Binge-Eating Disorder and New Pharmacologic Treatments

David S. Husted, MD, and Nathan A. Shapira, MD, PhD

Dr. Husted is a resident and Dr. Shapira is assistant professor, both in the Department of Psychiatry at the University of Florida College of Medicine in Gainesville.

Disclosure: Dr. Husted reports no affiliation with or financial interest in any commercial organization that might pose a conflict of interest. Dr. Shapira has received grant and/or research support from Ortho-McNeil; is a consultant for AstraZeneca, Forest, and Ortho-McNeil; and has served on the speaker’s bureaus of AstraZeneca, Forest, and Ortho-McNeil.

Acknowledgment: The authors would like to thank Holly Valerio for her assistance in compiling an exhaustive review of the literature for the preparation of this manuscript.

Please direct all correspondence to: Nathan A. Shapira, MD, PhD, Department of Psychiatry, University of Florida College of Medicine, PO Box 100256, Gainesville, FL 32610-0256; Tel: 352-392-3681; Fax: 352-392-2579; E-mail: [email protected].

Abstract

Is there a biological basis for binge-eating disorder (BED) and, if so, what role do medications have in the treatment of this disorder? BED has attracted significant attention since its inclusion in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. While the treatment of BED remains multi-faceted, with important behavioral and psychotherapeutic interventions, recent research has suggested that pharmacologic treatments are effective in reducing and eliminating bingeing behavior. This article reviews the genetic, neurochemical, and psychosocial contributions to the development of BED, explores the epidemiology of this disorder, and discusses the pharmacologic treatment options. Behavioral and psychotherapeutic treatments are briefly discussed as well.

Introduction

For decades, eating disorders have been considered a product of the societal bias that being thin is attractive. While environment certainly is an important factor in the development of an eating disorder, recent research indicates a largely biological etiology for eating disorders. Family and twin studies, neuroimaging, hypothalamic and gastrointestinal peptide studies, and studies demonstrating the role of neurochemicals, such as dopamine (D) and serotonin (5-HT), all support a biological explanation for eating disorders. Therefore, it is not surprising that psychotropics are being successfully used in the treatment of eating disorders.

Binge eating in the absence of compensatory behavior, such as purging, was first described in the literature almost 50 years ago.¹ However, this phenomenon of binge eating with characteristics dissimilar to bulimia nervosa attracted little attention from researchers or clinicians until the introduction of binge-eating disorder (BED) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).² In the DSM-IV, BED was described as an example of an eating disorder not otherwise specified, and was included in Appendix B, which contains provisional diagnoses.

As described by the DSM-IV, BED is characterized by recurrent episodes of bingeing (consumption of food within a discrete period of time that is larger than most people would consume under similar circumstances), with a sense of lack of control over eating during the episode and marked distress regarding the bingeing behavior.² Patients with BED must binge, on average, ≥2 days a week for a 6-month period, and refrain from the regular use of inappropriate compensatory behaviors (ie, purging, fasting, excessive exercise).² Furthermore, to be diagnosed with BED by DSM-IV criteria, the binge-eating episodes must be associated with three or more of the following: eating much more rapidly than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of being embarrassed by how much is being consumed, and feeling disgusted with oneself, depressed, or very guilty following overeating.²

Validity

Since the publication of the DSM-IV, debate has persisted concerning the validity of BED as a diagnostic entity. The diagnostic criteria for BED have been criticized for being vague at times. In particular, what constitutes a larger amount of food than most people would eat under similar circumstances has not been adequately defined. Furthermore, objective descriptions of “loss of control over eating” or eating “much more rapidly than normal” have not been established in the literature. However, whereas clinical assessments of food consumption rely on self-report, the bingeing behaviors seen in BED patients have been documented in a number of controlled laboratory studies.³ While these results have not proven the validity of BED as a diagnostic entity, they have certainly provided support for the existence of this disorder.

Despite not being officially recognized as a diagnostic entity, a large body of literature has been published concerning BED given the impact of this syndrome on the mental and physical health of the affected individual. High rates of obesity and psychiatric comorbidity have been demonstrated consistently in a number of studies.⁴ Studies have demonstrated that BED often occurs in patients with underlying or comorbid mood, anxiety, impulse-control, or substance disorders. In fact, depression has been identified as a prospective risk factor⁵ and a proximal antecedent⁶ to binge eating in women. Patients with BED suffer from recurrent episodes of uncontrollable overeating, which is markedly distressing to the affected individual. Patients with BED often are more distressed by their weight gain, though, than by their bingeing behavior or comorbid psychiatric illnesses.⁷ Seemingly as a result of their consistently excessive intake in calories, patients with BED are often overweight or obese,⁴ and characteristically suffer from obesity-related illnesses, such as hypertension, diabetes, and high cholesterol. In fact, one prospective study⁸ has demonstrated that even in the remission of bingeing behavior, affected persons continue to have a significantly higher risk of developing obesity.

Whether the drive to binge eat and the propensity for obesity even in the absence of bingeing share a common biological etiology in BED patients remains unclear. Beyond the health implications of obesity and the comorbid psychiatric disorders noted in BED, patients with BED also suffer from discrimination in job and housing opportunities, receive lower earnings, have greater difficulty achieving acceptance to university, and boast a lesser number of friends and romantic relationships.⁹

Epidemiology

Epidemiologic descriptions of BED are limited, which is largely due to the relatively recent introduction of BED into the psychiatric nomenclature. Based on the most methodologically rigorous study,¹⁰ point-prevalence of BED appears to be approximately 1%, suggesting BED is more common than bulimia nervosa. Subthreshold BED, which is characterized by obesity with infrequent or nondistressing binge eating, is more common than BED,¹¹ although studies concerning this phenomenon are limited.

BED seems to begin largely in adolescence or early adulthood, and is characterized by a variable course with frequent periods of remission followed by recurrence.¹¹ The gender difference in prevalence appears less pronounced in BED than bulimia nervosa, although as in all eating disorders, BED is more common in females than in males.¹² More minority woman meet diagnostic criteria for BED than for bulimia nervosa,¹² but the significance of this greater diversity observed in the BED population is not readily clear. Prospective risk factor studies that incorporate the role of gender and ethnicity are needed to improve the understanding of the etiology of BED. Current epidemiological studies are limited, however, by under-inclusion of males and insufficient range of ethnic minority groups. Of obese individuals, 23% to 46% report binge-eating behavior,¹³ and BED has been reported in 70% of participants in Overeaters Anonymous,⁷ 50% of patients who seek bariatric surgery,⁴ and 30% of participants in weight-loss programs.¹⁴

Etiology

Neurotransmitters and Peptides

Although the precise cause of BED remains unknown, preliminary data support a multifactorial etiology, with biological, familial, and psychosocial mechanisms implicated. A number of studies published in the literature demonstrate a significant role for 5-HT and D in the regulation of feeding behavior.¹¹ Compulsive overeaters who are obese may have lower levels of the D₂ receptor than do normal-weight controls.¹⁵ It has been demonstrated that 5-HT is also involved in modulating eating behavior by inhibiting food intake.¹⁶ Patients with bulimia nervosa were noted to have reduced orbitofrontal 5-HT_2A receptor binding, which was present even in patients in remission.¹⁷ Interestingly, patients with borderline personality disorder—another psychiatric diagnosis characterized by high levels of impulsivity—also have been noted to have altered orbitofrontal activity.¹⁸ Obese women with BED also have been demonstrated to have reduced 5-HT transporter binding,¹⁹ with improved transporter binding and a reduction in binge-eating behavior following group psychotherapy and fluoxetine treatment.²⁰ Interestingly, consistent with findings in other studies, resolution of binge eating did not prevent these women from continuing to gain weight. Increased 5-HT_1A receptor binding has been found in bulimia nervosa subjects, which could be secondary to up regulation given the decreased negative feedback from the overall reduction in 5-HT function.²¹ Perhaps the increased 5-HT_1A binding is an explanation for the well-known phenomenon that bulimia nervosa patients, and perhaps BED patients, require higher doses of selective serotonin reuptake inhibitors (SSRIs) than patients treated for other psychiatric disorders. A hyperactive hypothalamic-pituitary-adrenal axis also has been implicated in the development of BED and bulimia nervosa, with higher baseline cortisol levels noted in patients with BED versus controls.²²

Gastrointestinal peptides that interact with neuropeptide pathways located in the hypothalamus serve an important role in the regulation of feeding behavior and body weight. Given laboratory studies that demonstrate impaired satiety in patients with BED,³ it was theorized that these disorders could be associated with a diminished responsiveness of these satiety-related pathways.²³ The hypothalamic peptide neuropeptide Y,²⁴ and gut-related peptides, such as peptide YY²⁵ and cholecystokinin,²⁶ have been implicated in the etiology of bingeing behavior. To date, however, the data concerning the role of peptides in BED remains limited and, at times, contradictory.

Genetic Predisposition

As obesity can exist in the absence of binge eating and binge eating exists in the absence of obesity, the genetic and environmental factors that contribute to the onset of these two traits are clearly not identical. However, there is some overlap in etiological factors; as there is a high prevalence of obesity in binge eaters, onset of obesity can occur even prior to bingeing behavior, and the nonaffected twin of individuals with BED is significantly more likely to be obese.^27,28 This correlation between obesity and BED, which has been conclusively demonstrated in the literature, appears to be primarily genetic with little environmental contribution.²⁷ Similarly, a number of studies have demonstrated binge eating to be mainly a heritable trait, with a significantly greater concordance for BED noted amongst monozygotic twins than dizygotic twins.^27,28 In addition, if one of the twins in a twin-pair is diagnosed with BED, the other twin is likely to show a greater propensity for obesity even if he or she is unaffected by the disorder.²⁸ Preliminary results from a family study²⁹ demonstrate a significantly greater prevalence of BED in relatives of probands with BED than in relatives of probands without BED, further indicating heritability of this disorder.

a-melanocyte–stimulating hormone (a-MSH) has been demonstrated to have anorectic properties. Mutations of the melanocortin-4 receptor gene, which in turn affects the activity of a-MSH, has been demonstrated to be present in a significant number of severely obese patients (ie, patients with a body mass index of 44±2) who carry a diagnosis of BED by DSM-IV criteria.³⁰ A history of parental depression and obesity are also significantly associated with BED.³¹

Psychosocial Explanation

The affect regulation theory, which posits that binge eating functions as a coping skill to modulate negative emotions, remains one of the more prominent theories concerning the etiology of BED, and has been substantiated by a number of studies.^6,32 Interestingly, highly palatable foods (ie, carbohydrates and fats) appear to play a necessary role in conditioning the individual to use bingeing as a coping response to stress.³³ This may be related to greater reward obtained from carbohydrate and fat intake, which would then serve to alleviate the stress that induced the binge episode. In addition, a high carbohydrate bolus causes less satiety than protein, which also promotes greater food intake in one sitting.³⁴

People who binge tend to respond to stress with maladaptive coping strategies, and are less likely to seek social support or engage in active problem solving.³⁵ Women who binge eat tend to perceive their stressors as more intense than women who do not binge, and high stress environments seem to precipitate bingeing.³⁶ Indeed, experimentally-induced stress was noted to increase urges to binge eat in bulimia nervosa patients studied in a laboratory setting,³⁷ while good social support led to decreased risk of same-day binge eating.³⁸ In contrast to individuals with bulimia nervosa, patients with BED report a reduction in anxiety after binge eating, supporting the role of food as self-medication.³⁹

It is not surprising that patients with BED have a high incidence of depression, given that poor coping skills, poor social support, and high perceived stress are also factors in promoting affective disorders.⁴⁰ Likewise, there may be common genetic factors that predispose the individual to suffer from comorbid BED and depression.

Further factors that have been associated with binge eating include societal discrimination for being overweight, being shunned and/or bullied by peers, and physical and sexual abuse.⁴¹ Also, as in other eating disorders, individuals with BED typically demonstrate a counter-regulatory pattern of food intake.⁹ Whereas most individuals typically eat less after a large meal, those with counter-regulatory behavior eat more after large meals. Patients with eating disorders tend to place inordinate emphasis on weight and shape in evaluating their attractiveness and worth.

Dietary restraint is another factor that has been associated with bingeing, particularly in regard to bulimia nervosa patients.⁴² Intermittent caloric deprivation has been demonstrated to predict stress-induced overeating in normal subjects.⁴³ Caloric restriction has been shown to interact with stress to increase susceptibility to binge eat in animal models, as well.⁴⁴ In this animal model, neither stress alone nor caloric restriction alone was sufficient to induce bingeing. After precipitating bingeing behavior, stress was noted to continue to trigger binge eating even after the animal returned to ad lib feeding and normal body weight. While the dietary restraint theory has been a substantial factor in developing a cognitive-behavioral therapy (CBT) intervention in bulimia nervosa, additional research is needed to determine the role, if any, of dietary restraint in BED. Given the fact that up to one-half of patients with BED develop binge eating in the absence of dieting,⁴⁵ dietary restriction appears to serve a less prominent role in the etiology of BED.

Treatment

Management of patients with BED consists of an individualized program that includes behavioral weight control, psychotherapy, and often medications. Pharmacologic treatment of patients with BED involves a number of classes of medications, and is based on patient preference, whether BED is complicated by resultant physical ailments, and the existence of comorbid psychiatric disorders. The most commonly used types of medications to treat BED include antidepressants, anticonvulsants, and appetite suppressants. Given that a multi-faceted approach (ie, biological, psychological, and social) has proven to be effective in a variety of psychiatric disorders, it would be expected that such an approach would be helpful in treating BED. In addition, as the use of a combination of different types of psychotropics has proven to optimize treatment in many treatment resistant disorders, one would expect this approach to be helpful in BED.

However, few studies have explored the concurrent use of different classes of medication or the combination of medication and psychotherapy in the treatment of BED. One study⁴⁶ to date has been published demonstrating the benefit of exercise as an adjunct to CBT in the treatment of obese women with BED. Two studies^47,48 have explored the effect of combining CBT and antidepressants (desipramine or fluoxetine) in treating BED, and surprisingly found CBT to be more effective in decreasing binge frequency when used alone. However, one of the studies⁴⁷ did demonstrate a greater degree of weight loss with a combination of an antidepressant and CBT. No study to date has investigated the effect of combining appetite suppressants or anticonvulsants and psychotherapy, nor has any trial studied the benefit of using antidepressants, anticonvulsants, and appetite suppressants in combination.

Behavioral and Psychotherapeutic Interventions

The primary goal of specialized psychotherapy is to provide the patient with behavioral self-management strategies to enable a reduction in bingeing behavior. A psychotherapeutic approach appears to be less effective in achieving and maintaining a reduction in body weight. Thus, while weight loss is desirable from a health and self-image standpoint, it often remains a secondary goal of psychotherapy, as emphasizing this aspect in the treatment program ultimately can be discouraging to the patient and undermine the patient’s satisfaction in achieving bingeing cessation. Instead, focusing on improving body image even in the absence of weight loss often becomes a significant component of therapy. Improving dysfunctional interpersonal relationships, identifying and reducing stressors, and treating affective pathology are all further components of psychotherapy.

CBT frequently is conducted in a group therapy format, and treatment focuses on providing more mature ways of coping with stress, developing problem-solving skills, establishing healthy eating patterns, and self-monitoring food intake.⁴⁹ While a significant number of BED patients undergoing CBT demonstrate marked reduction in bingeing, frequently <50% of patients cease bingeing by the end of treatment.⁴⁹ In those BED patients who have demonstrated a suboptimal response to CBT, extending treatment for an additional 12 weeks has been shown to have a significant effect.⁵⁰

Cognitive-behavioral techniques to treat BED also can be delivered to patients using self-help formats, which makes treatment more cost effective and easily disseminated. Self-help interventions can be delivered using treatment manuals and videotapes, and can occur in an individual or group format. A number of studies have demonstrated no difference in efficacy between therapist-led or self-help CBT interventions in the treatment of BED.⁴⁹ Interpersonal psychotherapy, which has been studied extensively in the treatment of bulimia nervosa,⁴⁹ has been shown to be effective in preventing bingeing in BED patients,⁵¹ but no more so than CBT.

Behavioral weight-loss treatment involves educating patients concerning nutrition, instituting a healthy, lower-calorie diet, and formulating an appropriate exercise regimen.⁴⁹ Studies have demonstrated a significant reduction in body weight within the first year of a behavioral weight-loss treatment program; however, long-term results have proven to be unsatisfactory.^47,49 To date, no trial has examined the efficacy of specialized diets, such as a low-carbohydrate regimen in treating BED.

Dialectical behavioral therapy (DBT) is a form of therapy that targets emotional regulation, and has been used in treating borderline personality disorder. Given that individuals with BED utilize bingeing as a means of coping, it has been hypothesized that DBT would be effective treatment for BED. Indeed, in a controlled 20-week trial of DBT in BED patients,⁵² a bingeing abstinence rate of 89% posttreatment and 56% at 6-month follow-up was noted.

Pharmacologic Treatment

Antidepressants frequently are used to treat BED due to the common comorbid depression and anxiety associated with this disorder. Furthermore, due to the apparent role of 5-HT and D in the onset of BED, antidepressants that target these neurochemicals would be expected to be effective. SSRIs are the most extensively studies antidepressants for treating BED. In short-term placebo-controlled trials, citalopram (n=38; 20–60 mg for 6 weeks), fluoxetine (n=60; 20–80 mg for 6 weeks), fluvoxamine (n=85; 50–300 mg for 9 weeks), and sertraline (n=34; 50–200 mg for 6 weeks) all caused a significant reduction in binge eating and body weight.⁵³ Furthermore, in a trial involving the administration of fluoxetine (40–60 mg/day) and group psychotherapy to patients with BED, complete remission in binge eating was appreciated.²⁰ However, at least one placebo-controlled study⁴⁸ has demonstrated that the response to SSRIs may be short-term only, as fluoxetine was shown to be no more effective than placebo in reducing binge frequency or body weight following 16 weeks of treatment. However, the results of this study should be interpreted with caution given that the investigator failed to find a long-term effect either.

Therefore, to date, the long-term efficacy of SSRIs in the treatment of BED is unknown. However, by combining data from the placebo-controlled trials using SSRIs to treat BED, Carter and colleagues⁵³ confirmed their significant effect on bingeing frequency and bingeing cessation. To date, however, fluoxetine is the only medication that has received an indication from the Food and Drug Administration in the treatment of an eating disorder (for bulimia nervosa).

Studies involving the use of tricyclic antidepressants for the treatment of BED are limited, and those published in the literature have yielded mixed results. In a placebo-controlled trial involving desipramine, a reduction in bingeing behavior was noted in patients with nonpurging bulimia nervosa, but no reduction in body weight was observed.⁵³ However, imipramine was shown to be no better than placebo in reducing binge frequency and body weight.⁵³ This finding arguably was due to the high placebo response (70%) and small sample size of the study (n=23), however. Inositol, a precursor of phosphatidylinositol, which is an important second-messenger in the central nervous system, has been demonstrated to be effective in treating affective and anxiety disorders.⁵⁴ Based on this spectrum of clinical efficacy that parallels SSRIs, researchers have investigated the benefit of using inositol in treating BED. In a double-blind, placebo-controlled crossover trial,⁵⁴ inositol 18 g/day was demonstrated to lead to decreased bingeing behavior. The number of patients enrolled in the trial was quite small, however, limiting the conclusions that can be drawn from this study.

Venlafaxine was noted to be effective in reducing binge eating, body weight, and depressive symptoms in a retrospective review of 35 consecutive patients with BED treated with a mean dose of 222 mg/day for an average of 120 days.⁵⁵ In addition, bupropion has been more effective than placebo in treating uncomplicated obesity,⁵⁶ obesity associated with symptoms of depression,⁵⁷ and bulimia nervosa (despite the contraindication in these patients because of electrolyte abnormalities and a higher seizure risk).⁷ To date, no controlled trials have been published using bupropion for treatment of BED. However, clinicians experienced in the treatment of BED patients report bupropion to be effective in reducing binge eating and body weight at doses similar to the treatment of depression.⁷

Anticonvulsants, such as topiramate and zonisamide, also have been shown to be effective in treating obesity,^58,59 and have been therefore used in BED patients. Topiramate acts via modulation of g-aminobutyric acid and the blockade of glutamate receptors.⁵⁸ Although it is not known conclusively why anticonvulsants have proven to be helpful in reducing bingeing or body weight, this quality may potentially be related to their proven efficacy in treating the pathologic impulsivity seen in substance abuse, Cluster B, and impulse-control disorders. Growing evidence has indicated that bulimia nervosa and BED are associated with pathologic impulsivity, as well,⁵³ which would predict why anticonvulsants would be helpful in treating these eating disorders.

Furthermore, topiramate has been noted to cause anorexia clinically, unlike some older anticonvulsants (carbamazepine and valoproate) that are known to increase appetite and cause weight gain. Given the fact that glutamate agonists have been shown to induce an intense increase in food intake,⁶⁰ the anti-glutamatergic activity of topiramate would be a potential mechanism, which would lead to decreased food intake.⁶¹ Indeed, in a 14-week placebo-controlled study involving 61 obese patients with BED,⁶² topiramate 50–600 mg/day (median dose: 212 mg/day) significantly reduced binge-eating frequency and body weight versus placebo. In that study, 64% of subjects on topiramate experienced a bingeing cessation versus 30% of patients receiving placebo, and topiramate subjects experienced 5.9 kg of weight loss versus 1.2 kg for patients receiving placebo.⁶² In a 42-week open-label extension trial,⁶³ the positive effect on binge frequency and body weight was continued, although there was a high discontinuation rate. Most patients generally tolerate topiramate, although some may experience sedation, paresthesia, and cognitive impairment. Side effects can be avoided by initiation at a low dose and gradual titration to the target dose.

In a 12-week prospective, open-label trial involving 15 patients,⁶⁴ zonisamide also was noted to cause a significant reduction in binge frequency and body weight, which has prompted a controlled trial that is currently ongoing.

Lamotrigine is an anticonvulsant that has not been shown to cause weight gain; however, no study to date has explored its role in treating eating disorders. Furthermore, no studies to date have been published exploring the concurrent use of anticonvulsants and antidepressants.

Appetite suppressants act by reducing appetite and increasing satiety. Sibutramine is a norepinephrine, 5-HT, and D reuptake inhibitor that has received an indication by the FDA for the management of obesity. Sibutramine has been shown in a randomized, controlled, cross-over laboratory study⁶⁵ to suppress food intake during binge-eating episodes in BED patients, although the mechanism of this action remains unknown. In a randomized, double-blind, placebo-controlled trial,⁶⁶ sibutramine was noted to significantly reduce binge frequency, body weight, and depressive symptoms in 60 obese patients with BED when administered at a dose of 15 mg/day for a 12-week period. No significant complications were seen with the use of sibutramine, with dry mouth and constipation being the most frequent adverse effects reported.

The lipase inhibitor orlistat has not been formally studied in regards to treating BED. In obese patients without BED, however, orlistat at an average dose of 360 mg/day has been noted to be helpful in reducing body weight.⁷ Clinicians report that patients with BED whose bingeing behavior is in remission or who have responded well to psychological treatment and medication have similarly demonstrated reduced body weight when treated with orlistat.⁷

Conclusion

BED is relatively prevalent and has a significant impact on the physical and mental health of the affected individual. The etiology of BED remains unclear, although both biological and psychological factors appear to be involved. Psychosocial interventions remain a large component of treatment, with the focus being cessation of bingeing and improved self-image. While pharmacologic treatments are apparently effective in treating BED, it is still largely unclear which agents have a definite role in treating this disorder. With the exception of SSRIs, no class of medication has been studied extensively in BED patients. All of the studies involving treatment of BED have a small number of subjects and are conducted as single-center trials. The open-label extension trial involving topiramate⁶³ is the only medication trial with long-term data. No study to date has adequately explored the effect of concurrent pharmacologic and psychologic treatment of BED. Therefore, future research should focus on large, multicenter, placebo-controlled trials that study the long-term effect of single agents and combined therapy (multiple classes of medications used concurrently with psychotherapy). PP

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