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,
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
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
upropion, 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.
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
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)
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 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
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
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-
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-
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-
nation); diarrhea (1, zonisamide).
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
Table of Contents
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