CE ACTIVITY Acamprosate in the Treatment of Binge Eating Disorder: A Placebo-Controlled Trial Susan L. McElroy, MD1* ABSTRACT obsessive-compulsiveness of binge eat- 1 Objective: To assess preliminarily the ing, food craving, and quality of life. Anna I. Guerdjikova, PhD effectiveness of acamprosate in binge Among completers, weight and BMI 1 Erin L. Winstanley, PhD eating disorder (BED). decreased slightly in the acamprosate 1 group but increased in the placebo Anne M. O’Melia, MD Method: In this 10-week, randomized, 1 group. Nicole Mori, CNP placebo-controlled, flexible dose trial, 40 1 Jessica McCoy, BA outpatients with BED received acampro- Discussion: Although acamprosate did Paul E. Keck Jr., MD1 sate (N 5 20) or placebo (N 5 20). The not separate from placebo on any out- James I. Hudson, MD, ScD2 primary outcome measure was binge eat- come variable in the longitudinal analy- ing episode frequency. sis, results of the endpoint and completer analyses suggest the drug may have Results: While acamprosate was not some utility in BED. VC 2010 by Wiley associated with a significantly greater Periodicals, Inc. rate of reduction in binge eating episode frequency or any other measure in the Keywords: acamprosate; binge eating primary longitudinal analysis, in the end- disorder; obesity; glutamate point analysis it was associated with stat- istically significant improvements in binge day frequency and measures of (Int J Eat Disord 2011; 44:81–90) Introduction The treatment of BED remains a challenge.5 Cogni- tive behavioral and interpersonal therapies and selec- Binge eating disorder (BED), characterized by recur- tive serotonin-reuptake inhibitor (SSRI) antidepres- rent binge-eating episodes without inappropriate sants are effective for reducing binge eating, but usu- 1 compensatory weight loss behaviors, is an impor- ally are not associated with clinically significant tant public health problem. Its lifetime prevalence in weight loss.6–8 Sibutramine, topiramate, zonisamide, the United States general population is estimated to atomoxetine, and orlistat are effective for decreasing be 3% and it is associated with psychiatric comorbid- both binge eating and body weight, but are associ- ity, obesity, impaired quality of life, and disability.2–4 ated with problematic side effects and relatively high Accepted 10 August 2010 Medco; 2009: GlaxoSmithKline, Schering Plough, BristolMyersS- Financial disclosure and conflict of interest: Susan L. McElroy, MD, is quibb, Pfizer, QuantiaMD. Patents: Dr. Paul E. Keck, Jr. is a co in- employed by the University of Cincinnati College of Medicine, and the ventor on United States Patent No. 6,387,956: Shapira NA, Gold- Lindner Center of HOPE. Dr. McElroy is a consultant to, or member of smith TD, Keck, PE Jr. (University of Cincinnati) Methods of treating the scientific advisory boards of: Alkermes Inc., Eli Lilly and Company, obsessive-compulsive spectrum disorder comprises the step of and Schering-Plough. Dr. McElroy is a principal or co-investigator on administering an effective amount of tramadol to an individual. research studies sponsored by: Abbott Laboratories, Alkermes Inc., Filed March 25, 1999; approved May 14, 2002. Dr. Keck has AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly and Company, received no financial gain from this patent. Forest Labs, GalaxoSmith Kline, Jazz Pharmaceuticals, Inc., Marriott Dr. Hudson has been a consultant for Eli Lilly, Pfizer, and Foundation, National Institute of Mental Health, Orexigen Therapeu- Alkermes Inc., and has received grant support from Eli Lilly, tics, Inc., Shire, and Takeda Pharmaceutical Company Limited. Pat- Otsuka, and Ortho-McNeil Janssen Scientific Affairs. Drs. O’Melia, ents: Dr. Susan L. McElroy is also inventor on United States Patent No. Winstanley and Guerdjikova and Mrs. Mori and McCoy have no 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control conflicts of interest to disclose. Disorders, and, along with the patent’s assignee, University of Cincin- Supported by Forest Labs. nati, Cincinnati, OH, has received payments from Johnson & Johnson Pharmaceutical Research & Development, L.L.C., which has exclusive *Correspondence to: Susan L. McElroy, MD, Lindner Center of rights under the patent. HOPE, Research Institute, 4075 Old Western Row Road, Mason, OH 45040. E-mail: [email protected] Dr. Keck is employed by the University of Cincinnati College of 1 Lindner Center of HOPE, Mason, Ohio and University of Medicine and the Lindner Center of HOPE. Dr. Keck is presently or Cincinnati College of Medicine, Cincinnati, Ohio has been in the past year a principal or coinvestigator on research 2 Department of Psychiatry, Harvard Medical School and McLean studies sponsored by: Alkermes Inc., AstraZeneca, Cephalon, Glax- Hospital, Belmont, Massachusetts oSmithKline, Eli Lilly and Company, Epi-Q, Inc., Jazz Pharmaceuti- Published online 15 November 2010 in Wiley Online Library cals, Marriott Foundation, National Institute of Mental Health (wileyonlinelibrary.com). DOI: 10.1002/eat.20876 (NIMH), Orexigen, Pfizer, Inc., and Shire. Dr. Keck has been reim- VC 2010 Wiley Periodicals, Inc. bursed for consulting to, in the past year: 2010: Sepracor, Inc., International Journal of Eating Disorders 44:1 81–90 2011 81 MCELROY ET AL. discontinuation rates.9–17 Moreover, a substantial for bulimia nervosa and BED when administered number of patients do not respond adequately to at supratherapeutic doses (e.g., 200–400 mg 2 these psychological or pharmacological treatments. days 1),37,38 whereas bupropion, which is indicated Novel treatments are therefore needed for BED. for smoking cessation, has been shown superior to Several lines of evidence suggested that acampro- placebo in one randomized trial in bulimia nerv- 39 sate—a glutamate receptor modulator approved for osa. Thus, the ‘‘anticraving’’ properties of acam- maintenance of abstinence in patients with alcohol prosate in substance use disorders suggest it might dependence in many countries18,19—might be a have antibingeing properties in BED. useful treatment for BED. First, eating disorders, Finally, acamprosate is well tolerated. Compared including BED, may be related to addictive disor- with the antidepressants, antiepileptics, and antio- ders.20–23 Persons with BED from the general popu- besity agents used in BED, acamprosate is associ- lation have elevated rates of substance use disor- ated with substantially lower rates of sexual dys- ders.3 The binge eating of BED is characterized by function, cognitive impairment, hypertension, and craving for food and loss of control over eating that severe diarrhea, respectively. are similar to the craving for alcohol and drugs and These observations led us to hypothesize that the loss of control over the use of these substances that binge eating symptoms of BED would respond to are seen in persons with addictions. Indeed, eating the anticraving agent acamprosate. To test this hy- disorders with binge eating have been conceptual- pothesis, we conducted a single-center, random- 21 ized as forms of food addiction. ized, parallel-group, placebo-controlled, flexible- Second, increasing research indicates that the glu- dose study to assess the efficacy and tolerability of tamate system plays an important role in the regula- acamprosate during a 10-week course of treatment tion of food intake24,25 as well as the abuse of alco- in 40 outpatients with BED. We also evaluated the hol and illicit drugs,26,27 and that compounds that treatment effects of acamprosate on food craving, diminish glutamate system function may reduce various metabolic measures, including weight, and binge eating.11,12 Acamprosate, which antagonizes quality of life, in this patient group. the glutamate N-methyl-D-aspartate (NMDA) recep- tor, has been reported to reduce food craving and weight gain in patients with alcoholism.28 Topira- mate antagonizes the glutamate kainate receptor Method and is efficacious in alcohol dependence29,30 and bulimia nervosa,30,31 as well as BED.11,12 Treatment Patients with both the NMDA antagonist memantine and the Study participants were outpatients at the Lindner mGluR5 antagonist MTEP has been shown to reduce Center of HOPE, Mason, Ohio who were recruited by ra- consumption of highly palatable food in a baboon dio and newspaper advertisements requesting volunteers model of binge eating disorder.32 Memantine has for a medication study for binge eating. Patients were en- been shown to reduce binge eating in open-label tri- rolled into the study if they met the following inclusion als in patients with BED,33,34 and acamprosate, in criteria: (1) were male or female from 18 through 65 years addition to antagonizing NMDA receptors, may also of age; (2) met DSM-IV-TR criteria for BED; (3) weighed decrease mGluR5 function.35 85% of the midpoint of ideal body weight for height Third, it has been hypothesized that binge eating (according to the metropolitan height/weight tables); (4) and addiction may share a common pathophysiol- and had 3 binge eating episodes and 2 binge days in ogy, that highly palatable food and drugs of abuse the week before receiving study medication (confirmed compete for the same brain reward circuitry, and with prospective diaries while the patient received sin- that there may be a class of drugs that reduce crav- gle-blind placebo run in; see outcome measures). ing, ultimately by modulating neurotransmission Patients were excluded from participation in the study in the systems that comprise this circuitry.36 This if