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Objectives – To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose-controlled study design. Materials and methods – We conducted a multinational, randomized, double-blind trial in adults and children (≥6 years old) with epilepsy that was not being treated when randomized to 400 or 50 mg/day topiramate as target maintenance dosages. In addition to ≥2 lifetime unprovoked seizures, patients had to have one or two partial-onset seizures or generalized-onset tonic-clonic seizures in the 3-month retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure-free rate at 6 months and 1 year. Double-blind treatment continued until 6 months after the last patient was randomized. Results – Kaplan–Meier survival analyses for time to first seizure (intent-to-treat, n = 470) favored 400 mg/day over 50 mg/day ( P = 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference ( P = 0.046) favoring the higher dose was at day 14 when patients were receiving 100 or 25 mg/day. The probability of being seizure-free at 6 months was 83% in patients randomized to 400 mg/day and 71% in those randomized to 50 mg/day ( P = 0.005). Seizure-free rates at 12 months were 76% and 59%, respectively ( P = 0.001). Differences favoring the higher dose were significant in patients with partial-onset seizures ( P = 0.009) and in those with generalized-onset tonic-clonic seizures ( P = 0.005). The most common dose-related adverse events were paresthesia, weight loss, and decreased appetite. Discontinuations due to cognitive-related adverse events were 2% in the 50-mg group and 7% in the 400-mg group. Overall, 7% and 19%, respectively, discontinued with adverse events during the median treatment duration of 9 months. Conclusion – Topiramate is effective as monotherapy in adults and children. Because a therapeutic effect emerges during titration, clinicians should adjust dosages in step-wise fashion with intermediate stopping points, e.g., 100 mg/day, to evaluate patient response and achieve the optimal maintenance dosage. [ABSTRACT FROM AUTHOR]