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Combination therapy of zonisamide and bupropion for weight reduction in obese women: a preliminary, randomized, open-label study

Bupropion Plus Zonisamide for Obesity Combination Therapy of Zonisamide and Bupropion
for Weight Reduction in Obese Women:
A Preliminary, Randomized, Open-Label Study
Kishore M. Gadde, M.D.; Gretchen M. Yonish, R.D.;
Mariko S. Foust, R.D.; and H. Ryan Wagner II, Ph.D.
Received July 15, 2006; accepted Nov. 27, 2006. From the Obesity Clinical Trials Program, Duke University Medical Center, Durham, N.C. There was no external funding for this research.
Dr. Gadde has received research support from the National Institute
of Diabetes and Digestive and Kidney Diseases, GlaxoSmithKline, Elan, Objective: Zonisamide and bupropion have been
Johnson & Johnson, Eli Lilly, and Vivus; has served as a consultant forOrexigen, GlaxoSmithKline, and Vivus; and owns stock in Orexigen investigated for weight reduction in obese adults. We Therapeutics. Duke University was awarded U.S. patent 7,109,198 for conducted a preliminary study comparing the effect this combination therapy in September 2006 titled "Method for Treating on body weight of the combination of these 2 drugs Obesity" with Dr. Gadde as an inventor; Duke University has licensed versus zonisamide monotherapy.
this invention to Orexigen. Ms. Yonish, Ms. Foust, and Dr. Wagner report Method: This was a 12-week, randomized, open-
no additional financial affiliations or other relationships relevant to the label, parallel-group comparison of 2 active interven- subject of this article. Corresponding author and reprints: Kishore M. Gadde, M.D., tions conducted from October 2003 to June 2004.
Box 3292, Duke University Medical Center, Durham, NC 27710 Eighteen obese women (mean [SE] body mass index of 36.8 [1.2] kg/m2) were randomly assigned to re-ceive the combination of zonisamide and bupropion(N = 9) or zonisamide alone (N = 9). All subjects Bupropion, marketed as an antidepressant and smok-
were prescribed a balanced hypocaloric diet (500 ing cessation aid, has been demonstrated to pro- kcal/day deficit) and compliance was monitored mote weight loss in obese adults in 3 randomized con- with self-rated food diaries. Zonisamide therapy trolled trials.1–3 There is evidence from one randomized was started at 100 mg/day, with a gradual increase controlled trial that zonisamide, an antiepileptic drug, is to 400 mg/day over 4 weeks for both groups. In ad-dition, the group assigned to combination therapy superior to placebo in assisting obese individuals to lose received bupropion, which was started at 100 mg/day, weight.4 Bupropion is known to enhance the activity of with an increase to 200 mg/day after 2 weeks. Zoni- norepinephrine and dopamine, whereas zonisamide has samide was administered at night and bupropion in similar effects on serotonin and dopamine.1,4 We hypoth- the morning. Body weight in kilograms was the esized that because all 3 major neurotransmitters that regu- primary outcome measure.
Results: In an intent-to-treat analysis, carrying the
late appetite and energy homeostasis are targeted with the last observation forward for all randomly assigned combination of zonisamide and bupropion, the combina- participants with at least 1 postbaseline assessment, tion therapy might lead to greater weight loss than either the combination group lost more body weight than drug alone. Another reason for combining these drugs was the zonisamide group (mean [SE] = 7.2 [1.2] kg the hope that certain known adverse effects of zonisamide, [7.5%] vs. 2.9 [0.7] kg [3.1%]; F = 4.7, df = 4,56;p = .003) during the 12-week period. For the subset such as somnolence, psychomotor slowing, cognitive im- of 12 patients (combination, N = 7; zonisamide, pairment, fatigue, and depression, could potentially be off- N = 5) that completed the full 12-week treatment, set by the known side effects of bupropion, such as insom- the mean (SE) weight loss was 8.1 (1.4) kg (8.5%) nia, activation, and psychomotor agitation, as well as its for the combination group versus 3.0 (0.9) kg (3.3%) antidepressant effect. Further, zonisamide might poten- for the zonisamide group (F = 4.6, df = 4,40; p =.004). Six subjects in the combination group and 2 in tially reduce the seizure risk associated with bupropion.
the zonisamide group lost at least 5% of body weight.
Therefore, we conducted this preliminary investigation to Conclusion: In this short-term, open-label, pre-
examine the effect of the combination therapy on body liminary trial, combination treatment of zonisamide weight compared with zonisamide monotherapy.
and bupropion resulted in more weight loss thantreatment with zonisamide alone.
(J Clin Psychiatry 2007;68:1226–1229) Experimental Design This was a 12-week, randomized, open-label, parallel- group comparison of zonisamide versus zonisamide plus J Clin Psychiatry 68:8, August 2007 Gadde et al.
bupropion combination. The protocol was approved by the entire daily dose of bupropion was administered in the Duke University Medical Center's Institutional Review morning. Dose titration was flexible, based on tolerability.
Board before the trial began.
Medication compliance was overseen by comparing thenumber of capsules dispensed and returned.
Study Participants Study participants were selected from the clinic patient population and those responding to advertisement fliers Participants in both groups were instructed to follow a posted in the local area of Durham, N.C. Nineteen women balanced diet that was calculated to reduce their energy were screened, and 18 were randomly assigned from Octo- intake by 2100 kJ/day (500 kcal/day deficit) from the ber 2003 to June 2004. All participants provided written maintenance level of caloric intake using the World informed consent.
Health Organization equations for basal metabolic rate Included were women aged 21 to 55 years, with a body with adjustment for activity level.5 Study participants mass index of 30 to 44 kg/m2, mean (SE) = 36.8 (1.2) were asked to record their dietary intake in food diaries kg/m2. Given the potential risk of unbalanced gender dis- given to them. A registered dietician reviewed the food tribution across the 2 treatment groups creating difficulty diaries and provided advice via 10-minute individual ses- in interpreting results in this small sample study, we de- sions every 4 weeks.
cided to restrict participation to women only.
Exclusion criteria were obesity of a known endocrine Measurements and Visits origin, such as hypothyroidism or Cushing's syndrome; Screening assessments (baseline visit) included review serious or unstable medical illness; history of seizure dis- of medical history and physical examination. There was order or significant head trauma; history of bulimia or no run-in period. Subjects meeting eligibility criteria were anorexia; history of renal calculi; diabetes mellitus; un- started on the study drug(s) with follow-up visits taking controlled hypertension; untreated or uncontrolled thyroid place at weeks 2, 4, 8, and 12. During each visit, the fol- disease; major psychiatric disorder or alcohol or substance lowing assessments were performed: blood pressure, heart abuse within the past year; weight loss of greater than 4 kg rate, weight, adverse effects, and medication accountabil- in the past 3 months; history of bariatric surgery; current or ity. Body weight was measured on a calibrated electronic recent use of other weight-loss medications, herbs, or di- scale to the nearest 0.1 kg. Participants were weighed in a etary supplements known to affect body weight or have the hospital gown and weighed twice for accuracy with the potential to compromise patient safety in combination average of the 2 measurements recorded. Waist circumfer- with the study drugs; current participation in other weight- ence was assessed at baseline and study exit. Adverse loss programs; known hypersensitivity to sulfonamides, events were gathered via spontaneous reporting by par- zonisamide, or bupropion; women of childbearing poten- ticipants as well as by open-ended questions. Reportable tial not adhering to an acceptable form of contraception; adverse effects were problems that emerged during the pregnant or breast-feeding women; and individuals judged course of treatment or increased in severity relative to by the investigators to be inappropriate for reasons such as inability to follow instructions and study procedures.
Measures of Outcome Randomization and Study Drugs The primary study outcome of interest was change in Subjects were randomly assigned to 1 of the 2 study body weight in kilograms from baseline to study exit interventions via a computer-generated random-number using actual weight. In addition, we examined percent table. There was no stratification by demographic charac- change in weight and the number of participants in each teristics. Subjects and investigators were not blind to the group who achieved at least 5% weight loss. Secondary treatment assignment. The zonisamide group received zo- outcome measures included waist circumference, heart nisamide only, whereas the combination group received rate, and blood pressure.
zonisamide plus bupropion.
All study subjects received zonisamide, which was Statistical Analysis started at 100 mg/day, and the dose was increased to 200 All randomly assigned subjects who had at least 1 post- mg/day during the second week, 300 mg/day during the randomization assessment were included in the primary third week, and 400 mg/d from the fourth week onward.
analysis. Weight change over time was analyzed using The entire daily dose of zonisamide was administered at 2-way repeated measures analysis of variance with the bedtime. The subjects assigned to the combination group last-observation-carried-forward (LOCF) method of im- received bupropion in addition. Sustained-release bupro- putation for missing data. A repeated measures analysis pion was started at 100 mg/day, the dose was increased to of covariance adjusted for the demographic variables 200 mg/day at the beginning of the third week, and this of age, race, and baseline weight was conducted to con- dose was continued until the final visit (week 12). The firm the repeated measures analysis of variance results.
J Clin Psychiatry 68:8, August 2007 Bupropion Plus Zonisamide for Obesity were related to neuropsychiatric adverse events. One sub- Table 1. Baseline Characteristics of the Subjects in a Study
of Zonisamide Alone or in Combination With Bupropion

ject reported irritability, headache, and difficulty with con- for Obesitya
centration, language, and speech. The second subject re- Zonisamide + Bupropion ported mild short-term memory impairment. In both cases, the adverse effects resolved a few days after discontinuing the study drugs.
The baseline characteristics of participants were essen- tially similar between treatment groups (Table 1) with no statistically significant differences.
For the intent-to-treat last-observation-carried-forward aAge, weight, and body mass index are presented as group means (ITT-LOCF) analysis, 16 patients were included. Ex- (SE). There were no statistically significant differences between the cluded were 2 zonisamide subjects who had no post- groups with regard to baseline characteristics.
randomization assessments; for these participants, rea-sons were "lost to follow-up" and "consent withdrawn (nolonger a priority)." Figure 1. Pattern of Weight Change From Baseline to Week
12 in Obese Women Who Received Zonisamide Monotherapy

or Zonisamide Plus Bupropion Combined Therapya
The curves for weight loss in kilograms over the 12-week duration for the zonisamide and combination groups are shown in Figure 1. For the ITT-LOCF sample, the mean (SE) body weight changed from 96.4 (5.0) kg at baseline to 89.2 (4.9) kg at week 12 for the combination group (N = 9), whereas for the zonisamide group (N = 7), the corresponding change was 100.2 (8.8) kg to 97.4 (9.0) kg (treatment × time interaction: F = 4.7, df = 4,56; p = .003); i.e., mean weight change for the combination eight Loss, kg –6 group was –7.2 (1.2) kg (–7.5%) over the 12-week period versus –2.9 (0.7) kg (–3.1%) for zonisamide. Six subjects in the combination group and 2 in the zonisamide group lost at least 5% of body weight.
For the subset of patients completing the full 12-week aData are from intent-to-treat last-observation-carried-forward analysis treatment, the mean (SE) absolute weight for the combina- of 16 subjects (9 in the combination group, 7 in the zonisamidegroup) who had at least 1 postbaseline assessment.
tion group (N = 7) changed from 97.4 (6.5) kg at baselineto 89.2 (6.4) kg at week 12; for the zonisamide group(N = 5), the corresponding change was 97.9 (10.7) kg to Categorical outcomes were compared using Fisher exact 94.9 (10.9) kg (treatment × time interaction: F = 4.6, df = test. For secondary analyses, data of subjects completing 4,40; p = .004). Thus, the 2 treatments differed signifi- all visits were analyzed using 2-way repeated-measures cantly with regard to change in weight (–8.1 [1.4] kg analysis of variance or t tests as appropriate.
[–8.5%] vs. –3.0 [0.9] kg [–3.3%]).
A repeated measures ANCOVA adjusted for the subject age, race, and baseline weight yielded significant time ×treatment interaction for the LOCF (F = 7.0, df = 1,46; Characteristics and Disposition of Participants p = .011) and completer (F = 7.1, df = 1,34; p = .011) Of the 19 individuals screened for participation, 1 samples described above. To insure that the latter findings subject decided not to participate. Eighteen subjects were were not biased by patterns of missing data, the above randomly assigned in a 1:1 ratio to 1 of 2 treatments––9 model was reestimated after full-sample multiple im- to receive zonisamide monotherapy and 9 to receive putation using SAS version 9.1, PROC MI and PROC the combination of zonisamide and bupropion. Six MIANALYZE (SAS Institute, Cary, N.C.).6 As indicated participants—4 in the zonisamide group and 2 in the by the time × treatment interaction, weight loss over the combination group—withdrew early; thus, 12 subjects study duration again was significantly greater for subjects completed the full 12-week treatment. Reasons for early randomized to combination treatment (t = –2.60; p = .010).
withdrawal were adverse effects (2 in the combinationgroup), lost to follow-up (1, zonisamide), lack of effi- Secondary Measures cacy (1, zonisamide), and consent withdrawn (2, zonisa- Waist circumference decreased significantly for the mide). Both early withdrawals in the combination group overall study sample (p = .002); however, there was no J Clin Psychiatry 68:8, August 2007 Gadde et al.
significant difference between the groups. There were no controlled trial of zonisamide, weight loss achieved with significant changes in blood pressure or heart rate over zonisamide monotherapy in this study was of a smaller time for the overall sample or between the groups.
magnitude; higher rate of attrition in the zonisamide onlygroup might have affected the mean weight loss in this Safety and Tolerability group. Whereas our data do not suggest improved toler- The following adverse events were recorded (number ability for the combination treatment, we must keep in of subjects): anxiety (1, combination group); dry mouth mind that much larger samples are typically needed for (1, combination; 1, zonisamide); memory problems (2, assessment of safety and comparison of adverse effects.
combination); difficulty with concentration (1, combina- Future studies could consider using different doses of bu- tion; 1, zonisamide); language and speech difficulty (1, propion and zonisamide (e.g., higher dose of bupropion combination); irritability (1, combination; 1, zonisamide); combined with a lower dose of zonisamide), slower dose light-headedness (1, combination); drowsiness (1, zonisa- titration of zonisamide, inclusion of bupropion monother- mide); fatigue (1, zonisamide); metallic taste (1, zonisa- apy and placebo groups, larger samples, and trials of mide); nausea (1, combination); constipation (1, combi- longer duration.
nation); diarrhea (1, zonisamide).
Drug names: bupropion (Wellbutrin, Zyban, and others), zonisamide(Zonegran and others).
To our knowledge, this is the first study examining the effect of combination therapy of zonisamide and bupro- 1. Gadde KM, Parker CB, Maner LG, et al. Bupropion for weight loss: an pion on body weight in obese individuals. This prelimi- investigation of efficacy and tolerability in overweight and obese women.
Obes Res 2001;9:544–551 nary study has several limitations and weaknesses, such 2. Anderson JW, Greenway FL, Fujioka K, et al. Bupropion SR enhances as open-label administration of study treatments, small weight loss: a 48-week double-blind, placebo-controlled trial. Obes Res sample size, short duration, and no male subjects. Addi- 3. Jain AK, Kaplan RA, Gadde KM, et al. Bupropion SR vs placebo for tionally, 2 comparison groups—bupropion monotherapy weight loss in obese patients with depressive symptoms. Obes Res 2002; and placebo—were not included in the study design, thus limiting interpretation of the results.
4. Gadde KM, Franciscy DM, Wagner HR II, et al. Zonisamide for weight reduction in obese adults: a randomized controlled trial. JAMA 2003; Nevertheless, our data provide a preliminary sugges- tion that combined administration of zonisamide and bu- 5. World Health Organization. WHO Energy and Protein Requirements.
propion might be associated with a more robust weight- Geneva, Switzerland: World Health Organization; 1985 6. Gadbury GL, Coffey CS, Allison DB. Modern statistical methods for loss effect than zonisamide monotherapy. Relative to the handling missing repeated measurements in obesity trial data: beyond results reported in a previously published randomized LOCF. Obes Rev 2003;4:175–184 J Clin Psychiatry 68:8, August 2007
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