Obese adults who took 400 mg of the anticonvulsant zonisamide (Zonegran, Eisai) daily for 1 year as part of a clinical trial lost significantly more weight than their peers who took placebo, but they suffered more gastrointestinal, nervous system, and psychiatric adverse effects.
The findings from the National Institutes of Health (NIH)–sponsored study were published October 15 in Archives of Internal Medicine.
Zonisamide, 400 mg, demonstrated moderate efficacy of a magnitude similar to that of orlistat and lorcaserin, Kishore M. Gadde, MD, from the Obesity Clinical Trials Program at Duke University Medical Center, Durham, North Carolina, and colleagues report. However, mood changes and memory problems, nausea/vomiting, and other adverse events occurred at a higher frequency relative to placebo.
"Hence, for treatment of obesity, the drug's benefit-to-risk ratio needs thoughtful and cautious assessment," the authors conclude.
A Preliminary Signal
In a preliminary study involving 60 obese adults, Dr. Gadde and colleagues found that zonisamide at daily doses ranging up to 600 mg achieved a 5-kg greater weight loss than did patients taking placebo (weight change, –5.9 vs –0.9 kg) over 16 weeks (JAMA. 2003;289:1820-1825).
On the basis of the positive preliminary "signal" in this trial, Dr. Gadde told Medscape Medical News, a 1-year randomized, double-blind, placebo-controlled study testing zonisamide, 200 and 400 mg/d, against placebo in 225 obese men and women (mean body mass index, 37.6 kg/m2) was launched. All participants received diet and lifestyle counseling by a dietitian during the trial. Change in body weight at 1 year was the primary outcome.
Of the 225 participants, 218 (96.9%) returned for the 1-year assessment (71 in the placebo group, 73 in the 200-mg group, and 74 in the 400-mg group).
The researchers say patients in the placebo group and the 200-mg zonisamide group lost roughly the same amount of weight (no significant difference between placebo and 200 mg), whereas those in the 400-mg group lost significantly more weight (P = .009 vs placebo).
Table. Average Weight Loss at 1 Year by Group
| Group | Weight Change (95% Confidence Interval), kg |
| Placebo | –4.0 (–5.8 to –2.3) |
| 200 mg zonisamide | –4.4 (–6.1 to –2.6) |
| 400 mg zonisamide | –7.3 (–9.0 to –5.6) |
In addition, 23 patients (31.1%) who received placebo and 26 (34.2%) who received 200 mg of zonisamide lost at least 5% of their baseline body weight, a nonsignificant difference. However, more than half of patients (54.7%; n = 41) who received 400 mg of zonisamide lost at least 5% of their body weight (P = .007).
For 10% or greater weight loss, the corresponding numbers of patients for the placebo, 200-mg, and 400-mg groups were 6 (8.1%), 17 (22.4%), and 24 (32.0%; P < .001).
The investigators say the trial was not powered to detect differences in adverse events. They note, however, that altered taste, constipation, diarrhea, dry mouth, headache, fatigue, nausea/vomiting, somnolence, language/speech problems, impaired attention/concentration, memory problems, and anxiety-related and depression-related adverse events were more common with one or both of the zonisamide doses than with placebo.
'No Magic Bullet'
In this study, zonisamide, 400 mg daily, plus diet and lifestyle counseling provided "moderately successful" weight loss (7.3 kg [3.3 kg more than with placebo] at 1 year), as it did in prior trials, Mitchell H. Katz, MD, director of the Los Angeles County Department of Health Services in California, comments in an editor's note https://archinte.jamanetwork.com/article.aspx?articleid=1379160 published with the study.
"The problem is that the adverse effects at this dose are substantial: 18.7% of patients experienced headache, 13.3% experienced nausea/vomiting, 9.3% experienced anxiety, and 10.7% experienced impaired memory."
This trial, Dr. Katz says, answered a "sensible question: Could zonisamide at 200 mg achieve meaningful weight loss without substantial adverse effects? Unfortunately, the answer is no. Weight loss with the lower dose of zonisamide was almost identical to weight loss with placebo. Low-dose zonisamide produced adverse effects without a primary effect."
Dr. Katz concludes, "We need to continue to search for better weight loss aids. Until then, we have an effective and safe (albeit difficult to adhere to) regimen: eating less and exercising more."
The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases to Dr. Gadde. Dr. Gadde reported receiving grants from Bristol Myers Squibb, Forest Laboratories, National Institute of Diabetes and Digestive and Kidney Diseases, Pfizer, and Vivus in the past 36 months. He has been awarded several patents in the name of his institution for use of zonisamide as monotherapy and in combination with other drugs for treatment of obesity, as well as weight gain associated with psychotropic drugs. A complete list of author disclosures is given with the article.
Arch Intern Med. Published online October 15, 2012. Abstract Editor's Note