be used in schizoaffective disorder, though patients with a history of mania would still need lithium. Schizophreniform disorder is treated like schizophrenia, so it would be reasonable there as well, though not approved. The advantage across these conditions is avoiding dopamine blockade and its associated side effects—movement disorders, endocrine effects, weight gain, and metabolic disturbance.

Trials are ongoing for dementia-related psychosis. The upside is no movement disorders; the downside is trospium’s anticholinergic effects, particularly urinary retention in older men. Dose adjustments may help, and we’ll see where the data takes us.

Lisa Phipps:
That’s fascinating, and definitely more to come. Of course, people also asked about bipolar disorder, both with and without psychotic features.

Jonathan Meyer:
We’re really talking about bipolar I disorder, where psychotic mania occurs. There’s no evidence xanomeline has antidepressant properties, and its anti-manic potential is unknown. Because of the prolonged titration, it wouldn't be ideal for acute mania even if approved. It might have a role in maintenance therapy, but right now it’s not approved, and reimbursement would be unlikely. That said, we’ll stay tuned as data emerge.

Lisa Phipps:
What about special populations—pediatrics, geriatrics, pregnancy, breastfeeding?

Jonathan Meyer:
We have no data for pregnancy or lactation. Absence of data doesn’t mean harm, but it requires careful discussion. Other antipsychotics haven’t shown major congenital malformation signals, and overall, maternal stability is usually best for mother and baby. With a newer agent like xanomeline/trospium, some women may choose to switch medications during the first trimester. During breastfeeding, the lack of dopamine blockade is a benefit, but trospium may affect GI motility. Monitoring the infant is key, and dose reduction of breast milk rather than cessation can mitigate exposure.

Xanomeline/trospium could be an excellent option for adolescent-onset schizophrenia—no weight gain, no movement disorders, no endocrine dysfunction—but we don’t yet have pediatric FDA approval. For older adults, dose adjustments are recommended, and we must monitor urinary retention, especially in older men.

Lisa Phipps:
That’s particularly interesting given what we know about cumulative antipsychotic exposure in younger patients.

Jonathan Meyer:
In first-episode programs, the appeal is obvious. The downside is adherence, and people often ask about a long-acting injectable. A company has said they’re exploring it, but it’s complex given the two-drug formulation. If it happens, it would be wonderful—especially given possible benefits for cognition and negative symptoms.

Lisa Phipps:
People also asked about combining xanomeline/trospium with other medications, particularly clozapine.

Jonathan Meyer:
Adjunctive studies excluded anticholinergic antipsychotics like clozapine, olanzapine, and high-dose quetiapine, but found no safety issues combining with agents such as aripiprazole, risperidone, or paliperidone. Overall symptom reduction wasn’t dramatic, but some subgroups benefited.

With clozapine, the biology of treatment-resistant schizophrenia matters. These patients often don’t have dopamine overproduction, so adding xanomeline is unlikely to help residual positive symptoms. First, maximize clozapine levels—up to 1,000 ng/mL if tolerated—and ensure mood stabilization. Adding trospium on top of clozapine also raises significant GI and urinary risks. I would be very cautious and would not recommend switching patients off clozapine to use xanomeline/trospium based on current evidence.

Lisa Phipps:
Antidepressants came up as well—can we use them together?

Jonathan Meyer:
It hasn’t been studied, but there are no major pharmacodynamic concerns. The key issue is strong CYP2D6 inhibitors like fluoxetine or bupropion, which may require slower titration.

Lisa Phipps:
Many learners also connected cholinergic receptors with smoking in schizophrenia.

Jonathan Meyer:
There are nicotinic and muscarinic cholinergic receptors. While nicotinic receptor polymorphisms may relate modestly to cognition, muscarinic M1 deficits are strongly linked to cognitive and negative symptoms in schizophrenia. Xanomeline targets M1 and M4 receptors, and its effects are independent of smoking. Nicotinic approaches for cognition have largely failed so far.

This represents a major breakthrough—modulating the muscarinic system improves positive symptoms and may help cognition and negative symptoms. Other strategies are being explored, though managing procholinergic side effects remains a challenge.

Lisa Phipps:
That brings us to nausea management and trospium versus ondansetron.

Jonathan Meyer:
Tolerance hasn’t developed as hoped at lower doses, so titration is necessary. Most nausea occurs after dose increases. Ondansetron was used in trials, and I recommend prescribing it proactively. In some cases, increasing trospium—either via higher combo doses or supplemental trospium—can help, but urinary retention must be monitored. Flexibility is key, because this is currently the only muscarinic option available.

The effect sizes are impressive—among the strongest we’ve seen in decades—and for non-resistant patients, efficacy rivals other antipsychotics, with better tolerability.

Lisa Phipps:
It’s critical to remind people this must be taken without food, or trospium absorption is lost.

Jonathan Meyer:
Exactly. This is a major education point—for patients and caregivers. Timing matters: one hour before breakfast and two hours after dinner. Without proper administration, the medication won’t work as intended.

Lisa Phipps:
Final question—what excites you most right now?

Jonathan Meyer:
The possibility of multiple muscarinic agents in the next five years. Treating schizophrenia without D2-related adverse effects—and potentially improving cognition and negative symptoms—represents a true revolution. Hopefully, we’ll even see a long-acting injectable someday.

Lisa Phipps:
That would be marvelous. Thank you so much for joining us, Jonathan, and thanks to our listeners for tuning in. Be sure to check the show notes for additional resources on this topic.

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