Review

Current pharmacotherapy options for bulimia nervosa and binge eating disorder
1. 2. 3. Introduction Methods Pharmacotherapy trials in BN and BED: designs utilized and medications evaluated 4. 5. Antidepressants Antiepileptic drugs Antiobesity agents Drugs for ADHD Anti-addiction (or anti-craving) drugs 9. 10. 11. 12. 13. Hormonal treatments 5HT3 antagonists Lithium Other agents Expert opinion

Susan L McElroy, Anna I Guerdjikova, Nicole Mori & Anne M OMelia

Lindner Center of HOPE, Mason, OH, USA

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6. 7. 8.

Introduction: Growing evidence indicates binge eating, defined as the consumption of an abnormally large amount of food accompanied by a sense of loss of control, is an important public health problem. Although psychotherapy may be effective, not all patients respond adequately. Areas covered: This article provides an overview of bulimia nervosa (BN) and binge eating disorder (BED), the two conditions characterized by recurrent binge eating as a core feature, and reviews studies of specific medications in treating patients with BN or BED, focusing on randomized controlled trials (RCTs). Expert opinion: Although the evidence base is small, growing data indicate pharmacotherapy may be helpful for some patients with BN or BED. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are modestly effective for reducing binge eating over the short term in BN and BED. SSRIs may be modestly effective in BN over the long term. Topiramate has consistently been shown to decrease binge eating in BED and BN, but side effects may limit its usefulness. Single RCTs suggest zonisamide and atomoxetine may be effective in BED. Combination therapy may be required for optimal outcomes. It is not yet known whether the binge eating of BN and BED respond similarly to pharmacotherapy.
Keywords: binge eating, bulimia nervosa, medication management, pharmacotherapy Expert Opin. Pharmacother. (2012) 13(14):2015-2026

1.

Introduction

Binge eating is broadly defined as the consumption of an abnormally large amount of food accompanied by a sense of lack of control [1]. Two eating disorders, bulimia nervosa (BN) and binge eating disorder (BED), require binge eating as core defining features. BN is further defined by inappropriate compensatory weight loss behaviors and excessive concern for shape and weight. By contrast, for BED, binge eating must be associated with other indicators of loss of control and distress, but not with the inappropriate compensatory weight loss behaviors of BN [1-3]. Although not a defining feature, BED, like BN, is also associated with excessive weight and shape concerns. For the upcoming DSM-5, it has been proposed that BED be elevated from an example of eating disorder not otherwise specified (NOS) to a diagnosis in its own right along with BN in the category, Feeding and Eating Disorders [4]. It has also been proposed that the frequency and chronicity criteria for binge eating (at least once/week for at least three months) be the same for BN and BED. Of note, binge eating also occurs in anorexia nervosa, but is not required for its diagnosis. Binge eating is an important public health problem. BED is the most common eating disorder in the United States, with a lifetime prevalence of 2.8% in adults [5] and 1.6% in adolescents [6]. BN occurs with a lifetime prevalence of 1.0% in adults [5]

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Article highlights.
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Bulimia nervosa (BN) and binge eating disorder (BED) are prevalent conditions that do not always respond to psychotherapy. Growing clinical research shows that pharmacotherapy may have a role in the treatment of BN and BED, including in patients who respond inadequately to psychotherapy, patients with comorbid medical or psychiatric disorders, and those with chronic or intractable illness. Fluoxetine has regulatory approval for BN. No drug has regulatory approval for BED. Medication classes receiving the most study in BN or BED are antidepressants, antiepileptics, anti-obesity drugs, drugs for attention-deficit hyperactivity disorder (ADHD), and anti-addiction (or anti-craving) agents. Antidepressants appear modestly effective for BN and BED over the short term. Fluvoxamine and fluoxetine may be modestly effective for BN over the long term. Data regarding the efficacy of topiramate in the treatment of BED, and to a lesser extent BN, are consistently positive, but use of the drug is limited by its adverse event profile. Medications with one published positive randomized clinical trial for binge eating populations include ondansetron for BN and zonisamide and atomoxetine for BED. Preliminary results from Phase-II studies suggest lisdexamfetamine and intranasal naloxone may be helpful for BED. Combination therapy is sometimes required for optimal outcomes. More research is needed to determine which specific agents, including combinations of agents, might be most useful for which patient subgroups. Pharmacotherapy should be considered a therapeutic option for most patients with BN or BED, including those na ve to treatment, and when psychotherapy response has been inadequate. More research is needed to determine what place pharmacotherapy will fill in the therapeutic armamentarium for BN and BED.

BN and BED, but not all patients respond adequately [12-14]. Moreover, these treatments are generally not effective for some of the common comorbidities of binge eating, such as bipolar disorder or obesity. An increasing number of reviews [15-20] and guidelines [21-23] have recently discussed the role pharmacotherapy might play in treating patients with BN or BED. Only one drug, however, has been approved by the United States Food and Drug Administration (FDA) or any other regulatory agency for the treatment of binge eating, that being fluoxetine for BN. No drug is yet approved for the treatment of BED or binge eating behavior in general. In this paper, we first review the data supporting the effectiveness of specific medications or medication classes in treating BN and BED. We conclude by summarizing these data and discussing the role pharmacotherapy might play in the treatment of binge eating. We also suggest future areas for research in the pharmacotherapy for binge eating.
2.

Methods

This box summarizes key points contained in the article.

and 0.9% in adolescents [6]. Both BN and BED are more common in females, often chronic, and associated with psychiatric and medical comorbidity and disability [2,3,5-8]. As compared to BN, BED is more common in males, has a later age of onset in adult cohorts, and is more often associated with obesity, including severe obesity [5]. Binge eating episodes may be larger in BN than in BED [9]. Dieting often precedes binge eating in BN, whereas sporadic weight control attempts occur after binge eating in BED [3]. Studies are beginning to elucidate the psychobiology of binge eating behavior. This research suggests binge eating may be associated with abnormalities in homeostatic feeding, reward function, higher level self regulating processes, and neurotransmitter systems such as dopamine [2,10,11]. Specialized psychotherapies, in particular cognitive behavior therapy [CBT] and interpersonal therapy [IPT], and self-help strategies are effective for reducing binge eating in
2016

A PubMed search of all English-language articles published through May 2012 was conducted. The key search terms were: pharmacotherapy; antidepressants; antiepileptics; anti-obesity; antipsychotics; mood stabilizers; opioid antagonists; randomized control trial (RCT); and stimulants. These terms were paired with binge eating, binge eating disorder (BED), and bulimia nervosa (BN). We also paired the latter terms with the following individual medications: acamprosate, amphetamine, atomoxetine, exenatide, fenfluramine, lamotrigine, liraglutide, methylphenidate, naltrexone, pramlintide, sibutramine, topiramate, and zonisamide. We supplemented our search by review of reference lists of relevant articles. In evaluating the effectiveness of medications for binge eating, only placebo-controlled, randomized clinical trials (RCTs) involving 20 subjects (or 8 subjects for crossover designs), or meta-analyses of such trials, were reviewed. If RCTs were not available, the largest open-label studies of a drug were evaluated.
3.

Pharmacotherapy trials in BN and BED: designs utilized and medications evaluated

Two primary pharmacotherapy RCT designs have been utilized to evaluate medications in BN: short-term studies of patients who are actively binge eating and purging and longterm maintenance studies of patients whose bulimic symptoms have responded to an acute intervention. By contrast, most RCTs of BED have been short-term trials in actively binge eating patients. Monotherapy trials, in which medication alone is compared with placebo or a psychological treatment, and combination therapy trials, where medication plus a psychological treatment is compared with the psychological treatment alone and/or the medication alone, have been done in both conditions. Primary outcomes in the acute BN trials

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have usually been measures of the frequency of binge eating episodes and/or inappropriate compensatory behaviors (e.g., vomiting), or rates of remission or response of bulimic symptoms. Primary outcomes in the maintenance trials have usually been time to relapse or rate of relapse. Primary outcomes in BED trials have typically been the frequency of binge eating episodes (binge frequency) or binge days (a day during which at least one binge eating episode occurs; binge day frequency), the rate of remission or response of binge eating behavior, and less frequently, weight loss. Secondary outcomes for both conditions have been measures of global eating disorder pathology, mood symptoms, global clinical improvement, laboratory measures, and treatment adherence. Most studies excluded patients with serious or unstable comorbid psychiatric or medical disorders such as bipolar disorder, substance use disorders, diabetes, and hypertension or other forms of cardiovascular disease. The three major classes of drugs studied thus far in BN and BED in RCTs have been antidepressants, antiepileptics, and anti-obesity agents. Drug classes that have received less study include medications for attention-deficit hyperactivity disorder (ADHD), anti-addiction (or anti-craving) agents, 5HT3 antagonists, hormonal agents, and lithium. The individual studies are reviewed below according to drug class.
4.
4.1

Antidepressants

eating episodes, in BMI, or in treatment discontinuation for any reason. Dose response studies have not yet been done for BED. However, in the largest study of an antidepressant in BN (N = 387), fluoxetine 60 mg/d was superior to placebo for reducing binge eating and vomiting episodes, while 20 mg/d was shown to have an intermediate effect [28]. Fluoxetine 60 mg/d was also superior to placebo in reducing depression, carbohydrate craving, and pathological eating attitudes and behaviors. Fluoxetine has been shown efficacious in BN patients inadequately response to psychotherapy [29] and in BN patients treated in the primary care setting [30]. Post-hoc analyses suggest lack of early reduction in binge eating or vomiting predicts nonresponse for BN, while early response predicts remission for BED [31,32]. A RCT in BED patients with co-occurring depressive disorders found the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine decreased binge eating, body weight, and global measures of BED and depression [33]. Though effective in BN, bupropion was associated with an increased risk for seizures, and is contraindicated for the treatment of BN and anorexia nervosa [34]. A RCT of bupropion in BED with obesity (NCT00414167) is ongoing, and a retrospective analysis found that bupropion may be associated with greater weight loss than sertraline for BED patients [35]. No placebo-controlled RCTs comparing antidepressants with different mechanisms of action have been conducted in BN or BED.
Maintenance RCTs At least two relapse-prevention RCTs have been done with antidepressants in BN. In the first, 72 patients with DSMIII-R BN successfully treated with intensive inpatient psychotherapy were randomized to receive fluvoxamine (N = 33) or placebo (N = 39) as outpatients for 12 weeks [36]. At endpoint, the fluvoxamine group had significantly more patients reporting no binges in the past week than the placebo group (p < .05). Premature termination rates were high; 38% for fluvoxamine recipients compared with 14% for placebo recipients. In the second study, 150 outpatients with DSMIV BN, purging type responding to treatment with fluoxetine 60 mg/d for 8 weeks were randomly assigned to continue fluoxetine 60 mg/d (n = 76) or switch to placebo (n = 74) for 52 weeks [37]. Fluoxetine-treated patients exhibited a significantly longer time to relapse (defined as a return to baseline vomiting frequency that persisted for 2 weeks) than placebotreated patients (c2 = 5.79, af = 1, p < 0.02). At endpoint, fluoxetine was also superior for vomiting episodes, binge eating episodes, obsessive-compulsive symptoms, and clinical global outcome. The attrition rate, however, was very high, with 83% of fluoxetine recipients and 92% of placebo recipients discontinuing prematurely. Comparable relapse prevention RCTs of antidepressant monotherapy in BED have not yet been conducted, but preliminary data has suggested that some patients with BED who initially respond to SSRIs
4.2

Short-term RCTs Antidepressants are presently the most extensively studied drug class in BN and BED. A meta-analysis of 10 RCTs of antidepressants in patients with BN found the pooled relative risk (RR) for remission of binge episodes was 0.88 (95% confidence intervals [CI] = 0.82, 0.93; p < 0.001), favoring antidepressants over placebo [24]. In the meta-analysis, there was no evidence of statistically significant differences in efficacy among different classes of antidepressants, which included tricyclics, monoamine oxidase inhibitors [MAOIs], fluoxetine, miansain, trazodone, and bupropion [24]. However, patients treated with antidepressants were more likely to discontinue prematurely due to adverse events. Patients receiving tricyclics dropped out due to any cause more frequently than those receiving placebo, though the opposite was found for fluoxetine. Subsequent small RCTs of sertraline and fluvoxamine found these drugs were also superior to placebo for reducing binge eating and purging in BN [25,26]. In BED, at least nine RCTs have evaluated antidepressants [18]. A meta-analysis of seven of these studies (1 with a tricyclic, 6 with selective serotonin reuptake inhibitors [SSRIs]) showed significantly higher binge eating remission rates for the antidepressant group compared with the placebo group: 40.5 vs. 22.2% (RR = 0.77 [95% CI = 0.65, 0.92; p = .003]) [27]. Antidepressants were also superior for reducing depressive symptoms. No differences between groups at the end of treatment were found in the mean frequency of binge

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with decreased binge eating and weight loss may maintain these benefits for up to 6 months with continuation of the SSRI [38].
4.3

binge eating and body weight in BED patients with obesity [43].
5.

Antiepileptic drugs

RCTs of combination treatment

In 2001, Bacaltchuk et al. published a Cochrane review of RCTs comparing antidepressants with psychological treatments or their combination for reducing symptoms in BN [39]. Remission rates for antidepressant monotherapy were 20 vs. 39% for psychological treatment alone (RR = 1.28; 95% CI = 0.98, 1.67). Dropout rates were higher for antidepressants alone than psychological treatments alone (RR = 2.18; 95% CI = 1.09, 4.35). Remission rates for the combination of antidepressants plus psychological treatments were 42 vs. 23% for antidepressant monotherapy (RR = 1.38; 95% CI = 0.98, 1.93). Remission rates for psychological treatments alone were 36 vs. 49% for the combination (RR = 1.21; 95% CI = 1.02, 1.45). Dropout rates were higher for the combination compared with psychological treatments alone (RR = .57; 95% CI = .38, .88). The only statistically significant difference was that combination therapy was superior to psychological treatment alone. The authors concluded that combined antidepressant -- psychological approaches were more effective than psychotherapy alone, but that there may have been an insufficient number of trials to show combination therapy or psychotherapy alone superior to antidepressants alone. They also concluded that psychotherapy was more acceptable to patients and that the addition of antidepressants to psychotherapy reduced its acceptability. The few controlled combination therapy RCTs in BED had contrasting results. In one, diet counseling with psychological support plus imipramine was superior to diet counseling and psychological support plus placebo for 8 weeks in decreasing binge eating (p < .01) and weight (p < .001) [40]. Benefits were maintained at 8 month follow up despite discontinuation of imipramine. In another study, 16 weeks of cognitive behavior therapy (CBT) with placebo or CBT with fluoxetine were both superior to fluoxetine alone and placebo alone for decreasing binge eating [41]. There was no additive effect for the combination of fluoxetine plus CBT over CBT alone for decreasing binge eating, and no single or combined treatment was effective for weight loss. In a third study, 116 BED patients receiving group behavioral weight control treatment for 20 weeks were randomized twice to adjunctive CBT or no CBT and to fluoxetine (40 -- 80 mg daily) or placebo [42]. CBT, but not adjunctive fluoxetine, was effective for reducing binge eating. Fluoxetine, however, was effective for decreasing depressive symptoms. Neither CBT alone, fluoxetine alone, nor their combination were effective for weight loss.
Other antidepressants Open-label data suggest milnacipran, reboxetine, and duloxetine may be effective in BN, including in treatment resistant cases [18], and that venlafaxine may be effective for reducing
4.4

The antiepileptic drugs studied thus far in binge eating populations in RCTs include carbamazepine, lamotrigine, topiramate, phenytoin, and zonisamide [44].
Carbamazepine Among 16 patients with DSM-III BN participating in a crossover RCT for 12 -- 18 weeks, no significant difference in response was seen between carbamazepine and placebo [45]. The one patient who had a remission in her BN symptoms while receiving carbamazepine had comorbid cyclothymic disorder; her mood symptoms also respond to carbamazepine.
5.1

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Topiramate Five placebo-controlled RCTs of topiramate have been published to date in binge eating populations, two in BN [46-48] and three in BED [49-51]. In all five studies, comprising 670 patients, topiramate was superior to placebo for reducing binge eating. The details of these studies are summarized below. The first study of topiramate in BN was a 10-week trial in 69 patients [46,47]. Topiramate (median dose 100 mg/d) was superior to placebo in reducing the frequency of binge and purge days (days during which at least one binge eating or purging episode occurred; p = .004); other measures of eating disorder symptomatology; and body weight. Significantly more topiramate recipients (52%) than placebo recipients (24%) achieved 50% reduction in the number of binge and/or purge days (p = .012). Numerically, more topiramate recipients (63%) than placebo-recipients (53%) finished the trial. The most common side effects associated with topiramate were fatigue, flu-like symptoms, and parasthesia. In the second RCT in BN, 60 patients received topiramate (titrated to 250 mg/d by the sixth week with the dosage then held constant) or placebo for 10 weeks [48]. Topiramate was associated with significant decreases in the frequency of binging/purging, body weight, and all scales on the SF 36 Health Survey (all ps < .001). Comparable numbers of patients in the two groups completed the trial, and all patients tolerated topiramate well. In the first RCT in BED, 61 patients with obesity received topiramate (median dose 212 mg/d) or placebo for 14 weeks [49]. Topiramate was significantly superior to placebo in reducing binge frequency, as well as obsessivecompulsive features of binge eating, global severity of illness, body weight, and BMI. Dropout rate, however, was high with 14 (47%) topiramate recipients and 12 (39%) placebo recipients failing to complete the trial. Paresthesia, dry mouth, headache, and dyspepsia were the most common side effects associated with topiramate. The second RCT in BED was a multicenter trial in which 407 patients were randomized to receive topiramate
5.2

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(median final dose 300 mg/d) or placebo for 16 weeks [50]. Compared with placebo, topiramate significantly reduced weekly binge day frequency, binge frequency, weight, and BMI (all ps < 0.001). Topiramate also significantly decreased obsessive-compulsive features of BED; trait impulsivity; other measures of eating disorder psychopathology; and disability. Significantly more topiramate-treated patients (58%) achieved remission compared with placebo-treated patients (29%; p < 0.001). Discontinuation rates were 30% in each group. Paresthesia, upper respiratory tract infection, somnolence, and nausea were the most frequent topiramate side effects. The third RCT of topiramate in BED was a 3-center study in which 73 obese patients were randomized to 19 sessions of CBT in conjunction with topiramate (mean final dose 206 mg/d) or placebo for 21 weeks [51]. Compared with patients receiving placebo, patients receiving topiramate showed a significantly greater rate of weight reduction (the primary outcome measure) over the course of treatment (p < .001), as well as a significantly greater mean weight loss (--6.8 kg vs. --0.9 kg for placebo). A significantly higher rate of topiramate-treated patients (84%) attained remission of binge eating as compared to placebo-treated patients (61%; p = .03). There was no difference between groups in completion rates. Paresthesia and taste perversion were more frequent with topiramate, whereas insomnia was more frequent with placebo. Topiramate has also been reported to reduce BN or BED symptoms in patients with treatment-resistant illness, including those with comorbid depressive or bipolar disorders, traumatic brain injury or epilepsy, those receiving the drug adjunctively with antidepressants and/or mood stabilizers, and those with binge eating symptoms after bariatric surgery [44,52,53]. On the other hand, there are reports of topiramate misuse in eating disorder patients [44].
Zonisamide In the only placebo-controlled RCT of zonisamide published to date in a binge eating sample, 60 patients with DSMIV BED and obesity received zonisamide (mean [SD] endpoint dose 436 159 mg/d) or placebo for 12 weeks [54]. Zonisamide was superior to placebo for reducing binge frequency, body weight, BMI, and measures of global severity, disinihibition of eating, and obsessive-compulsive features of binge eating. Attrition, however, was high, with 60% of zonisamidetreated patients and 40% of placebo-treated patients failing to complete the 12-week treatment period. Eight zonisamide recipients discontinued for adverse events. The most common side effects observed with zonisamide were dry mouth, somnolence, headache, nausea, nervousness, and altered taste.
5.3

greater amount of weight loss (1.17 kg for lamotrigine vs. 0.15 kg for placebo) and statistically significant reductions in fasting levels of glucose, insulin, and triglycerides.
Phenytoin In a crossover RCT, 19 of 20 women with binge eating syndrome completed six weeks each of phenytoin and placebo in a counter-balanced design [56]. Patients given phenytoin first experienced a 37% decrease in binge frequency (p < .01), but showed no change in binge frequency when switched to placbo. Patients given placebo first experienced no change in binge frequency, and did experience a 39% decrease after switching to phenytoin (p < .01). The significantly fewer binges found in the phenytoin-first group than in the placebo-first group (p < .02) indicated a carryover effect for the phenytoin-first sequence.
5.5

Long-term and other studies No long-term placebo-controlled RCTs of antiepileptic drugs in BN or BED have been published. An open-label extension study suggested that the anti-binge eating and weight loss effects of topiramate were maintained up to 1 year in BED patients, but treatment termination was common, including for adverse effects [57]. Another open-label study found that zonisamide with CBT was superior to CBT alone for maintenance of binge eating response and weight loss in BED patients receiving treatment for 1 year [58].
5.6

Other antiepileptics In patients with comorbid bipolar disorder, valproate has been reported to improve binge-purge symptoms in BN [59], but to worsen binge eating and enhance weight gain in BED [52]. A case series of 9 obese patients with BED treated with oxcarbazepine had inconsistent findings [60].
5.7

6.

Antiobesity agents

The antiobesity agents studied thus far in BN or BED in RCTs have been the serotonin releasing agent D-fenfluramine, the serotonin and norepinephrine reuptake inhibitor sibutramine, and the gastrointestinal lipase inhibitor orlistat. Although D-fenfluramine may reduce binge eating in BN and BED [18,61], and sibutramine reduces binge eating and body weight in BED [62-64], both compounds have been removed from the worldwide market for safety concerns, and will not be reviewed in detail.
Orlistat Orlistat has been shown to reduce binge eating symptoms and enhance weight loss in two RCTs in patients with BED and obesity [65,66]. In the first study, 50 patients were randomized to receive individual CBT delivered by guided self help (CBTgsh) in combination with orlistat 120 mg three times daily or CBTgsh in combination with placebo for 12 weeks, and evaluated again at 3-month follow-up [65]. Binge eating
6.1

Lamotrigine In the only RCT in a binge eating population, lamotrigine and placebo had similarly high rates of reduction of weekly binge eating frequency in 51 patients with BED and obesity [55]. Lamotrigine, however, was associated with a numerically
5.4

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remission rates were significantly higher for orlistat than placebo at posttreatment (64 vs. 36%) but not at 3-month followup (52% in both groups). Rates for achieving at least 5% weight loss were significantly higher for the orlistat group at both posttreatment (36 vs. 8%) and 3-month follow-up (32 vs. 8%). In the second study, 89 patients were randomized to orlistat 120 mg three times daily or placebo in combination with a mildly hypocaloric diet for 24 weeks [66]. Mean percentage weight loss (the primary outcome) was significantly greater for orlistat-recipients than for placebo-recipients (--7.4 vs. --2.3%; p = .0001). Waist circumference, hip circumference, total percentage body fat, total cholesterol level, diastolic blood pressure, and insulin level were also significantly improved with orlistat. Although the mean number of binge eating episodes per week was numerically but not significantly decreased for orlistattreated patients, Eating Disorder Inventory scores at week 24 were significantly lower for orlistat than placebo (p = .011). More patients in the placebo group (29%) than the orlistat group (11%) discontinued prematurely. Orlistat has not been evaluated in BN. Moreover, orlistat misuse has been reported in patients with BN [67] and BED [68].
Other anti-obesity agents Phentermine, the most commonly prescribed medication for obesity in the US, is currently under evaluation as a component in combination with topiramate (Qnexa) and with pramlintide for weight loss in obesity [69-71]. There are no published RCTs of phentermine, alone or in combination with topiramate or pramlintide, in BN or BED. Open-label trials evaluating phentermine in combination with fenfluramine [72] or fluoxetine [73] in BED patients had mixed results.
6.2

placebo (943 222; p < .02). Additionally, the frequency of bulimia was significantly lower after methylamphetamine (0 of 8 patients) than after placebo (4 of 8 patients; p < .05). Preliminary results from a recently completed fixed-dose Phase-III study of lisdexamfetamine in 270 BED patients suggested it may be superior to placebo for reducing binge eating [76]. A smaller flexible-dose RCT of lisdexamfetamine in BED (NCT01090713) is ongoing.
8.

Anti-addiction (or anti-craving) drugs

A growing number of anti-craving medications [77] have been systematically evaluated in binge eating populations, but with mixed results.
Opioid antagonists Two placebo-controlled RCTs of naltrexone at standard doses in binge eating populations, one in BN and the other in BED, were largely negative [78,79]. Similarly, a recently completed 6-week RCT of the novel opioid antagonist ALKS 33, 10 mg/d, in 68 patients with BED found no outcome differences between drug and placebo [80]. Other studies, however, have suggested that naltrexone administered in supratherapeutic doses (200-400 mg/day) or in conjunction with an antidepressant may decrease binge eating, including in patients with treatment-resistant illness or comorbid diabetes [81-85]. Preliminary results of a six month Phase-II study of intranasal naloxone in 129 patients with BED suggested this agent may be superior to placebo in reducing time spent binge eating [86]. A large program sponsored by Orexigen showing that naltrexone in combination with bupropion (Contrave) is associated with more weight loss in obesity than either drug alone [70,71] suggests this combination may have utility for BED, especially since the combination improved control over eating [87].
8.1

7.

Drugs for ADHD

Placebo-controlled RCTs of the selective norepinephrine reuptake inhibitor atomoxetine and the stimulants lisdexamfetamine and methylamphetamine have been done in binge eating samples.
Atomoxetine In the one study of atomoxetine, 40 BED patients were randomized to receive flexibly dosed drug (mean endpoint dose 106 mg/d) or placebo for 10 weeks [74]. Atomoxetine was superior to placebo in decreasing binge eating, global severity of BED, obsessive features of BED, hunger, and body weight. Fifteen patients (6 receiving atomoxetine) did not complete the trial. The most common atomoxetine side effects were dry mouth, nausea, nervousness, insomnia, headache, constipation, and sweating.
7.1

Stimulants In a crossover RCT, 8 patients with BN received methylamphetamine or placebo intravenously followed by a test meal [75]. Significantly fewer mean (SD) calories were consumed after methylamphetamine (224 111) than after
7.2

Acamprosate In the only study of acamprosate in a binge eating population, 40 patients with BED received drug (mean endpoint daily dose 2597 mg/d) or placebo for 10 weeks [88]. Acamprosate was not associated with a significantly greater decrease in binge frequency or any other outcome measure in the primary longitudinal analysis. However, in the secondary endpoint analysis, the drug was associated with statistically significant improvement in binge day frequency and in measures of obsessive-compulsive symptoms of binge eating, food craving, and quality of life. Among completers, BMI decreased significantly more for acamprosate-recipients than placeborecipients (p = .04). In addition, the drug was well tolerated with a significantly higher completion (79%) rate than for placebo (45%, p = .05). Diarrhea was the more common side effect.
8.2

Other anti-addiction agents The g -amminobutyric acid (GABA) B-receptor agonist baclofen, which may reduce alcohol intake in alcohol
8.3

2020

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dependence, was reported to decrease binge eating in BN and BED in a 10-week open-label trial when given at 60 mg/d [89].
9.

Hormonal treatments

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Two placebo-controlled RCTs have assessed hormonal agents with antiandrogenic properties in BN patients with mixed results. In the first study, 46 women were randomized to the testosterone receptor antagonist flutamide (n = 9), citalopram (n = 15), flutamide plus citalopram (n = 10), or placebo (n = 12) for 3 months [90]. Final flutamide and citaprolam doses were 500mg/d and 40mg/d, respectively. Binge eating was significantly reduced compared with placebo only in the group receiving the combination (p = .04). Vomiting was not significantly decreased in any group. Two patients discontinued flutamide for increases in serum transaminase levels which resolved upon drug discontinuation. In the second study, treatment with spironolactone, an aldosterone antagonist with antiandrogenic properties marketed as a diuretic, for 56 days had no effects on binge eating or vomiting compared with placebo in 93 patients with BN [91].
10.

an open-label trial in 12 patients with BED, the sodium salt of g hydroxybutyrate, sodium oxybate (mean endpoint dose 7.1 [2.0] g/d), was associated with significant reductions in binge eating and body weight [97]. Placebo-controlled RCTs of the wakefulness-promoting agent armodafinil (NCT01010789) and the dietary supplement chromium (NCT00904306) in BED are ongoing. There are no published controlled studies of antipsychotics in BN or BED. Rather, second generation antipsychotics have been reported to induce or exacerbate binge eating in patients with eating disorders [98], as well as in patients with psychotic disorders [99].
13.

Expert opinion

5HT3 antagonists

One 4-week placebo-controlled RCT of ondansetron has been conducted in 26 women with severe BN, defined as the occurrence of at least 7 binge/vomit episodes per week [92]. Ondansetron, self-administered in 4 mg capsules up to 6/d upon the urge to binge or vomit, was associated with a significantly greater decrease in binge/vomit frequencies, a significant decrease in the time spent engaging in bulimic behaviors, and with a significant increase in normal meals consumed compared with placebo. However, at study endpoint, participants receiving ondansetron continued to display over a mean of 5 binge/vomit episodes per week. Moreover, reports of QT interval prolongation with ondansetron prompted the FDA to advise that ondanestron not be used in patients with congenital long QT syndrome, and that ECG monitoring be conducted when using the drug in certain clinical situations, including in patients with electrolyte abnormalities [93]. There have been no studies of 5-HT3 antagonists in BED.
11.

Lithium

A placebo-controlled RCT in 91 patients with BN found lithium (mean level. 62 mEq/l) was not superior to placebo in decreasing binge eating episodes, except possibly in depressed patients [94]. However, case reports have described the successful treatment with lithium of patients with BN or BED and comorbid bipolar disorder [18,53].
12.

Other agents

The glutamate modulating agent memantine has been reported to reduce binge eating in BED in two open-label trials [95,96]. In

Pharmacotherapy research of BN and BED is in its early stages. Fluoxetine is the only medication with regulatory approval in BN, and no medication has approval for use in BED. Many of the available pharmacotherapy studies in BN and BED are limited by small sample size, high placebo response and dropout rates, and unclear generalizability of findings to real world clinical situations. Very few placebo-controlled maintenance trials in patients whose binge eating was in remission have been published. There has only been one placebo-controlled pharmacotherapy study in BN patients who were inadequately responsive to psychotherapy; comparable studies have not been done for BED. There have been no controlled pharmacotherapy studies in adolescents or older adults with BN or BED, or in children with loss of control eating. Except for obesity and major depressive disorder in BED, there has been no pharmacotherapy study of patients with BN or BED and a specified psychiatric or medical comorbidity. Moreover, it is not yet known whether the binge eating in BN and BED respond similarly to pharmacotherapy. Yet many individuals with binge eating receive pharmacotherapy [14], and several conclusions regarding the pharmacotherapy of BN and BED from extant research can be reached (Table 1). Substantial evidence indicates antidepressants are modestly efficacious for binge eating in both BN and BED over the short-term [15,17-19,23,24]. A smaller body of data suggests they may be modestly effective as maintenance agents in BN [36,37]. Antidepressants, including the SNRI duloxetine, may also be useful for the depressive symptoms and/or syndromes that may accompany BN and BED. They do not, however, appear to have clinically significant benefits on body weight in BED, and their long-term efficacy in BED is not known. Antidepressants may enhance the anti-binge eating effects of CBT in BN or BED, but available data are mixed [39-42]. It is unknown whether these findings would generalize to antidepressants with different pharmacodynamic profiles, such as bupropion or vilazodone. Considerable double-blind, placebo-controlled data show that topiramate is effective for the binge eating of BN and BED [46-51]. Topiramate also may be effective for other correlates of binge eating, such as purging in BN, and for
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S. L. McElroy et al.

Table 1. Pharmacological treatment of bulimia nervosa and binge eating disorder: summary of evidence.
Drug/Class Bulimia Nervosa +++ +++ + +++ +++ ND +/+++ ND ND ND + ND + Binge eating disorder +++ +++ ++ ND +/+/+/+++ ++ +++ ++ ++ +/+/+

Antidepressants (acute) SSRIs Tricyclics SNRIs MAOIs Antidepressants (long term) Antiepileptics Lamotrigine Phenytoin Topiramate Zonisamide Anti-Obesity Drugs Orlistat Anti-ADHD drugs Atomoxetine Stimulants Anti-Addiction Drugs Acamprosate Opioid Antagonists Opioid Antagonists (high dose)

+++: At least 2 positive placebo-controlled RCTs; ++: 1 positive placebocontrolled RCT with no negative RCTs; +: Positive open studies; +/-: Mixed results; -: Placebo-controlled RCT data mostly negative; MAOIs: Monoamine oxidase inhibitors; ND: No data; RCT: Randomized placebo-controlled trial; SSRIs: Selective serotonin reuptake inhibitors; SNRIs: Selective serotonin norepinephrine reuptake inhibitor.

weight loss in BED with obesity. One RCT showed topiramate may enhance the effectiveness of CBT in BED [51], while an open-label study found topiramates anti-binge-eating and weight loss effects in BED may persist for up to one year (though drug discontinuation rates were high, in part due to adverse events) [57]. Orlistat, when used in combination with CBT or dietary therapy, leads to enhanced weight loss and possibly reduced binge eating in BED [65,66]. Drugs shown efficacious in one published RCT include ondansetron for BN [92], and zonisamide and atomoxetine for BED [54,74]. Preliminary reports from Phase-II studies suggest lisdexamfetamine and intranasal naloxone may be helpful for BED [76,86]. In light of the nascent status of pharmacotherapy research in binge eating, some authorities suggest psychotherapy should be the first-line treatment of BN and BED [13,17,21]. However, this recommendation needs to account for a number of factors. These include patient preference; the incomplete effectiveness and availability of psychotherapy; the potential lack of generalizability of psychotherapy study findings; and the fact that pharmacotherapy can be combined with or added to psychotherapy. Moreover, both BN and BED are most likely each heterogeneous conditions [100]. Thus, while some patients respond to psychotherapy alone, others respond optimally only with pharmacotherapy,
2022

including combinations of medications [101]. Identification of factors predicting requirement of pharmacotherapy, along with the particular medications most likely to be effective, will help realize personalized treatment of BN and BED. Despite the preliminary status of the knowledge base, pharmacotherapy should be considered a therapeutic option for ve to treatmost BN and BED patients, including those na ment, but especially when psychotherapy response has been inadequate. Patients with binge eating should be educated about psychological and medical options, including the view that psychotherapy is considered a treatment of choice for BN and BED, but that the knowledge base for pharmacotherapy is growing. For patients who decline psychotherapy, or have an inadequate response, fluoxetine (or another SSRI) should be offered as a first-line option for BN; for BED, topiramate or an antidepressant should be offered. Though bupropion is contraindicated for BN, it has been used in BED, in part due to its weight loss effects. Zonisamide may be considered in patients unable to tolerate topiramate, especially if they responded to the drug. Some patients with BN or BED may require combination pharmacotherapy for optimal results [14,101,102]. Pharmacotherapy of BN and BED should also be guided by co-occurring conditions. Although empirical data are largely lacking, antidepressants may be helpful for BN or BED patients with a depressive or anxiety disorder; topiramate or zonisamide for those with comorbid obesity and/or an obesity-related complication; atomoxetine or stimulants for those with comorbid ADHD; and anti-addiction or anticraving drugs for those with co-occurring substance use disorders. Similarly, no empirical data are available for treating BN or BED patients with bipolar disorder. In such patients with obesity or fear of taking a mood stabilizer because of possible weight gain, agents effective in mania or bipolar depression that have minimal effects on weight may be considered, such as the second generation antipsychotics aripiprazole, lurasidone, or ziprasidone for predominantly manic presentations, and lamotrigine or lurasidone for predominantly depressive presentations. For patients with BN or BED who have mood-stabilizing responses but continue to have binge eating, augmentation with topiramate or antidepressants may be considered. Electrolyte disturbances must be monitored for in patients with purging behavior who are treated with lithium. When treating BN or BED patients with pharmacotherapy, it is important that psychological strategies be pursued and optimized. This includes strongly recommending psychotherapy to patients who have an inadequate response to pharmacotherapy, including those who initially refuse psychotherapy. In summary, pharmacotherapy has an important role in the management of BN and BED, including in patients inadequately responsive to psychotherapy, patients with comorbid psychiatric or medical disorders, and those with chronic or intractable illness. However, the available pharmacotherapeutic armamentarium for both conditions and its supporting evidence

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Current pharmacotherapy options for bulimia nervosa and binge eating disorder

base is far from adequate. Further study is needed to clarify which specific agents, and combinations of agents, might be most useful for which patient subgroups, as well as to delineate the larger role of pharmacotherapy in relationship to other treatments. Novel medical treatments for binge eating are needed and rational drug discovery devoted to binge eating needs to occur. In the meantime, current and future medications with psychotropic benefits and/or favorable effects on appetite and weight might be considered as potential therapeutic agents for BN and BED.

Declaration of interest
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This study has been supported by the Lindner Centre of Hope, and the University of Cincinnati. S McElroy is a Bibliography
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consultant to or member of the scientific advisory boards of: Alkermes, Corcept, MedAvante, Shire, and Teva; She is a principal or co-investigator on studies sponsored by: the Agency for Healthcare Research & Quality (AHRQ), Alkermes, AstraZeneca, Cephalon, Eli Lilly and Company, Marriott Foundation, National Institute of Mental Health, Orexigen Therapeutics, Inc., Shire, Takeda Pharmaceutical Company Ltd., and Transcept Pharmaceutical, Inc; She is also an inventor on United States Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and along with the patients assignee, University of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & Johnson, which has exclusive rights under the patent. All other authors declare no conflict of interest.
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Affiliation
Susan L McElroy1,2,3 MD, Anna I Guerdjikova1,2,4 PhD, Nicole Mori1,2,5 RN MSN & Anne M OMelia1,2,6 MD 1 Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA 2 University of Cincinnati College of Medicine, Psychiatry & Behavioral Neuroscience, 260 Stetson St., Cincinnati OH 45219, USA 3 Chief Research Officer, Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA Tel: +1 513 536 0700; Fax: +1 513 536 0709; E-mail: susan.mcelroy@lindnercenter.org 4 Associate Research Director, Harold C. Schott Eating Disorders Program, Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA 5 Nurse Practitioner, Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA 6 Medical Director, Harold C. Schott Eating Disorders Program, Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA

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