Walter H. Kaye, MD

Eating disorders (ED) are associated with significant comorbid psychopathology and the most extensive medical complications of any psychiatric disorder. Disordered behaviors that present across diagnoses (eg, restriction, binge eating, compensatory behaviors) are linked with acute medical risks that often require careful medical monitoring and clinical intervention. Yet, individuals with EDs frequently express hesitancy towards recovery and have great difficulty controlling their ED symptoms.

EDs are typically chronic and follow a treatment-refractory trajectory. Existing research indicates that even the most effective evidence-based outpatient treatment yields recovery for only around one-half of patients.

 In our clinic, we often encounter patients like “Hayley,” “Georgia,” and “Michael” (see Case Vignettes) for whom outpatient treatment has been unsuccessful. Like many other eating disorder treatment programs, our program seeks to optimize recovery by providing more intensive treatment with stepped levels of care.

Hayley is a 24-year-old graduate student and a competitive runner who competes regularly. She has a diagnosis of anorexia nervosa, restricting type (AN-R), which developed when she was 20 after a period of binging. Two years ago, Hayley began working with a multidisciplinary outpatient team, but she has continued to lose weight. She attributes the weight loss to her unwillingness to eat the large amount of food it would take to offset the calories she burns while running and training. She initially presented to her primary care physician feeling weak then was admitted to an inpatient eating disorders unit for bradycardia. Upon discharge from the hospital she was referred to a partial hospitalization treatment program.

Most research explores the efficacy of treatment at the outpatient level; little is known about the comparative value of the higher levels of care for patients with EDs.

 However, these approaches are important alternatives for treatment-refractory EDs because they provide the more intensive treatment and meal support that many severely ill patients need.

 Common reasons for needing higher levels of care include substantial weight loss that might be life threatening; difficulty eating enough food to gain weight; severe binge/purge behaviors; incapacitating ED symptoms; comorbid substance abuse; and anxiety, depression, obsessive compulsive disorder, or suicidal intent.

It is not unusual that such behaviors result in medical instability with symptoms of cardiovascular compromise, electrolyte disturbances, or hypoglycemia. It is important to note that some individuals have a lack of insight about their behaviors or are not motivated to engage in treatment. Because of these factors, the mortality rate for anorexia nervosa and bulimia nervosa can be 5% or higher.

 Higher levels of care provide a structured and protective environment that can be essential for these serious, life-threatening disorders.

Georgia, aged 17 years, has bulimia nervosa (BN) with comorbid major depressive disorder, panic attacks, and a history of sexual trauma. She has been engaging in polysubstance abuse, including alcohol, marijuana, prescription painkillers, and cocaine, since the age of 12. She has been hospitalized several times for suicide attempts and accidental drug overdoses. She binges and purges daily and states that she is only able to reduce these behaviors when using substances. Her outpatient therapist feels overwhelmed by all of Georgia’s comorbidities and is not sure how to help her reduce these self-destructive behaviors, so she refers Georgia to a PHP program.

Higher levels of care for EDs include various types of programs, with different levels of intensity.

The treatment goals for EDs are similar and include:

• Interrupting binge, purge, and restrictive behaviors;

• Providing psychoeducation regarding regular eating;

Psychotherapy approaches among higher levels of care are typically informed by cognitive behavioral and dialectical behavioral therapies. Family-based treatment is often incorporated for children and adolescents. Patients might transition between levels of care due to variables such as symptom severity, medical status, motivational status, treatment history, and financial limitations.

There are several different levels of care from which to choose:

 is the highest level of care available. This setting can be in a medical hospital and is intended for patients with acute medical instability. Alternatively, this may be in a psychiatric hospital if there are severe behavioral symptoms. In either event, subspecialty medical and behavioral consultation are readily available, meals are supervised, and one-to-one monitoring is available.

 offer full-time treatment in a non-hospital setting. Patients receive multidisciplinary care that includes nutritional support, medication management, and individual and group therapy.

(PHP), or daytreatment, offer treatment in an outpatient setting approximately six to 10 hours a day, between three and seven days per week. Patients typically spend nights and sometimes weekends on their own, allowing them to practice the skills they are learning in social, occupational, and leisure settings outside of treatment.

 (IOPs) offer treatment approximately three hours a day, from three to five days per week. At both the PHP and IOP levels, patients receive meal support, group therapy, individual therapy, dietary sessions, and medication management.

Treatment efficacy for higher levels of care. 

Randomized controlled trials (RCTs) are necessary to avoid the confounding effects of psychopathology severity and evaluate the comparative efficacy of different levels of care. Since patients with more severe symptoms and greater functional impairment are more likely to present to higher levels of care than those with mild ED pathology (and milder ED pathology is associated with better outcomes), reliable findings are dependent on patients matched with controls based on symptom severity or random assignment to level of care.

Unfortunately, RCTs that compare different levels of care are limited given significant costs and ethical considerations related to randomizing acutely ill patients. As such, literature on higher levels of care treatment efficacy is scarce and consists largely of open trials assessing outcome at discharge. A 2015 review of PHP and residential programs identified that duration of treatment was similar between these levels of care, and all but one study reported improvements in outcomes (ie, body mass index [BMI], number of binge/purge episodes) at discharge.

There have been several, more recent naturalistic studies of higher levels of care treatment that also offer support for the effectiveness of care in most patients.

 However, less than half of the open trials identified in the review reported follow-up data after discharge.

 Moreover, follow-up completion rates tend to be low; the average rate of follow-up completion was 66% for PHP and 37% for residential. Although most of the studies reported that positive treatment outcomes at discharge were maintained or improved at follow-up, the missing data at follow-up make long-term results difficult to interpret.

As previously mentioned, the literature on treatment efficacy at higher levels of care is preliminary and consists largely of open trials. Within the context of these trials, researchers have begun to study the predictors of long-term recovery. However, more is known about predictors of recovery from EDs in general, regardless of type of treatment, and no study has looked at how predictors of successful outcome might differ depending on level of care received.

 conducted a metaanalysis of predictors of treatment outcome that included a large number of patients treated at a higher level of care. Their findings indicate that patients with higher BMI, fewer binge/purge behaviors, greater motivation to recover, lower depression, lower shape/weight concern, fewer comorbidities, better interpersonal functioning, and fewer familial problems at baseline had better outcomes both at end-of-treatment and follow-up. The most robust predictor of outcome at both end-of-treatment and follow-up was the meditational mechanism of greater early symptom change.

The literature consistently corroborates that early behavioral change predicts later symptom remission.

 Given that higher levels of care treatment settings typically involve meal supervision and more opportunities to quickly learn skills, these settings may be uniquely well-suited to facilitating early symptom change.

When determining the appropriate level of care, practitioners should consider practice guidelines published by reputable organizations as well as individual variables important in predicting treatment response. The American Psychiatric Association (APA), Royal Australian and New Zealand College of Psychiatrists (RANZCP), and National Institute of Clinical Excellence (NICE) published guidelines for ED treatment that outline factors to consider in making decisions regarding level of care.

Michael is a 12-year-old boy who has avoidant/restrictive food intake disorder (ARFID), generalized anxiety disorder, and panic attacks. He endorses fear of food contamination and reports eating the same foods at the same time every day to avoid illness and/or vomiting. Michael has seen outpatient providers over the past few years for low weight, stunted growth, and gastrointestinal complaints. He was recently admitted to an inpatient eating disorders unit for low weight. Following discharge, he was unable to maintain weight at the outpatient level due to food-related fears resulting in restricted intake. As such, he was readmitted to the inpatient unit; he was later referred to PHP for continued care.

The NICE and RANZCP guidelines recommend first seeking outpatient care and suggest transfering to higher levels of care if there is no improvement of symptoms. Alternatively, the APA advises consideration of various factors when making initial treatment recommendations (

). All guidelines clearly outline criteria for determining medical stability and recommend that patients who do meet these requirements be considered for admission to inpatient hospitalization (

). A recent update on the medical management of EDs offers a list of criteria that indicate medical instability in adolescents that deviates slightly from the APA recommendations.

The RANZCP and APA guidelines suggest that inpatient treatment may be needed if ED symptoms are uncontrolled and require 24-hour supervision. Inpatient care and partial hospitalization also are appropriate when there is significant risk of suicide or self-harm. The NICE and APA guidelines advise considering logistical issues concerning the geographic location of treatment; they recommend that patients first receive care at facilities close to their home. Research indicates that PHPs are more cost-effective than residential or inpatient treatment; therefore, financial factors are important considerations.

 Clinicians might also consider recent scientific developments related to variables that account for significant variance in treatment response.

As any clinician who works with patients who have EDs knows, there are, unfortunately, many patients who are treatment resistant in outpatient care. For patients like Hayley, Georgia, and Michael, specialized higher levels of care facilities can be a relief for the clinician and life-changing for the patient.

Hayley was able to achieve her ideal body weight with PHP and stepped down to IOP. She decided not to return to competitive sports before returning to her outpatient team. Georgia stopped using drugs and alcohol within the structure of PHP, participated in weekly family therapy, and learned skills for coping with emotional dysregulation. Michael restored his weight in PHP through repeated food exposures that helped him increase his food volume and variety and decrease his fears surrounding contamination.

For many of the complex, severely ill patients who present to treatment, intensive treatment with stepped levels of care can offer a cost-effective structure that promotes positive behavioral change.

Dr Anderson is Associate Clinical Professor Director of Training, Ms Simpson is Milieu Therapist, and
	Dr Kaye is Professor and Founder and Executive Director, Eating Disorders Program, Department of Psychiatry, University of California, San Diego, CA. The authors report no conflicts of interest concerning the subject matter of this article.

1. Lock J. An update on evidence-based psychosocial treatments for eating disorders in children and adolescents. 

2. Hay P, Bacalchuk J, Stefano S. Psychotherapy for bulimia nervosa and binging. 

3. Galsworthy-Francis L, Allan S. Cognitive behavioural therapy for anorexia nervosa: a systematic review. 

4. Friedman K, Ramirez A, Murray S, et al. A narrative review of outcome studies for residential and partial hospital-based treatment of eating disorders. 

5. Arcelus J, Mitchell A, Wales J, et al. Mortality rates in patients with anorexia nervosa and other eating disorders. 

6. Crow S, Petersen C, Swanson S, et al. Increased mortality in bulimia nervosa and other eating disorders. 

7. Yager J, Devlin M, Halmi K, et al. Guideline watch: practice guideline for the treatment of patients with eating disorders. 

8. Yager J, Devlin J, Halmi K, et al. Guideline watch (August 2012): practice guideline for the treatment of patients with eating disorders, 3rd Edition. 

9. Brown T, Cusack A, Anderson L, et al. Efficacy of a partial hospital programme for adults with eating disorders. 

10. Hayes N, Welty L, Slesinger N, et al. Moderators of treatment outcomes in a partial hospitalization and intensive outpatient program for eating disorders. 

11. Vall E, Wade T. Predictors of treatment outcome in individuals with eating disorders: A systematic review and meta-analysis. 

12. Nazar BP, Gregor LK, Albano G, et al. Early response to treatment in eating disorders: a systematic review and diagnostic test accuracy meta-analysis. 

13. Wales J, Brewin N, Cashmore R, et al. Predictors of positive treatment outcome in people with anorexia nervosa treated in specialized inpatient unit: the role of early response to treatment. 

14. Hay P, Chinn D, Forbes D, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of eating disorders. 

15. NICE. Core Interventions in the Treatment and Management of Anorexia Nervosa, Bulimia Nervosa and Related Eating Disorders (Clinical Guideline 9). London: National Collaborating Centre for Medical Health; 2004.

16. Golden N, Katzman D, Sawyer S, et al. Update on the medical management of eating disorders in adolescents. 

17. von Wietersheim J, Zeeck A, KÃ¼chenhoff J. Status, possibilities and limitations of therapies in psychosomatic day clinics. 

18. Williamson D, Thaw J, Varnado-Sullivan P. Cost-effectiveness analysis of a hospital-based cognitive-behavioral treatment program for eating disorders. 

19. Vall E, Wade T. Predictors of treatment outcome in individuals with eating disorders: A systematic review and meta-analysis. 

Articles

Eating disorders (ED) are associated with significant comorbid psychopathology and the most extensive medical complications of any psychiatric disorder.

Higher Levels of Care for Eating Disorders: A Practical Guide

Eating disorder behaviors can range from dangerous caloric restriction to eating that feels out of control-often combined with unhealthy weight control behaviors, such as self-induced vomiting or laxative abuse. Anorexia nervosa, bulimia nervosa, and binge eating disorder are the most prevalent eating disorders. Diagnostically, anorexia nervosa requires low body weight, intense fear of or behavior that interferes with weight gain, and disturbance in the perception of one’s weight or shape.

Criteria for bulimia nervosa include recurrent binge eating (eating a large amount of food in a discrete period of time accompanied by a sense of loss of control) and actions meant to counteract weight gain (eg, self-induced vomiting), as well as overvaluation of body weight or shape. Binge eating disorder involves recurrent binge eating without inappropriate compensatory behavior. Individuals with eating disorders frequently report extreme body dissatisfaction, anhedonia, anxiety, and difficulty tolerating negative emotions, although these are not required for diagnosis.

The cause of eating disorders remains unknown. Given that eating disorders reflect a discrepancy between the physiological need to eat and the drive to eat, it has been hypothesized that these individuals have a fundamental disturbance of appetite regulation. In recent years, advances in brain imaging have provided new insights into neural pathways that play a role in emotions, reward, salience, and inhibition of eating.

Mabel is a 16-year-old girl who is hospitalized with unstable vital signs and a BMI of 17.5. Her family describes her as an anxious, shy, and perfectionistic child who tended to ruminate about academics, social relationships and, more recently, food. Mabel says that she has always been a picky eater. She started to lose weight after she got braces and switched to softer foods 2 years ago. She reports that her food rules became progressively more restrictive and she began exercising regularly. She became increasingly anhedonic, cognitively rigid, and sensitive to perceived criticism. She interprets her family’s efforts to support her weight restoration efforts as “nagging” and judgmental.

Current treatments-psychotherapy or pharmacotherapy-often have limited efficacy in ameliorating eating disorder symptoms and may not fully normalize eating behavior. Furthermore, many psychological interventions used to treat eating disorders are adaptations of treatments for other psychiatric disorders (eg, depression, anxiety) and were not developed for the specific, unique needs of patients with eating disorders.

The lack of a mechanistic understanding of eating disorders has thwarted efforts to develop more powerful, evidence-based interventions. Alterations in brain circuitry linked to reward and inhibition in particular appear to be involved in the maladaptive eating behavior characteristic of anorexia nervosa, bulimia nervosa, and binge eating disorder.

What is it about the brains of those with eating disorders that might drive dysfunctional eating behavior? It is well known that gut and hypothalamic mechanisms contribute to the regulation of energy metabolism and eating behaviors. However, in recent years, studies in humans have revealed that higher-order, corticolimbic systems likely play a role in the pathophysiology of eating disorders.

 These systems integrate behavior with eating and can override homeostatic signals (

The first of these networks codes for perceived importance of a food stimulus and comprises the insula and anterior cingulate. The insula, along with the frontal operculum, also processes basic sensory information about food. The second pathway includes the nucleus accumbens, putamen, and caudate, as well as the orbitofrontal cortex and amygdala. These regions code for the rewarding and motivating value of eating and contribute to approach or avoidance behavior.

The third network helps control consumption based on consideration of both short- and long-term outcomes (eg, weight gain). It includes the dorsal caudate and dorsal anterior cingulate, lateral prefrontal cortex, and parietal cortex. These systems interactively weigh the reward value of food and the consequences of consuming it, and they integrate this information with homeostatic and motivational drives to guide eating behavior.

Mounting evidence suggests that an altered balance of reward and inhibition may contribute to disordered eating.

 In anorexia nervosa, severely restricted food intake appears to be related to overactive inhibitory control in combination with underactive reward circuitry. In contrast, dysregulation of both inhibitory and reward drives may manifest in the alternating over- and under-consumption characteristic of bulimia nervosa. Binge eating disorder may be related to altered sensitivity of ventral reward regions. Findings also suggest that these brain-based differences are linked to temperament traits, such as anxiety and harm avoidance, which persist after remission and may underlie the development of eating pathology.

The brain has different responses to the anticipation and consumption of food. People with binge eating-bulimia nervosa or binge eating disorder-demonstrate reduced response when anticipating food reward in the insula and ventral striatum, but increased response to the receipt of food in these same regions. Alternatively, individuals with anorexia nervosa demonstrate increased and anxious sweet-taste anticipation in the insula, striatum, and prefrontal cortex and reduced responses in the insula and striatum to the tastes themselves.

 Differences in the way the brains of individuals with current or past eating disorders anticipate and process food rewards likely drive their approach to food.

Processing of other salient stimuli also seems to be altered, which suggests a generalized deficit. In healthy individuals, the ventral striatum and dorsal caudate typically show greater responses to reward than to punishment. In contrast, imaging research in eating disorders demonstrates dysfunctional neural valuation of reward and punishment. For example, when making choices about monetary rewards, the brains of women with histories of anorexia nervosa or bulimia nervosa don’t differentiate between wins and losses in the ventral striatal regions.

 Women with remission of symptoms of anorexia nervosa also show reduced reward response to money (

 This suggests that individuals who have eating disorders may have difficulty evaluating rewards.

Individuals with eating disorders also have problems with inhibitory control. Individuals with bulimia nervosa and binge eating disorder frequently demonstrate reduced inhibition that extends beyond food (eg, substance use, shoplifting, self-injury). Neuroimaging studies suggest this may relate to failure to appropriately engage frontostriatal circuits that regulate behavior. Some functional MRI (fMRI) findings show that adults and adolescents with bulimia nervosa have reduced inhibitory activation.

 Other results have shown increased activation of frontostriatal regions in adolescents with binge-purge syndromes.

 Inefficient or insufficient activation in these control-related regions may clinically manifest as difficulty in stopping eating during binge episodes, as well as difficulty in resisting urges to purge.

Enhanced cognitive control in anorexia nervosa may contribute to an ability to restrict intake even when emaciated. Recent fMRI studies of individuals with anorexia nervosa reveal increased activity within dorsolateral cognitive circuitry associated with decision-making and inhibitory control (see 

 Although further research is needed, findings suggest that increased activation in control-related regions during the delay of gratification may underlie the extreme dietary restriction characteristic of anorexia nervosa.

Mabel explains that her difficulty with eating is driven by a lack of interest in food and increased anxiety about making meal choices. She reports that without a structured meal plan, she fasts to avoid the negative thoughts and mood that accompany eating. She also reports significant physical discomfort (eg, bloating) after eating a small amount of food. To avoid discomfort, when unsupervised, she typically eats only yogurt and small bites of fruit and vegetables in the evening. She is also quite anhedonic.

This case suggests both under- response to reward and over-control, despite extreme nutritional deprivation. It also suggests that external structure may be effective in helping Mabel restore weight.

Similarities to and differences from substance abuse

There are many similarities between substance abuse and eating disorders, particularly bulimia nervosa and binge eating disorder, including problems in the interconnected reward and inhibitory circuits. Meta-analyses suggest increased rates of drug and alcohol abuse in persons with bulimia nervosa. Women and adolescent girls with bulimia nervosa or binge eating disorder show deficient activation in brain regions related to inhibitory control similar to patterns of activation reported in drug and alcohol users.

 Moreover, the increased activation in response to food cues seen in bulimia nervosa and binge eating disorder mirrors increased activation in these regions in substance users exposed to drug-related cues.

 These similarities in brain activation may be related to underlying similarities in neurotransmitter activity: animal models of binge eating and human neuroimaging studies implicate similar neurotransmitters as those involved in substance use disorders, particularly those key to cognitive control, reward, and salience.

In contrast, rates of drug and alcohol abuse are decreased in patients with anorexia nervosa. Individuals with anorexia nervosa demonstrate opposite patterns of neural activation in response to reward compared with persons with bulimia nervosa, binge eating disorder, or substance abuse. The over-control of individuals with anorexia nervosa, particularly those with the restricting subtype, may protect them from developing dysregulated substance use disorders.

Some pharmacological treatments have shown success. Fluoxetine is currently considered the gold-standard medication for bulimia nervosa and is the only FDA-approved agent for the treatment of this disorder. Studies have shown greater amelioration of bulimia nervosa symptoms at higher dosages (60 mg/d), whether at the initiation of treatment or during rapid titration.

Lisdexamfetamine, an appetite-suppressing amphetamine, is the only medication that is FDA-approved specifically for treating binge eating disorder. Clinical trials indicate that it leads to the cessation of binge eating behavior in up to 50% of patients.

 However, 80% of persons treated with lisdexamfetamine report significant adverse effects, and there is a risk of abuse and dependence.

Results of pharmacological treatment studies for anorexia nervosa have been mixed despite frequent off-label use.

 Psychological and behavioral treatments are necessary to fully address the complex psychological and medical syndromes associated with eating disorders. Viewing eating pathology from the perspective of an altered balance in self-regulatory control and reward processing provides a foundation for developing more specific, effective interventions for these debilitating disorders.

Current treatments for eating disorders, particularly for chronic anorexia nervosa in adults, are inadequate. Randomized, controlled trials of cognitive and psychodynamic treatments suggest that neither differs from treatment as usual in promoting weight restoration, and many patients drop out of treatment before full weight restoration.

 Strategies that focus on brain-based differences are needed, in particular to treat adult anorexia nervosa.

Treatment of adolescent anorexia nervosa is more promising: considerable evidence supports the use of family-based treatment (FBT).

 FBT is a manualized form of eating disorder–focused family therapy in which parents are enlisted to ensure appropriate food intake and other health-oriented behaviors associated with recovery. Parent utilization addresses the motivational deficits inherent in anorexia nervosa. Despite the effectiveness of this treatment in younger patients, to date there have been no published results of clinical trials of FBT in adults. Adult anorexia nervosa treatment may be improved by enlisting caretakers to oversee recovery-oriented behaviors in a modified, age-appropriate manner.

Treatment of anorexia nervosa in adults may also be improved by directly targeting the brain-based temperament traits characteristic of the disorder. Imaging studies in adults who have anorexia nervosa have shown that differences in reward processing are linked to elevated anxiety or harm avoidance.

 Anxious temperament and harm avoidance are present before anorexia nervosa develops, and both tend to persist after symptom remission.

 The combination of increased anxiety in anticipation of food and diminished brain reward response to receiving it may be what makes it so difficult for people with anorexia nervosa to eat.

If clinicians can work with these traits rather than against them, treatment effectiveness may improve.

 For example, increasing predictability and structure around meals while maintaining caloric sufficiency can potentially help mitigate anticipatory anxiety and increase compliance with meals.

After discharge from the hospital, Mabel, her mother, and her sister begin taking part in a brief intensive family treatment program. They devise a contingency management plan (eg, behavioral contract) to establish a system of external rewards and consequences to reduce eating disorder behaviors. Mabel reports decreased anxiety about meals when she knows what to expect and expresses a desire to avoid the negative consequences of reduced time with friends that is built into her contract if she engages in eating disorder behavior.

Eating disorders are chronic and debilitating illnesses, and current treatments are ineffective for many patients. Neuroimaging research suggests eating disorder symptoms may result from dysfunction in circuits underlying reward and inhibition. The brain-based temperament traits of eating disorders are stable across illness and recovery. This suggests that treatments that work with these traits and target disturbances in inhibitory control, reward sensitivity, and salience may better address disease-specific mechanisms contributing to disordered eating-and may also enhance adherence and motivation, and thereby improve outcomes.

Dr Ely and Dr Berner are Postdoctoral Fellows, and Dr Wierenga is Associate Professor of Psychiatry at the University of California, San Diego. Dr Kaye is Professor and Program Director of the Eating Disorders Treatment and Research Program in the department of psychiatry at the University of California, San Diego. The authors report no conflicts of interest concerning the subject matter of this article.

 Wierenga CE, Ely A, Bischoff-Grethe A, et al. Are extremes of consumption in eating disorders related to an altered balance between reward and inhibition? 

 Oberndorfer TA, Frank GK, Simmons AN, et al. Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa. 

 Wagner A, Aizenstein H, Venkatraman VK, et al. Altered striatal response to reward in bulimia nervosa after recovery. 

 Wagner A, Aizenstein H, Venkatraman VK, et al. Altered reward processing in women recovered from anorexia nervosa. 

 Wierenga CE, Bischoff-Grethe A, Melrose AJ, et al. Hunger does not motivate reward in women remitted from anorexia nervosa. 

 Marsh R, Horga G, Wang Z, et al. An fMRI study of self-regulatory control and conflict resolution in adolescents with bulimia nervosa. 

 Lock J, Garrett A, Beenhakker J, Reiss A. Aberrant brain activation during a response inhibition task in adolescent eating disorder subtypes. 

 Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. 

 Kaye W, Wierenga C, Bailer U, et al. Does a shared neurobiology for foods and drugs of abuse contribute to extremes of food ingestion in anorexia. 

 Fluoxetine Bulimia Nervosa Collaborative Study Group. Fluoxetine in the treatment of bulimia nervosa: a multicenter, placebo-controlled, double-blind trial. 

 McElroy SL, Hudson JI, Mitchell JE, et al. Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder: a randomized clinical trial. 

 Aigner M, Treasure J, Kaye W, Kasper S. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of eating disorders. 

 Zipfel S, Wild B, Gross G, et al. Focal psychodynamic therapy, cognitive behaviour therapy, and optimised treatment as usual in outpatients with anorexia nervosa (ANTOP study): randomised controlled trial. 

 Lock J. An update on evidence-based psychosocial treatments for eating disorders in children and adolescents. 

 Frank GK, Bailer UF, Henry S, et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride. 

 Kaye WH, Bulik CM, Thornton L, et al. Comorbidity of anxiety disorders with anorexia and bulimia nervosa. 

 Steinglass J, Sysko R, Mayer L, et al. Pre-meal anxiety and food intake in anorexia nervosa. 

 Kaye WH, Wierenga CE, Knatz S, et al. Temperament-based treatment for anorexia nervosa. 

 Craig QA. How do you feel-now? The anterior insula and human awareness. 

 Haber SN, Knutson SD, Paulus MP. The reward circuit: linking primate anatomy and human imaging. 

 Wittmann M, Lovero KL, Lane SD, Paulus MD. Now or later? Striatum and insula activation to immediate versus delayed rewards. 

New insights into neural pathways that play a role in anorexia nervosa, bulimia nervosa, and binge eating disorder.

Neurobiology of Eating Disorders: Clinical Implications

Anorexia nervosa (AN) is a disorder with no proven treatment that is effective in reversing core symptoms, and it may have the highest mortality rate of any psychiatric illness. It is a very difficult disorder to treat, in part, because those with AN often lack motivation to engage in treatment. Many people in today’s society diet frequently and want to lose weight, but very few develop AN. Considerable evidence suggests that heritability contributes to the development of an eating disorder. It may be that genes code for certain temperament traits in childhood, such as perfectionism, anxiety, obsessiveness, that create a susceptibility for the development of AN during adolescence.

Recent studies offer new understanding of alterations of neural circuitry that may contribute to development of AN. In particular, findings from these studies suggest how individuals with AN can severely restrict their caloric intake for years. In contrast, most people have difficulty adhering to a diet for a long period of time, and experience a high rate of recidivism after they lose weight. How are individuals with AN able to ignore signals regarding hunger that otherwise motivate eating, even when they are severely emaciated?

Understanding such questions may lead to the development of more effective treatments targeted at the underlying mechanisms of the disorder. For example, future treatments could address the neural circuitry of reward and the modulation of salient stimuli, such as food, as well as the circuitry contributing to anxious temperament or self-awareness of body states.


One reason that it is difficult to get persons with AN to gain and maintain weight is because little in life is more rewarding to them than starvation. Clinically, individuals with AN have long been noted to be anhedonic and ascetic, and able to sustain not only the self-denial of food but also most comforts and pleasures in life.

 Behavioral studies show that individuals with AN have an enhanced ability to delay reward (ie, show less reduction in the value of a monetary reward over time) compared to healthy cohorts and this ability to delay reward may help them to maintain persistent food restriction.

Persons with AN may be unable to appreciate rewarding stimuli because they are preoccupied with consequences.

 Thus, an altered balance between reward and inhibition appears to be a hallmark of AN. In fact, a recent review showed that persons with AN tend to have low reward reactivity but a high sensitivity to punishment in both the ill and recovered states.

 Imaging data support this hypothesis and suggest that altered reward sensitivity and increased behavioral inhibition in AN are related to underactive limbic (reward) circuitry and overactive executive (inhibition) neural circuitry.

 Clinically, this bias is likely to interfere with motivation as well as the ability to learn from experience. That is, ill persons with AN tend to perceive their actions as incorrect or flawed and are highly sensitive to criticism, rather than being able to appropriately proportion reward and punishment in order to learn from experience.

The altered response to feedback occurs in regions associated with cognitive control and habit performance supports the clinical observation of enhanced inhibitory control and difficulty in changing behavior.

 Developing strategies that incorporate an understanding of reward insensitivity into behavioral contingency management may improve treatment compliance and outcome by enhancing motivation and reducing uncertainty.


Persons with AN have exaggerated anxiety related to food and eating and exaggerated harm avoidance-a multifaceted temperament trait that contains elements of anxiety, inhibition, and inflexibility.

 Harm avoidance and anxiety in AN are implicated in the function of executive dorsal caudate and limbic regions, including altered dopamine and serotonin function.

 Animal studies confirm that related concepts, such as risk avoidance and inhibition, correlate with dopamine function in the dorsal caudate and related regions.

 Findings from an imaging study suggest that dopamine release in the dorsal caudate is associated with increased anxiety in recovered AN.

 In contrast, controls showed euphoria associated with limbic dopamine release, consistent with many, but not all control responses to amphetamine.

If persons with AN experience endogenous dopamine release as anxiogenic, rather than hedonic, it may explain their pursuit of starvation, because food refusal may be an effective means of diminishing such anxious feelings. Moreover, elevated anxiety and harm avoidance contribute not only to the maintenance of symptoms but may also predict poor outcome. This suggests that a treatment designed to reduce or manage harm avoidance/anxiety may improve outcome.


Altered sensitivity for one’s internal bodily signals (interoceptive awareness) might be a precipitating and reinforcing factor in AN. Disturbed interoceptive awareness of satiety and hunger, or even a primary alteration of gustatory processes, could play a role in assessing body states and responding to hunger cues. The anterior insula is involved in integrating interoceptive information (eg, internal physical sensations including taste, pain, hunger) with motivational and emotional processes, supporting feeling states, and giving rise to conscious visceral perception of homeostatic states. Altered insula activity found in AN supports the notion that these individuals might suffer from a fundamentally and physiologically altered sense of self, and that brain circuits may misperceive signals regarding hunger and satiety.

 Indeed, many of the symptoms of AN, such as distorted body image, lack of recognition of the symptoms of malnutrition (eg, a failure to appropriately respond to hunger), and diminished motivation to change, might be related to disturbed interoceptive awareness. Such disturbances could also be tied to the preponderance of alexithymia (ie, difficulty identifying emotions) in persons with AN.


Reward insensitivity, anxiety, and interoceptive awareness are highly interrelated in persons with AN and together contribute to appetite dysregulation and abnormal mealtime behavior. Arguably the most critical issue in treating individuals with AN is addressing food refusal and the pursuit of emaciation. There is an anxiety-reducing effect of dietary restraint and reduced daily caloric intake for persons with AN, whereas food consumption stimulates dysphoric mood.

 Moreover, enhanced inhibition, self-control, and/or an ability to delay reward may help to maintain persistent food restriction.


Disturbed interoceptive awareness of satiety or hunger, or even an alteration of primary gustatory processes could play a role in assessing body states and responding to hunger cues. Imaging data further suggest that anticipatory anxiety contributes to restricted eating; for example, individuals able to restrict their eating have an exaggerated anticipatory response to food cues that is both anxious and aversive, and diminished insula and striatal response to receipt of food.

 This finding is consistent with the notion of reduced reward and/or enhanced satiety signals in regions that compute hunger-satiety homeostasis.

 The disconnect between anticipating and experiencing food stimuli may contribute to restricted eating.

Brain imaging provides new insights into neural processes, which suggests that AN behavior is driven by a powerful neurobiology. Our clinical experience is that persons with AN and their families recognize and relate to these temperament traits, and welcome an explanation based on biology. AN tends to be a chronic disorder and it is very difficult for persons with the disorder to change. In turn, this inflexibility frustrates significant others, who often “burn-out” and give up over time.

Developing effective treatments that diminish core symptoms will take time. Still, helping families understand why these behaviors occur, and using techniques such as the family based Maudsley approach,

 that incorporate strategies to better manage temperament and encourage improved nutrition, have been shown to contribute to better outcomes. Improved treatment strategies may reduce caregiver stress and improve the long-term prognosis of disease recovery for those suffering from AN.

This article was originally posted online on 2/24/2014.

Dr Kaye is Director of the Eating Disorders Program and Professor in the department of psychiatry at the University of California, San Diego, School of Medicine.

1. Frank G, Bailer UF, Henry S, et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11C]raclopride. 

. 2005;58:908-912.
2. Steinglass J, Albano A, Simpson H, et al. Fear of food as a treatment target: exposure and response prevention for anorexia nervosa in an open series. 

. 2012;45:615-621.
3. Halmi K, Agras WS, Crow S, et al. Predictors of treatment acceptance and completion in anorexia nervosa. 

. 2005;62:776-781.
4. Harrison A, O’Brien N, Lopez C, Treasure J. Sensitivity to reward and punishment in eating disorders. 

. 2010;177:1-11.
5. Bischoff-Grethe A, McCurdy D, Grenesko-Stevens E, et al. Altered brain response to reward and punishment in adolescents with anorexia nervosa. 

. 2013;214:331-340.
6. Wagner A, Aizenstein H, Venkatraman M, et al. Altered reward processing in women recovered from anorexia nervosa. 

. 2007;164:1842-1849.
7. Tchanturia K, Davies H, Roberts M, et al. Poor cognitive flexibility in eating disorders: examining the evidence using the Wisconsin Card Sorting Task. 

. 2012;7:e28331.
8. Cloninger C, Przybeck T, Svrakic D, Wetzel R. 

The Temperament and Character Inventory (TCI): A Guide to Its Development and Use

. St. Louis: Center for Psychobiology of Personality; 1994:19-28.
9. Kaye W, Wierenga C, Bailer U, et al. Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa. 

Trends Neurosci [Special Issue on Neural Control of Appetite]

. 2013;36:110-120.
10. Kaye W, Wierenga C, Bailer U, et al. Does a shared neurobiology for foods and drugs of abuse contribute to extremes of food ingestion in anorexia and bulimia nervosa? 

. 2013;73:836-842.
11. Eagle D, Wong J, Allan M, et al. Contrasting roles for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats. 

. 2011;31:7349-7356.
12. Simon N, Montgomery K, Beas B, et al. Dopaminergic modulation of risky decision-making. 

. 2011;31:17460-17470.
13. Bailer U, Narendran R, Frankle W, et al. Amphetamine induced dopamine release increases anxiety in individuals recovered from anorexia nervosa. 

. 2012;45:263-271.
14. Oberndorfer T, Frank G, Fudge J, et al. Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa. 

. 2013;170:1143-1151.
15. Wagner A, Aizenstein H, Frank GK, et al. Altered insula response to a taste stimulus in individuals recovered from restricting-type anorexia nervosa. 

. 2008;33:513-523.
16. Kaye W, Strober M, Klump KL. Neurobiology of eating disorders. In: Martin A, Scahill L, Charney DS, Leckman JF, Eds. 

Pediatric Psychopharmacology, Principles & Practice

. New York: Oxford University Press; 2003:224-237.
17. Steinglass J, Sysko R, Mayer L, et al. Pre-meal anxiety and food intake in anorexia nervosa. 

. 2010;55:214-218.
18. Frank G, Kaye W. Current status of functional imaging in eating disorders. 

. 2012;45:723-736.
19. Small D. Individual differences in the neurophysiology of reward and the obesity epidemic. 

. 2009;33(Suppl 2):S44-48.
20. Le Grange D, Lock J. Family-Based Treatment of Adolescent Anorexia Nervosa: The Maudsley Approach. http://www.maudsleyparents.org/whatismaudsley.html. Accessed February 14, 2014.

How are individuals with anorexia nervosa able to ignore signals regarding hunger that otherwise motivate eating, even when they are severely emaciated? Expert insights and online coverage by Psychiatric Times during National Eating Disorders Awareness Week.

Eating Disorders: Understanding Anorexia Nervosa

Eating disorders have the highest mortality rate of any psychiatric illness (5% to 10%).

 Anorexia nervosa, bulimia nervosa-or a combination of the two-share body image distortions and are associated with a great deal of other comorbid symptoms. Anorexia especially is often chronic and difficult to treat; patients restrict their food intake, become emaciated, and face repeat hospitalizations. Persons with bulimia tend to be of normal body weight, and some form of purging in the form or vomiting or laxatives often follows binge episodes.

The challenge for clinicians is to find better treatments. Fortunately, in the last decade, new evidence has emerged to help clinicians understand and treat patients.

Here to offer a preview of his presentation at the 

US Psychiatric and Mental Health Congress

 in San Diego is Dr Walter H. Kaye, Professor of Psychiatry and Director of the Eating Disorders Treatment and Research Program at the University of California,

Kaplan AS, Strasburg, K. Chronic eating disorders: a different approach to treatment resistance. 

http://www.psychiatrictimes.com/eating-disorders/content/article/10168/1432278

Podcasts

Anorexia nervosa, bulimia nervosa-or a combination of the two-share body image distortions and are associated with a great deal of other comorbid symptoms.

Advances in the Treatment of Eating Disorders

Bulimia nervosa (BN) is a disorder with a complex cause. The disorder is most commonly seen in women, generally with onset in adolescence. It is characterized by binge eating (consumption of an unusually large amount of food accompanied by feeling a loss of control), inappropriate compensatory measures to prevent weight gain (including purging by vomiting, abuse of laxatives and diuretics, strict dieting, and excessive exercise), obsessive fears of being fat, and negative self-evaluation influenced largely by body shape and weight.

BN is often associated with anxiety, depression, obsessionality, substance abuse, and poor impulse control.

Antidepressants are the mainstay of pharmacological treatment for BN. In the 1980s and early 1990s they were established as more effective than placebo in treating BN in double-blind, placebo-controlled trials that tested a variety of medication classes, including tricyclic antidepressants, monoamine oxidase inhibitors, and more recently, SSRIs.

Success was most commonly measured by a decrease in the number of bingeing and purging episodes, and although the studies varied widely, many patients achieved short-term reductions of 50% to 75% in one or both areas.