What is the Place of Muscarinic Receptor Modulators in the Clinical Care of Patients With Schizophrenia?

Christoph Correll, MD
Professor of Psychiatry and Molecular Medicine
The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Hempstead, NY

Christoph Correll, MD, Professor of Psychiatry at the Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, and Chair of the Department of Child and Adolescent Psychiatry at Charité University, Berlin, Germany. Dr. Correll is an internationally recognized expert in schizophrenia and related disorders, with a focus on the identification, characterization, and treatment of severe psychiatric conditions.

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Transcript

[00:00 – 04:59] The Place of Muscarinic Modulators in Schizophrenia Treatment

Hello, I’m Dr. Christoph Correll, and today I’ll be talking about what is the place of muscarinic receptor modulators in the clinical care of patients with schizophrenia. Since 26th of September, 2024, we have a new class of antipsychotics available to us. That is revolutionary in my mind because for seven decades, we’ve only had postsynaptic dopamine blockade as our only answer to a presynaptic hyperdopaminergic problem.

These medications, both full postsynaptic dopamine receptor antagonists and also the two partial agonists, have been foundational for the treatment of schizophrenia and other psychotic disorders. However, they’ve also had downsides. We know that not everyone who is treated with a postsynaptic dopamine receptor blocker can respond in terms of positive symptom reduction, and that may be related to the fact that not only postsynaptic dopamine receptors are blocked, but also presynaptic autoreceptors, which might, again, disinhibit some of the presynaptic dopamine tone.

There may also be subtypes of people with schizophrenia that have an EIM balance, excitation inhibition between too much glutamatergic input into the midbrain and maybe too little GABA-ergic attenuation of that glutamatergic signal. Now, with the M1M4 agonist, xanomeline-trospium, we have a tool in our hands that reduces presynaptic dopamine as being a presynaptic answer to a presynaptic problem rather than having a postsynaptic answer. Moreover, our current antipsychotics, as we knew them for seven decades, the postsynaptic dopamine blockers, also have some specific side effects that we all know and patients often dislike and which also can reduce quality of life and functioning.

What are these big five side effect clusters? You know them. It’s one, neuromotor side effects, so that would be dystonia, parkinsonism, akathisia, and tardive dyskinesia. We have also weight gain.

There is cardiometabolic side effects. There is dopamine blockade-related increase in prolactin and sexual side effects, and there is also either over sedation or insomnia. None of these five side effects are part of the muscarinic agonist or positive allosteric modulator class, so when we stimulate either M1 and M4 receptors or M4 receptors, we have antipsychotic effects, presynaptic reduction of dopamine tone without any of the baggage of these side effects that we know.

[05:00 – 06:59] Advantages of Muscarinic Modulators Over Traditional Antipsychotics

There are new side effects that are mostly gastrointestinal in nature. We have nausea and vomiting as the two procholinergic side effects, for example, with xanomeline-trospium, and we also have anticholinergic side effects with trospium, which is a peripherally restricted anticholinergic, and that would be dry mouth, constipation, and dyspepsia. These side effects, though, seem to resolve within the first or emerge in the first two weeks and then resolve by week three.

How would we use this new class of medications? Well, xanomeline-trospium as the first member of this class is approved at the moment for monotherapy in the treatment of schizophrenia. There are ongoing trials to look at the value of adding a muscarinic agonist to ongoing postsynaptic dopamine blocking medications, which could be synergistic, where there may be an additional need to reduce the hyperdopaminergia. So this combination treatment may be something that we will use in the future, but we surely will have a period where there is often an overlap, because when we stop the current antipsychotic, that may not be sufficient.

We don’t do this cold turkey, but we would have an overlapping switch, most likely, to the muscarinic agonist. These studies have not been done how to best switch, but I would say most likely we would do a similar switch strategy as when we’re switching overlappingly or with a cross titration from a partial D2 agonist to a full antagonist to a partial D2 agonist. Which combination should we be careful about and shouldn’t be a combination that is permanent? That is combining the xanomeline-trospium with a anticholinergic antipsychotic, and those are the three “pines” that would be olanzapine, quetiapine, or clozapine. So here the positive allosteric modulator would not have a problem like amraclidin as an example, because it doesn’t have an anticholinergic built in. Who are the candidates for muscarinic agonists in our current treatment paradigm? Well, often patients are on an inpatient unit started on olanzapine or risperidone to get people out of the hospital quickly, and there may be good efficacy, but also emerging side effects that could be problematic long term. So here a very strong muscarinic agonist or modulator would be a nice option to switch people over while they’re still having some residual symptoms maybe, and we want them to be on long-term treatment with very little of the side effects that we know from the current antipsychotics.

Also, since there are data that at least the M1 agonist xanomeline could potentially help cognitive dysfunction, here we could also give it particularly to patients that need cognitive improvement. What about secondary cognitive and negative symptoms due to too much postsynaptic D2 blocker treatment? That makes sense.

[07:00 – 08:29] Clinical Application: Switching and Combination Strategies

When we switch over, we may release some of this subtle anti-dopaminergic-related symptomatology. Do we want to use these medications, muscarinic modulators, early in the phase of the illness? Well, potentially yes, because we don’t know how much the dopamine blockade may lead to upregulation postsynaptically and could maybe affect the overall outcome, and this all also needed to be studied much more. I already mentioned that the new class of muscarinic modulators doesn’t have any of the five big side effects, neuromotor, like dystonia, akathisia, parkinsonism, TD, prolactin elevation, and sexual side effects, weight gain and metabolic abnormalities, or sedation and insomnia. And when we have patients who have good antipsychotic control but have these side effects, we may want to switch to a member of the muscarinic modulators that doesn’t have any of these side effects built into the molecules.

Whether or not muscarinic modulation can also help us to treat current treatment-resistant schizophrenia and maybe replace clozapine or could be a candidate before we go to clozapine is unclear, but norclozapine actually is an M1M4 agonist, and these data need to be collected, and certainly we will try this new class, particularly in patients where the older class is not as helpful. We have to be also aware of what to not do. Since the muscarinic agonism is relevant for efficacy, we should avoid pancholinergic treatments, so anticholinergics that are given for the treatment of extrapyramidal symptoms should be stopped because they might either reduce the efficacy centrally, but also for xanomeline-trospium add to the anticholinergic burden. Also, we shouldn’t add xanomeline-trospium to olanzapine, quetiapine, or clozapine because that could add to the peripheral anticholinergic side effects.

[08:30 – 09:29] Expanding Uses of Muscarinic Modulators in Psychiatry

And then there is a future potential use of the muscarinic agonist or receptor activator class for conditions where there’s too much presynaptic dopamine or where the current dopamine receptor blockers have been effective. Examples might be Parkinson’s psychosis, Alzheimer’s dementia-related psychosis, bipolar mania, agitation and aggression associated with bipolar disorder or schizophrenia or Alzheimer’s dementia, irritability associated with autism, impulsive aggression associated with ADHD or tic disorders.

But this is all future music because currently the first member of the class, xanomeline-trospium an M1M4 agonist is only approved for schizophrenia, but there’s big potential for this class to help patients with schizophrenia and potentially also other psychiatric disorders. Thank you for attention and I hope that this was helpful information.