Objective: Levodopa-induced dyskinesias (LID) may be amenable to interventions with striatal serotonergic receptors. Preclinical evidence suggests that co-administration of serotonergic agonists with selective receptor properties (buspirone: 5-HT1A receptor) and zolmitriptan (5-HT1B/1D receptors) resulted in synergistic reduction of LID in animal models.

Background: In a proof-of-concept pilot study, an oral buspirone-zolmitriptan combination (10/1.25 mg t.i.d.) was added to a levodopa regimen of PD patients experiencing moderate-to-severe LID, to evaluate on control of both dyskinesia and overall control of Parkinsonism.

Method: This randomized, placebo-controlled, 2-way crossover study investigated two 1-wk treatment periods. The 30 study completers experienced at least moderately disabling peak-effect LID that lasted >2 hrs/day (NCT02439203). A blinded observer viewed video-recorded LID post-levodopa challenge to determine summed Abnormal Involuntary Movement Scale (AIMS) scores. The primary endpoint was change in dyskinesia severity (duration and amplitude), while the secondary endpoint was Parkinsonian motor symptomatology, assessed by summed UPDRS Motor Exam scores (with rigidity assessment omitted).

Results: Addition of the buspirone/zolmitriptan regimen significantly reduced LID; AIMS versus placebo scores: mean treatment effect vs placebo: -4.2 [-6.1, -2.3]. No significant worsening of UPDRS Part III scores (ON state) occurred: mean treatment effect vs placebo: 0.6 [-0.1, 1.3]. Treatment was well tolerated and no serious adverse events were encountered. A post-hoc analysis of buspirone/zolmitriptan effect on other Parkinsonian features will be reported.

Conclusion: In this short, proof-of-concept pilot study, addition of buspirone/zolmitriptan to the patients PD medication regimen significantly reduced LID severity without worsening Parkinsonian motor function. The buspirone/zolmitriptan oral formulation (JM-010) has been modified in ongoing multi-center clinical trials investigating PD patients with LID (in the EU: NCT03956979; in the US: NCT04377945).

References: Muñoz A, Li Q, Gardoni F, et al. Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia. Brain 2008;131(12):3380–3394.

Politis M, Wu K, Loane C, et al. Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients. J Clin Invest 2014;124(3):1340–1349.

Thomsen M, Stoica A, Christensen KV, Fryland T, Mikkelsen JD, Hansen JB. Synergistic effect of serotonin 1A and serotonin 1B/D receptor agonists in the treatment of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Exp Neurol 2022;358:114209.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/buspirone-zolmitriptan-combination-exerts-synergistic-reduction-in-dyskinesia-without-worsening-parkinson-disease-motor-symptomatology/