Drugs DOI 10.1007/s40265-014-0327-0

REVIEW ARTICLE

Pharmacological Approaches to the Management of Binge Eating Disorder Kimberly A. Brownley • Christine M. Peat Maria La Via • Cynthia M. Bulik



Ó Springer International Publishing Switzerland 2014

Abstract In the USA, binge eating disorder (BED) is the most common eating disorder, with a lifetime prevalence of *3.5 % in adult women, 2.0 % in adult men, and 1.6 % in adolescents. BED is characterized by frequent episodes of binge eating that are accompanied by a sense of loss of control over eating and result in marked psychological distress. BED is highly co-morbid with obesity and with depression and other psychiatric conditions, and it is associated with substantial role impairment. Currently, there are no US FDA-approved pharmacological treatments for BED. Animal and human studies implicate underlying dysregulation in dopamine, opioid, acetylcholine, and serotonin neurocircuitry within brain reward regions in the pathogenesis and maintenance of BED. To date, the efficacy of various agents that target these and other neurotransmitter systems involved in motivated feeding behavior, mood regulation, and impulse control have been investigated in the treatment of BED. Several antidepressant and anticonvulsant agents have demonstrated efficacy in reducing binge eating frequency, but only in limited cases have these effects resulted in patients achieving abstinence, which is the primary goal of treatment; they

also range from less (fluvoxamine) to more (topiramate) effective in achieving weight loss that is both clinically meaningful and significantly greater than placebo. Collectively, the literature on pharmacological treatment approaches to BED is limited in that very few agents have been studied in multiple, confirmatory trials with adequate follow up, and almost none have been evaluated in large patient samples that are diverse with respect to age, sex, and ethnicity. In addition, prior trials have not adequately addressed, through study design, the high placebo response commonly observed in this patient population. Several novel agents are in various phases of testing, and recent animal studies focusing on glutamate-signaling circuits linking the amygdala to the lateral hypothalamus offer new avenues for exploration and potential therapeutic development. Studies of newly FDA-approved medications for long-term obesity treatment and further explorations of dietary supplements and neutraceuticals with appetite- and mood-altering properties may also be worthwhile.

K. A. Brownley (&)  C. M. Peat  M. La Via  C. M. Bulik Department of Psychiatry, CB #7175, University of North Carolina, Chapel Hill, NC 27599-7175, USA e-mail: [email protected]

Binge eating is a behavior characterized by the consumption of an objectively large amount of food in a discrete period of time. Binge eating is the core behavioral feature of binge eating disorder (BED), as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [1]. Briefly, BED is characterized by recurrent (one or more per week) and persistent (for the past 3 months) episodes of binge eating, with those episodes being associated with a sense of loss of control over eating (either that one cannot stop or control what or how much one is eating) and marked distress about binge

C. M. Bulik Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA C. M. Bulik Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden

1 Overview of the Diagnosis and Epidemiology of Binge Eating Disorder (BED)

K. A. Brownley et al.

Key Points Evidence supporting pharmacological treatment for binge eating disorder (BED) is growing yet is insufficient in scope and magnitude to warrant definitive recommendations, largely because no agents have demonstrated clear efficacy for achieving or sustaining binge abstinence—the primary goal of treatment. In the limited studies to date, topiramate and lisdexamfetamine dimesylate appear to have the most favorable profiles for achieving both abstinence and clinically meaningful weight loss. Future studies are needed to address longer-term efficacy of pharmacological treatments in general, as well as response trajectories and patient characteristics that influence response rate, and the efficacy of newly (and soon-to-be) US FDAapproved anti-obesity agents in BED. Promising animal studies are paving the way to discovery of novel and specific therapeutic targets for reducing binge-like eating behavior, which eventually may lead to new pharmacological treatments for BED.

eating. To receive a BED diagnosis, an individual must also endorse at least three additional criteria such as eating until feeling uncomfortably full and eating alone to avoid embarrassment, among others. Importantly, BED is distinguished from bulimia nervosa by an absence of regular compensatory behaviors such as purging, laxative abuse, or excessive exercise. BED is the most common eating disorder. Approximately 3.5 % of adult women, 2.0 % of adult men, and 1.6 % of adolescents living in the USA have BED in their lifetime [2, 3], with some studies suggesting a slightly higher prevalence among Hispanic than other racial/ethnic groups [4, 5]. In adults, BED is 2- to 10-fold more common among obese individuals, with higher prevalence observed in obese individuals seeking weight-loss treatment and those with greater obesity severity [6–9]. BED confers risk for obesity, metabolic syndrome, and diabetes mellitus and is also highly co-morbid with other psychiatric conditions including depression, anxiety, and substance abuse [10– 17]. A recent population-based study [18] examined other correlates of BED and found that over 46 % reported role impairment due to their eating disorder in the last 12 months, with approximately 13 % of those individuals reporting severe impairment; in addition, BED increased risk for chronic pain, headaches, diabetes, and hypertension beyond that of other co-morbid psychiatric conditions.

Diagnosing BED is challenging in pediatric populations, especially young children who may struggle to grasp the concept of binge eating cognitively and to remember what and how much food they consume over a specific period of time; children also may not have unlimited access to food (i.e., food availability under parental control), which can reduce the likelihood they will meet the binge eating frequency criterion for BED. Diagnosing BED is also challenging in obese individuals after they undergo bariatric surgery because the amount of food consumption is anatomically limited by their reduced stomach capacity. In these two subgroups, loss-of-control (LOC) eating is used to describe recurrent, psychologically distressing, disinhibited ‘binge-like’ eating behavior. Reports of LOC eating range from 25 to 40 % in children [19, 20] and 8 to 50 % in post-surgery patients [21]. Much like BED, LOC eating has detrimental psychological and physical health consequences [22, 23], including excessive weight gain in children and weight regain in post-bariatric surgery patients [21, 22], and LOC eating may be a precursor to BED [24].

2 Etiology and Pathophysiology of BED The etiology and pathophysiology of binge eating are not entirely clear but likely include a combination of predisposing factors and proximal triggers [25] and alterations in underlying brain reward and mood regulation neurocircuitry that maintain behavior [26]. Past dieting behavior and current weight are recognized as key vulnerability factors. Caloric deprivation including abstinence from ‘forbidden’ foods, a common weight-loss strategy used by overweight and obese individuals, increases binge eating and predicts binge eating onset [27– 30]. Many dieters tend to forego physiological hunger cues for less reliable cognitive strategies (e.g., focusing on weight loss goals, belief that hunger is inherent in dieting) to control food consumption. This strategy becomes problematic, however, when those cognitive processes are disrupted (e.g., by negative emotions), rendering an individual more vulnerable to disinhibited eating. Indeed, negative affect is a key proximal trigger for acute episodes of binge eating [31–33], with one study reporting this scenario in 84 % of cases [34]. Although the act of binge eating provides short-term relief from distressing mood symptoms, it frequently fosters other negative feelings (shame, disgust) and is followed by increased symptoms of depression [35, 36]. Thus, the individual experiences a vicious cycle of emotional turmoil and binge eating that can accelerate over time and degrade one’s sense of control. Support for this model comes from studies using ecological momentary assessment in which negative affect was both a significant

Pharmacological Management of BED

predictor and a consequence of binge eating in persons with BED [37]. Hunger, per se, is not necessarily a reliable predictor of binge eating [38]; however, binge eating often occurs in response to specific food cravings [34], particularly cravings for sweets [39–42]. Among obese women, those with BED report higher sweet food cravings than those without BED [40, 43]. The likelihood of engaging in binge eating increases with exposure to highly palatable food [44], especially under conditions of energy restriction and stress [45, 46]. The neurobiology of BED is not well-described but animal studies have implicated dysregulation in multiple neurotransmitter systems involved in food reward and addiction [47–49]. These studies have shown that binge eating behavior can be shaped by repeated, intermittent presentation of highly palatable foods [49–53] through opioid- and dopamine-mediated pathways [52, 54], and that subsequent withdraw of palatable food evokes symptoms of anxiety [55]. Consistent with these phenotypic findings, candidate gene studies indicate that binge eating is associated with functional polymorphisms in the dopamine transporter (DAT1) gene [56] and in the dopamine D4 (DRD4) [57] and D2 receptor (DRD2) [58] genes. In humans, neuroimaging studies have described diminished activation in brain regions involved in reward anticipation and processing [59, 60] and shown that intake of palatable foods is reduced by naloxone in individuals with BED but not in non-bingeing obese or normal-weight individuals [61]. The lateral hypothalamus is widely recognized for the critical role it plays in the regulation of motivated feeding behavior. Recent studies focusing on the neural circuits linking motivational states to dysregulated feeding behavior are providing new insights about hypothalamic pathways through which exposure to highly palatable foods facilitates overeating. These studies show, for example, that activating inhibitory input from the bed nucleus of the stria terminalis of the extended amygdala to glutamatergic neurons in the lateral hypothalamus leads to voracious feeding behavior and preferential consumption of caloriedense substances in well-fed animals [62]. Studies such as these suggest that highly specific substrates may be available as therapeutic targets for reducing binge-like eating behavior.

3 Rationale for Medical Management of BED BED constitutes a significant public health problem affecting tens of millions in the USA and countless others worldwide. Thus, there is a clear imperative for developing and delivering effective treatment that addresses both the

psychological and physical health burdens of BED. Psychological treatments, such as cognitive behavioral therapy (CBT) and interpersonal psychotherapy, demonstrate efficacy for reducing binge eating behavior and improving related psychopathology, but they often fall short in affecting sustained weight loss [63, 64]. There is concern within the community of BED treatment providers that weight-focused treatments can have unintended detrimental effects on some patients by triggering new or rekindling old restrictive eating behaviors [65–67]. Nonetheless, for patients who enter treatment with pre-existing metabolic disease (e.g., morbid obesity, diabetes), weight loss can be important to staying engaged in treatment and to reducing morbidity and mortality over the longer term. Thus, it is worthwhile to continue to search for treatments that not only help patients achieve abstinence from binge eating but also assist patients in meeting their healthy weight goals. Although several medications have demonstrated shortterm efficacy in BED, there are currently no medications approved for the treatment of BED in the USA or elsewhere. The goal of this paper is to provide an up-to-date review of pharmacological approaches to BED, which will serve to focus attention on gaps in knowledge and promising areas for future research.

4 Search Strategy In 2006, with funding from the US Agency for Healthcare Research and Quality, we published an evidence-based review of psychological, behavioral, and pharmacological interventions for eating disorders [63, 64]. That review was based on a systematic search of six major databases for randomized controlled trials (RCTs) on the treatment of BED that were published from 1980 through September 2005. To identify studies on BED, we used the search terms ‘binge eating’, ‘randomized controlled trials’ (MeSH) or ‘single-blind method’ (MeSH) or ‘double-blind method’ (MeSH) or ‘random allocation’(MeSH). The primary exclusion criteria were sample size less than ten for RCTs or less than 50 for non-randomized trials, study population does not meet Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) [68] criteria for BED, and article not available in print or published in a language in which the study team was not proficient. That search identified 26 trials, of which 13 included a pharmacological intervention. All studies were doublereviewed and assigned a quality rating following published guidelines [68]. Using the same search terms, in 2011 we conducted a modified PubMed search to identify relevant BED RCTs published since the 2006 review; this search identified more than 900 abstracts that were subsequently dual-reviewed and rated for quality. Lastly, in February

6 wk

12 wk

SSRIa

SSRIa,b

SSRIa,c,d,e,f

Citalopram (CelexaÒ) 60 mg/ day (Forest Laboratories) [80]

Escitalopram (LexaproÒ) 30 mg/ day (H. Lundbeck A/S) [81]

Fluoxetine (ProzacÒ) 80 mg/day (Lilly) [82] 6 wk

Duration

Mechanism*

Drug (brand) and maximum dose (manufacturer)

PL

PL

PL

Comparator

60 (36)

44 (35)

38 (31)



Measures: binges/wk, categorical response Over time: greater rate of reduction in binges/ wk vs. PL Endpoint: no difference in binges/wk or response vs. PL

ITT

Endpoint: greater reduction in binge frequency (episodes and days) but no difference in response vs. PL

Over time: no differences in rate of reduction in binge frequency vs. PL

Measures: binges/wk, binge days/wk, categorical response

Endpoint: greater reduction in binge days/wk vs. PL; no difference in response

Over time: greater rate of reduction in binge episodes and binge days/wk vs. PL

Measures: binges/wk, binge days/wk, categorical response$

Behavioral/bingerelated outcomesà

Mixed-model RMANOVA

ITT and completer

Mixed-model RMANOVA

ITT

Mixed-model RMANOVA

Analysis§

Table 1 Summary of randomized controlled trials of antidepressants for binge eating disorder

Measures: BMI, weight Over time: greater rate of reduction in weight and BMI vs. PL Endpoint: greater reduction in weight and BMI vs. PL

Over time: greater rate of reduction in illness severity vs. PL Endpoint: greater reduction in illness severity and depression vs. PL

Endpoint: greater reduction in weight and BMI but no differences in other biomarkers vs. PL

Over time: greater rate of reduction in weight and BMI vs. PL

Measures: BMI, weight, ghrelin, glucose, insulin, lipids

Endpoint: greater reduction in weight and BMI vs. PL

Over time: greater rate of reduction in weight and BMI vs. PL

Measures: BMI, weight

Biological/weight-related outcomes

Measures: CGI-S, HDRS

Endpoint: greater reduction in illness severity vs. PL

Over time: greater rate of reduction in illness severity vs. PL

Measures: CGI-I, CGI-S, HDRS, YBOCS-BE

Over time: greater rate of reduction in illness severity, obsessions and compulsions vs. PL Endpoint: greater reduction in YBOCS-BE total, obsessions and compulsions vs. PL

Measures: CGI-I, CGI-S, HDRS, YBOCS-BE

Psychological outcomes

K. A. Brownley et al.

SSRIa,c,d,e,f 12 months CBT ? FLX

CBT

65 (60)

108 (86)

Completer

Nonparametric ANOVA

ITT

ANCOVA

Fluoxetine (ProzacÒ) 60 mg/day (Lilly) [85]

CBT ? FLX

CBT

PL

116 (74)

Logistic regression ANCOVA

16 wk

PL ? BWL ± CBT

SSRIa,c,d,e,f

5 months

Fluoxetine (ProzacÒ) 60 mg/day (Lilly) [84, 96]

Analysis§

ITT



SSRIa,c,d,e,f

Comparator

Fluoxetine (ProzacÒ) (?BWL ± CBT) 60 mg/day (Lilly) [83, 95]

Duration

Mechanism*

Drug (brand) and maximum dose (manufacturer)

Table 1 continued

Endpoint: significant differences in binge frequency across groups but post hoc comparisons = NR 6-month F/up: no difference in binge frequency across groups

Measures: binges/month

12-month F/up: greater binge frequency and lower % abstinent vs. CBT and CBT ? FLX

Endpoint: no differences in % abstinent or binge frequency vs. PL; greater binge frequency and lower % abstinent vs. CBT and CBT ? FLX

Measures: binges past 28 days by daily selfmonitoring and EDEQ, abstinence (yes/no)

12-, 18-, and 24-month F/up: no difference in binge frequency or change in binge frequency vs. PL

Endpoint: no difference in binge frequency or % abstinent vs. PL

Measures: binges/ month, abstinence (yes/no)

Behavioral/bingerelated outcomesà

6-month F/up: NR

Endpoint: significant differences in all MMPI-2 subscales and in EDI-2 bulimia and impulsivity subscales across groups but post hoc comparisons = NR

Measures: EDI-2, MMPI-2

12-month F/up: higher eating, shape and weight concerns, and dietary restraint vs. CBT and CBT ? FLX

Endpoint: no differences vs. PL; higher eating, shape and weight concerns, dietary restraint, disinhibition, body dissatisfaction and depression vs. CBT and CBT ? FLX

Measures: BDI, BSQ, EDEQ, TFEQ

12-, 18-, and 24-month F/up: lower depression and greater reduction in restraint from end-oftreatment vs. PL

Endpoint: lower depression and higher self-esteem vs. PL; lower symptom score for FLX ? CBT vs. FLX, CBT, or PL alone

Measures: BDI, BSI, BSQ, IIP, RSE, TFEQ

Psychological outcomes

6-month F/up: no differences in % weight loss across groups

Endpoint: significant differences in % weight loss across groups but post hoc comparisons = NR

Measures: weight

Endpoint: no difference in BMI vs. PL, CBT, or CBT ? FLX 12-month F/up: no difference in BMI or weight change

Measures: BMI, weight

12-, 18-, and 24-month F/up: no difference in weight or change in weight vs. PL

Endpoint: no difference in weight vs. PL

Measures: weight

Biological/weight-related outcomes

Pharmacological Management of BED

Duration

24 wk

12 wk

9 wk

Mechanism*

SSRIb

SSRIb

SSRIb

Drug (brand) and maximum dose (manufacturer)

Fluvoxamine (LuvoxÒ) 300 mg/ day (Solvay) [86]

Fluvoxamine (LuvoxÒ) 300 mg/ day (Solvay) [87]

Fluvoxamine (LuvoxÒ) 300 mg/ day (Solvay) [88]

Table 1 continued

PL

PL

CBT ? FLV

CBT ? FLX

FLX 60 mg/day

CBT

Comparator

85 (67)

20

108 (99)



ITT

Mixed-model RMANOVA

Over time: greater rate of reduction in binge frequency vs. PL Endpoint: no difference in response

Endpoint: NR

Over time: greater rate of reduction in symptom severity, greater rate of global symptom improvement vs. PL

Measures: CGI-I, CGI-S, HDRS

Endpoint: no differences in changes in any psychological measures vs. PL

Endpoint: no differences in reduction in binge frequency vs. PL Measures: binges/wk by diary, categorical response

Measures: BDI, CGI-I, CGIS, EDE, HDRS, SCL-90

1-year F/up: no change in restraint or in eating, weight, or shape concerns from endpoint, but tests of between-group differences = NR

Endpoint: significant reduction in eating, weight, and shape concerns in CBT but not FLV or FLX group; however, tests of betweengroup differences = NR; greater reductions in eating, weight, and shape concerns in FLV ? CBT vs. FLX ? CBT; greater reduction in trait anxiety in FLV vs. CBT; greater reduction in state anxiety in FLV ? CBT vs. CBT; depression reduced in all groups

Measures: BDI, EDE, STAI1, STAI-2

Psychological outcomes

Measures: binges/wk by diary

Endpoint: significant reduction in CBT, CBT ? FLX, and CBT ? FLV but not in FLV or FLX groups; however, tests of between-group differences = NR 1-year F/up: significant reduction in CBT but not FLV group or FLX group, but tests of between-group differences = NR

Completers

RMANOVA

Measures: binge episodes/month

Behavioral/bingerelated outcomesà

Friedman’s ANOVA

Analysis§

Endpoint: NR

Over time: greater rate of reduction in BMI vs. PL

Measures: BMI

Endpoint: greater reduction in weight vs. PL

Measures: weight

1-year F/up: significant reduction from baseline in CBT, CBT ? FLV, and CBT ? FLX groups

Endpoint: significant reduction in CBT, CBT ? FLX, and CBT ? FLV but not FLV or FLX groups; no difference in BMI reduction between CBT, CBT ? FLV, and CBT ? FLX groups; however, FLV vs. PL and FLV vs. CBT differences = NR

Measures: BMI

Biological/weight-related outcomes

K. A. Brownley et al.

6 wk

12 wk

8 wk

SSRIa,c,d,e,g,h

SNRIa,b

NDRIa

Sertraline (ZoloftÒ) 200 mg/day (Pfizer) [90]

Duloxetine (CymbaltaÒ) 120 mg/day (Lilly) [91]

Bupropion (WellbutrinÒ) 300 mg/day (GlaxoSmithKline) [92]

24 wk

SSRIa,c,d,e,g,h

Sertraline (ZoloftÒ) 200 mg/day (Pfizer) [89]

Duration

Mechanism*

Drug (brand) and maximum dose (manufacturer)

Table 1 continued

PL

PL

PL

FLX 40–80 mg/day

Comparator

61 (54)

40 (27)

34 (26)

42 (31)



ITT

Mixed-model RMANOVA

ITT

Mixed-model RMANOVA

Endpoint: no difference in % abstinent vs. PL

Endpoint: NR

Over time: greater rate of reduction in BMI vs. PL Endpoint: NR

Measures: BMI Over time: no differences in rate of change in any psychological outcomes vs. PL

Endpoint: no difference in binge frequency reduction vs. PL

Endpoint: no differences in reduction in weight or BMI vs. PL

Over time: greater rate of reduction in weight vs. PL

Measures: BMI, weight

Over time: greater rate of reduction in BMI vs. PL

Measures: BMI

Over time: significant reductions in weight and BMI in both groups; between-group differences = NS

Measures: weight, BMI

Biological/weight-related outcomes

Measures: BDI, EDE, FCI

Endpoint: greater reduction in depressive symptom severity vs. PL

Over time: greater rate of reduction in binge frequency (episode and days) vs. PL

Measures: binge episodes/wk by diary, abstinence Over time: no differences in rate of reduction in binge frequency vs. PL

Over time: greater rate of reduction in severity of binge eating depressive symptoms vs. PL

Measures: binges/wk by diary and binge days/ wk, categorical response

Over time: greater rate of reduction in binge frequency vs. PL

ITT

Measures: CGI-I, CGI-S, HDRS

Over time: significant reductions in global symptom severity, binge eating severity, depression, bulimia, body dissatisfaction, and interoceptive awareness in both groups; between-group differences = NS

Measures: BDI, BES, CGI-S, EDI-2

Psychological outcomes

Over time: greater rate of reduction in global symptom severity, greater rate of increase in global symptom improvement vs. PL Measures: CGI-I-BE, CGI-IDD, CGI-S-BE, CGI-S-DD, HAM-A, IDS-C, TFEQ, YBOCS-BE

Measures: binges/wk by diary

Over time: significant reductions in binge frequency in both groups; betweengroup difference = NS

Mixed-model RMANOVA

Measures: binges/wk

RMANOVA

Behavioral/bingerelated outcomesà

Completer

Analysis§

Pharmacological Management of BED

12 wk

8 wk

NRIa

SNRIa

Desipramine (NorpraminÒ) 300 mg/day (Hoechst Marion Roussel) [93]#

Imipramine (TofranilÒ) 75 mg/ day (Novartis) [94] PL

PL

Comparator

31 (29)

30 (23)



Completer

RMANOVA

Completer

RMANCOVA

Analysis§

24-wk F/up: greater reduction in binge frequency vs. PL

Endpoint: greater reduction in binge frequency vs. PL

Measures: binges/wk by interview

4-wk F/up: group differences = NR

Endpoint: greater reduction in binge frequency vs. PL

Measures: binges/wk by diary and binge days/ wk

Behavioral/bingerelated outcomesà

24-wk F/up: greater % reduction in depression vs. PL

Endpoint: greater reduction in depression vs. PL

Measures: HDRS, SDS

4-wk F/up: group differences = NR

Endpoint: greater reductions in disinhibition and hunger, and greater increases in dietary restraint vs. PL

Measures: TFEQ, BDI, Semantic Differential Scale

Psychological outcomes

24-wk F/up: greater reduction in weight vs. PL

Endpoint: greater reduction in weight vs. PL

Measures: weight, WHR, BP, glucose, lipids

4-wk F/up: group differences = NR

Endpoint: no differences in weight or BMI change vs. PL

Measures: weight, BMI

Biological/weight-related outcomes

Number with BED randomized (number completed)

All reported differences are statistically significant, p B 0.05

#

Sample described as ‘‘non-purging bulimics’’ but would meet DSM-5 frequency and duration criteria for BED

Binge reduction response categories: none, moderate, marked, abstinent. For the purposes of this review, abstinence is defined as zero binges in the most recent monitoring period, which in most studies was the past 4 wk; the term ‘remission’ is reserved for characterizing prolonged (3 months or more) periods of binge abstinence

$

à

‘Over time’ denotes a time-trend analysis in which time is modeled as a continuous variable using repeated-measures random regression analysis, also known as mixed-model RMANOVA; ‘endpoint’ is a more conservative analysis based on RMANOVA and does not assume (or model) a trend in time. Both analyses include a time 9 treatment interaction; however, the time-trend analysis yields a measure of the difference in rate of change (slope with respect to time), whereas the endpoint analysis estimates the difference between groups in change from baseline to last observation/end-of-treatment (delta) (see McElroy et al. [80] for further explanation and references). If a study included both ITT and completer analyses, only ITT results (which are more conservative) are reported here

§

 

* Predominant mechanism(s) of action, although may have less potent effects on other neurotransmitter systems. Indications: a major depressive disorder, b generalized anxiety disorder, c obsessive compulsive disorder, d panic disorder, e premenstrual dysphoric disorder, f bulimia nervosa, g post-traumatic stress disorder, h social anxiety disorder

ANCOVA analysis of covariance, ANOVA analysis of variance, BDI Beck Depression Inventory [138], BED binge eating disorder, BES Binge Eating Scale [139], BMI body mass index, BP blood pressure, BSI Brief Symptom Inventory [140], BSQ Body Shape Questionnaire [141], BWL behavioral weight loss, CBT cognitive behavioral therapy, CGI Clinical Global Impression (I improvement, I-BE improvement for binge eating, I-DD improvement for depressive disorder, S severity, S-DD severity for depressive disorder, S-BE severity for binge eating [142]), DSM-5 Diagnostic and Statistical Manual of Mental Disorders (5th edition), EDE Eating Disorders Examination [143], EDE-Q Eating Disorders Examination Questionnaire [144], EDI Eating Disorder Inventory [145], FCI Food Craving Inventory [43], F/up follow-up, FLV fluvoxamine, FLX fluoxetine, HAM-A Hamilton Anxiety Inventory [146], HDRS Hamilton Depression Rating Scale [147], IDS-C clinician-rated Inventory of Depressive Symptomatology [148], IIP inventory of interpersonal problems [149], ITT intent-to-treat, MMPI-2 Minnesota Multiphasic Personality Inventory-2, NDRI norepinephrine-dopamine reuptake inhibitor, NR not reported, NRI norepinephrine reuptake inhibitor, NS non-significant, PL placebo, RMANCOVA repeated measures analysis of covariance, RMANOVA repeated measures analysis of variance, RSE Rosenberg Self-Esteem Scale [150], SCL-90 symptom checklist-90, SDS Self Depression Rating Scale [151], SNRI serotonin–norepinephrine reuptake inhibitor, SSRI selective serotonin reuptake inhibitor, STAI State-Trait Anxiety Inventory [152], TFEQ Three Factor Eating Questionnaire [153], WHR waist-hip ratio, wk week, YBOCS-BE Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [80, 154]

Duration

Mechanism*

Drug (brand) and maximum dose (manufacturer)

Table 1 continued

K. A. Brownley et al.

16 wk

16 wk

24 wk

Glutamate/ aspartate Nachannel inhibitora,b

Carbonic anhydrase inhibitorc,d

Carbonic anhydrase inhibitorc,d

Carbonic anhydrase inhibitorc,d

Lamotrigine (LamictalÒ) 400 mg/day (GlaxoSmithKline) [99]

Topiramate (TopamaxÒ) 600 mg/day (Ortho McNeil) [100]

Topiramate (TopamaxÒ) 600 mg/day (Ortho McNeil) [101]

Topiramate (TopamaxÒ) 100 mg/day (Ortho McNeil) [102]

14 wk

Duration

Mechanism*

Drug (brand) and maximum dose (manufacturer)

CBT

Sertraline 50–150 mg/ day

PL

PL

PL

Comparator

35 (30)

407 (283)

61 (35)

51 (31)



Measures: binges/wk Endpoint: binge frequency significantly reduced in topiramate ? CBT ? sertraline group but not CBT ? sertraline or CBT groups; between-group differences = NR

Completer

Endpoint: greater reduction in binge frequency (episodes and binge days/wk) greater % abstinence vs. PL

Measures: weight, BMI Endpoint: weight and BMI significantly reduced in topiramate ? CBT ? sertraline group; between-group differences = NR

Endpoint: drive for thinness and bulimia scores significantly reduced in topiramate ? CBT ? sertraline group; between-group differences = NR

Endpoint: greater reduction in weight and BMI vs. PL

Measures: EDI-2, SCL-90-R

Endpoint: greater reduction in global symptom severity; obsession and compulsion scores; motor and non-planning impulsiveness; cognitive restraint, disinhibition, and hunger; and social and family disability vs. PL

Over time: greater rate of reduction in global symptom severity; obsession and compulsion scores; motor and non-planning impulsiveness; cognitive restraint, disinhibition, and hunger; and social and family disability vs. PL

Over time: greater rate of reduction in binge frequency (episodes and days/wk) and a shorter time to abstinence vs. PL

Over time: greater rate of reduction in weight and BMI vs. PL

Measures: BMI, weight

Endpoint: greater reduction in diastolic BP vs. PL

Endpoint: greater global symptom improvement vs. PL Measures: BIS, CGI, HDRS, MADRS, SD, TFEQ, YBOCSBE

Over time: greater rate of reduction in weight and BMI vs. PL

Measures: BMI, weight, WHR, BP, body fat, glucose, insulin, lipids

Endpoint: greater reductions in insulin, glucose, and triglycerides vs. PL

Over time: no differences in rates of change vs. PL

Measures: BMI, weight, ghrelin, glucose, insulin, leptin, lipids

Biological/weight-related outcomes

Over time: greater rate of reduction in global symptom severity and in obsession and compulsion scores vs. PL

Measures: CGI, HDRS, YBOCSBE

Measures: binge episodes by diary, binge days/wk, categorical response

RMANOVA

ITT

Mixed-model RMANOVA

Over time: greater rate of reduction in binge frequency (episodes and days/wk) vs. PL

ITT

Endpoint: greater reduction in binge frequency (episodes and binge days/wk) vs. PL

Measures: binge episodes by diary, binge days/wk, abstinence

Endpoint: no differences in binge frequency or % abstinent vs. PL

Over time: no differences in rates of change vs. PL

Over time: no differences in rate of change in binge frequency vs. PL Endpoint: no differences vs. PL

Measures: BIS, CGI-I, CGI-S, EDE, EOC, MADRS, SD, TFEQ, YBOCS-BE, YMRS

Psychological outcomes

Measures: binge episodes/wk by diary, binge days/wk, categorical response

Behavioral/binge-related outcomesà

Mixed-model RMANOVA

ITT

Mixed-model RMANOVA

Analysis§

Table 2 Summary of randomized controlled trials of anticonvulsants for binge eating disorder

Pharmacological Management of BED

21 wk

Carbonic anhydrase inhibitorc,d

Carbonic anhydrase inhibitorc

Carbonic anhydrase inhibitorc

Topiramate (TopamaxÒ) 300 mg/day (?CBT) (Ortho McNeil) [103]

Zonisamide (ZonegranÒ) 600 mg/day (Generic) [104]

Zonisamide (ZonegranÒ) 150 mg/day (?CBT) (Generic) [105] CBT

PL

PL ? CBT

Comparator

52 (30)

60 (30)

73 (56)



ITT

Mann– Whitney U, Wilcoxon

ITT

Mixed-model RMANOVA

Over time: no difference in rate of reduction in binge frequency vs. PL

ITT

1-year F/up: greater reduction in binge frequency vs. CBT

Endpoint: no difference in binge frequency reduction vs. CBT

Measures: binges in past 28 days

Endpoint: no difference in binge frequency reduction or response vs. PL

Over time: greater rate of reduction in binge/wk vs. PL

Measures: binges/wk by diary, binge days/wk, categorical response

Endpoint: greater % abstinent vs. PL

Measures: binge days/wk by diary, abstinence (yes/no)

Behavioral/binge-related outcomesà

Mixed-model RMANOVA

Analysis§

1-year F/up: greater reduction in binge severity, restraint, and anxiety vs. CBT

Endpoint: greater reductions in weight and shape concerns, binge severity, and depression vs. CBT

Measures: BDI, BES, EDE-Q, STAI

Endpoint: greater reduction in global symptom severity, disinhibition, and hunger vs. PL

Over time: greater rate of reduction in global symptom severity, obsessions and compulsions, and disinhibition vs. PL

Measures: CGI-I, CGI-S, HDRS, TFEQ, YBOCS-BE

1-year F/up: no difference vs. CBT

Endpoint: greater reduction in BMI vs. CBT

Measures: BMI

Endpoint: greater reduction in weight and BMI and greater increase in ghrelin vs. PL; no differences in changes in other biomarkers vs. PL

Over time: greater rate of reduction in weight and BMI vs. PL

Measures: BMI, weight, ghrelin, glucose, insulin, leptin, lipids

Endpoint: greater percentage achieved [10 % weight loss vs. PL

Over time: greater rate of reduction in weight vs. PL

Endpoint: NR

Measures: BMI, weight

Over time: no difference in rate of reduction in depression or binge severity vs. PL

Biological/weight-related outcomes

Measures: BDI, BES

Psychological outcomes

Number with BED randomized (number completed)

b

bipolar disorder,

c

epilepsy,

d

migraine

à

All reported differences are statistically significant, p B 0.05

‘Over time’ denotes a time-trend analysis in which time is modeled as a continuous variable using repeated-measures random regression analysis, also known as mixed-model RMANOVA; ‘endpoint’ is a more conservative analysis based on RMANOVA and does not assume (or model) a trend in time. Both analyses include a time 9 treatment interaction; however, the time-trend analysis yields a measure of the difference in rate of change (slope with respect to time), whereas the endpoint analysis estimates the difference between groups in change from baseline to last observation/end-of-treatment (delta) (see McElroy et al. [80] for further explanation and references). If a study included both ITT and completer analyses, only ITT results (which are more conservative) are reported here

§

 

* Predominant mechanism(s) of action, although may have less potent effects on other neurotransmitter systems. Indications: a major depressive disorder,

BDI Beck Depression Inventory [138], BED binge eating disorder, BES Binge Eating Scale [139], BIS Barrat Impulsivity Scale [155], BMI body mass index, BP blood pressure, CBT cognitive behavioral therapy, CGI Clinical Global Impression (I improvement, S severity [142]), EDE Eating Disorders Examination [143], EDE-Q Eating Disorders Examination Questionnaire [144], EDI Eating Disorder ˚ sberg Depression Rating Inventory [145], EOC Emotional Overeating Questionnaire [156], F/up follow-up, HDRS Hamilton Depression Rating Scale [147], ITT intent-to-treat, MADRS Montgomery–A Scale [157], PL placebo, Na sodium, NR not reported, RMANOVA repeated measures analysis of variance, SCL-90-R symptom checklist-90-revised, SD Sheehan Disability Scale [158], STAI State-Trait Anxiety Inventory [152], TFEQ Three Factor Eating Questionnaire [153], WHR waist-hip ratio, wk week, YBOCS-BE Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [80, 154], YMRS Young Mania Rating Scale

24 wk

16 wk

Duration

Mechanism*

Drug (brand) and maximum dose (manufacturer)

Table 2 continued

K. A. Brownley et al.

360 mg/day (?CBTgsh) (Roche/ GlaxoSmithKline) [107]

Lipase inhibitorb

Orlistat (XenicalÒ/ alliÒ) PL ? CBTgsh

PL

11 wk

Phenethylamine/ amphetamine prodruga

Lisdexamfetamine dimesylate/ SPD489 (VyvanseÒ) 30, 50, and 70 mg/day (Shire) [77–79]

12 wk

PL

10 wk

s-NRIa

Atomoxetine (StratteraÒ) 120 mg/day (Lilly) [106]

Comparator

Duration

Mechanism*

Drug (brand) and maximum dose (manufacturer)

50 (39)

271 (213)

40 (25)



ITT

ANCOVA

Mixed-model RMANOVA

ITT

Mixed-model RMANOVA

Analysis§

3-month F/up: no difference in binge frequency or % abstinent vs. PL

Endpoint: no differences in reduction in binge frequency but greater % abstinent vs. PL

Measures: binges/ month, binge days/ month, abstinence

Endpoint: greater reduction in binge frequency in 50 and 70 mg/day, but not 30 mg/day vs. PL

Endpoint: greater reductions in binge frequency (episodes and days) and greater % abstinent vs. PL Measures: binge days/ wk

Over time: greater rate of reduction in binge frequency (episodes and days) vs. PL

Measures: binges/wk by diary, binge days/ wk, categorical response

Behavioral/bingerelated outcomesà

Table 3 Summary of randomized controlled trials of other medications for binge eating disorder

Endpoint: greater percentage achieving C5 % weight loss vs. PL 3-month F/up: greater percentage sustaining C5 % weight loss vs. PL

3-month F/up: no differences in restraint; eating, shape, or weight concerns; depression; or self-esteem vs. PL

Measures: weight, BMI

Measures: NR

Endpoint: greater reductions in weight and BMI vs. PL

Over time: greater rate of reduction in weight and BMI vs. PL

Measures: BMI, weight

Biological/weight-related outcomes

Endpoint: no differences in restraint; eating, shape, or weight concerns; depression; or self-esteem vs. PL

Measures: BDI, EDE-Q, RSE

Endpoint: greater % with improvement in global symptoms, and greater reductions in YBOCSBE and TFEQ total scores, binge eating severity, in all 3 treatment groups vs. PL; greater reductions in impulsivity and SF-12 total score in 70 mg/day vs. PL

Measures: BES, BIS, CGI, HAM-A, MADRS, SF-12, TFEQ, YBOCSBE

Endpoint: greater reductions in obsessions and global symptom severity vs. PL

Over time: greater rate of reduction in obsessions, hunger, and global symptom severity vs. PL

Measures: CGI-I, CGI-S, HDRS, TFEQ, YBOCS-BE

Psychological outcomes

Pharmacological Management of BED

Lipase inhibitor

l-Opioid antagonistc,d

Orlistat (Xenical / alliÒ) 360 mg/day (?HC diet) (Roche/ GlaxoSmithKline) [109]

ALKS 33 10 mg/ day (Alkermes) [110]

b

Lipase inhibitorb

Orlistat (XenicalÒ/ alliÒ) 360 mg/day (?BWL) (Roche/ GlaxoSmithKline) [108]

Ò

Mechanism*

Drug (brand) and maximum dose (manufacturer)

Table 3 continued

6 wk

24 wk

16 wk

Duration

PL

PL ? HC diet

L

PL ? BW

Comparator

62 (42)

89 (71)

39 (35)



ITT

Mixed-model RMANOVA

ITT

ANCOVA

ITT

RMANOVA

Analysis§

Endpoint: no differences in binge frequency or % abstinent

Over time: no difference in rate of reduction in binge frequency (episodes or days) vs. PL

Measures: binge episodes/wk by diary, binge days/ wk, abstinence

Endpoint: no difference in binge frequency or % meeting DSM-IV criteria for BED

Measures: binge episodes/wk by diary

6-month F/up: NR

Endpoint: no differences in reduction in binge frequency or % abstinent vs. PL

Measures: binges in past 28 days, abstinence

Behavioral/bingerelated outcomesà

Over time: NR Endpoint: no differences in weight, BMI, or WC vs. PL

Endpoint: no differences in severity of symptoms, obsessions, compulsions, cognitive restraint, disinhibition, hunger, cravings, or depression vs. PL

Measures: weight, BMI, WC

Endpoint: greater % weight loss and lower waist and hip circumference, total fat mass, total cholesterol, diastolic BP and insulin vs. PL

Measures: weight, BMI, WC, leptin, insulin, glucose, lipids, BP, caloric intake

Over time: NR

Measures: BDI, CGI-S, FCI, TFEQ, YBOCS-BE

Endpoint: lower total eating disorder score, perfectionism, and interoceptive awareness vs. PL; no difference in % meeting DSM-IV criteria for GAD or MDD vs. PL

Measures: BDI, EDI, HADS, NHP

6-month F/up: NR

Endpoint: no differences in reduction in BMI vs. PL

6-month F/up: NR

Measures: weight, BMI

Endpoint: no differences in reduction in restraint; eating, shape, or weight concerns; or depression vs. PL

Biological/weight-related outcomes

Measures: S-BDI, S-EDE

Psychological outcomes

K. A. Brownley et al.

Mechanism*

GABA agonist/ glutamate antagonistc

GABAB receptor agoniste

Drug (brand) and maximum dose (manufacturer)

Acamprosate (CampralÒ) 2,997 mg/day (Merck) [111]

Baclofen (LioresalÒ) 60 mg/day

Table 3 continued

48 days

10 wk

Duration

PL (crossover design)

PL

Comparator

12 (7)

40 (24)



Completer

RMANOVA

ITT

Mixed-model RMANOVA

Analysis§

Endpoint: significant reductions in binge frequency and severity but differences vs. PL = NR

Measures: binge days and binge severity (0–5) by diary

Over time: no difference in rate of reduction in binge frequency (episodes or days) or time to abstinence vs. PL Endpoint: greater reduction in binge days/wk vs. PL; no difference in % abstinent

Measures: binge episodes/wk by diary, binge days/ wk, abstinence

Behavioral/bingerelated outcomesà

Endpoint: significant reduction in binge severity but difference vs. PL = NR; no difference in reduction in cravings and higher depression vs. PL

Endpoint: no difference in weight change vs. PL

Measures: weight

Endpoint: no differences in changes in weight, BMI or other biomarkers vs. PL

Endpoint: greater reduction in obsessions, cravings, and greater increases in mental health vs. PL

Measures: BDI, BES, FCI, HADS

Over time: no difference in rate of reduction in weight or BMI vs. PL

Measures: weight, insulin, glucose, cholesterol

Biological/weight-related outcomes

Over time: no difference in rate of reduction in symptom severity, obsessions, or compulsions vs. PL

Measures: CGI-S, FCI, MADRS, SF12, TFEQ, YBOCS-BE

Psychological outcomes

Pharmacological Management of BED

Dietary supplementf

Chromium picolinate (ChromaxÒ) 600 and 1,000 lg/day (Nutrition 21, LLC) [127] 24 wk

Duration

PL

Comparator

24 (19)



Sensitivity analysis: same results as primary analysis

Over time: no differences in rate of reduction in binge frequency vs. PL

Completer Sensitivity analyses excluding 1 outlier

Measures: binges in past 28 days

Behavioral/bingerelated outcomesà

Mixed-model RMANOVA

Analysis§

Sensitivity analysis: same results as primary analysis

Over time: greater rate of reduction in eating, shape, and weight concerns in 1,000 lg/day vs. PL; greater rate of reduction in weight concerns in 600 lg/day vs. PL

Measures: EDE-Q, QIDS-SR16

Psychological outcomes

Sensitivity analysis: greater rate of reduction in weight in 600 and 1,000 lg/day vs. PL

Over time: no differences in rate of reduction in weight vs. PL; greater rate of reduction in glucose in 600 and 1,000 lg/day vs. PL

Measures: weight, BMI, fasting glucose

Biological/weight-related outcomes

Number with BED randomized (number completed)

à

All reported differences are statistically significant, p B 0.05

‘Over time’ denotes a time-trend analysis in which time is modeled as a continuous variable using repeated-measures random regression analysis, also known as mixed-model RMANOVA; ‘endpoint’ is a more conservative analysis based on RMANOVA and does not assume (or model) a trend in time. Both analyses include a time 9 treatment interaction; however, the time-trend analysis yields a measure of the difference in rate of change (slope with respect to time), whereas the endpoint analysis estimates the difference between groups in change from baseline to last observation/end-of-treatment (delta) (see McElroy et al. [80] for further explanation and references). If a study included both ITT and completer analyses, only ITT results (which are more conservative) are reported here

§

 

* Predominant mechanism(s) of action, although may have less potent effects on other neurotransmitter systems. Indications: a attention deficit hyperactivity disorder, b weight loss, c alcohol dependence, d cocaine dependence, e substance dependence, f potentiates actions of insulin

ANCOVA analysis of covariance, BDI Beck Depression Inventory [138], BED binge eating disorder, BES Binge Eating Scale [139], BIS Barrat Impulsivity Scale [155], BMI body mass index, BP blood pressure, BWL behavioral weight loss, CBTgsh cognitive behavioral therapy using guided self-help, CGI clinical global impression (I improvement, S severity [142]), DSM-IV Diagnostic and Statistical Manual of Mental Disorders (4th edition), EDE-Q Eating Disorders Examination Questionnaire [144], EDI Eating Disorder Inventory [145], FCI Food Craving Inventory [43], F/up follow-up, GABA gamma-aminobutyric acid, GAD generalized anxiety disorder, HADS Hospital Anxiety and Depression scale [159], HAM-A Hamilton Anxiety Inventory ˚ sberg Depression Rating Scale [157], MDD major depressive disorder, [146], HC hypocaloric diet, HDRS Hamilton Depression Rating Scale [147], ITT intent-to-treat, MADRS Montgomery–A NHP Nottingham Health Profile questionnaire [160], NR not reported, PL placebo, QIDS-SR16 16-item Quick Inventory of Depression Symptomatology-Self Report [148], RMANOVA repeated measures analysis of variance, RSE Rosenberg Self-Esteem Scale [150], S-BDI Spanish-language version BDI [161], S-EDE Spanish-language version EDE-Q [162], SF-12 Outcomes Study 12-item Short-Form Health Survey [163], s-NRI selective norepinephrine reuptake inhibitor, TFEQ Three Factor Eating Questionnaire [153], WC waist circumference, wk weeks, YBOCS-BE Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [80, 154]

Mechanism*

Drug (brand) and maximum dose (manufacturer)

Table 3 continued

K. A. Brownley et al.

Pharmacological Management of BED

2014 and again in July 2014 we conducted a very targeted PubMed search (binge eating disorder AND RCT) in which we identified BED RCTs published since our 2011 search and hand-searched recent review articles on BED and searched ClinicalTrials.gov for currently registered, ongoing BED treatment trials. Thus, the searches conducted in 2011 and 2014 complemented but did not replicate or duplicate the search used for the 2006 review. In October 2014, a final search of ClinicalTrials.gov was conducted. For the purposes of this report, studies were excluded from review if they used medications no longer available in the USA; included patients with other eating disorders and failed to present the data separately by diagnosis; or, in the case of studies identified via ClinicalTrials.gov, had not yet posted findings.

5 Current State of the Science on Pharmacological Treatment for BED A total of 37 published pharmacotherapy trials for BED were identified, including 25 placebo-controlled trials and 13 head-to-head trials involving two or more active treatment arms (either another drug or a psychological/ behavioral comparator). Eight of these studies are not discussed further: seven [69–75] used drugs (d-fenfluramine, sibutramine, rimonabant) that are no longer available in the US market, and one [76] failed to present the results separately in BED and non-BED participants. Twelve additional trials were identified via ClinicalTrials.gov, but only three had posted data for review (NCT01291173 [77], NCT01718483 [78], and NCT01718509 [79]). All 32 of the included trials (reflecting 31 publications) are summarized in Tables 1 (antidepressant medications), 2 (anticonvulsant medications), and 3 (‘other’ medications). The primary goal of treatment in BED is to achieve a reduction in and ultimately cessation of binge eating (i.e., abstinence). Remission refers to the resolution of all diagnostically relevant symptoms such that the individual no longer meets threshold criteria for BED. Secondary goals include achieving and maintaining healthy weight and improving psychological well-being (e.g., reducing negative mood symptoms and overly intrusive shape and body concerns). In Tables 1, 2, and 3 the results are broadly summarized across three major outcome categories (behavioral, psychological, and biological) reflecting treatment effects on rate of change and overall change in binge eating frequency and severity, symptoms of depression and anxiety, eating-related psychopathology (e.g., shape and weight concerns, cognitive disinhibition, body image, etc.), and biomarkers of metabolic health (e.g., weight, glucose, etc.). The summaries describe time-trend (rate of change)

and endpoint findings according to the specific analytic strategy(s) used by each study. Binge abstinence and remission outcomes were not uniformly reported across studies, with many not reporting either outcome, some reporting remission but failing to define it, and others using the term ‘remission’ but clearly reporting ‘abstinence’. In the majority of studies (n = 16), the active treatment was an antidepressant (ten different drugs); other drug classes studied included anticonvulsants, an antiobesity drug, opioid and glutamate antagonists, GABA agonists, a CNS stimulant, and an essential mineral dietary supplement. 5.1 Antidepressants Five different selective serotonin reuptake inhibitors (SSRIs) have been studied over active treatment periods ranging from 6 to 52 weeks: these include citalopram (60 mg/day) [80], escitalopram (30 mg/day) [81], fluoxetine (80 mg/day) [82], fluoxetine (60 mg/day) [83–86], fluvoxamine (300 mg/day) [86–88], and sertraline (200 mg/day) [89, 90]. Other antidepressants studied in the treatment of BED include a serotonin–norepinephrine reuptake inhibitor (duloxetine 120 mg/day) [91], a norepinephrine–dopamine reuptake inhibitor (bupropion 300 mg/ day) [92], and two tricyclic antidepressants that predominantly inhibit norepinephrine reuptake (desipramine 300 mg/day) [93] and serotonin reuptake (imipramine 75 mg/day) [94]. 5.1.1 Selective Serotonin Reuptake Inhibitors Compared with placebo, citalopram [80], escitalopram [81], and sertraline [89, 90] were associated with a greater rate of reduction in binge frequency, clinician-rated symptom severity, and weight/body mass index (BMI), culminating in greater reductions in all three outcomes at end of treatment. The mean absolute weight loss that was associated with these agents ranged from *1 kg (escitalopram) [81] to *5.6 kg (sertraline) [90]. Citalopram was also associated with greater reductions in binge eatingrelated obsessions and compulsions [80]. In contrast, neither fluoxetine 60 mg/day for 16 weeks [84] nor fluoxetine 80 mg/day for 6 weeks [82] was superior to placebo in reducing binge frequency or achieving abstinence at end of treatment, and only the latter approach resulted in significantly greater weight loss than placebo (–3.3 vs. ?0.7 kg). In two separate head-to-head trials, fluoxetine was compared to sertraline over 24 weeks and to CBT over 16 weeks. The results indicated that fluoxetine 40–80 mg/ day was no different than sertraline 200 mg/day in improving binge behavior or any psychological or weightrelated outcomes [89], and that compared to CBT,

K. A. Brownley et al.

fluoxetine was superior in reducing anxiety but no different or inferior in reducing binge eating, weight, and eatingrelated psychopathology [84]. Four studies examined the augmentation effect of fluoxetine when paired with CBT [83–86]. In one study [83, 95], CBT ? fluoxetine was associated with significantly greater improvements in symptom severity than CBT alone, fluoxetine alone, and placebo after 16 weeks of treatment, but these effects did not persist at 2-year followup. A second study [84] produced slightly different results: after 16 weeks, CBT ? fluoxetine was associated with greater reductions in eating-related psychopathology, body dissatisfaction, and depression than fluoxetine alone and placebo, but not compared to CBT alone, and this general pattern of effects was sustained at 12-month follow-up [96]. Finally, findings were mixed in two longer augmentation trials, with CBT ? fluoxetine being superior to CBT alone in reducing BMI and eating-related psychopathology after 24 weeks [86] but not being superior to CBT alone or fluoxetine alone after 48 weeks [85]. Fluvoxamine 300 mg/day was evaluated in three independent studies with treatment duration ranging from 9 to 24 weeks. One study [88] reported a greater rate of reduction in binge frequency, symptom severity, and BMI, but after 9 weeks these trends did not manifest as significant end-of-treatment differences from placebo. Likewise, no differences in binge frequency or symptom severity measures were observed after 12 [87] or 24 [86] weeks of treatment compared to placebo. Mean weight loss, as reported in two [87, 88] of the three studies, was quite modest (–0.45 and –1.22 kg). On the basis of one study, fluvoxamine may be beneficial for reducing anxiety but appears to be inferior to CBT in reducing binge eating and weight [86]. On the other hand, fluvoxamine augmentation of CBT may be useful in the treatment of BED, as this combination therapy was more effective than CBT alone and more effective than CBT ? fluoxetine in reducing eating-related psychopathology [86]. Across studies evaluating efficacy of SSRIs, placebo response rates ranged from approximately 15 to 50 % and active treatment response rates ranged from approximately 22 to 50 %. In some studies, the high placebo response rate co-occurred with a disproportionately high rate of active treatment dropout (e.g., see Hudson et al. [88]), leading to disparate findings based on treatment completers and intent-to-treat analyses. None of the studies reported remission of BED as an outcome; six (of six reporting) found no difference in abstinence between active treatment and placebo. Given the vast majority of trial participants were overweight or obese, mean weight loss approached clinical significance ([5 % of total weight [97]) for sertraline but not for other SSRIs. The true significance of the weight loss observed in sertraline-treated patients is

difficult to interpret, however, in light of a corresponding mean weight loss of 2.4 kg observed in placebo-treated patients in that same study. 5.1.2 Mixed Norepinephrine Reuptake Inhibitors Compared with placebo, 12 weeks of duloxetine 120 mg/ day [91] was associated with more rapid rates of reduction in binge frequency and severity, depression, and weight; however, at end of treatment only the effect on depression was significant. Duloxetine-treated patients lost, on average, 2.8 kg (approximately 2 % total body weight). Bupropion 300 mg/day for 8 weeks was no more effective than placebo in reducing binge frequency or psychological symptoms, and it was associated with more rapid but overall clinically non-significant (\2 kg) weight loss [92]. 5.1.3 Tricyclic Antidepressants Desipramine and imipramine efficacy were evaluated in two placebo-controlled trials. Compared with placebo, imipramine was associated with significantly greater reductions in binge eating, weight, and symptoms of depression after 8 weeks of treatment and at 32-week follow-up [94]. Similarly, after 12 weeks of treatment, desipramine was associated with greater reductions in binge eating and eating-related psychopathology than placebo [93]. Mean weight loss was 2.2 kg in imipramine-treated patients and 3.5 kg in desipramine-treated patients, neither of which was significantly greater than placebo. Desipramine has also been studied in an augmentation design [98]. Using a stepped approach in which patients first underwent 3 months of CBT followed by either 6 months of weight loss therapy (WLT) alone or 6 months of WLT ? desipramine, there appeared to be no advantage of the combination approach over WLT alone. A numerically higher rate of abstinence at end of treatment with active treatment than with placebo was reported in both desipramine studies: 60 versus 15 % in the placebo-controlled trial [93] and 37 versus 19 % in the augmentation trial [98]. Abstinence was not reported in the imipramine trial and none of the trials reported on BED remission. 5.2 Antiepileptics Lamotrigine [99], topiramate [100–103], and zonisamide [104, 105] are primarily indicated for the treatment of seizure disorders; however, they are also used in the treatment of bipolar depression and obesity. In patients with BED, 16 weeks of treatment with topiramate 600 mg/ day [101] or zonisamide 600 mg/day [104], but not lamotrigine 400 mg/day [99], was more effective than placebo in reducing weight; approximate mean between-group

Pharmacological Management of BED

differences were -4.7, -3.8, and -1.4 kg, respectively. Likewise, topiramate and zonisamide, but not lamotrigine, were associated with a greater rate of reduction in binge frequency and in the severity of binge-related symptoms, including obsessions and compulsions. Only topiramate was superior to placebo in end-of-treatment abstinence rate (58 vs. 29 % [101]). Both topiramate and zonisamide have been studied as adjuncts to CBT. Despite no clear benefit at end of treatment, CBT ? zonisamide was superior to CBT alone in reducing binge eating, eating-related psychopathology, and anxiety at 1-year follow-up [105]. One study compared a complex treatment of topiramate ? sertraline ? CBT with sertraline ? CBT; unfortunately, the data were reported in such a way that the precise between-group effects were concealed [102]. 5.3 Other Drugs 5.3.1 Selective Norepinephrine Reuptake Inhibitor Atomoxetine is approved for the treatment of attention deficit hyperactivity disorder (ADHD) but, because of its weaker effects on serotonin and dopamine transport, has also been studied for its potential antidepressant/reward properties in other psychiatric conditions. Compared with placebo, 10 weeks of treatment with atomoxetine 120 mg/ day [106] was associated with a greater rate of reduction in binge frequency, psychological symptoms including bingerelated obsessions, and weight, and these early gains manifested as significant differences in these outcomes at end of treatment. Mean weight loss was 2.7 kg (2.5 % of baseline weight) in the group of patients treated with atomoxetine. Notably, a significantly greater percentage of patients achieved abstinence with atomoxetine (70 %) than with placebo (32 %). 5.3.2 Phenethylamine/Amphetamine Prodrug Lisdexamfetamine dimesylate (SPD489) is used to treat ADHD and is currently under investigation in several BED clinical trials, three of which have released data on ClinicalTrials.gov. Lisdexamfetamine dimesylate has been filed with the US FDA for approval as a treatment for BED. In the initial forced-dose titration study in adults aged 18–55 years (NCT01291173 [77]), participants were treated with 30, 50, or 70 mg/day of active drug or placebo for 11 weeks. Pair-wise comparisons suggested that SPD489 doses of 50 and 70 mg/day were superior to placebo in reducing binge eating frequency, all three doses were effective in reducing psychological symptoms, and 70 mg/ day was effective in reducing impulsivity and general physical and mental health complaints. These findings were

replicated and extended in subsequent studies focusing on patients with moderate to severe BED to include greater reductions in weight and binge eating-related obsessions and compulsions than placebo (NCT01718483 [78], NCT01718509 [79]). 5.3.3 Lipase Inhibitor The anti-obesity agent orlistat has been evaluated in three independent placebo-controlled studies, each employing a different co-treatment: 12 weeks of guided self-help CBT [107], 16 weeks of behavioral weight loss (BWL) therapy [108], and 24 weeks of hypocaloric (HC) diet [109]. Orlistat was associated with greater weight loss than placebo when paired with CBT and HC diet but not with BWL; mean percentage weight loss was 3.3, 7.9, and 2.8 % in groups treated with orlistat combined with CBT, HC diet, and BWL, respectively, compared with 1.6, 3.6, and 1.2 % in groups treated with CBT, HC diet, or BWL alone. There were no differences between treatment groups in end-ofstudy reductions in binge frequency, but orlistat ? CBT was associated with a greater percentage abstinence than CBT alone [107]. Likewise, there were few differences in psychological outcomes with the exception of greater reductions in total eating disorder symptoms, perfectionism, and interoceptive awareness in patients treated with orlistat ? HC diet compared with HC diet alone. 5.3.4 l-Opioid Antagonist ALKS 33 is indicated for the treatment of alcohol and cocaine dependence. On the basis of a single trial in 62 outpatients with BED, ALKS 33 does not appear to be effective in reducing binge frequency or weight [110]. The rate of abstinence did not differ between the ALKS 33treated (35 %) and the placebo-treated (53 %) groups. On the basis of this single trial, the fate of ALKS 33 is unclear; however, notably, it is not among Alkermes’ featured pipeline compounds (http://www.alkermes.com/Products). 5.3.5 GABA-receptor Agonist Acamprosate is a mixed GABA agonist/glutamate antagonist with demonstrated efficacy in the treatment of alcohol dependence. When compared with placebo over 10 weeks of treatment, acamprosate was associated with a greater reduction in binge days per week but no difference in achieving percentage abstinence (32 vs. 20 %, respectively) [111]; it also had no clear benefit in reducing weight or improving glucose regulation, but it was associated with significantly greater reductions in obsessions and cravings. Baclofen is a GABAB receptor agonist used to treat withdrawal symptoms and cravings in patients with substance

K. A. Brownley et al.

dependence. In one small placebo-controlled, double-blind, crossover study (n = 12), baclofen was associated with a small but statistically significant reduction in binge frequency compared with placebo [112]. In this study, binge frequency was determined on the basis of self-report diary data and not verified through a diagnostic interview or equivalent instrument; thus, results may not be representative of effects in individuals meeting diagnostic criteria for BED. Furthermore, no data on abstinence or BED remission were presented. 5.3.6 Insulin–Serotonin ‘Sensitizer’ Chromium is an essential mineral that directly enhances insulin [113, 114] and serotonergic [115, 116] activity and may also have downstream effects on dopaminergic signaling [117–121]. Chromium supplementation improved appetite and mood dysregulation in patients with atypical depression [122–125] and reduced hunger and cravings in overweight women [126]. In 24 overweight individuals with BED randomized to 6 months of active treatment versus placebo [127], chromium picolinate was associated with numerically, but not statistically significant, greater reductions in binge eating, weight, and symptoms of depression than placebo. The abstinence rate did not differ across treatment groups (Brownley unpublished data).

6 Limitations and Future Directions for Pharmacological Treatments for BED A 2008 meta-analysis based on a subset of studies reviewed here found statistically significant effects favoring drug versus placebo for reducing binge eating and weight [128]. Pooled analyses showed that 48.7 % of drugtreated patients and 28.5 % of placebo-treated patients achieved abstinence and that drug-treated patients lost, on average, 3.2 % body weight (approximately 3.5 kg more than placebo-treated patients), with anticonvulsants emerging as most effective for reducing the rate of ‘nonremission’ (*37 %) and weight (*4.6 kg). Additional placebo-controlled single-agent studies (n = 5) included in the current review indicated the abstinence rate ranged from 32 [111] to 56 % [91] for drug-treated patients and from 20 [111] to 75 % [99] for placebo-treated patients. One study reported no difference in weight gain with acamprosate (*0.3 kg) relative to placebo (*1.2 kg), and four studies reported modest weight loss with drug compared with placebo: duloxetine [ placebo (*2.5 kg), lamotrigine [ placebo (*1.33 kg), bupropion [ placebo (*1.25 kg), and ALKS 33 [ placebo (*0.07 kg). Therefore, the present review extends earlier findings indicating a wide range of binge eating and weight responses to

pharmacological treatment in patients with BED, and it highlights several short-comings in the literature that warrant further study. First, most studies reported beneficial changes in binge behavior; however, they used inconsistent windows of time for assessing binge abstinence (e.g., 2 weeks, 28 days), making cross-study comparisons difficult. In addition, in some cases the binge eating effect was observed early in treatment (expressed as a greater rate of reduction in the group receiving active drug) but was not sustained through end of treatment or follow-up; this was evident in studies of fluoxetine [82], fluvoxamine [88], duloxetine [91], and zonisamide [104] in which time trend analyses suggested an early advantage with active treatment but endpoint analyses indicated no benefit over placebo. Furthermore, in other cases the effect of treatment on binge response was selectively reported using one or the other but not both metrics. Thus, only tenuous conclusions can be drawn about the efficacy of fluoxetine for BED. Failure to achieve rapid reduction in binge frequency has been shown to predict poor outcome (non-abstinence) in BED patients treated with fluoxetine [129], orlistat [130], or CBT [131]. Therefore, future studies need to report both rate-of-change and endpoint results to further elucidate the clinical relevance of rapid response to pharmacological treatments for BED. This same argument can be made for examining weight outcomes in BED. Methodologically, several multiarmed studies failed to perform/report results of post hoc tests, making it impossible to identify specific treatment group differences [85, 86, 102]; in addition, outcomes were not stratified by initial BMI/metabolic status. These study design elements limit the capacity to examine the clinical significance of observed weight loss (which is generally acknowledged as 5 % for improving cardiometabolic health outcomes [97]) and to differentiate weight loss trajectories that may be beneficial from those that may be harmful. Moving forward, studies must avoid these pitfalls so that future meta-analytic techniques can take full advantage of all available datapoints and begin to empirically address concerns raised by some advocates of nonweight-focused interventions [65]. Second, most of the studies reviewed here included small sample sizes and were characterized by high rates of attrition and placebo response (up to 75 % achieving abstinence), which have been widely documented in this patient population [87, 99, 103, 132, 133]. Reasons for the high dropout in BED trials are not entirely clear but certainly include some participants’ inability to tolerate medication adverse effects (i.e., constipation, decreased libido/sexual dysfunction, gastrointestinal upset, and sedation). Reasons for high placebo response rates in BED trials are also not well-elucidated but may include nonspecific effects commonly observed in eating disorder

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treatment trials (e.g., shifts in behavior secondary to engaging in regular behavior monitoring, and psychological improvements secondary to initial self-disclosure of highly stigmatized behavior in a safe setting). Another significant limitation in the literature is that most of the evidence comes from single short-term studies with very limited follow-up periods, so findings cannot be viewed as definitive and cannot be extrapolated to longterm management of BED. Furthermore, the short followup periods have essentially rendered remission as a nonreportable outcome either by loosely defined DSM-5 standards (i.e., absence of binge eating for a ‘sustained period of time’) or the more strict definition of three consecutive months of abstinence. Larger trials that are designed with appropriate recruitment, retention, and statistical plans, and that include longer treatment and followup periods will be critical for moving this research forward. In future trials, it will also be important to report on abstinence from binge eating and remission from BED as outcomes and for these outcomes to be measured using a consistent metric and/or standardized method of measurement and analysis. Moving forward, it will also be important to gather additional information about treatment harms and costs so the relative sustainability of various treatment approaches can be considered. In behavioral intervention trials for BED, it has been noted that some individuals respond very quickly but others show a delayed response to treatment [130, 131]. Future studies that consider pharmacological switch and augmentation strategies for individuals who fail to adequately respond to behavioral treatment are warranted. These future studies should give consideration to atomoxetine and duloxetine, which have apparent efficacy as monotherapies but have been overlooked in augmentation studies thus far. The augmentation potential of complementary and alternative medicine approaches also warrant further examination in BED. We recently reported augmentation effects of chromium in depressed women treated with sertraline [134]. Thus, a logical next step would be an adequately powered trial of chromium supplementation alone and in combination with an SSRI in BED patients with co-morbid depression. On the horizon are several newly FDA-approved or pending-approval medications for long-term obesity treatment, including lorcaserin (BelviqÒ), phentermine/topiramate extended-release (QsymiaÒ), buproprion/naltrexone, and liraglutide. In particular, when taken as an adjunct to lifestyle modification, QsymiaÒ has shown considerable promise in helping patients achieve the clinical benchmark of 5 % weight loss [135]. Studies are warranted to evaluate the efficacy of these novel agents in BED patients with comorbid obesity, including highly vulnerable populations such as post-bariatric surgery patients who may be at

increased risk for developing disordered, binge-like eating behaviors that complicate the long-term success of surgery [21]. Lastly, given the predominance of white, young adult females in BED treatment trials to date, it is imperative that future trials include a broader age range of participants and over-sample among racial and ethnic minorities and men.

7 Conclusions Despite advances in the past decade, no drug has FDA approval for the treatment of BED. This void largely reflects the fact that the volume of studies examining any one particular drug is insufficient to derive definitive treatment recommendations. Encouraging findings have not been followed up with well-designed replication studies. Based on promising findings in a series of independent studies (albeit studies using different effective doses and treatment periods), the most reasonable choices for off-label use appear to be topiramate, sertraline, and lisdexamfetamine dimesylate because of consistent effects in reducing binge eating and weight. Based on single trials, the tricyclic antidepressants desipramine and imipramine and the SSRIs citalopram and escitalopram may also be worthy of consideration. Importantly, even in the most promising trials, significant numbers of treated patients experienced inadequate response. Therefore, there is little justification for medication as first-line monotherapy, but rather it should be considered as one component of a multi-pronged treatment strategy that includes psychotherapy, nutrition counseling, and other supportive services [136, 137]. In this regard, findings are mixed for augmenting CBT with medication, with some but not all studies supporting the use of fluvoxamine, fluoxetine, zonisamide, and orlistat. Further confirmatory studies are needed to demonstrate the efficacy of most medications and to inform best practices regarding comedication/psychological treatment for BED. Acknowledgments Drs. Brownley, Peat, and Bulik have received funding from the Agency for Healthcare Research and Quality (AHRQ) for conducting a systematic review of treatment and outcomes in binge eating disorder. None of these funds were used in the preparation of this manuscript. Dr. Bulik is a consultant and contract recipient for Shire Pharmaceuticals. Drs. Brownley and Peat have been consultants for Shire Pharmaceuticals. Dr. La Via reports no conflicts of interest.

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Pharmacological approaches to the management of binge eating disorder.

In the USA, binge eating disorder (BED) is the most common eating disorder, with a lifetime prevalence of ~3.5 % in adult women, 2.0 % in adult men, a...
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