Zonisamide is a structurally and pharmacologically novel antiepileptic drug - a sulfamate-substituted monosaccharide - with proven anticonvulsant efficacy when used adjunctively in refractory partial epilepsy.10-12 Mechanisms hypothesized to account for zonisamide's antiepileptic properties include antagonism of voltage-gated sodium and T-type calcium channels, blockade of potassium-evoked glutamate release, modulation of central dopaminergic and serotonergic function, and carbonic anhydrase inhibition.10-16 Several lines of evidence suggest that zonisamide might be a useful treatment for BED. First, like the anticonvulsant topiramate,17-19 zonisamide has been associated with anorexia and weight loss in clinical trials in epilepsy patients10,11,20 and in patients with obesity.20 Topiramate has also been shown to reduce binge eating and weight in patients with binge eating disorder associated with obesity. 21 Although zonisamide and topiramate have distinct pharmacologic profiles, both drugs share several pharmacologic actions. These include sodium channel blockade, carbonic anhydrase inhibition, and reduction of glutamate neurotransmission. 10,11,13,16,17 Regarding the latter property, animal studies have shown that stimulation of the lateral hypothalamus by glutamate and glutamate agonists causes an intense, rapid, dose-dependent increase in food intake,22 whereas glutamate antagonism of the nucleus tractus solitarius reduces food intake.23 Second, unlike topiramate, zonisamide also modulates the function of serotonin and dopamine14, 15 --two neurotransmitters involved in the regulation of feeding behavior24 and the mechanisms of some medications with efficacy in either binge eating (SSRIs, d-fenfluramine) 25-29 or obesity (sibutramine, stimulants).30 Third, a broad range of antidepressants have been reported to reduce binge eating in both bulimia nervosa31 and binge eating disorder25-28,32 and preliminary observations suggest zonisamide may have thymoleptic properties.33,34 Fourth, in an open-label trial of zonisamide in 15 patients with BED conducted by our group, zonisamide was effective in reducing binge eating frequency, severity of illness, and weight (S.L. McElroy, J Clin Psychiatry, under review).35 We therefore propose to conduct a double-blind, placebo-controlled, randomized, parallel group, 16-week study of zonisamide in 60 outpatients with binge eating disorder and obesity.