Mental health

REVIEW

Emerging Treatments in Eating Disorders

Michael Lutter1

Published online: 25 May 2017 # The American Society for Experimental NeuroTherapeutics, Inc. 2017

Abstract Eating disorders (EDs), including anorexia nervosa, bulimia nervosa, and binge-eating disorder, consti- tute a class of common and deadly psychiatric disorders. While numerous studies in humans highlight the important role of neurobiological alterations in the development of ED- related behaviors, the precise neural substrate that mediates this risk is unknown. Historically, pharmacological interven- tions have played a limited role in the treatment of eating disorders, typically providing symptomatic relief of comorbid psychiatric issues, like depression and anxiety, in support of the standard nutritional and psychological treatments. To date there are no Food and Drug Administration-approved medi- cations or procedures for anorexia nervosa, and only one Food and Drug Administration-approved medication each for bulimia nervosa (fluoxetine) and binge-eating disorder (lisdexamfetamine). While there is little primary interest in drug development for eating disorders, postmarket monitor- ing of medications and procedures approved for other indica- tions has identified several novel treatment options for pa- tients with eating disorders. In this review, I utilize searches of the PubMed and ClinicalTrials.gov databases to highlight emerging treatments in eating disorders.

Keywords Anorexia nervosa . Bulimia nervosa .

Binge-eating disorder . Treatment

Introduction

Eating disorder (ED) research is informed by, but distinct from, 2 mature fields of study: the neurobiology of feeding and psychopathology. In the first circumstance, the neurobio- logical basis of feeding and body weight homeostasis are well understood in preclinical models, such as rodents. However, rodent models are notoriously difficult to model psychosocial stressors, such as Western ideals of thinness, which promote the development of EDs. In the other circumstance, human clinical studies are well-suited to the study of psychological processes contributing to the development of EDs, but often- times lack the mechanistic insight necessary for the develop- ment of therapeutic interventions.

One alternative approach is to study the action of approved medications to gain mechanistic insight into potential thera- peutic targets. While no medications are Food and Drug Administration-approved for treatment of anorexia nervosa (AN), fluoxetine is approved for treatment of bulimia nervosa (BN) and lisdexamfetamine is approved for treatment of binge-eating disorder (BED). Preclinical studies have sug- gested that activation of serotonin-2C receptors on the mid- brain dopamine neurons by fluoxetine or the stimulant d- fenfluramine reduces episodes of binge-like eating in mice [1]. As lisdexamfetamine has similar psychopharmacological properties as d-fenfluramine, it does suggest that both fluoxe- tine and lisdexamfetamine may target the dopaminergic sys- tem as a common biological substrate, perhaps through mod- ulation of reward processing. Clinical studies testing this hy- pothesis have not yet been reported in humans and will be needed to confirm this hypothesis. Alternatively, several stud- ies have found that elevated rates of impulsivity and behav- ioral disinhibition contribute to binge-eating episodes in pa- tients with BN and BED [2–6]. Psychopharmacologic studies support a role for fluoxetine and lisdexamfetamine in treating

* Michael Lutter [email protected]

1 Eating Recovery Center of Dallas, 4716 Alliance Blvd. #400, Plano, TX 75093, USA

Neurotherapeutics (2017) 14:614–622 DOI 10.1007/s13311-017-0535-x

binge-eating episodes by reducing impulsivity and behavioral disinhibition in this population [7–11], suggesting another po- tential pathway to target in the treatment of EDs.

In the current review, I will try to bridge the knowledge gap between basic neuroscience research and clinical studies of disordered eating to highlight novel therapeutic strategies. Even though there are several treatments under evaluation for various of aspects of EDs (e.g., correcting bone loss in AN), this review will focus on weight restoration in AN and decreasing binge eating in BN and BED.

Experimental Procedures

Search Criteria

The PubMed (https://www.ncbi.nlm.nih.gov/pubmed) and ClinicalTrials.gov (https://clinicaltrials.gov/) databases were searched between 1 January 2017 and 8 March 2017. The search terms Banorexia nervosa treatment^, Bbulimia nervosa treatment^, and Bbinge-eating disorder treatment^ were utilized for the PubMed search, while Banorexia nervosa^, Bbulimia nervosa^, and Bbinge-eating disorder^ were used for ClinicalTrials.gov search. For the PubMed search, Banorexia nervosa treatment^ 7460 articles were identified, for Bbulimia nervosa treatment^ 3360 articles were identified, and for Bbinge-eating disorder^ 1860 articles were identified. Articles for Food and Drugs Administration-approved treatments and behavioral interventions were excluded from consideration. For the ClinicalTrials.gov search, 180 studies were identified for Banorexia nervosa^, 170 studies were identified for Bbulimia nervosa^, and 392 studies for Bbinge-eating disorder^ were identified. Studies without an inter- vention and studies in Bunknown^ or Bterminated^ status were excluded from consideration.

Weight Restoration in AN

Neuroendocrine

Starvation alters the levels of numerous circulating hormones. While most of these disturbances are corrected by refeeding, there has been interest in determining if pharmacologically targeting specific endocrine pathways could facilitate recov- ery from AN [12]. The Bhunger^ hormone, ghrelin, is one such candidate for the treatment of AN. Ghrelin is an acylated-peptide hormone synthesized in the enteroendocrine cells of the stomach [13], which is released by calorie restric- tion and stress to stimulate appetite and increase food intake [14, 15].

While ghrelin levels appear to be appropriately elevated in AN [16], several studies have found derangements in the reg- ulation of behavioral responses by ghrelin. Whereas high

circulating ghrelin levels are associated with activation of brain-reward regions measured by functional magnetic reso- nance imaging in a food-cue task, patients with AN displayed a negative relationship between ghrelin levels and brain acti- vation in response to high-calorie foods [17]. Furthermore, underweight patients with AN demonstrated progressively de- creased ghrelin levels after exposure to palatable food, where- as plasma ghrelin concentrations significantly increased after exposure to palatable food in healthy controls and weight- restored patients with AN, suggesting that dysregulation of ghrelin release may contribute to reduced motivation to con- sume palatable food in underweight patients with AN [18].

In a pilot study of female patients with restricting-type AN, intravenous ghrelin administration for 14 days increased cal- orie intake and decreased gastrointestinal (GI) complaints in 4 of 5 patients [19]. Intranasal administration of growth hormone-releasing peptide 2 (a ghrelin receptor agonist) 3 times daily before meals improved body weight and hypogly- cemia in a severely emaciated patient with AN [20]. Finally, RM-131, a novel ghrelin receptor agonist, is currently in clin- ical trials for treatment of AN [21].

Several other endocrine factors are also under investigation for treatment of AN. Oxytocin is a hypothalamic neuropeptide that regulates food intake and levels of oxytocin have long been known to be low in patients with AN [22, 23]. Polymorphisms in the oxytocin receptor gene and methylation of the oxytocin receptor gene have also been associated with disordered eating in several initial studies [24–26], suggesting a potential link between oxytocin signaling and the develop- ment of ED behaviors. While a preliminary study of intranasal oxytocin found that a single dose of oxytocin did not increase short-term calorie intake in patients with AN [27], other stud- ies report that intranasal administration of oxytocin altered attentional bias for fat shape and eating stimuli [28], and also decreased attentional vigilance to disgust in patients with AN [29], suggesting that it might have beneficial effects in other cognitive functions. Additionally, a clinical trial is currently underway to determine if intranasal oxytocin affects smell and food consumption in patients with AN [30]. Finally, androgen deficiency has been associated with hypometabolism of the brain and symptoms of depression, anxiety, and ED thoughts in women with AN [31, 32], and low-dose transdermal testos- terone has been shown to improve depressive symptoms, spa- tial cognition, and lean body mass in initial small studies [33, 34]. Currently, the effect of transdermal testosterone on body mass index in patients with AN is being investigated in a phase II clinical trial [35].

Neuromodulation

Recent advances in the field of neuromodulation now offer the hope of nonpharmacological treatment options for an array of mental illnesses, including EDs and associated diagnoses,

Emerging Treatments in Eating Disorders 615

such as major depression and anxiety disorders. Transcranial direct current stimulation (tDCS) is a method for directly mod- ulating the excitability of cortical regions using low-intensity electrical current. A pilot study of tDCS of the left dorsolateral prefrontal cortex (PFC) in 7 patients with AN found that the procedure was well tolerated and associated with a modest short-term benefits in 5 of 7 patients on eating scales, with a sixth patient reporting improvement in depressive symptoms without an effect on the eating scales [36]. These findings support a need for further studies on the potential efficacy of tDCS in AN; currently, 2 studies are registered as actively recruiting [37, 38].

Repetitive transcranial magnetic stimulation (rTMS) is an- other noninvasive approach that allows for stimulation or de- pression of selected cortical areas. Several initial studies have examined the efficacy of stimulation of the PFC by rTMS in the treatment of AN. A pilot study of 10 individuals with AN found that a single session of rTMS was well tolerated and improved feelings of fullness and anxiety [39]. A study of neuronavigated rTMS in 2 individuals with AN found that 19 to 20 sessions of high-frequency stimulation of the left dorsolateral PFC reduced ED symptomatology [40]. A study of 28 individuals with binge–purge subtype of AN or BN, reported that 20 to 30 sessions of high-frequency stimulation of the dorsomedial PFC resulted in reduced binge/purge be- haviors in 16 of 28 participants [41]. A study of 5 patients with treatment-resistant AN found that 20 sessions of high- frequency stimulation of the left dorsolateral PFC resulted in significant improvement in eating pathology at 6-month fol- low in 3 of 5 patients [42]. Finally, a study of single-session stimulation of the left dorsolateral PFC in 60 patients with AN found a trend (p = 0.056) toward improvement in core ED symptoms [43], supporting the need for follow-up studies of multiple-session stimulation. Two studies are currently regis- tered for the study of rTMS in AN [44, 45].

In addition to tDCS and rTMS, which are noninvasive, deep brain stimulation (DBS) is another neuromodulatory technique currently under investigation in the treatment of AN. DBS allows for direct modulation of the neuronal activity of deep structures in the brain by neurosurgical implantation of electrodes. DBS is an established therapy for the treatment of refractory cases of movement disorders and obsessive– compulsive disorder (OCD). Given the shared neural circuitry of AN and OCD, some have hypothesized that DBS may be effective for the treatment of AN as well [46, 47]. Several studies have provided support for this hypothesis by reporting a potential role for DBS in the treatment of severe, enduring cases of AN. Stimulation of the nucleus accumbens by DBS in 4 patients with severe AN found an improvement in body weight restoration with body weight > 85% at last follow-up in all individuals [48]. A case report of a women with AN who received DBS of the ventral striatum for severe comorbid OCD found improvements in the ED pathology in addition

to reduction in OCD symptoms [49]. DBS of the subcallosal cingulate in 6 patients with severe, treatment-resistant AN found that 4 of 6 patients reported improvements in mood and anxiety symptoms and 3 of 6 patients reported improve- ments in body weight restoration and quality of life [50]. In the largest study to date, an open-label trial of 16 treatment- refractory patients with AN receiving DBS of the subcallosal cingulate found significant improvements in body mass index, depression, anxiety, and affective regulation at 1-year follow- up [51]. Currently, 3 clinical trials are underway to study the role of DBS in the treatment of AN [52–54].

Preclinical Models of Restricted Eating

While the risk of developing AN is highly heritable, the lack of genetically validated rodent models of voluntary food restric- tion have limited attempts to identify potential medications based on pathophysiology. Our group has recently identified the first 2 rare, highly penetrant genetic variants that increase the risk of developing an EDs [55]. Importantly, mice that are genetically manipulated to replicate the disease-associated hu- man variants display several behavioral phenotypes relevant to EDs, including decreased willingness to work for a high-fat diet after being fasted overnight [56, 57]. These mouse lines with impaired behavioral responses to a negative energy state are the first monogenic models of AN and offer a unique opportunity for screening of novel pharmaceutical compounds. Based upon a bioinformatic analysis of potential genetic pathways affected in these mouse models, we identified rosiglitazone as a poten- tial novel medication to treat symptoms of AN [58]. Of note, rosiglitazone has been associated with body weight gain when used to treat patients with diabetes mellitus and has also been studied as a potential treatment for major depression [59], which is frequently comorbid with AN. Esrra-null mice admin- istered rosiglitazone display increased food intake, body weight, and adipose tissue compared with vehicle-treated litter- mate mice (data not shown). While further behavioral and neu- robiological characterization of these mice is necessary before translational studies are initiated, it does demonstrate the poten- tial benefit of the approach (Tables 1 and 2).

Additional Approaches

Genetic variants in the epoxide hydrolase 2 gene have been associated with the risk of developing AN [60]. The epoxide hydrolase 2 protein catalyzes the conversion bioactive epox- ides on polyunsaturated fatty acids into corresponding diols and is important for a number of metabolic pathways, includ- ing cholesterol synthesis [61], suggesting that omega-6 fatty- acid supplementation may affect the clinical course of AN [62]. Several other diverse approaches are also currently under consideration as well, including cannabinoid receptor signal- ing [63, 64], probiotics [65], and fish oil [66].

616 Lutter

Binge Eating in BN and BED

Neuroendocrine

While not all patients with BN and BED are over- weight, efforts to find new treatments for obesity have

contributed to the understanding of appetite regulation with important implications for binge eating. One par- ticularly important area of research is in satiety hor- mones, which are secreted by the GI tract in response to nutrients to help terminate meals. Since impairments in satiety have been associated with overeating in

Table 1 Synopsis of emerging treatments for weight restoration in Anorexia Nervosa

Intervention Classification Proposed mechanism of action Supporting evidence

RM-131 Gut neuroendocine Appetite stimulating ghrelin receptor agonist Successful Phase II clinical trials proof-of-concept trial on 22 patients with AN

Oxytocin Pituitary hormone Affects social and feeding behaviors Changes in attention to food/shape stimuli, clinical trial on-going

Testorterone Sex hormone Corrects hypometabolism in brain of underweight patients

Increases lean body mass in two RCTs

tDCS Neuromodulation Modulates excitation of cortical regions Improvement in eating and depressive symptoms in 5/7 patients

rTMS Neuromodulation Stimulation or depression of cortical regions Improvement in eating symptoms in 4 case series, trend toward benefit in 1 RCT

DBS Neuromodulation Stimulation of subcallosal cingulate Several case series, one open-label trial of 16 patients

Rosiglitazone PPARg-agonist Increases mitochondrial biogenesis in brain Increases food intake and body weight in one rodent model of restriction

Omega-6 fatty acids Nutraceutical Reduction in inflammation Clinical study on-going

Cannabinoid signaling Neurotransmission Stimulate appetite, reduce inflammation Clinical study on-going

Lactobacillus reuteri Probiotic Normalizes bowel flora, improves gut function Clinical study on-going

Abbrevations: tDCS transcranial direct current stimulation, rTMS repetitive transcranial magnetic stimulation, DBS deep brain stimulation, PPARg peroxisome proliferator-activated receptor gamma, RTC randomized controlled trial

Table 2 Synopsis of emerging treatments for binge-eating episodes in Bulimia Nervosa and Binge-Eating Disorder

Intervention Classification Proposed mechanism of action Supporting evidence

CCK Gut neurohormone Increases satiety Reduced post-prandial levels in BN, clinical study of CCK receptor agonist on-going

GLP-1 Gut neurohormone Increases satiety Reduced post-prandial levels in BN, liraglutide FDA-approved for weight loss, clinical study on-going in BN and BED

PYY Gut neurohormone Increases satiety Reduced post-prandial levels in BN

Topiramate Antiepileptic Suppresses appetite Mono-therapy associated with weight loss in obesity, combination with phenteramine reduced binge-eating in a case series, clinical study on-going

Zonisamide Antiepileptic Suppresses appetite Reduces binge-eating in BED in 1 RTC and in BN in 1 open-label pilot study

Naltrexone, nalmefene Mu-opioid antagonist

Suppresses appetite Naltrexone-bupropion combination FDA approved for weight loss, nalmefene improves BED in a case report, clinical studies on-going

tDCS Neuromodulation Modulates excitation of cortical regions Positive effects 1 case series in BED and 1 RCT in BN

rTMS Neuromodulation Stimulation or depression of cortical regions Positive effects in 4 small studies, 1 failed RCT in BN

Lorcaserin Neurotransmission Agonist of serotonin 2C receptor FDA approved for weight loss, reduces binge-episodes in mouse model of binge-eating

Erythromycin Antibiotic Prokinetic agent Clinical study on-going

Memantine Neurotransmission Modulates signaling on NMDA receptor Clinical study on-going

Baclofen Neurotransmission GABA-B receptor agonist Clinical study on-going

Abbreviations: CCK cholecystokinin, GLP-1- glucagon-like peptide 1, PYYpolypeptide YY, tDCS transcranial direct current stimulation, rTMS repetitive transcranial magnetic stimulation, RTC randomized controlled trial

Emerging Treatments in Eating Disorders 617

clinical populations, targeting satiety responses may rep- resent a new target for treatment of binge-eating.

While numerous satiety hormones have been identified, most research has focused on cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and polypeptide YY (PYY) [67]. CCK is released by L cells of the intestine in response to lipids and proteins, and CCK has numerous post- prandial functions, including decreasing appetite, slowing gastric emptying, and increasing gall bladder stimulation [68]. Postprandial levels of CCK have been reported to be blunted in patients with BN [69, 70]. One clinical study is currently investigating the role of novel CCK receptor agonist in BN [71].

GLP-1 is a cleavage product of the glucagon gene and is secreted primarily by the enteroendocrine L cells of the intes- tines in response to many nutrients, including monosaccha- rides, peptides and amino acids, and fatty acids [72]. GLP-1 has numerous functions, including slowing of gastric empty- ing, increasing insulin release, and suppressing appetite. Pharmacologic agonists of GLP-1 receptor signaling have been approved for the treatment of diabetes and, more recent- ly, chronic weight management [73]. Several studies have reported blunted postprandial levels of GLP-1 in patients with BN [74, 75], although it is unclear if these differences directly contribute to the development of disordered eating or are a consequence of it. One study is currently registered to exam- ine the potential benefits of the GLP-1 agonist liraglutide on binge eating in BN and BED [76].

PYY is also synthesized by enteroendocrine L cells in the intestine in response to multiple nutrients and has similar ef- fects on reducing GI track motility, increasing insulin secre- tion, and suppressing appetite [77]. Several studies have ex- amined the PYY levels in patients with EDs with mixed re- sults. Some studies have found a blunted increase in PYY levels after test meals in patients with BN [78–80], while no difference in PYY levels were observed in female patients with BED [81]. Furthermore, there was a negative correlation between postprandial PYY levels and binge frequency in women [80], although it is again unclear if altered PYY levels contribute to the development of disordered eating behaviors or are a consequence of it. While several clinical trials are investigating the use of intranasal PYY in the treatment of obesity, no trials are currently registered to examine PYY agonists in the treatment of EDs.

Antiepileptic Drugs

Several medications originally developed for the treatment of seizures have been found to affect body weight. Topiramate modulates the activity glutamate and γ-aminobutryic acid re- ceptors and voltage-dependent sodium channels, although the precise mechanism by which it causes weight loss is not well understood [82]. While topiramate alone promotes weight loss

in patients with metabolic disorders, such as type 2 diabetes, it was associated with a significantly increased risk of serious adverse events, including liver failure, serious injuries or falls, kidney stones, and viral infection with leukopenia, making it less appealing as a monotherapy for treatment of obesity [83]. More recently an extended release formulation of topiramate and the stimulant phentermine has been approved for the treat- ment of obesity primarily through appetite suppression [84]. A small study found that the topiramate/phentermine combina- tion reduced binge-eating in 2 patients with BED, supporting a need for larger studies [85]. One study is currently testing topiramate/phenteramine in the treatment of BED and BN (NCT02553824). In addition to topiramate, another antiepi- leptic drug, zonisamide, has been associated with weight loss in clinical populations [86]. Furthermore, 2 small trials of zonisamide in patients with BED with obesity [87] and with BN [88] found significant reductions in ED behaviors, al- though the discontinuation rate was very high in both studies. No current clinical trials are registered for zonisamide in BED or BN.

Opioid Antagonists

While inhibition of mu-opioid receptor signaling has long been known to decrease Bhedonic^ feeding in rodents [89], most clinical trials attempting to use the mu-opioid antagonist naltrexone in the treatment of obesity and binge eating have been disappointing [90–92]. However, in recent years the use of naltrexone as part of combination therapies has been more widely investigated as researchers have come to appreciate redundancies in feeding systems [93]. One such combination, naltrexone with the antidepressant bupropion, has been ap- proved for the treatment of obesity demonstrating a 3% to 7% decrease in body weight primarily through a reduction in calorie intake [94]. As depression is frequently comorbid with BED, the naltrexone–bupropion combination is especially at- tractive to clinicians hoping to minimize polypharmacy in their patients. Additionally, other formulations of opioid an- tagonists, including intranasal naloxone and nalmefene, have shown some beneficial effects in BED [95, 96]. Currently, 1 clinical trial is actively investigating the efficacy of naltrex- one–bupropion in BED [97] and 1 trial examining intranasal naloxone in BED [98].

Neuromodulation

Similar to AN, several research groups are currently investing nonpharmacological approaches to the treatment of binge eat- ing. A recent study found that a single session of tDCS of the dorsolateral PFC reduced urges to binge in 39 patients with BN [99], while a similarly designed study reported reduction in urges to binge in 30 patients with BED [100]. Several pre- liminary studies of women with BN suggested that rTMS of

618 Lutter

the left dorsolateral PFC [101–103] and dorsomedial PFC [104] reduced food cravings, but a randomized double- blinded study of 47 women with BN found no clinical benefit of rTMS to the left dorsolateral PFC [105].

Several registered clinical trials are currently following up on the potential for neuromodulation to treat BED. One group investigating low-frequency (1 Hz) rTMS of the dorsomedial PFC is also studying high frequency (20 Hz) stimulation of the dorsomedial PFC in BN [106]. A separate study is investigat- ing 1-session 10-Hz stimulation of the dorsolateral PFC in BN [107]. Another group is measuring the effect of 10-Hz stimu- lation of the dorsolateral PFC on binge-eating episodes in patients with BED [108]. Direct current stimulation of the PFC is also currently under investigation in the treatment of BN and BED [109].

Preclinical Models of Binge-Like Eating

At present there are no monogenic models of BED as no specific genomic variants have been linked to the risk of de- veloping BN or BED. However, there are behavioral models that are useful as preclinical models of binge-like eating. One model that has been particularly informative involves repeti- tive limited access to palatable food, such as high-fat food, that produces binge-like bouts of eating (up to 50% of the daily calorie intake within 2 h) in both rats and mice [110, 111]. One important feature of this model is that it does not require forced calorie restriction or stress to induce the binge- like episodes. This model has identified several potential nov- el therapies, including DBS of the nucleus accumbens [112, 113], the serotonin 2C receptor agonist lorcaserin [105], and the nociceptin receptor antagonist LY2940094 [114].

Additional Approaches

Erythromycin, used for its nonantibiotic effect to stimulate GI motility in patients, is currently being investigated in patients with BN to determine if it reduces binge/purge frequency [115]. Memantine, which modulates the glutamatergic N- methyl-D-aspartate receptor, is being tested for efficacy in reducing binge/frequency and body dysmorphia in patients with BN [116]. Finally, a clinical trial is testing the potential of the γ-aminobutryic acid-B receptor agonist baclofen to de- crease binge frequency in BN and BED [117].

Conclusions

While EDs have historically been under studied relative to their burden on society, new insights from related fields have identified several potential therapeutic interventions. Research from the field of feeding and body weight homeostasis has found several endocrine factors that that can stimulate (e.g.,

ghrelin) or suppress (e.g., GLP-1, PYY) appetite. These fac- tors are now being tested for the treatment of restricted and binge eating, respectively. Central nervous system drugs orig- inally approved for other indications, such as antiepileptic drugs and opioid antagonists, may reduce binge-eating epi- sodes. Neuromodulation techniques developed for treatment of mood and anxiety disorders show promising results as an adjunctive treatment for AN, BN, and BED. Finally, the ex- plosion in genetic research has led to novel rodent models of ED-like behaviors that allow for rapid preclinical screening of compounds. It is now incumbent upon funding agencies to evaluate rigorously the efficacy of these emerging therapies.

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