Randomized placebo‐controlled trial of zonisamide in patients with Parkinson's disease

Abstract

Background: We previously showed that zonisamide significantly improved parkinsonian symptoms by a multicenter, double-blind clinical trial. Aim: To confirm the efficacy of zonisamide on Parkinson's disease, a phase 3, randomized, placebo-controlled, multicenter, double-blind trial was carried out in Japan. Methods: Participants had advanced Parkinson's disease taking L-dopa with at least one other antiparkinson drug, but were developing a deterioration of response to L-dopa therapy. The trial consisted of a 2-week initial phase (singleblind, with administration of placebo) and a 12-week treatment phase (doubleblind, with patients randomly assigned to either placebo, or zonisamide 25 or 50 mg/day). Patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Results: A total of 185 patients (mean age 64.8 years; mean duration 7.5 years) were included in the efficacy analysis (placebo, zonisamide 25 mg, 50 mg; 63, 61, 61 patients, respectively). When compared with the placebo group, the UPDRS Part III total score at final assessment (the primary end-point for efficacy) significantly improved (P = 0.029) in the zonisamide 25 mg group. After 12 weeks of therapy, the UPDRS Part III total score significantly improved in both the zonisamide 25 mg (P = 0.038) and 50 mg groups (P = 0.049), compared with the placebo group. Neither the zonisamide 25 mg nor 50 mg group differed significantly from the placebo group in the incidence of adverse events (P = 0.363 and P = 0.713, respectively). Conclusion: These findings confirmed that zonisamide is well tolerated and efficacious in the treatment of advanced Parkinson's disease.

Adjunct zonisamide to levodopa for DLB parkinsonism

“…The effect size of zonisamide 50 mg/d for DLB parkinsonism observed in this study was similar to that for PD parkinsonism. 3 – 5 …”

Effect of zonisamide on parkinsonism in patients with dementia with Lewy bodies: A phase 3 randomized clinical trial

“…However, its use has been tempered by concerns about the exacerbation of neuropsychiatric symptoms, including delirium and BPSD, suggesting that doses should be carefully titrated, taking into account the therapeutic benefits versus the possibility of adverse events (AEs) [3][4][5][6]. Zonisamide has been available in Japan for the treatment of parkinsonism since 2009 following clinical trials demonstrating that it improved motor dysfunction and wearing-off in patients with PD, without worsening dyskinesia and psychiatric symptoms such as https://doi.org/10.1016/j.parkreldis.2019.12.005 Received 21 November 2018; Received in revised form 1 October 2019; Accepted 7 December 2019 hallucinations [7][8][9]. Although the pharmacological mechanisms underlying the antiparkinsonian effects of zonisamide remain unclear, dopaminergic (activation of dopamine synthesis and release [10], and inhibition of monoamine oxidase-B [11]) and nondopaminergic (blockade of sodium channels [12] and T-type calcium channels [13,14]) pathways appear to be implicated, in addition to gammaaminobutyric acid (GABA)-ergic transmission via striatal opioid δ1-receptor-associated interaction pathways [15].…”

Zonisamide enhances neurite outgrowth from adult rat dorsal root ganglion neurons, but not proliferation or migration of Schwann cells

“…Drug repositioning or repurposing is a strategy to discover new efficacies of drugs currently applicable to patients, and may significantly diminish the cost and time for developing drugs as compared with conventional approaches (Padhy and Gupta 2011). Zonisamide, a benzisoxazole derivative, was initially developed as an anti-epileptic drug (Jain 2000), and has been successfully repositioned for Parkinson's disease (Murata et al 2015;Murata et al 2016). Yagi et al (2015) found that zonisamide promoted neurite outgrowth from cultured motor neurons and facilitated axonal regeneration after sciatic nerve injury in mice.…”