Dose-dependent Safety and Efficacy of Zonisamide: A Randomized, Double-blind, Placebo-controlled Study in Patients with Refractory Partial Seizures


Address correspondence and reprint requests to Dr. M.J. Brodie at Epilepsy Unit, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow, G11 6NT Scotland, U.K. E-mail:


Summary: Purpose: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy.

Methods: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (≥50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed.

Results: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of “all seizures” and simple partial (SP) + CP seizures. For all seizures, a significant dose–response relation was observed (p < 0.0001).The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase.

Conclusions: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.