Mesdopetam may be novel treatment for Parkinson’s psychosis

Dyskinesia therapy candidate shows antipsychotic effects in rat model

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by Steve Bryson, PhD |

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Mesdopetam (IRL790), an investigational therapy for levodopa-induced dyskinesia in Parkinson’s disease, was found to reduce signs of psychosis in a rat model, a study reported.

Psychosis is a common nonmotor symptom in people with Parkinson’s, characterized by hallucinations and/or delusions — hallucinations being things patients see, hear, or feel that do not exist, while delusions are irrational ideas that are not based on reality.

Laboratory data showed that mesdopetam normalized psychosis-related brain wave activity similarly to the antipsychotic medications clozapine and pimavanserin, the active ingredient in the approved treatment Nuplazid.

“These new results strongly support that mesdopetam has potential as a novel therapeutic in [Parkinson’s disease psychosis],” Nicholas Waters, executive vice president and head of R&D at IRLAB Therapeutics, which is developing mesdopetam, said in a company press release.

Waters also noted “the excellent safety and tolerability profile seen in clinical studies with mesdopetam.”

The study, “Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson’s disease psychosis,” was published in the journal Neurotherapeutics.

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‘Urgent clinical need’ for treatments for Parkinson’s psychosis

To date, Nuplazid (pimavanserin), developed by Acadia Pharmaceuticals, is the only medication that’s been approved in the U.S. to treat hallucinations and delusions associated with Parkinson’s disease psychosis. However, while clinical trials found the therapy reduced these symptoms in the short term, a recent analysis of long-term clinical use indicated that relatively few patients experience robust improvement of their psychosis symptoms.

The antipsychotic medication clozapine, used off-label, meaning it’s not approved for this indication, has been shown to lessen psychosis in Parkinson’s without significantly worsening patients’ motor symptoms. However, its use in individuals with dementia can increase the risk of falls, impaired cognitive function, and adverse cardiovascular events.

“Thus,” noted study researchers in Sweden, some of whom are employed by IRLAB, “improved treatments for [Parkinson’s disease psychosis] remains an urgent clinical need.”

Mesdopetam is an investigational therapy from IRLAB that’s being developed for the treatment of dyskinesia — the uncontrolled, involuntary movements and muscle stiffness associated with long-term use of levodopa, the standard Parkinson’s treatment.

This therapy works by targeting a specific dopamine receptor, called the D3 dopamine receptor, which has been linked to the development of dyskinesia. This receptor also has been suggested as a therapeutic target for antipsychotic treatment in schizophrenia, a condition marked by hallucinations and delusions.

To determine whether mesdopetam has the potential to treat psychosis in Parkinson’s, the team directly compared the treatment effects of clozapine, mesdopetam, and Nuplazid in a Parkinson’s psychosis rat model.

After stimulating Parkinson’s-like symptoms in the animals, the rats were given a compound called MK-801, which induced psychosis-like episodes. These episodes were marked by spontaneous movements and oscillations in high-frequency brain wave activity distributed widely across the brain, measured by an electroencephalogram (EEG).

High-frequency brain waves are fast electrical signals produced by the brain during thinking, concentrating, or problem-solving. During psychosis episodes, there can be abnormalities in brain wave patterns, including alterations in high-frequency brain waves.

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Researchers tested clozapine, mesdopetam and Nuplazid in lab

Along with MK-801, the rats were treated with clozapine, mesdopetam, or Nuplazid.

Although all three antipsychotic compounds showed tendencies toward normalizing excessive locomotion behavior, none of them provided significant benefits. Still, all of the compounds suppressed the MK-801-induced high-frequency brain waves, commonly in a brain region called the medial prefrontal cortex (mPFC). This region plays an essential regulatory role in numerous cognitive functions.

At the same time, each drug also displayed several selective effects in different brain regions with respect to the changes in high-frequency brain waves.

The researchers suggested that high-frequency brain wave reduction in the mPFC may be particularly important to achieve an antipsychotic effect. In contrast, targeting different receptors may explain the drug-specific changes in brain activity patterns.

Our results indicate that mesdopetam shares certain key treatment effects with existing antipsychotic treatments for [Parkinson’s disease psychosis] and consequently may have the potential to become a novel antipsychotic treatment option in this condition.

A noted feature of these MK-801-induced high-frequency brain waves was that they shared a common frequency in several brain structures at any given moment in time, a phenomenon known as functional coupling. Studies have suggested that this type of increased functional coupling may be a distinguishing Parkinson’s-related feature.

All three compounds reduced MK-801-induced functional coupling, suggesting that this reduction by the antipsychotic drugs “may represent a reversal toward a more normal conscious state,” the team noted.

MK-801 also significantly decreased the complexity of recorded brain activity over time, with the antipsychotic drugs tending to reverse this state toward a more complex structure, resembling near-normal values. However, these changes were specific to each drug, suggesting these measurements “may provide complementary information on each compound’s specific pharmacological properties,” the researchers wrote.

Lastly, the team confirmed that mesdopetam targeted the D3 dopamine receptor because it changed the overall, or global, brain state similarly to SB-277011-A, a compound known to bind to this receptor. When directly compared, the closest similarities to mesdopetam were seen for SB-277011-A and Nuplazid, whereas clozapine displayed different characteristics.

“Our results indicate that mesdopetam shares certain key treatment effects with existing antipsychotic treatments for [Parkinson’s disease psychosis] and consequently may have the potential to become a novel antipsychotic treatment option in this condition,” the researchers concluded.

Waters also noted that the work done in this study may help advance research into Parkinson’s disease psychosis.

“The brain state characterization presented in the paper is an impressive new technique which enables a new level of understanding of the brain mechanisms underlying [Parkinson’s disease psychosis] and provides a great tool for evaluation of potential new therapies,” Waters said.

The paper notes that national and local guidelines for animal welfare were followed in this work, with all procedures given advanced approval from the Swedish Ethical Committee for Northern Sweden or the Malmö/Lund ethical committee of animal experiments. The rats were given unlimited access to food and water.