HE PREVALENCE OF OBESITY HAS increased dramatically in the past decade in the United States and many other developed countries. 1,2 Because obesity is associated with a significantly increased risk for type 2 diabetes, coronary heart disease, hypertension, numerous other major illnesses, and overall mortality from all causes, 3,4 weight reduction is critical for the obese patient. 5,6 There is good evidence that pharmacotherapy can enhance weight loss when combined with interventions aimed at changing lifestyle, 7 although pharmacological therapies currently approved by the US Food and Drug Administration fail to provide adequate benefit for many obese patients because of adverse effects, contraindications, or lack of positive response. 7 Hence, there is impetus for developing new treatments for the management of obesity. Zonisamide is a marketed antiepileptic drug. In short-term clinical trials of zonisamide in epileptic patients concomitantly receiving other antiepileptic agents, weight loss was an adverse effect. 8 Whereas the anticonvulsant activity of zonisamide is believed to be related to its sodium and calcium channel (T-type) blocking activity, 8 this drug is also known to exert dose-dependent biphasic dopaminergic 9 and serotonergic 10 activity. With this backg r o u n d , w e h y p o t h e s i z e d t h a t zonisamide would be therapeutic for obese patients seeking to lose weight. METHODS This study was conducted at Duke University Medical Center, Durham, NC, from March 2001 to March 2002. The protocol was approved by the medical center's institutional review board before the trial began. Study Participants Study participants were selected from the clinic patient population and those responding to advertisement fliers posted in the local area, and were enrolled between March 2001 and July 2001. Sixty-eight individuals were screened for participation and 60 were