Examining Novel Treatment Methods in Schizophrenia

In this discussion, Christoph Correll, MD, professor of psychiatry and molecular medicine at the Zucker School of Medicine at Hofstra Northwell in New York, delves into the groundbreaking FDA approval of xanomeline/tropsium chloride, a novel treatment for schizophrenia that moves beyond traditional dopamine blockade. Unlike conventional antipsychotics, this combination offers a presynaptic solution to a presynaptic problem, reducing psychosis without the burden of neuromotor, metabolic, or sedation-related side effects.  

But what does this mean for patients who remain treatment-resistant? Could this new class of muscarinic modulators replace existing therapies like clozapine—or even extend to conditions beyond schizophrenia? Dr Correll unpacks the science, the clinical data, and the future potential of this transformative approach.  

Don't miss these other clinical pearls from Dr Correll:

>>Beyond D2 Receptor Manipulation: Novel Agents for Schizophrenia Treatment

>>Strategies to Manage Adverse Effects From Schizophrenia Treatment
 

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

Read the Transcript: 

Brionna Mendoza, Psych Congress Network: How do xanomeline and tropsium chloride differ from traditional pharmacological approaches to schizophrenia treatment? What questions remain about this novel treatment, and are there any additional indications that we might anticipate in the near future?

Christoph Correll, MD: There is a new era in psychiatry that started on the 26th of September 2024 when xanomeline/tropsium chloride, a combination of 2 drugs was FDA approved. Why am I saying this? Doesn't that sound a little dramatic? Well, I believe this is really a paradigm shift, particularly in psychosis treatment and research, but also, as I will explain, it will affect other indications. 
What is xanomeline/trospium? Xanomeline is an M1 M4 muscarinic receptor agonist that is paired with a peripherally restricted anticholinergic that is trospium chloride. That peripherally restricted anticholinergic is added to xanomeline itself because xanomeline targets M1 M4 receptors that are muscarinic receptors in the brain, but it's not fully selective. There are some spillover in some peripheral receptors, and that can lead to pro cholinergic side effects: nausea, vomiting, and also some blood pressure alterations. That's why this drug that was actually discovered in the 90s and tested in Alzheimer's disease patients, leading to cognitive improvement, leading to decrease in agitation and psychosis, was actually shelved because it had too many side effects.

But by adding trospium chloride, these side effects can be buffered. There is some additional anticholinergic load, which might be dry mouth, also constipation. But overall, this drug is pretty well tolerated, at least in the three, 5-week studies that had been conducted with titration. It's a 2-day starting dose of 50 milligrams xanomeline plus 20 milligrams trospium, then it goes to 5 days of 100 milligrams xanomeline and 20 milligrams trospium, and then it's all BID. And then as of day 8, there's a titration of 125 milligrams xanomeline plus 30 milligrams trospium. And overall, that was only a 1% difference in dropout for side effects. It was about 5.6% versus 4.5% on placebo. The reason why we're so excited about it is because it's a presynaptic answer to a presynaptic problem in schizophrenia and psychosis or in other conditions where there's just too much hyper dopaminergic.

So far, since the 1950s, we've had a postsynaptic answer to a presynaptic problem, meaning we have pan anti-dopaminergic drugs that yes, drop the dopamine transmission in the striatum area where we think psychosis is. But unfortunately, there's also a blockade in other areas where we need dopamine: the front lobe for thinking and for also not having negative symptoms and the reward system as a limbic pathway. And also, as you all know, we can have a spillover into the sensory motor striatum, which gives you dystonia, akathisia, parkinsonism, and tardive dyskinesia. So the xanomeline/tropsium, which is the first member of a class of muscarinic modulators or receptor activators, doesn't have any of the 5 big side effects we're used to with the postsynaptic dopamine blockers. So there is no, as I just mentioned, neuromotor side effect burden, no weight gain, no metabolic abnormalities, no postsynaptic blockade related production elevation and sexual side effects.

There's also no activation or sedation effects and no insomnia or sedation. So that's quite exciting. Yes, they're GI side effects, but they seem to emerge in the first 2 weeks, and it's usually done by about week 3. There are other muscarinic modulators that are coming that are not sitting on the receptor site where acetylcholine is, and you can have the spillover into other muscarinic receptors, but it's a positive allosteric modulator. It's on the allosteric side of the receptor, enhancing binding of endogenous acetylcholine and the transmission. So it activates again, the muscarinic system, but without having these peripheral side effects. So there's no peripheral anticholinergic needed either. So in that sense, we have a new class of medications that downtone presynaptic dopamine, which in now 3 studies with xanomeline/tropsium, one study with emraclidine, which is the M4 muscarinic positive allosteric modulator, have shown strong antipsychotic effects with effect sizes of about 0.65 pooled together for the 3 xanomeline/tropsium studies.

In the one emraclidine study about 0.68, putting that into context with about a 0.42 effect size for all antipsychotics pooled together in acutely exacerbated patients, that's what the studies were done in, and we have about a 0.55 and 0.56 effect size with risperidone or olanzapine. So in that sense, we think these are powerful medications—might actually also treat those patients that currently are not as well treated where we may still have too much presynaptic dopamine or other mechanisms of the illness. So I hope that it's not just a safer or for some patients better tolerable treatment for psychosis, but it might actually even treat patients that are currently not helped well enough. And that's being tested right now with the ARISE program where xanomeline/tropsium is added to other postsynaptic dopamine blocking, anti-psychotics that are not helpful enough, whether it's partial non-response. 

So where else could these drugs be used? Well, maybe also in treatment-resistant patients. So maybe this drug or class can replace clozapine, nor clozapine is an M1 M4 agonist. So maybe that was partly some of the secret of clozapine. We know that the M1 receptor is responsible for improving cognition. So maybe we have now at least those drugs that have an activating muscarinic M1 receptor effect can also help cognition. And then anything where our partial agonist or full antagonist were helpful outside of depression, so that would be mania. It could be TIC disorders, it could be maybe agitation in bipolar disorder or schizophrenia, agitation or psychosis and Alzheimer disease, psychosis also in Parkinson disease. So we'll see where this class will fall. But I'm very excited about having a new mechanism of action that can either stand on its own legs, having different side effects, but also different efficacy maybe for different subgroups, but also being prepared to maybe having rational polypharmacy, postsynaptic dopamine blockade in people who can partially respond to it, may also tolerate it, and then having the muscarinic agonism added to it. 

Now we'll have to find out much more in clinical care where this might fit the best, but we're in the beginning and I'm very excited about that. 

Christoph Correll, MD, is Professor of Psychiatry at The Zucker School of Medicine at Hofstra/Northwell, New York, USA, and Professor and Chair of the Department of Child and Adolescent Psychiatry, Charité University Medicine, Berlin, Germany. He is board certified in general psychiatry and child and adolescent psychiatry, having completed both residencies at The Zucker Hillside Hospital, NY. Since 1997, he has been working in New York, USA, and since 2017 he is also working in Germany again. Dr Correll focuses on the early identification and treatment of youth and adults with severe mental illness, clinical trials, epidemiology, psychopharmacology, meta-analyses, and physical health in mental health. Since 2014, the beginning of this metric, he has been listed every year by Clarivate/Web of Science as one of the “most influential scientific minds” and “top 1% cited scientists in the area of psychiatry.”