Mesdopetam Shows Potential to Tackle Parkinson’s Psychosis
Mesdopetam is a dopamine receptor antagonist that has shown promise in reducing psychosis symptoms in a rat model of Parkinson’s disease.
The Basics: PD and dopamine
Parkinson’s disease (PD) is a progressive neurological disorder that primarily affects movement but can also lead to cognitive and psychological symptoms. The condition arises from the gradual degeneration of neurons in a part of the brain called the substantia nigra, which is responsible for producing dopamine. Dopamine is a critical brain chemical that influences movement, mood, and motivation. In PD, the loss of dopamine-producing neurons results in motor symptoms such as tremors, rigidity, and slowed movement. Dopamine functions through D1, D2, and D3 receptors: D1 and D2 are essential for regulating movement, while D3 is involved in mood and certain motor functions. Long-term dopamine treatments, like levodopa (considered the gold standard for PD treatment combined with carbidopa), can lead to dyskinesia and psychosis, which are associated with D3 receptors. Mesdopetam is a novel antagonist that targets both D2 and D3 receptors, with a preference for the D3 receptor.
Breaking it down
Researchers investigated the neurophysiological effects of three antipsychotic drugs, clozapine, pimavanserin, and the novel compound mesdopetam, in a rodent model of Parkinson’s disease-associated psychosis (PD-P). This model uses rats with unilateral 6-OHDA lesions to simulate dopaminergic degeneration. The rats were primed with levodopa and administered MK-801, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist used to induce symptoms resembling psychosis.
The rats underwent behavioural tests and neurophysiological analyses to assess spontaneous motor behaviour. These tests included high-frequency oscillations (HFO), which are brain waves with faster frequencies than normal and are thought to play a role in the pathology of PD. Testing also included assessments of functional connectivity and signal complexity.
The results are in
All tested antipsychotics displayed similar neurophysiological effects, showing tendencies to normalise excessive locomotor behaviour. This included a reduction in MK-801-induced HFOs and abnormal synchronisation in the brain waves of PD-P rats, specifically within the medial prefrontal cortex. Drug-specific effects were observed in HFO peak frequency and signal complexity across various brain structures. The neurophysiological profile of mesdopetam closely resembled that of the D3 receptor antagonist (SB277011-A), suggesting it may primarily act through D3 receptor antagonism.
The study revealed that the neurophysiological measures provided more sensitive indicators of drug effects than behavioural assessments.
Not so fast
Behavioural assessments showed high variability, and the antipsychotic treatment effects did not reach statistical significance, limiting the ability to correlate neurophysiological changes with behavioural outcomes. PD is a complex disease, and the PD-P model has limitations. The MK-801-induced altered state may not fully capture all aspects of clinical psychosis – while the 6-OHDA lesions and levodopa priming represent later stages of Parkinson’s disease, which may affect the generalisability of the findings.
Why does it matter?
Psychosis associated with Parkinson’s disease is common, with visual hallucinations affecting more than one-quarter of people diagnosed with PD. To date, pimavanserin is the only medication approved in the U.S. for treating hallucinations and delusions related to PD psychosis. Clozapine is an antipsychotic medication used off-label for PD-induced psychosis and has been shown to alleviate psychosis in patients with Parkinson’s without significantly worsening motor symptoms.
Take home messages
1. This research investigated the neurophysiological effects of three antipsychotic drugs (clozapine, pimavanserin, and mesdopetam) in a rat model of Parkinson’s disease psychosis.
2. Clozapine, pimavanserin, and mesdopetam showed similar neurophysiological effects, including reduction of MK-801-induced high-frequency oscillations and abnormal brain synchronisation.
3. Mesdopetam, a novel compound, targeting D2 and D3 receptors, showed a neurophysiological profile similar to a selective D3 receptor antagonist.
Guest Author: Conor McQuaid, PhD
Reviewer: Barbara Fahmy, MS OTR, MPA
This article was written as part of a series of ‘journal club’ summaries for Scientific Writers Ltd and is based on the following publication.
First Author: Stan T, et al.
Journal: Neurotherapeutics
Date online: 16 February 2024
Other references:
Waters S, Sonesson C, Svensson, P, et al. Preclinical pharmacology of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl] (propyl)amine (IRL790), a novel dopamine transmission modulator for the treatment of motor and psychiatric complications in Parkinson disease. J Pharmacol Exp Ther. 2020;374(1):113-125
Wientraub D, Espay AJ, Sharma VD, et al. Pimavanserin for psychosis in Parkinson’s disease dementia: subgroup analysis of the HARMONY Trial. Parkinsonism Relat. Disord. 2024; 119:105951
