Xanomeline, a novel cholinergic antipsychotic drug, shows dose dependent effects of rodent EEG

Additional Authors

Deepshila Gautam

Abstract

Schizophrenia is a debilitating disorder of the mind, affecting nearly 1% of the worldwide population. Affected individuals experience reality in a highly distorted fashion. Symptoms can include delusions, hallucinations, disorganized speech, trouble with thinking and a profound lack of motivation to engage in social activities. For nearly seventy-five years, the standard of care has not evolved much in this area and involved the use of dopaminergic antagonists that are only partially effective at best. Principally, these dopaminergic D2 antagonists combatted the so called “positive symptoms” like hallucinations and delusions. Other symptoms were largely unaffected. Recently, there was a paradigmatic change in that, for the first time, the Federal Drugs Administration (FDA) has approved a new drug, a cholinergic agonist at the M1 and M4 receptors as a new treatment for this troubling condition. While this drug appears to be effective against positive and negative symptoms like social withdrawal upon use over many weeks, the brain-wide changes in neural network activity after acute use is not well understood. Knowing that it has an immediate effect on brain networks would be a good biomarker that can allow us to construct hypotheses to better understand its locus of action within the brain. As a first step, we tested quantitative electroencephalographic (EEG) changes in rodents implanted with chronic epidural electrodes. We hypothesized that xanomeline would increase the activity of the prefrontal cortex, reflected as a reduction in slow wave (0.5-9 Hz) activity and an increase in high frequency gamma (30-100 Hz) band activity. As hypothesized, we saw robust reductions (P<0.005; two way-ANOVA with treatment and frequency as factors) in slow wave activity while gamma relative power (as a fraction of the total power) increased significantly. We conclude that quantitative EEG is a viable biomarker approach to monitor the brain activity of the latest antipsychotic drug, xanomeline. Our finding lay the groundwork for future translational studies in clinical subjects.

Start Time

16-4-2025 9:00 AM

End Time

16-4-2025 11:30 AM

Presentation Type

Poster

Presentation Category

Health

Student Type

Clinical Doctoral Student (e.g., medical student, pharmacy student)

Faculty Mentor

Siva Digavalli

Faculty Department

Pharmaceutical Sciences

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Apr 16th, 9:00 AM Apr 16th, 11:30 AM

Xanomeline, a novel cholinergic antipsychotic drug, shows dose dependent effects of rodent EEG

Schizophrenia is a debilitating disorder of the mind, affecting nearly 1% of the worldwide population. Affected individuals experience reality in a highly distorted fashion. Symptoms can include delusions, hallucinations, disorganized speech, trouble with thinking and a profound lack of motivation to engage in social activities. For nearly seventy-five years, the standard of care has not evolved much in this area and involved the use of dopaminergic antagonists that are only partially effective at best. Principally, these dopaminergic D2 antagonists combatted the so called “positive symptoms” like hallucinations and delusions. Other symptoms were largely unaffected. Recently, there was a paradigmatic change in that, for the first time, the Federal Drugs Administration (FDA) has approved a new drug, a cholinergic agonist at the M1 and M4 receptors as a new treatment for this troubling condition. While this drug appears to be effective against positive and negative symptoms like social withdrawal upon use over many weeks, the brain-wide changes in neural network activity after acute use is not well understood. Knowing that it has an immediate effect on brain networks would be a good biomarker that can allow us to construct hypotheses to better understand its locus of action within the brain. As a first step, we tested quantitative electroencephalographic (EEG) changes in rodents implanted with chronic epidural electrodes. We hypothesized that xanomeline would increase the activity of the prefrontal cortex, reflected as a reduction in slow wave (0.5-9 Hz) activity and an increase in high frequency gamma (30-100 Hz) band activity. As hypothesized, we saw robust reductions (P<0.005; two way-ANOVA with treatment and frequency as factors) in slow wave activity while gamma relative power (as a fraction of the total power) increased significantly. We conclude that quantitative EEG is a viable biomarker approach to monitor the brain activity of the latest antipsychotic drug, xanomeline. Our finding lay the groundwork for future translational studies in clinical subjects.