Objective: To determine the effect of mirtazapine, a clinically-available anti-depressant, on psychosis and dyskinesia in Parkinson’s disease (PD).

Background: Psychosis and dyskinesia cause significant morbidity to as many as 50-95% of patients with advanced PD. There is increasing evidence indicating that antagonising serotonin 2A receptors (5-HT_2AR) may alleviate PD psychosis and dyskinesia. Mirtazapine is a clinically-available anti-depressant that acts through complex interactions with a breadth of pharmacological targets, including 5-HT_2AR. Here, we hypothesised that mirtazapine is potentially efficacious to reduce PD psychosis and dyskinesia.

Methods: Five common marmosets were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Stable and reproducible psychosis-like behaviours (PLBs) and dyskinesia were induced by chronic administration of L-3,4-dihydroxyphenylalanine (L-DOPA). Mirtazapine (vehicle, 0.1, 1 and 10 mg/kg) was then administered to the animals, in combination with L-DOPA, after which its effects on L-DOPA-induced dyskinesia, PLBs and parkinsonism were determined.

Results: We found that, in combination with L-DOPA, mirtazapine (10 mg/kg) significantly reduced PLBs severity, by 50% (P < 0.05), when compared to L-DOPA/vehicle treatment. Moreover, mirtazapine (10 mg/kg) significantly reduced duration of on-time with disabling PLBs, when compared to L-DOPA/vehicle (by 64%, P < 0.01). Mirtazapine (10 mg/kg) also reduced dyskinesia severity, by 29%, when compared to vehicle (P < 0.01). Accordingly, mirtazapine (10 mg/kg) significantly reduced duration of on-time with disabling dyskinesia, by 71%, when compared to vehicle. Importantly, mirtazapine did not alter the anti-parkinsonian effect of L-DOPA, as measured by parkinsonian disability scores and on-time duration.

Conclusions: These results suggest that mirtazapine is a potential drug candidate to effectively reduce the severity of PD psychosis and dyskinesia. Because it is already available in the clinic, our results could rapidly lead to proof-of-concept clinical trials where the anti-psychotic and anti-dyskinetic actions of mirtazapine would be assessed.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-clinically-available-anti-depressant-mirtazapine-alleviates-both-psychosis-and-dyskinesia-in-the-mptp-lesioned-marmoset/