There is good evidence that pharmacotherapy can enhance weight loss when combined with interventions aimed at changing lifestyle, 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. 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. The researchers of the present study hypothesized that zonisamide would be therapeutic for obese patients seeking to lose weight.
The study was conducted at Duke University Medical Center, Durham, NC, from March 2001 to March 2002. Participants were selected from the clinic patient population, and included 55 women and 5 men with a mean BMI of 36.3 and a mean age of 37.0. Patients were randomly assigned to receive zonisamide (n=30) or placebo (n=30). Nine patients dropped out prematurely; thus 51 or 60 completed the first 16 weeks. All participants were prescribed a balanced hypocaloric diet (500 kcal/day deficit) and compliance was monitored with self-rated food diaries. Zonisamide therapy was started at 100 mg/d orally, with gradual increase to 400 mg/d and further increase to 600 mg/ d for patients losing less than 5% of body weight at the end of 12 weeks. Placebo dosing was identical. The study had two phases. The first was the 16-week, randomized, double-blind, parallel-group comparison. At the end of this phase, participants wishing to continue received the same treatment in a single-blinded fashion for an additional 16-week extension phase. Increased physical activity was also encouraged for participants in both groups. Patients were examined at weeks 0, 2, 4, 8, and 16 in the acute phase and every 4 weeks in the extension phase. Study participants completed the Impact of Weight on Quality of Life (IWQOL) questionnaire at baseline, week 8, and week 16.
The prescribed mean highest daily dose of zonisamide was 427 mg, corresponding to 4.27 capsules, were as the placebo group received 500 mg, corresponding to 5.00 capsules. For the subset of patients completing the initial 16-week phase as randomized, the mean absolute weight for the zonisamide group changed from 97.2 kg at baseline to 90.9 kg at week 16 for the placebo group, the corresponding change was 97.6 kg to 96.5kg. Thus the difference between treatment groups in the achieved weight loss over time was significant. In addition, zonisamide therapy led to improvement of some risk factors associated with obesity. Waist circumference decreased more significantly with zonisamide therapy compared with placebo. A reduction in systolic blood pressure was noted with zonisamide therapy. Zonisamide was associated with a significant improvement of quality of life as noted by decreased scores on the following IWQOL measures: mobility, general health, occupational functioning, and activities of daily living. Zonisamide was tolerated well, with few adverse effects. This short-term, preliminary trial sowed that zonisamide and a hypocaloric diet resulted in more weight loss than placebo and hypocaloric diet in the treatment of obesity.
K Gadde, D Franciscy, HR Wagner, KR Krishnan. Zonisamide for weight loss in obese adults. JAMA 289(14):1820-1825 (April 2003) [Correspondence: Kishore M. Gadde, MD, Obesity Clinical Trials Program, Duke University Medical Center, Box 3812, Durham, NC 27710. email: email@example.com]
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