Drug therapy for patients with eating disorders

The purpose of this article is to review the psychopharmacology treatment literature for patients with eating disorders including bulimia nervosa, anorexia nervosa and binge eating disorder. The best-developed treatment literature concerns bulimia nervosa, which has been studied now in several dozen pharmacological treatment studies. The agents most commonly used are the antidepressants, with particular focus on the selective serotonin reuptake inhibitors including fluoxetine hydrochloride. These agents clearly impact significantly on the frequency of abnormal eating behaviors such as binge eating and purging. However, subjects treated with these drugs rarely achieve remission. Pharmacotherapy of anorexia nervosa has also traditionally focused on the use of antidepressants and there is some evidence that the use of SSRIs may help in preventing relapse in weight restored patients. Recently interest has developed in the use of atypical neuroleptics to help with the obsessionality and resistance to treatment frequently seen in low weight patients, the most commonly employed agent being olanzapine. Pharmacotherapy of binge-eating disorder is now being intensively investigated. In general medication alone seems inferior to psychotherapy in the short term. Antidepressants can increase the amount of weight loss when combined with psychological treatment and also appear to benefit symptoms such as depression. Further data are needed, but a number of drugs appear promising.     

Evidence-based pharmacotherapy of eating disorders

The objective was to review scientific evidence for efficacy and safety of pharmacotherapy in adults or children with an eating disorder (ED). We conducted a computer search for all randomized controlled trials (RCTs) published between 1960 and May 2010 for treatment of anorexia nervosa (AN), bulimia nervosa (BN) or binge-eating disorder (BED). For drugs for which no RCT was found, open trials or case reports were retrieved. Clinically relevant RCTs in the treatment of AN have used atypical antipsychotics, selective serotonin reuptake inhibitors (SSRIs), and zinc supplementation. Olanzapine demonstrated an adjunctive effect for in-patient treatment of underweight AN patients, and fluoxetine helped prevent relapse in weight-restored AN patients in 1/2 studies. For treatment of BN, controlled studies have used SSRIs, other antidepressants, and mood stabilizers. In 9/11 studies, pharmacotherapy yielded a statistically significant although moderate reduction in binge/purge frequency, and some additional benefits. For BED, RCTs have been conducted using SSRIs and one serotonin norepinephrine reuptake inhibitor (SNRI), mood stabilizers, and anti-obesity medications. In 11/12 studies, there was a statistically significant albeit limited effect of medication. Meta-analyses on efficacy of pharmacotherapy for BN and BED support moderate effect sizes for medication, but generally low recovery rates. Treatment resistance is an inherent feature of AN, where treatment should focus on renourishment plus psychotherapy. For BN and BED, combined treatment with pharmacotherapy and cognitive behaviour therapy has been more effective than either alone. Data on the long-term efficacy of pharmacotherapy for EDs are scarce. Short- and long-term pharmacotherapy of EDs still remains a challenge for the clinician.     

Current pharmacotherapy options for bulimia nervosa and binge eating disorder

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

Dysregulation of brain reward systems in eating disorders: neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa

Food intake is mediated, in part, through brain pathways for motivation and reinforcement. Dysregulation of these pathways may underlay some of the behaviors exhibited by patients with eating disorders. Research using animal models of eating disorders has greatly contributed to the detailed study of potential brain mechanisms that many underlie the causes or consequences of aberrant eating behaviors. This review focuses on neurochemical evidence of reward-related brain dysfunctions obtained through animal models of binge eating, bulimia nervosa, or anorexia nervosa. The findings suggest that alterations in dopamine (DA), acetylcholine (ACh) and opioid systems in reward-related brain areas occur in response to binge eating of palatable foods. Moreover, animal models of bulimia nervosa suggest that while bingeing on palatable food releases DA, purging attenuates the release of ACh that might otherwise signal satiety. Animal models of anorexia nervosa suggest that restricted access to food enhances the reinforcing effects of DA when the animal does eat. The activity-based anorexia model suggests alterations in mesolimbic DA and serotonin occur as a result of restricted eating coupled with excessive wheel running. These findings with animal models complement data obtained through neuroimaging and pharmacotherapy studies of clinical populations. Information on the neurochemical consequences of the behaviors associated with these eating disorders will be useful in understanding these complex disorders and may inform future therapeutic approaches, as discussed here. This article is part of a Special Issue entitled 'Central Control of Food Intake'.     

Addictive behavior disorders]

"Addiction" used to remind anyone of the use or abuse of chemical substances. In recent years, however, researchers and clinicians have begun to classify other excessive behaviors including gambling, eating shopping and self-injury into the addictive behavior. Above all, pathological gambling and bulimia nervosa patients often make trouble for psychiatrists and psychologists, not only for their family. On the other hand, the neural substrata underlying substance dependence have been revealed. Especially, it is implicated that the mesolimbic neuron plays a crucial role on the reward system. The recent studies suggest that reduced activation of the reward system might be related to the addictive behaviors such as pathological gambling, binge eating and sexual behavior. Further biological researches about the addictive behavior would help our deeper understanding of its disorders. As to the pharmacotherapy, many studies have demonstrated the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating the addictive behaviors.     

Current pharmacotherapy options for bulimia nervosa and binge eating disorder

Introduction: Growing evidence indicates binge eating, defined as the consumption of an abnormally large amount of food accompanied by a sense of loss of control, is an important public health problem. Although psychotherapy may be effective, not all patients respond adequately.

Areas covered: This article provides an overview of bulimia nervosa (BN) and binge eating disorder (BED), the two conditions characterized by recurrent binge eating as a core feature, and reviews studies of specific medications in treating patients with BN or BED, focusing on randomized controlled trials (RCTs).

Expert opinion: Although the evidence base is small, growing data indicate pharmacotherapy may be helpful for some patients with BN or BED. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are modestly effective for reducing binge eating over the short term in BN and BED. SSRIs may be modestly effective in BN over the long term. Topiramate has consistently been shown to decrease binge eating in BED and BN, but side effects may limit its usefulness. Single RCTs suggest zonisamide and atomoxetine may be effective in BED. Combination therapy may be required for optimal outcomes. It is not yet known whether the binge eating of BN and BED respond similarly to pharmacotherapy.     

Eating disorders: an overview of treatment responses and the potential impact of vulnerability genes and endophenotypes

Anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) are the three main eating disorders. Antidepressants, antipsychotics, anticonvulsants, prokinetic agents, opiate antagonists, appetite suppressants, tetrahydrocannabinol, cyproheptadine, zinc and ondansetron have been tested, and are frequently associated with psychological treatment. Selective serotonin reuptake inhibitors have a proven efficacy in BN and binge eating disorder. Other treatments, such as atypical antipsychotics in AN, anticonvulsants in BN and BED, and naltrexone and ondansetron in BN, may be promising, but lack the appropriate trials. The development of genetic researches in eating disorders may help the clinician to choose the most appropriate treatment in forthcoming years, using genetic polymorphisms of vulnerability genes, those linked to endophenotypes, or genes implicated in the metabolism of the drug treatment.     

Eating disorders: an overview of treatment responses and the potential impact of vulnerability genes and endophenotypes

Anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) are the three main eating disorders. Antidepressants, antipsychotics, anticonvulsants, prokinetic agents, opiate antagonists, appetite suppressants, tetrahydrocannabinol, cyproheptadine, zinc and ondansetron have been tested, and are frequently associated with psychological treatment. Selective serotonin reuptake inhibitors have a proven efficacy in BN and binge eating disorder. Other treatments, such as atypical antipsychotics in AN, anticonvulsants in BN and BED, and naltrexone and ondansetron in BN, may be promising, but lack the appropriate trials. The development of genetic researches in eating disorders may help the clinician to choose the most appropriate treatment in forthcoming years, using genetic polymorphisms of vulnerability genes, those linked to endophenotypes, or genes implicated in the metabolism of the drug treatment.     

Genetic Risk Factors in Eating Disorders

Eating disorders such as anorexia nervosa and bulimia nervosa involve complex and interacting mechanisms. Formal genetic studies suggest that there is a substantial genetic influence for these disorders. Animal models of eating disorders are scarce. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Most of the studies, including meta-analysis, have yielded negative results; only a single positive finding has been replicated independently. Recently, systematic genome-wide scans based on families with two or more individuals with an eating disorder (anorexia nervosa or bulimia nervosa) revealed initial linkage regions on chromosomes 1, 3, and 4 (anorexia nervosa) and 10p (bulimia nervosa). Fine mapping of one of these regions led to the identification of genes where an association with anorexia nervosa was detected. Currently treatment of patients with eating disorders can not rely on results of molecular genetic studies.     

Pharmacotherapy of bulimia nervosa and binge eating disorder

This paper reviews the use of medication in the treatment of bulimia nervosa and of binge eating disorder. There is now compelling evidence from double blind, placebo-controlled studies that antidepressant medication is useful in the treatment of bulimia nervosa. What is less clear is which patients are most likely to benefit from antidepressant medications and how to best sequence the various therapeutic interventions available. The utility of antidepressant medications in bulimia nervosa has led to their evaluation in binge eating disorder. The limited information currently available suggests that antidepressant treatment may be associated with a reduction in binge frequency in obese patients with binge eating disorder, but does not lead to weight reduction. Additional studies of the use of medication in the treatment of binge eating disorder and of the role of pharmacotherapy in the treatment of bulimia nervosa are needed.     

Decreased platelet monoamine oxidase activity in female bulimia nervosa.

The involvement of brain serotonin systems in the pathophysiology of eating disorders has been repeatedly demonstrated in recent studies. Platelet MAO activity is an index of brain serotonin activity and lowered platelet MAO levels have been found in association with impulsive behaviors. In addition, some preliminary reports indicate that platelet MAO could be lowered in eating disorder patients. Methods: 47 patients with DSM-IV eating disorders were studied, including 30 with bulimia nervosa and 17 with anorexia nervosa binge eating-purging type. Platelet MAO activity was measured by isotopic methods using C-14 benzylamine and compared with a control group of 30 healthy subjects. Impulsive personality features were studied with specific rating scales. Results: Platelet MAO activity was significantly lower (4.4+/-2.4 nmol/h/10(8) platelets) in the bulimic patients than in the control group (6.9+/-2.5) (p<0.001). No significant differences were found between pure bulimics and binge eating-purging anorectics. Platelet MAO was inversely and significantly correlated with scores on impulsivity scales and with borderline personality disorder characteristics. Conclusions: Platelet MAO activity is lowered in patients with bulimia, which may reflect dysfunction in impulse control mechanisms. Since platelet MAO has a predominant genetic component, there is need for studies on the association of low platelet MAO and higher risk for developing eating disorders.     

Emerging drugs for eating disorder treatment

Anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) comprise the currently recognised eating disorders. Although distinct diagnostic entities, they share certain forms of comorbid psychopathology, particularly anxiety and mood disorders. BN and BED have been studied most intensively as targets for pharmacotherapy. The list of drugs tested in eating disorders is substantial; however, the number of therapeutic classes of medications tested in these conditions is relatively modest. Antidepressant medications, including tricyclic antidepressants, selective serotonin re-uptake inhibitors, as well as some of the novel antidepressants, have shown evidence of some therapeutic value in both BN and BED. Their efficacy in AN, however, has been disappointing. The pharmacological options for AN are very limited. The number of controlled trials that have been conducted is small, and the research that has been successfully completed has generally failed to demonstrate medication efficacy. Patients with BN typically show reduced binge eating and purging frequency in medication trials, but rarely attain abstinence. In BED, patients often measure the value of their medication therapy by its ability to stimulate weight loss, which is another area on which future pharmacotherapy may improve. Novel pharmacological interventions are needed for each of these conditions. Peptide hormones are increasingly being evaluated for eating disorder treatment, including ghrelin agonists, neuropeptide Y1 and -5 antagonists, orexin receptor antagonists, corticotropin-releasing factor receptor 2 antagonists, histamine 3 antagonists, melanocortin 4 receptor antagonists, beta3-adrenoceptor agonists, 5-hydroxytryptamine-2A antagonists and growth hormone agonists. Although these compounds are in early phases of clinical testing for eating disorder treatments, data from these studies will be instructive in the quest for effective pharmacotherapy for these conditions. An overview of the current pharmacotherapy options for eating disorders is presented with a discussion of the emerging potential treatments.     

Pharmacological approaches in the treatment of binge eating disorder

Binge eating disorder (BED) is a newly defined diagnostic category characterized by recurrent episodes of binge eating not followed by the inappropriate compensatory weight loss behaviors characteristic of bulimia nervosa. BED is usually associated with overweight or obesity and psychopathology. Pharmacotherapy may be a useful component of a multidimensional treatment approach. Although pharmacotherapy research in BED is still in its preliminary stages. some drugs have been shown to be promising agents. This paper reviews available pharmacological treatment studies of BED and related conditions. Currently, three main classes of drugs have been studied in double-blind, placebo controlled trials in BED: antidepressants, anti-obesity agents, and anticonvulsants. Serotonin selective reuptake inhibitors (SSRIs) are the best studied medications. Thus, fluoxetine, fluvoxamine, sertraline and citalopram have been shown to modestly but significantly reduce binge eating frequency and body weight in BED over the short term. More recently, the anti-obesity agent sibutramine and the anticonvulsant topiramate have been shown to significantly reduce binge eating behavior and body weight in BED associated with obesity. Special issues concerning current pharmacological trials and future research directions in this area are also discussed.     

Milnacipran in the treatment of bulimia nervosa: a report of 16 cases.

Controlled trials in patients with bulimia nervosa have demonstrated efficacy of antidepressant medications with serotonergic function (e.g. fluoxetine) as well as noradrenergic function (e.g. desipramine). Sixteen out-patients with bulimia nervosa according to DSM-IV criteria were treated in a drug surveillance with 100 mg of milnacipran, a specific serotonin and noradrenaline reuptake inhibitor (SNRI). Ten patients completed the 8-week observation period. The reasons for premature attrition were improvement in one patient (no. 12), a generalized exanthema in one patient (no. 7), severe nausea in one patient (no. 8) and non-compliance due to non-drug-related reasons in three patients (no. 1, 2, and 16). An intent-to-treat analysis exhibited a significant reduction in weekly binge eating and vomiting frequency from baseline to the end of treatment. Three patients stopped binge eating and purging completely during the last week of treatment. Furthermore, there was a concomitant decrease of depression ratings (HAMD, BDI). Our preliminary data give rise to the notion that milnacipran may be promising in the treatment of bulimia nervosa.     

Enhanced platelet serotonin 5-HT2A receptor binding in anorexia nervosa and bulimia nervosa.

Some evidence exists to suggest that serotonin 5-HT_2A receptor function is altered in anorexia nervosa and bulimia nervosa. In order to further investigate the 5-HT_2A receptor in eating disorders, platelet [³H]lysergic acid diethylamide ([³H]LSD) binding was studied in ten patients with anorexia nervosa, 23 patients with bulimia nervosa and 33 healthy controls. At admission, B_max for platelet [³H]LSD binding was significantly higher both in the anorexia nervosa group (30.6±4.2 fmol/mg protein; mean±S.D.) and in the bulimia nervosa group (30.8±7.6 fmol/mg protein) than in the control group (23.5 ±6.3 fmol/mg protein; p=0.01 and p=0.003, respectively). K_d was borderline significantly higher among anorexics (median 1.45 nM) and significantly higher among bulimics (median 1.66 nM) than among controls (median 0.95 nM; p=0.05 and 0.003, respectively). The Global Assessment of Functioning score and the body mass index were both significantly negatively correlated to K_d (r=−0.40; p=0.03 and r=−0.41 p=0.03, respectively), but not to B_max. The present study indicates that patients with anorexia nervosa as well as patients with bulimia nervosa have an enhanced 5-HT_2A receptor binding and provides further evidence for a serotonergic dysfunction in eating disorders.     

Candidate gene polymorphisms in eating disorders

Anorexia nervosa and bulimia nervosa are complex disorders characterized by disordered eating behaviour. Attitudes towards weight and shape as well as the perception of body shape are disturbed. A substantial genetic influence on these disorders has been suggested by formal genetic studies. Obsessive-compulsive behaviour, perfectionism and anxious personality traits seem to occur premorbidly in several patients. Disturbances of neurotransmitter, neuropeptide and neuroendocrine systems have been reported in acutely ill and followed-up patients. Hence, these systems might be involved in the etiology of these eating disorders.

Genetic studies on candidate genes have mainly focussed on the serotonergic system and on genes involved in body weight regulation. Up to now, polymorphisms and variations in various genes (e.g. genes for 5-HT receptors, leptin gene, melanocortin MC₄ receptor gene) have been assessed for association and transmission disequilibrium pertaining to anorexia nervosa and/or bulimia nervosa. Most of the studies yielded negative results. Four studies of a polymorphism (−1438 G/A) within the promoter of the 5-HT_2A gene (5-HT_2A) revealed an association of the A-allele to anorexia nervosa. However, three studies could not confirm this result. Furthermore, a meta-analysis did not support the positive association. Currently, combined efforts within the European Union will answer the question of whether or not the A-allele is involved in the predisposition to anorexia nervosa. A transmission disequilibrium test is being performed in about 300 trios consisting of a patient with anorexia nervosa and both parents. As candidate gene approaches did not unequivocally identify susceptibility genes (alleles) for anorexia nervosa or bulimia nervosa, systematic model-free genome-wide screenings should also be performed in order to identify currently unknown genes involved in eating disorders. This kind of approach has already been initiated for anorexia nervosa. Genetic research on eating disorders will hopefully lead to new pharmacological treatment strategies.     

Emerging drugs for eating disorder treatment

Anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) comprise the currently recognised eating disorders. Although distinct diagnostic entities, they share certain forms of comorbid psychopathology, particularly anxiety and mood disorders. BN and BED have been studied most intensively as targets for pharmacotherapy. The list of drugs tested in eating disorders is substantial; however, the number of therapeutic classes of medications tested in these conditions is relatively modest. Antidepressant medications, including tricyclic antidepressants, selective serotonin re-uptake inhibitors, as well as some of the novel antidepressants, have shown evidence of some therapeutic value in both BN and BED. Their efficacy in AN, however, has been disappointing. The pharmacological options for AN are very limited. The number of controlled trials that have been conducted is small, and the research that has been successfully completed has generally failed to demonstrate medication efficacy. Patients with BN typically show reduced binge eating and purging frequency in medication trials, but rarely attain abstinence. In BED, patients often measure the value of their medication therapy by its ability to stimulate weight loss, which is another area on which future pharmacotherapy may improve. Novel pharmacological interventions are needed for each of these conditions. Peptide hormones are increasingly being evaluated for eating disorder treatment, including ghrelin agonists, neuropeptide Y1 and -5 antagonists, orexin receptor antagonists, corticotropin-releasing factor receptor 2 antagonists, histamine 3 antagonists, melanocortin 4 receptor antagonists, β₃-adrenoceptor agonists, 5-hydroxytryptamine-2A antagonists and growth hormone agonists. Although these compounds are in early phases of clinical testing for eating disorder treatments, data from these studies will be instructive in the quest for effective pharmacotherapy for these conditions. An overview of the current pharmacotherapy options for eating disorders is presented with a discussion of the emerging potential treatments.     

Investigational drugs for eating disorders

The eating disorders anorexia nervosa, bulimia nervosa and binge eating disorder are common, significant public health problems which are treated with nutritional, psychotherapeutic and pharmacological interventions. A number of drugs (mostly antidepressant drugs) are currently used in their treatment to some benefit, but there is substantial room for improvement. A wide variety of compounds are listed as under investigation for the treatment of eating disorders. They have a diverse variety of mechanisms of action, reflecting the complex nature of the control of food intake. While none of these compounds are close to release at present, the diversity of mechanisms under study lend some optimism that more effective approaches will be identified.     

Investigational drugs for eating disorders

The eating disorders anorexia nervosa, bulimia nervosa and binge eating disorder are common, significant public health problems which are treated with nutritional, psychotherapeutic and pharmacological interventions. A number of drugs (mostly antidepressant drugs) are currently used in their treatment to some benefit, but there is substantial room for improvement. A wide variety of compounds are listed as under investigation for the treatment of eating disorders. They have a diverse variety of mechanisms of action, reflecting the complex nature of the control of food intake. While none of these compounds are close to release at present, the diversity of mechanisms under study lend some optimism that more effective approaches will be identified.     

Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.