Zonisamide for Weight Reduction in Obese Adults: A 1-Year Randomized Controlled Trial

Study Questions:

What is the efficacy and tolerability of zonisamide, an antiepileptic drug, for enhancing weight loss in obese patients receiving diet and lifestyle guidance?


A 1-year, randomized, double-blind, placebo-controlled trial was conducted in 225 nondiabetic obese men and women. Interventions were daily dosing with placebo (n = 74), 200 mg of zonisamide (n = 76), or 400 mg of zonisamide (n = 75), in addition to diet and lifestyle counseling by a dietitian for 1 year. Primary outcome was change in body weight at 1 year.


Mean age was 43 years, 60% were women, and mean body mass index (BMI) was 37.6 [4.9]. Of the 225 randomized patients, 218 (96.9%) provided 1-year follow-up assessments. Change in body weight was −4.0 kg (95% confidence interval, −5.8 to −2.3 kg; mean −3.7%) for placebo, −4.4 kg (−6.1 to −2.6 kg; mean −3.9%; p = 0.79 vs. placebo) for 200 mg of zonisamide, and −7.3 kg (−9.0 to −5.6 kg; mean −6.8%; p = 0.009 vs. placebo) for 400 mg of zonisamide. In the categorical analysis, 31.1% assigned to placebo, 34.2% (p = 0.72) assigned to 200 mg of zonisamide, and 54.7% (p = 0.007) assigned to 400 mg of zonisamide achieved 5% or greater weight loss; for 10% or greater weight loss, the corresponding numbers were 8.1%, 22.4%; p = 0.02), and 32.0% (p < 0.001). Gastrointestinal, nervous system, and psychiatric adverse events occurred at a higher incidence with zonisamide than with placebo.


Zonisamide at the daily dose of 400 mg moderately enhanced weight loss achieved with diet and lifestyle counseling, but had a high incidence of adverse events.


In this study, all subjects underwent a dietary consult monthly that included the advice to decrease the total caloric intake by 500 kcal and do regular exercise, and were given a stipend for travel (maximum $180 or 1 year). Mean weight change in the placebo group of these obese patients (mean weight of 245 lbs. and BMI 37.8) was only 9 lbs. For comparison, the posted average amount of weight lost with Weight Watchers is 0.5-2 lbs. per week.

Clinical Topics: Prevention, Diet

Keywords: Isoxazoles, Incidence, Follow-Up Studies, Body Mass Index, Weight Loss, Nervous System, Cardiovascular Diseases, Energy Intake, Obesity, Diet

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