Muscarinic Acetylcholine Receptors in Schizophrenia: A Shift From Dopamine D2 to Muscarinic Agonists

In this video, Craig Chepke, MD, DFAPA, scientific director, Psych Congress, explains the vital differences between dopamine D2 receptor antipsychotics and muscarinic agonists for the treatment of schizophrenia, including mechanisms of action and side effect profiles.

Read the transcript:

Craig Chepke, MD, DFAPA: Hi, my name is 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. I'm also the scientific Director of Psych Congress.
Psych Congress Network: Can you explain the role of muscarinic acetylcholine receptors in the neurobiology of schizophrenia and how this differs from the traditional focus on dopamine D2 receptors?

Dr Chepke: Historically, the treatment of schizophrenia has revolved around fundamentally 1 receptor: the dopamine D2 receptor. Of course, antipsychotics have a lot of different other receptor binding, but every other medication approved for schizophrenia has at least had some dopamine D2 binding, either as an antagonist or partial agonist.

However, there is a new exciting wave of medications that are coming out that are muscarinic activators. The first one is a muscarinic agonist at 2 different muscarinic acetylcholine receptors, the M4 and the M1 receptor, and it acts as agonist stimulating both of those. Now, what is unique about this is that there's no dopamine binding whatsoever, but there is antipsychotic efficacy. Now, even though there's antipsychotic efficacy, the FDA has not categorized this as an atypical antipsychotic, or as an antipsychotic at all. It is a muscarinic agonist for the treatment of schizophrenia. So truly a new generation, a new wave of treatments.

There are a lot of differences between what the muscarinic agonists do, but also what they don't do compared to the D2 antagonist or partial agonists. The most important thing is that they're more selective. D2 antagonists will block every dopamine-2 receptor in the brain and in the body. The pancreas has a lot of D2 receptors, and that can cause a flood of insulin release, which leads to insulin resistance. When the muscarinic M1 and M4 receptors are activated, it leads through a cascade of events to the decreased release of dopamine, but not everywhere in the brain, only in the portions that we believe are relevant to the symptoms of schizophrenia, namely psychosis, a reduction of the dopamine release in the ventral striatum. That's important because it's not reducing it in the dorsal striatum, which is where the motor side effects from D2 binding antipsychotics can come from, does not reduce it in the areas of the brain that release prolactin in the tuberoinfundibular pathway , and not in the mesocortical pathway, which could lead to secondary negative or cognitive symptoms. It's much more precise. It's able to do the job that we want it to do without causing the collateral damage.

Furthermore, it does so in a way that is more congruent with what we believe the actual pathophysiology of schizophrenia is. The dopamine-2 receptor antagonists block post-synaptic receptors to diminish the signal. But the pathophysiology of schizophrenia, we believe, is pre-synaptic. There's too much release of dopamine, so blocking it downstream never made any sense. It's like being in a sinking ship and just bailing out water instead of fixing the leak. No matter how much you bail, that leak is still going to keep coming. And that's why a post-synaptic solution for a pre-synaptic problem doesn't make sense.

So, this is a radically different approach. It was just FDA-approved the first agent, which is a combination of xanomeline and tropsium.

We haven't had it in our hands yet to try it and see how is in the real world, but the clinical trial evidence looks excellent. There's very high effect sizes, and the tolerability profile is very distinct. While there are side effects, things like gastrointestinal issues, nausea, vomiting for some individuals, we don't see the weight gain, the movement disorder, adverse effects, prolactin, elevation, the things that we think are characteristic of most D2 antagonists. Importantly, there's no boxed warning either, just as there are for all other antipsychotics approved for schizophrenia. So truly, it's a new era in the treatment of schizophrenia and one that I'm excited about, not for me, but for our patients who are living with schizophrenia.

Thank you so much for joining me today, and 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. He attended NYU School of Medicine and completed his psychiatry training at Duke University. As part of an interdisciplinary treatment team in his practice, he employs a person-centered care model to tailor treatments to each individual's needs, integrating traditional pharmacotherapy with psychotherapeutic and physical health and wellness interventions. His clinical and academic interests include serious mental illness, movement disorders, ADHD, and sleep medicine. 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.