Objective: To evaluate the efficacy and safety of zonisamide as an adjunct therapy for improving motor function and reducing OFF-time in patients with Parkinson’s disease (PD).

Background: Zonisamide, an anti-epileptic drug with dopaminergic and glutamatergic modulation properties, has been investigated for its potential benefits in PD. While previous studies suggest improvements in motor symptoms and reductions in OFF-time, its overall therapeutic effect remains uncertain.

Method: A systematic review and meta-analysis were conducted following PRISMA guidelines. PubMed was searched for randomized controlled trials (RCTs) comparing zonisamide (25–100 mg) to placebo in PD patients. Primary outcomes included changes in Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) scores and OFF-time, measured as standardized mean differences (SMD). Secondary outcomes included cognitive function (Mini-Mental State Examination, MMSE) and the risk of serious adverse events (SAEs), reported as risk ratios (RR) with 95% confidence intervals (CI). A random-effects model was used for data synthesis.

Results: Five RCTs (PMID: 17200492, 26094993, 29367449, 31982288, 36323130) met the inclusion criteria, comprising 872 patients receiving zonisamide (25–100 mg) and 888 patients receiving placebo (Figure 1). Zonisamide 25 mg showed a modest improvement in UPDRS-III scores (SMD: -2.7 ± 9.17) compared to placebo, while zonisamide 50 mg showed a similar effect (SMD: -2.6 ± 9.82). Higher doses (100 mg) demonstrated a smaller effect (SMD: -2.6 ± 10.24). OFF-time reduction was observed at 50 mg (SMD: -1.1 ± 2.78) and 100 mg (SMD: -1.43 ± 2.78). MMSE scores remained stable across doses, with minimal cognitive impact. The risk of SAEs was not significantly different between zonisamide and placebo (25 mg: RR = 0.72, 95% CI: 0.28–1.86; 50 mg: RR = 0.65, 95% CI: 0.24–1.74).

Conclusion: Zonisamide at 25–50 mg demonstrated modest motor improvements and OFF-time reduction in PD patients, with a favorable safety profile. Higher doses (100 mg) did not offer additional benefits. These findings support zonisamide as a potential adjunct therapy for motor fluctuations in PD, though further large-scale trials are needed to confirm long-term efficacy.

Figure 1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/zonisamide-for-motor-symptoms-and-off-time-reduction-in-parkinsons-disease-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials/