Topiramate for the Treatment of Binge Eating Disorder Associated With Obesity: A Placebo-Controlled Study

Topiramate for the Treatment of Binge Eating Disorder Associated With Obesity: A Placebo-Controlled Study Susan L. McElroy, James I. Hudson, Julie A. Capece, Karen Beyers, Alan C. Fisher, and Norman R. Rosenthal, for the Topiramate Binge Eating Disorder Research Group Background: In a single-center, placebo-controlled study, topiramate reduced binge eating and weight in patients with binge eating disorder (BED) and obesity. The current investigation evaluated the safety and efficacy of topiramate in a multicenter, placebo-controlled trial. Methods: Eligible patients between 18 and 65 years with ⱖ 3 binge eating days/week and a body mass index (BMI) between 30 and 50 kg/m2 were randomized. Results: A total of 407 patients enrolled; 13 failed to meet inclusion criteria, resulting in 195 topiramate and 199 placebo patients. Topiramate reduced binge eating days/week (⫺3.5 ⫾ 1.9 vs. ⫺2.5 ⫾ 2.1), binge episodes/week (⫺5.0 ⫾ 4.3 vs. ⫺3.4 ⫾ 3.8), weight (⫺4.5 ⫾ 5.1 kg vs. .2 ⫾ 3.2 kg), and BMI (⫺1.6 ⫾ 1.8 kg/m2 vs. .1 ⫾ 1.2 kg/m2) compared with placebo (p ⬍ .001). Topiramate induced binge eating remission in 58% of patients (placebo, 29%; p ⬍ .001). Discontinuation rates were 30% in each group; adverse events (AEs) were the most common reason for topiramate discontinuation (16%; placebo, 8%). Paresthesia, upper respiratory tract infection, somnolence, and nausea were the most common AEs with topiramate. Conclusions: This multicenter study in patients with BED associated with obesity demonstrated that topiramate was well tolerated and efficacious in improving the features of BED and in reducing obesity. Key Words: Binge eating disorder, efficacy, impulsivity, obesity, safety, topiramate

B

inge eating disorder (BED) is characterized by recurrent episodes of distressing, uncontrollable eating of excessively large amounts of food (binge eating) without the inappropriate compensatory weight loss behaviors of bulimia nervosa or anorexia nervosa (American Psychiatric Association 2000; Dingemans et al. 2002). The prevalence of BED in the United States general population is estimated to be 1%–2% (Hudson et al. 2006a; Striegel-Moore and Franko 2003), with a lifetime prevalence of 3% (Hudson et al. 2006a). It is associated with psychopathology (especially compulsive, impulsive, and affective disorders) (Gold and Star 2004; Hudson et al. 2006a; McElroy and Kotwal 2006; Nasser et al. 2004; Yanovski et al. 1993), medical comorbidity (especially obesity) (Bulik and Reichborn-Kjennerud 2003; Johnson et al. 2001), impaired quality of life (Rieger et al. 2005), and disability (Hudson et al. 2006a). Binge eating disorder is common in patients presenting for weight management and bariatric surgery (Adami et al. 1995; Dymek-Valentine et al. 2004; Hudson et al. 2006a; Striegel-Moore and Franko 2003; Yanovski 2003), particularly those with severe obesity (body mass index [BMI] ⱖ 40 kg/m2) (Hudson et al. 2006a, 2006b). In addition, familial factors underlying BED,

From the Psychopharmacology Research Program (SLM), Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio; Biological Psychiatry Laboratory (JIH), McLean Hospital, Belmont, Massachusetts; Department of Psychiatry (JIH), Harvard Medical School, Boston, Massachusetts; Ortho-McNeil Neurologics (JAC, KB), Titusville, New Jersey; Ortho-McNeil Janssen Scientific Affairs (ACF); and PriCara (NRR), Unit of Ortho-McNeil, Raritan, New Jersey. Address reprint requests to Susan L. McElroy, M.D., Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, PO Box 670559, 231 Albert Sabin Way, Cincinnati, OH 45267-0559; E-mail: [email protected]. Received June 14, 2006; revised August 10, 2006; accepted August 11, 2006.

0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.08.008

which likely include genetic factors, might contribute to the development of severe obesity (Hudson et al. 2006b). Treatment objectives for BED generally include reduction of binge eating, weight loss or prevention of weight gain, and management of comorbid psychopathologic and medical conditions (Appolinario and McElroy 2004; Carter et al. 2003; Grilo and Masheb 2005; National Institute for Clinical Excellence 2004). Currently, no treatments are approved by the Food and Drug Administration (FDA) for BED. The National Institute for Clinical Excellence guidelines from the United Kingdom recommends the use of cognitive behavioral therapy (CBT), interpersonal therapy, and selective serotonin-reuptake inhibitor (SSRI) antidepressants (National Institute for Clinical Excellence 2004). Each of these treatments has limitations. Both CBT and interpersonal therapy often result in reduced binge eating and associated psychopathology but are usually not associated with statistically significant weight loss (Devlin et al. 2005; Grilo and Masheb 2005; Grilo et al. 2005b; National Institute for Clinical Excellence 2004; Wilfley et al. 2002). By contrast, although several SSRIs have been associated with statistically significant weight loss in placebo-controlled, short-term monotherapy trials (Appolinario and McElroy 2004; Arnold et al. 2002; Carter et al. 2003; Hudson et al. 1998; McElroy et al. 2000, 2003b), fluoxetine was ineffective for binge eating and weight loss in two recently published controlled studies that compared it with CBT (Devlin et al. 2005; Grilo et al. 2005b). However, five treatments have significantly reduced both binge eating and body weight in controlled trials: orlistat combined with CBT (Grilo et al. 2005a), sibutramine (Appolinario et al. 2003; Milano et al. 2005), zonisamide (McElroy et al. 2006), atomoxetine (McElroy et al. in press), and topiramate (McElroy et al. 2003a). Of note, these five medications were efficacious for treating obesity without psychopathology. Specifically, orlistat and sibutramine have FDA indications for the long-term treatment of obesity, whereas topiramate, zonisamide, and atomoxetine were efficacious for weight loss in obese patients without psychopathology in primarily short-term, double-blind, placebo-controlled trials (n ⫽ 6 for topiramate, n ⫽ 1 BIOL PSYCHIATRY 2007;61:1039 –1048 © 2007 Society of Biological Psychiatry

1040 BIOL PSYCHIATRY 2007;61:1039 –1048 for zonisamide, and n ⫽ 1 for atomoxetine) (Gadde et al. 2006; Li et al. 2005). Topiramate, which is approved for use in epilepsy and migraine prophylaxis, has multiple sites of action that might contribute to its neurostabilizing effects. These sites include sodium, calcium, and potassium channels; gamma-aminobutyric acid (GABA)A and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol4-yl) propionate acid (AMPA)/kainate–type glutamate receptors; and carbonic anhydrase inhibition. In the earlier study of topiramate in BED with obesity, 61 outpatients at a single center were randomized to 14 weeks of topiramate or placebo (McElroy et al. 2003a). Topiramate-treated patients displayed a 94% reduction of binge eating and a 5.9-kg weight loss, whereas placebo-treated patients showed a 46% reduction of binge eating and a 1.2-kg weight loss. Topiramate was also associated with significantly greater improvement in global severity and compulsive features of BED. Importantly, patients maintained improvements in both binge eating behavior and body weight in a 42-week open-label extension of this study (McElroy et al. 2004). The objective of the present study was to replicate the earlier single-center study (McElroy et al. 2003a) in a more comprehensive multicenter trial. Toward this end, we conducted a 19-center, randomized, parallel-group study to assess the efficacy and safety of topiramate in 407 outpatients with moderate-to-severe BED with obesity. Moderate-to-severe BED was defined as having current BED with at least 3 binge days/week in the 2 weeks before randomization. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association 2000) criteria require an average of 2 binge days/ week for 6 months but do not specify a minimum frequency within the prior 2 weeks. Several other design modifications were implemented in the present trial in an attempt to improve upon limitations of the earlier trial (McElroy et al. 2003a). These included extending the duration of treatment from 14 to 16 weeks; excluding patients with lifetime bipolar disorder, current clinically significant depression, and those with a BMI ⬎ 50 kg/m2 (to reduce discontinuations from impaired impulse control and poor health) (McElroy et al. 2004); and decreasing the maximum allowable topiramate dosage from 600 mg/day to 400 mg/day and the rate at which the topiramate dosage could be titrated upward (to increase tolerability) (Biton et al. 2001).

Methods and Materials Study Design This was a 16-week, outpatient, randomized, double-blind, parallel-group, flexible-dose investigation conducted at 19 centers in the United States. The study consisted of three phases: a 2– 6-week screening period, a 16-week double-blind treatment period, and either a 12-week open-label maintenance period or a 1-week taper and discontinuation period for those not entering the maintenance phase (the results of the 12-week maintenance study will be presented in a subsequent publication). During the screening period, after a designated washout for protocol-prohibited medications, eligible patients maintained a diary for ⱖ 14 days and recorded their binge eating episodes. Patients documenting ⱖ 3 binge days/week during this period and continuing to meet other entry criteria were randomized to receive either placebo or topiramate. Study medication was started at 25 mg/day and was titrated weekly over an 8-week period to 400 mg/day or the maximum tolerated dose. During this 8-week period, the fastest rate at which study medication was increased was by 25 mg/day/week for the www.sobp.org/journal

S.L. McElroy et al. first 4 weeks to 100 mg/day by week 4, to 150 mg/day by week 5, to 200 mg/day by week 6, to 300 mg/day by week 7, and to 400 mg/day by week 8. For the last 8 weeks of the double-blind treatment period, the study medication dose was to remain at the dose achieved during titration; however, a single dose reduction to the previously tolerated dose was permitted to manage tolerability. Study medication was prescribed in a twice-daily divided regimen. Setting/Patient Population Study participants were outpatients from a combination of private practice and university settings. They were recruited by radio and newspaper advertising requesting volunteers for a study of a medication for the treatment of binge eating with obesity and through clinical referrals. This study was conducted between October 16, 2003, and February 28, 2005. Patients were entered into the study if they satisfied the following inclusion criteria: men or women between 18 and 65 years of age; a current diagnosis of BED as defined by the DSM-IV (American Psychiatric Association 2000) and supported by both the Structured Clinical Interview for DSM-IV Axis I Disorders, Research Version, Patient Edition (SCID I/P) (First et al. 2002) and the Eating Disorders Examination (Fairburn and Cooper 1993); ⱖ 3 binge days/week during the 2-week screening period before baseline; current obesity, defined as a BMI ⱖ 30 and ⱕ 50 kg/m2; and being in otherwise good health (uncomplicated and well-controlled type 2 diabetes or hypertension were allowed). Also, women of childbearing potential had to be nonpregnant, not lactating, and using a medically accepted form of birth control. Patients were excluded from study participation if they met any of the following criteria: a current or lifetime history of major organic psychiatric disease, a psychotic disorder, or a bipolar disorder; clinically significant depression (defined as a Montgomery-Åsberg Depression Rating Scale [MADRS] [Montgomery and Asberg 1979] score ⬎ 24 at the screening or baseline visits); current or recent (within 3 months of start of study medication) substance abuse or dependence (excluding nicotine or caffeine); enrollment in a formal psychotherapy program (including CBT, self-guided CBT, interpersonal therapy, and dietary behavioral therapy) for BED or any other psychiatric disorder ⱕ 6 months before the screening phase; a history of factitious disorder, malingering, or a personality disorder that might interfere with assessment or compliance with study procedures; a serious or unstable concurrent medical illness; any medical condition that might potentially compromise topiramate absorption, metabolism, or excretion; a history of nephrolithiasis or seizures; or known hypersensitivity to or a prior adverse event with topiramate. Written informed consent was obtained from all participants before they underwent any study procedures, and approval was provided for this study at each participating site by an independent ethics committee or institutional review board. The study was conducted in compliance with the Declaration of Helsinki. Outcome Measures The primary efficacy measure was the number of binge eating days/week. A binge eating day was defined as a day on which a patient had at least one binge eating episode. As in the prior controlled topiramate study (McElroy et al. 2003a), binge eating episodes were defined according to DSM-IV criteria (American Psychiatric Association 2000) and assessed by clinical interview and review of patient take-home diaries. Patients were given verbal and written instructions, with examples, for determining binge episodes. In the diaries, patients recorded binges, duration

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S.L. McElroy et al. of binges, and food consumed during binges so that, upon review with the patient, binges could be confirmed by the investigator. Secondary efficacy measures were binge eating episodes/ week, body weight, BMI, the CGI Scale (Guy 1976), the YaleBrown Obsessive-Compulsive Scale modified for binge eating (Y-BOCS-BE) (Goodman et al. 1989), the Barratt Impulsiveness Scale, Version 11 (BIS-11) (Barratt and Stanford 1995), the Three-Factor Eating Questionnaire (TFEQ) (Stunkard and Messick 1985), the MADRS, the Hamilton Anxiety Scale (HAM-A) (Hamilton 1959), and the Sheehan Disability Scale (SDS) (Sheehan et al. 1996). The Y-BOCS-BE scale measures obsessiveness of binge eating thoughts or urges and compulsiveness of binge eating behaviors (Goodman et al. 1989). The BIS-11 is a commonly used scale that assesses three domains of impulsivity: motor impulsiveness, nonplanning impulsiveness, and attentional impulsiveness (Barratt and Stanford 1995). The TFEQ is a valid and reliable self-report scale that assesses three domains of eating behavior often disturbed in persons with obesity: dietary (cognitive) restraint, disinhibition, and hunger (Stunkard and Messick 1985). Safety assessments included monitoring vital signs, physical examination, clinical laboratory parameters, and adverse events. Adverse events were coded according to the World Health Organization Adverse Reaction Terms Dictionary. Medication compliance was assessed through count of returned study tablets. Randomization Patients were randomized to receive topiramate or placebo in a 1:1 ratio according to computer-generated coding. Randomization was balanced by use of permuted blocks. Statistical Analyses Sample size was based on a two-sided ␹2 test (significance level, .05; 90% power) and the results from the prior topiramate study (estimated placebo response, 30%; expected improvement rate with topiramate, 17%) (McElroy et al. 2000). Thus, a sample size of 171 subjects/group (N ⫽ 342 total) was estimated. The primary efficacy analysis was performed in a modified ITT population, which excluded patients with ⱖ 1 of the following inclusion/exclusion criteria violations: no BED diagnosis; did not have ⱖ 3 binge eating days/week in each week of the 2-week period before baseline; had a baseline BMI ⬍ 30 kg/m2; or had a screening or baseline MADRS ⬎ 24. Efficacy analyses were also performed in the ITT population, defined as all randomized participants who were dispensed study medication and had ⱖ 1 post-baseline efficacy evaluation. The primary analysis for the primary efficacy variable and other continuous efficacy variables was a repeated measures random regression (Diggle et al. 1995; Gibbons et al. 1993). The linear model for the mean of the outcome variable included terms for treatment, time, center, and treatment ⫻ time interaction. The measure of effect was the treatment ⫻ time interaction, which represented the difference between groups in the rate of change of the outcome variable. We modeled time as a continuous variable, expressed as log (week ⫹ 1). For analysis of frequency of binge eating days and frequency of binge eating episodes, a logarithmic transformation was used: log [(binge eating days/week) ⫹ 1] and log [(binge eating episodes/week) ⫹ 1]. Standard errors were estimated with generalized estimating equations with compound symmetry as a working covariance structure, as implemented by SAS (Cary, North Carolina) and used in

several previous studies of BED (Devlin et al. 2005; Grilo and Masheb 2005; Grilo et al. 2005a; Hudson et al. 1998; McElroy et al. 2000, 2003b). Because there was only one primary efficacy variable, no multiplicity adjustments were made for the secondary efficacy analyses. A two-way analysis of covariance (ANCOVA) was used as a secondary analysis for continuous variables, with treatment and study center as factors and baseline value as a covariate to evaluate end point results. After logarithmic transformation, mean change and percentage change in binge eating days and binge eating episodes were analyzed with ANCOVA. Categorical efficacy variables (CGI-Improvement and response categories) were analyzed with the Cochran-MantelHaenszel technique with modified ridit scoring stratified by the investigator. Efficacy response categories were categorized as ⬍ 50% reduction in binge eating days ⫽ no response; 50%–74% reduction ⫽ moderate response; 75%–99% reduction ⫽ marked response; 100% reduction ⫽ remission. Time to recovery (defined as the 4th consecutive week during which the subject had Table 1. Patient Demographics and Baseline Characteristics Characteristic Mean ⫾ SD age, years Gender, n (%) Men Women Race, n (%) White Black Other Mean ⫾ SD weight, kg Mean ⫾ SD BMI, kg/m2 Mean ⫾ SD Baseline Binge Daysb Mean ⫾ SD Baseline Binge Episodesb Mean ⫾ SD Age at Start of Symptoms, yearsb Mean ⫾ SD Time Since Start of Symptoms, yearsb Montgomery-Åsberg Depression Rating Scaleb Barratt Impulsiveness Scale, Version 11 ⫾ SDb Overall score Motor impulsiveness Nonplanning impulsiveness Attentional impulsiveness Yale-Brown Obsessive-Compulsive Scale, Modified for Binge Eating ⫾ SDb Total score Obsessions Compulsions Three-Factor Eating Questionnaire ⫾ SDb Cognitive restraint Disinhibition Hunger Hamilton Anxiety Scale ⫾ SDb Sheehan Disability Scale ⫾ SDb Overall score School/work disability Social life disability Family life disability CGI-Severity ⫾ SDb

Topiramate n ⫽ 202a 44 ⫾ 11.5 32 (15.8) 170 (84.2)

Placebo n ⫽ 202a 45 ⫾ 11.6 32 (15.8) 170 (84.2)

153 (75.7) 164 (81.2) 38 (18.8) 27 (13.4) 11 (5.4) 11 (5.4) 106 ⫾ 18.5 107 ⫾ 18.3 38 ⫾ 5.1 39 ⫾ 5.5 4.6 ⫾ 1.3 4.6 ⫾ 1.3 6.6 ⫾ 4.6 6.3 ⫾ 3.6 25.4 ⫾ 13.5 23.9 ⫾ 14.3 18.6 ⫾ 14.3 20.6 ⫾ 14.5 5.9 ⫾ 5.4

6.7 ⫾ 5.5

64.2 ⫾ 11.5 22.8 ⫾ 4.7 25.4 ⫾ 5.3 16.0 ⫾ 4.2

65.7 ⫾ 11.2 23.1 ⫾ 4.3 25.8 ⫾ 5.0 16.8 ⫾ 4.5

21.1 ⫾ 4.9 10.3 ⫾ 3.1 10.8 ⫾ 2.5

21.5 ⫾ 4.9 10.6 ⫾ 3.1 10.9 ⫾ 2.4

6.7 ⫾ 3.8 13.9 ⫾ 1.8 10.8 ⫾ 2.9 5.1 ⫾ 4.8

6.8 ⫾ 3.8 14.1 ⫾ 1.7 11.3 ⫾ 2.7 5.5 ⫾ 5.1

11.9 ⫾ 7.9 3.2 ⫾ 2.8 4.4 ⫾ 3.2 4.5 ⫾ 3.1 4.8 ⫾ 0.9

12.3 ⫾ 7.9 3.4 ⫾ 3.0 4.5 ⫾ 3.2 4.3 ⫾ 3.0 4.8 ⫾ 0.9

BMI ⫽ body mass index; CGI ⫽ Clinical Global Impression. Demographic characteristics are listed for safety population. b Modified intent-to-treat population (topiramate, n ⫽ 195; placebo, n ⫽ 199; see text for definition). a

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1042 BIOL PSYCHIATRY 2007;61:1039 –1048

S.L. McElroy et al. 619 Patients Assessed for Eligibility

212 Patients Excluded Did Not Meet Inclusion Criteria (118) Refused to Participate (59) Other Reasons – Lost to Follow-up (35) 407 Patients Randomized

204 Assigned to Topiramate Group

203 Assigned to Placebo Group

Intent-to-Treat (ITT) Population 142 Completed Double-blind Phase 57 Discontinued Double-blind Phase Subject Choice (12) Adverse Event (29) Lack of Efficacy (1) Lost to Follow-up (13) Other (2)

Intent-to-Treat (ITT) Population 141 Completed Double-blind Phase 61 Discontinued Double-blind Phase Subject Choice (21) Adverse Event (16) Lack of Efficacy (3) Lost to Follow-up (17) Other (4)

Modified ITT (mITT) Population 140 Completed Double-blind Phase 55 Discontinued Double-blind Phase Subject Choice (11) Adverse Event (28) Lack of Efficacy (1) Lost to Follow-up (13) Other (2)

Modified ITT (mITT) Population 140 Completed Double-blind Phase 59 Discontinued Double-blind Phase Subject Choice (21) Adverse Event (15) Lack of Efficacy (3) Lost to Follow-up (17) Other (3)

202 Safety Population*

202 Safety Population*

199 ITT Population† 195 mITT Population‡

202 ITT Population† 199 mITT Population‡

140 Completers (mITT)§

140 Completers (mITT)§

Figure 1. Population Flow Diagram. *Safety: all randomized patients for whom at least one post-baseline safety measure was available. †ITT: all randomized patients who received study medication and had at least one valid post-baseline efficacy evaluation. ‡mITT: all ITT patients excluding those with ⱖ 1 major inclusion/exclusion violation (no diagnosis of binge eating disorder [BED]; did not have ⱖ 3 binge days/week at baseline; had baseline body mass index [BMI] ⬍ 30 kg/m2; or Montgomery-Åsberg Depression Rating Scale [MADRS] ⬎ 24). §Completers: all randomized patients who completed all study visits up to and including visit 10 and exceeded 99 days of taking study medication.

no binge eating episodes) and time to response (defined as the 4th consecutive week in which there was ⱖ 50% decrease in the frequency of binge eating days from baseline) were analyzed with a log-rank test. All analyses were specified before the blind was broken. The Fisher exact test was conducted to evaluate differences in the rate of adverse events.

Results Study Participants Overall, 619 patients were screened, and 407 patients were randomized to topiramate (n ⫽ 204) or placebo (n ⫽ 203). After excluding patients with no BED diagnosis (n ⫽ 6), patients who did not have ⱖ 3 binge eating days/week in the 2 weeks before randomization (n ⫽ 6) and a single patient who had a BMI ⬍ 30 kg/m2, the mITT population comprised www.sobp.org/journal

394 patients (Table 1), with 195 randomized to topiramate and 199 to placebo. At baseline, there were no significant differences between the mITT and the ITT groups in demographic or clinical features. A summary of patient disposition and reasons for withdrawal is provided in the Population Flow Diagram (Figure 1). Seventy percent in each group completed the 16 weeks of double-blind treatment. The median final daily dose of topiramate was 300 mg/day (range, 25– 400 mg/day) versus 400 mg/day for placebo. The mean duration of topiramate treatment was 93.6 ⫾ 33.0 days versus 93.3 ⫾ 33.6 days for placebo. The mean number of binge eating days/week decreased from baseline to 16 weeks in the topiramate group by 3.7 (from 4.6 to .9, or 72% ⫾ 38%), whereas it decreased by 2.4 (from 4.6 to 2.2, or 47% ⫾ 41%) in the placebo group (Figure 2). Topiramate was also associated with a decreased median number of binge eating days/week, from 4.5 at baseline to 0 beginning at week 5

S.L. McElroy et al.

Figure 2. The mean number of binge eating days/week.

throughout the remainder of the double-blind treatment phase (Figure 3). The mean number of binge eating episodes/week decreased from baseline to 16 weeks in the topiramate group by 5.3 (from 6.6 to 1.3, or 73% ⫾ 37%) and by 3.5 (from 6.3 to 2.8, or 47% ⫾ 41%) in the placebo group (Figure 4). Body mass index decreased steadily with topiramate but showed little change with placebo (Figure 5). The primary efficacy analysis with random regression showed that patients receiving topiramate had a significantly greater rate of reduction in binge eating days/week than patients receiving placebo [␹2 ⫽ 51, p ⬍ .001] (Table 2). Topiramate was also associated with a significantly greater rate of improvement (treatment ⫻ time interaction) than placebo for the following variables: binge eating episodes/week; body weight; BMI; CGISeverity scores; total, obsessive, and compulsive scores of the Y-BOCS-BE; overall, motor, and nonplanning impulsiveness scores of the BIS-11; cognitive restraint, disinhibition, and hunger subscores of the TFEQ; and overall, social, and family life disability scores of the SDS (Table 2). No between-group differences in the rate of change in MADRS, HAM-A, the SDS school/ work disability or the BIS-11 attentional impulsiveness scores were observed (Table 2). In the secondary analyses, with baseline-to-end point ANCOVA, topiramate was associated with a significant decrease in

Figure 3. The median number of binge eating days/week.

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Figure 4. The mean number of binge eating episodes/week.

binge eating days/week; binge eating episodes/week; overall, motor, and nonplanning impulsiveness scores of the BIS-11; overall, obsessive, and compulsive scores of the Y-BOCS-BE; cognitive restraint, disinhibition, and hunger subscores of the TFEQ; overall, social, and family life disability scores of the SDS, and CGI-Severity scores, compared with placebo (Table 3). There was no significant difference between groups in the change in MADRS, the attentional impulsiveness of the BIS-11, the HAM-A, and the school/work disability score of the SDS (Table 3). Looking at categorical outcome measures at end point, among the 195 patients receiving topiramate and the 198 patients receiving placebo, CGI-Improvement ratings were: very much improved (n ⫽ 101 [52%] for topiramate; n ⫽ 43 [22%] for placebo), much improved (n ⫽ 34 [17%] for topiramate; n ⫽ 23 [12%] for placebo), minimally improved (n ⫽ 30 [15%] for topiramate; n ⫽ 50 [25%] for placebo), no change (n ⫽ 23 [12%] for topiramate; n ⫽ 71 [36%] for placebo), minimally worse (n ⫽ 4 [2%] for topiramate; n ⫽ 9 [5%] for placebo), and much worse (n ⫽ 3 [2%] for topiramate; n ⫽ 2 [1%] for placebo) (p ⬍ .001 for difference between groups in level of response). Response categories for binge eating days at end point were: remission (n ⫽ 113 [58%] for topiramate; n ⫽ 57 [29%] for placebo), marked (n ⫽ 23 [12%] for topiramate; n ⫽ 21 [11%] for placebo), moderate (n ⫽ 20 [10%] for topiramate; n ⫽ 36 [18%] for placebo), and none (n ⫽ 39

Figure 5. Body mass index.

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Table 2. Effect of Topiramate Treatment on Outcome Measures for Patients with Binge Eating Disorder (N ⫽ 394) Randomly Assigned to 16 Weeks of Double-Blind Treatment with Topiramate or Placebo Effect of Topiramate Outcome Measures

Treatment ⫻ Time Interactiona

SE

␹2 (df ⫽ 1)

p Value

⫺.211 ⫺.232 .232

.027 .031 .212

50.97 48.21 1.20

⬍ .001 ⬍ .001 .274

⫺.980 ⫺.340 ⫺.608 .027

.322 .142 .149 .130

9.02 7.67 15.87 .04

.003 .006 ⬍ .001 .835

⫺3.154 ⫺1.527 ⫺1.621

.352 .178 .191

64.21 60.04 59.00

⬍ .001 ⬍ .001 ⬍ .001

.837 ⫺1.310 ⫺1.156 .245

.171 .161 .167 .167

22.12 54.98 41.24 2.14

⬍ .001 ⬍ .001 ⬍ .001 .143

⫺1.072 ⫺.168 ⫺.459 ⫺.459 ⫺.584 ⫺1.995 ⫺.712

.266 .095 .105 .104 .063 .165 .059

15.44 3.07 18.14 18.38 68.15 100.13 100.10

⬍ .001 .080 ⬍ .001 ⬍ .001 ⬍ .001 ⬍ .001 ⬍ .001

Binge Daysb Binge Frequencyc Montgomery-Åsberg Depression Rating Scale Barratt Impulsiveness Scale, Version 11 Overall score Motor impulsiveness Nonplanning impulsiveness Attentional impulsiveness Yale-Brown Obsessive-Compulsive Scale, modified for binge eating Total score Obsessions Compulsions Three-Factor Eating Questionnaire Cognitive restraint Disinhibition Hunger Hamilton Anxiety Scale Sheehan Disability Scale Overall score School/work disability Social life disability Family life disability CGI-Severity Weight Change BMI

Abbreviations as in Table 1. Difference in rate of change between the topiramate and placebo groups, with time modeled as log (weeks ⫹ 1). b Log ([binge days/week] ⫹ 1). c Log ([binges/week] ⫹ 1). a

[20%] for topiramate; n ⫽ 84 [42%] for placebo) (p ⬍ .001 for difference between groups in level of response). Response categories for binge eating episodes at end point were: remission (n ⫽ 113 [58%] for topiramate; n ⫽ 57 [29%] for placebo), marked (n ⫽ 26 [13%] for topiramate; n ⫽ 27 [14%] for placebo), moderate (n ⫽ 19 [10%] for topiramate; n ⫽ 38 [19%] for placebo), and none (n ⫽ 37 [19%] for topiramate; n ⫽ 76 [38%] for placebo) (p ⬍ .001 for difference between groups in level of response). Examining time to recovery and response, topiramate was associated with a significantly shortened time to recovery from binge eating (p ⬍ .001) and time to response of binge eating (p ⬍ .001). Efficacy results for the ITT population were similar to those reported for the mITT population. Adverse events occurring in ⱖ 10% of patients in either treatment group are summarized in Table 4. Treatment-emergent adverse events occurring significantly more often in the topiramate group compared with the placebo group included paresthesia, upper respiratory tract infection, taste perversion, difficulty with concentration/attention, and difficulty with memory not otherwise specified. Most adverse events were mild to moderate in severity. Twenty-nine (15%) discontinuations in the topiramate group and 16 (8%) in the placebo group were attributed to adverse events (Figure 1). The most common adverse events causing topiramate discontinuation were difficulty with memory not otherwise specified (3% for topiramate vs. 1% for placebo) and depression (2% for topiramate vs. 1.5% for www.sobp.org/journal

placebo). Three patients in each group experienced serious adverse events. Serious adverse events reported in topiramatetreated patients included acute cholecystitis, major depression, and tibial fracture; serious adverse events reported in placebo-treated patients included asthma exacerbation, stomach virus, and arrhythmia. No clinically meaningful differences in any laboratory test or vital sign parameter, other than weight, were documented in the treatment groups. One patient discontinued topiramate for clinically asymptomatic hyperchloremic acidosis, which was mild and resolved with drug discontinuation.

Discussion This study replicates a 14-week single-center study (McElroy et al. 2003a) that found topiramate to be superior to placebo for the treatment of BED associated with obesity. In the present 16-week, 19-center study, patients receiving topiramate experienced highly significant rates of reductions in binge eating days and binge eating episode frequency, weight, BMI, overall severity of BED, and compulsive features of BED compared with patients receiving placebo. In addition, topiramate was associated with greater improvement in measures of hunger, impulsive features, and disability. Topiramate was well tolerated during the 16-week treatment period. As in the earlier study, no withdrawal symptoms were reported upon drug discontinuation. The present study had a lower discontinuation rate than the earlier trial (29% vs. 43%)

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S.L. McElroy et al. Table 3. Mean Change from Baseline to Endpoint in Efficacy Measures Outcome Measures Binge days per week Binge episodes per week Montgomery-Å´sberg Depression Rating Scale Barratt Impulsiveness Scale, Version 11 Overall Score Motor Impulsiveness Non-planning Impulsiveness Attentional Impulsiveness Yale-Brown Obsessive-Compulsive Scale, modified for binge eating Total Score Obsessive Compulsive Three-Factor Eating Questionnaire Cognitive Restraint Disinhibition Hunger Hamilton Anxiety Rating Scale Sheehan Disability Scale Overall Score School/Work Disability Social Life Disability Family Life Disability Clinical Global Impression-Severity of Illness Score

Topiramate* N ⫽ 195

Placebo* N ⫽ 199

⫺3.5 ⫾ 1.9 ⫺2.5 ⫾ 2.1 ⫺5.0 ⫾ 4.3 ⫺3.4 ⫾ 3.8 ⫺.2 ⫾ 7.0

P ⬍ .001 ⬍ .001

⫺.7 ⫾ 6.2

.893

⫺3.9 ⫾ 9.0 ⫺1.4 ⫾ 7.9 ⫺1.8 ⫾ 3.8 ⫺.9 ⫾ 3.7 ⫺1.6 ⫾ 4.5 .01 ⫾ 3.7 ⫺.6 ⫾ 3.6 ⫺.5 ⫾ 3.1

⬍ .001 .004 ⬍ .001 .230

⫺14.3 ⫾ 8.9 ⫺7.9 ⫾ 8.9 ⫺6.7 ⫾ 4.6 ⫺3.8 ⫾ 4.8 ⫺7.6 ⫾ 4.8 ⫺4.2 ⫾ 4.8

⬍ .001 ⬍ .001 ⬍ .001

3.5 ⫾ 4.5 1.6 ⫾ 4.5 ⫺5.0 ⫾ 4.7 ⫺2.0 ⫾ 3.5 ⫺4.5 ⫾ 4.6 ⫺1.9 ⫾ 4.1 ⫺.7 ⫾ 4.9 ⫺1.3 ⫾ 4.5

⬍ .001 ⬍ .001 ⬍ .001 .493

⫺6.8 ⫾ 7.6 ⫺1.6 ⫾ 2.6 ⫺2.6 ⫾ 3.2 ⫺2.7 ⫾ 3.0

⫺4.9 ⫾ 7.6 ⫺1.4 ⫾ 2.9 ⫺1.7 ⫾ 3.1 ⫺1.8 ⫾ 2.9

.001 .181 ⬍ .001 ⬍ .001

⫺2.2 ⫾ 1.6 ⫺1.1 ⫾ 1.4

⬍ .001

*Modified intent-to-treat population (see text for definition).

(McElroy et al. 2003a). This might be because the earlier trial accepted a broader range of patients, including those with stable bipolar disorder and acute depressive episodes, and the present study used a slower topiramate dosage titration and a lower maximum topiramate dose (400 vs. 600 mg/day). The reduction in binge eating frequency and the overall improvement observed with topiramate are at least equal in magnitude to those reported in controlled studies of CBT, interpersonal therapy, SSRIs, sibutramine, zonisamide, atomoxetine, and orlistat plus CBT in patients with BED (Appolinario and McElroy 2004; Carter et al. 2003; Devlin et al. 2005; Grilo and Masheb 2005; Grilo et al. 2005b; McElroy et al. in press; McElroy et al. 2006; Wilfley et al. 2002; Wonderlich et al. 2003). The weight loss effect seems greater for topiramate than for CBT (Devlin et al. 2005; Grilo and Masheb 2005; Grilo et al. 2005b; Wilfley et al. 2002), interpersonal therapy (Wilfley et al. 2002), and SSRIs (Appolinario and McElroy 2004; Arnold et al. 2002; Carter et al. 2003; Hudson et al. 1998; McElroy et al. 2000, 2003b), and comparable to that for sibutramine (Appolinario et al. 2003; Milano et al. 2005), zonisamide (McElroy et al. 2006), atomoxetine (McElroy et al. in press), and orlistat alone (Golay et al. 2005) or plus CBT (Grilo et al. 2005a). Importantly, with this study, topiramate is the first treatment shown to be superior to placebo in improving the impulsive features and disability of BED with obesity. However, accurate determination of the comparative efficacy of topiramate to other treatments for BED with obesity will require appropriately designed controlled comparative trials. Until such comparative data are available, the findings of this study, taken together with the earlier study (McElroy et al. 2003a, 2004), suggest that topiramate should be

considered a viable option along with CBT, interpersonal therapy, and SSRIs for patients with BED (National Institute for Clinical Excellence 2004). In particular, topiramate might be considered a first-line therapy for BED patients with obesity, along with CBT, interpersonal therapy, SSRIs, and possibly sibutramine and orlistat, as well as a second-line or even add-on therapy for BED patients in general who have an inadequate response to the latter treatments. The mechanism of action of topiramate in BED is unknown. One possibility is that topiramate decreases binge eating by suppressing appetite or enhancing satiety. Topiramate has been shown to induce weight loss in rodent models in part by reducing caloric intake, although the mechanism by which it does this is unknown (Picard et al. 2000; York et al. 2000). One possible mechanism involves the effects of topiramate on the neuropeptide Y (NPY) or glutamate systems. Specifically, NPY is one of the most potent anorexigenic peptides within the hypothalamus (Ramos et al. 2005). Also, stimulation of the lateral hypothalamus by glutamate and glutamate agonists increases food intake (Duva et al. 2002; Stanley et al. 1993; Zeni et al. 2000), whereas glutamate antagonism of the nucleus tractus solitarius decreases food intake (Zheng et al. 2002). Topiramate reduces glutamate neurotransmission by antagonizing AMPA/ kainate glutamate receptors (Kaminski et al. 2004; White 2005). A second possible mechanism is that topiramate might directly induce weight loss, which secondarily decreases binge eating. In rodents, topiramate is believed to induce weight loss by stimulation of energy expenditure as well as reduction of energy intake (Picard et al. 2000; York et al. 2000). More generally, carbonic anhydrase inhibitors have been hypothesized to induce weight loss by inhibiting carbonic anhydrase–mediated de novo lipogenesis (Winum et al. 2005). A third possible mechanism is that topiramate decreases binge eating by altering the rewarding properties of food (Gold and Star 2004). By analogy, preliminary controlled trials suggest that topiramate is effective in patients with alcohol and cocaine dependence (Johnson et al. 2003; Kampman et al. 2004), possibly by reducing the rewarding properties of these drugs through its GABAergic and antiglutamatergic properties combining to modulate corticomesolimbic dopamine function (Johnson et al. 2003). Similarly, in rodent brain, topiramate has been shown to inhibit nicotine-induced elevation of dopamine (Schiffer et al. 2001). A fourth possible mechanism is that topiramate reduces binge eating via a general effect on impulsivity rather than having a specific effect on binge eating. In favor of this mechanism is that Table 4. Adverse Events Occurring in ⱖ 10% of Patients Adverse Event, n (%) Paresthesia Upper Respiratory Tract Infection Somnolence Nausea Taste Perversion Dry Mouth Difficulty with Concentration/Attention Difficulty with Memory Not Otherwise Specified Headache

Topiramate n ⫽ 202

Placebo n ⫽ 202

p Valuea

113 (55.9) 37 (18.3) 34 (16.8) 32 (15.8) 28 (13.9) 27 (13.4) 26 (12.9)

25 (12.4) 20 (9.9) 26 (12.9) 25 (12.4) 2 (1.0) 22 (10.9) 5 (2.5)

⬍ .001 .022 .327 .391 ⬍ .001 .543 ⬍ .001

25 (12.4) 25 (12.4)

12 (5.9) 29 (14.4)

.037 .661

Safety population (see text for definition). a Fisher exact test.

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1046 BIOL PSYCHIATRY 2007;61:1039 –1048 topiramate is associated with reductions of other impulsive behaviors, such as alcohol and cocaine use (Johnson et al. 2003; Kampman et al. 2004), binge eating and purge behaviors in bulimia nervosa (Hoopes et al. 2003), and aggression in borderline personality disorder (Nickel et al. 2004, 2005). Possibly, these disorders share similar biological determinants of impulsivity, and topiramate might benefit these conditions via an anti-impulsivity effect that spans diagnostic categories. Indeed, some have argued that conditions with binge eating should be viewed as belonging to a family of disorders characterized by pathological impulsivity, often referred to as impulse control, or impulsive-compulsive spectrum, disorders (Hollander et al. 2006; McElroy and Kotwal 2006). Several limitations of this study should be considered. The first is the uncertain accuracy of the self-report methods used to obtain binge eating data. However, patient diaries were used to enhance patient recall of binge eating episodes, and randomization and double-blinding should have equalized any patient or investigator bias in the recording or rating of overeating as binge eating episodes. A second limitation is that because the duration of double-blind therapy was only 16 weeks, it is unknown if the results would generalize to longer periods of treatment. Although the beneficial effects on binge eating and weight persisted for 42 weeks in an open-label extension of the earlier trial (McElroy et al. 2004) and a 4-month extension trial of the present study will be published, this limitation can only be adequately addressed in controlled long-term treatment studies. A third limitation is that because more topiramate-treated patients experienced adverse events than placebo-treated patients, blindness to treatment assignment might have been compromised in some cases. Thus, use of an active control might have led to less of a difference between topiramate and placebo on binge eating frequency and other outcome measures. A fourth limitation is that patients with lifetime bipolar disorder, clinically significant depressive symptoms, recent substance use disorders, severe personality disorders, and a variety of clinically significant medical disorders (including those with BMIs ⱖ 50 kg/m2) were excluded from participation. It is, therefore, unknown if topiramate would be efficacious in the treatment of BED among patients with these comorbid conditions. Also, because patients with BED with BMIs ⬍ 30 kg/m2 were excluded, it is unknown if topiramate would be efficacious in non-obese patients with BED. In summary, in this 16-week, multicenter study in outpatients with BED and obesity, topiramate treatment was well tolerated and efficacious in improving binge eating behavior, obesity, and other features associated with BED. This study was sponsored by Ortho-McNeil Neurologics, Titusville, New Jersey. SLME is a consultant to or member of the scientific advisory boards of Abbott Laboratories, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutica, Ortho-McNeil, and Wyeth. SLME is a principal or co-investigator on research studies sponsored by AstraZeneca, Bristol-Myers Squibb, Esai, Eli Lilly, Forrest Labs, National Institutes of Mental Health, Ortho-McNeil, Pfizer, Sanofi-Synthelabo, and Somaxon Pharmaceuticals. In addition, SMLE is inventor on US Patent No. 6,323,236B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and along with the patent’s assignee, University of Cincinnati, Cincinnati, Ohio, receives payments from Johnson and Johnson Pharmaceutical Research and Development, which has exclusive rights under the patent. JIH has received grant support and consulting fees from OrthoMcNeil Pharmaceutical and from Eli Lilly & Company. JAC is www.sobp.org/journal

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