Guido K.W. Frank, MD

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by restricted eating, significant weight loss, and a profound fear of weight gain. AN and the related disorder, bulimia nervosa, have a lifetime prevalence of 1% to 2% of the population.

 Weight loss in AN results in serious medical consequences and higher levels of care are often necessary to restore weight. AN has the highest risk of mortality of any nonsubstance-use psychiatric disorder and, too often, a poor prognosis.

 Reluctance to recover is sustained by ego-syntonic symptoms that reinforce the illness.

 Only 13% to 50% of patients are considered recovered 1 to 2 years posttreatment, and a sizeable subset (20% to 30%) go on to develop a chronic and unremitting course of AN.

Limited effectiveness of both pharmacological and psychological treatments contributes to this chronicity. Family-based therapy, which works in alliance with parents to maintain eating and restore weight, has had some success in adolescent patients, but not all younger patients achieve adequate benefit. For older patients with AN, evidence-based therapies remain underdeveloped.

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Historically, AN has been considered a consequence of psychosocial factors.

 However, considerable recent evidence supports powerful genetic and neurobiological contributions to AN behavior.

 Many affected individuals have an anxious, obsessive, inflexible, and perfectionist temperament that presents in childhood before the onset of AN, becomes exaggerated during illness, and persists in a mild-to-moderate form after recovery. Comorbid depression is common, as is denial of illness and lack of motivation to change.

Recent studies have shed new light on underlying mechanisms driving such AN symptoms.

 For example, when people are hungry, activation of brain circuits normally makes them feel irritable and uncomfortable and makes food more rewarding and motivating. These neural processes appear to be miscoded in AN and sensitized with weight loss.

 Instead, when these individuals become hungry and are presented with food, they experience brain circuit activity associated with considerable anxiety; further, dopamine-related brain mechanisms that motivate and initiate eating fail to activate. Such findings open the door to identifying new targets and new pharmacological approaches in AN.

It is important to note that there are no US Food and Drug Administration (FDA)–approved medications to treat AN. Nonetheless, given the risk of significant physical and psychological consequences of this disorder, off-label prescribing of some agents has become widespread.

For patients with AN who show signs of treatment resistance, the most common medication intervention is atypical antipsychotics. Although promising case reports, open trials, and chart reviews began appearing in the late 1990s, the controlled-trial literature on atypical antipsychotics in AN remains disturbingly limited, which is a testament to the notorious difficulties in recruiting and retaining patients with AN in medication trials. To date, there have been 8 randomized, placebo-controlled trials (RCTs) involving placebo groups. Only 1 of these involved more than 40 patients, and the total number of randomized patients in all trials was less than 350.

Olanzapine is by far the most studied medication for AN, with 5 trials taking place between 2007 and 2019. All but 1 were considered positive, although the degree of benefit typically was small. Two trials involving use of quetiapine had mixed results, and 1 trial with risperidone was negative.

 In the closest thing to a landmark medication study in AN, Attia et al reported results of a relatively large, multisite RCT of olanzapine in adult outpatients in 2019.

 Five sites in North America randomized 152 patients to olanzapine or placebo during a 6-year recruitment period. The 16-week trial used a target olanzapine dose of 10 mg/d (mean, 7.77 mg/d), and investigators found a significant increase in weight for the olanzapine group versus placebo. However, the difference in weight gain (ie, 1 lb of body weight/month for a woman of average height) was modest between the groups; patients using olanzapine gained an average of approximately 1.5 lb of body weight/month. Weight restoration is the primary outcome in any AN trial, but use of a medication hopefully also will impact the powerful thought processes and psychiatric symptoms that drive the illness. Importantly, the authors reported that use of olanzapine showed “no significant benefit for psychological symptoms.”

Despite these limitations, expert articles and guidelines most likely recommend olanzapine as the antipsychotic of choice to treat AN, because so few RCTs have involved use of other medications. In our experience, a few types of patients may particularly benefit from olanzapine. For individuals who desire some degree of weight restoration but are struggling due to lack of appetite or drive to eat, olanzapine may provide improvement. In addition, patients with very high anxiety presenting more as fear than cognitive rigidity may benefit from the sedative-like properties of olanzapine.

However, there are substantial roadblocks to successful use of olanzapine for AN. The quality that led to early interest in and dominant study of olanzapine—its well-known propensity to cause weight gain—makes it unacceptable to the vast majority of patients with AN. At best, many of these individuals are ambivalent about weight gain, and even those who have accepted it as a necessary aspect of recovery frequently fear loss of control over the process. It is critical to understand that improvement in body image for AN patients can significantly lag weight restoration. If a medication adds weight but has little impact on thought process, the patient may experience an intolerable emotional state that greatly heightens the risks of nonadherence and resumption of weight loss.

With 14 atypical antipsychotics available for use in the United States, it is astonishing that so few have been studied in RCTs of AN. Given the highly complex and variable receptor-binding properties of this class, leading to clinically relevant heterogeneity—for example, some atypical antipsychotics are known to treat depression better than others—it is premature to conclude that atypical antipsychotics have only minimal benefit for AN based on results reported with use of 3 of the earlier medications. Lack of RCTs with newer, relatively weight-neutral antipsychotics, especially those having a somewhat different mechanism of action (eg, aripiprazole), may be a serious oversight.

Over the past decade, and with the 2019 olanzapine trial notwithstanding, nearly all additions to the literature on the use of atypical antipsychotics in patients with AN have involved aripiprazole. Five peer-reviewed articles from 4 different sites in 3 countries have described very interesting findings from case series and retrospective chart reviews.

 These reports often show benefit for weight gain, but most notably, they have included remarkably similar descriptions of an impact on thought processes related to AN, particularly the loosening of rigid and entrenched rules and distortions. Observations have included reduced eating-specific anxiety and distress; less rigid food choices; diminished obsessional thoughts about food, exercise, weight, and body image; and fewer eating disorder (ED) rituals. Additionally, many patients reported reduced symptoms of depression and non-ED–related anxiety, which will be discussed in the next section. Therefore, regardless of any direct impact on weight, aripiprazole may indirectly enhance weight restoration by improving cognition and thereby promoting a better response to psychological and dietary treatments. RCTs are needed to further investigate these findings.

What may account for this possible difference between olanzapine and aripiprazole in AN? Olanzapine—as well as most other current atypical antipsychotics, including quetiapine and risperidone—is a 5-HT2

 antagonist. Aripiprazole, in contrast, is a D

 partial agonist, meaning it acts differently at dopamine and serotonin receptors. Theoretical arguments have addressed how use of aripiprazole at lower doses (typically, 1-5 mg/d, with occasional titration up to 10 mg/d) may facilitate learning and behavior change in individuals with AN.

For example, basic research has indicated that dopamine receptor stimulation may be beneficial in suppressing previous fears after extinction training. Moreover, neurobiological research suggests that AN is associated with heightened responsiveness in brain reward circuits, which may be due to a hypersensitive dopamine system. Aripiprazole may downregulate D

 receptor activity, which may improve brain function, reduce anxiety, and aid in the psychotherapeutic process.

Additionally, almost all patients described in this research on aripiprazole use were being treated concurrently with antidepressants. In contrast, no RCT has formally studied atypical antipsychotic augmentation of antidepressants in AN. Although some RCTs allowed patients already on antidepressants to continue them, use was not systematic or evaluated, and the overall numbers were too small to yield meaningful results. We believe that, particularly for medications such as aripiprazole with known significant effects as augmenters, combination treatment may be 1 key to showing a more robust response in controlled trials. On a practical note, adherence also has improved with use of aripiprazole, because it often is better tolerated. Still, some patients encounter akathisia, which we have been able to minimize by initiating therapy with very low doses (eg, as low as 0.5 mg/d in some patients).

AN is associated with high levels of comorbid conditions. More than 40% of individuals with AN have a lifetime comorbid anxiety or mood disorder, over 30% have an impulse control disorder, and about 27% have a substance use disorder.

 Recent data showed that individuals with AN had a 25% risk of receiving any noneating disorder diagnosis during the first 2 years of longitudinal follow-up and a 55% risk of developing comorbid conditions 2 decades after inclusion.

 Comorbid conditions have been associated with greater illness severity and mortality.

Research on eating disorders traditionally has not focused on comorbidities, but new data highlight the need for treatment of those conditions. Whether eating disorder outcomes will be affected by treatment of comorbid psychiatric illnesses is uncertain, but improving quality of life and reducing suicide rates are similarly important goals.

Few medications specific to AN have been approved by the FDA, yet affected patients frequently receive prescriptions for psychotropics.

 However, studies on pharmacological interventions in AN commonly have not been designed to discern whether individuals taking these medications had more severe illness or higher comorbidity than did others. Because depression and anxiety predict more negative treatment outcome in AN, and comorbid psychiatric disorders are associated with higher mortality among this patient population, use of medication to target these conditions is supported.

 Research may have to adapt and focus more on outcome measures that go beyond weight gain; these may include the study of quality of life, mood, and anxiety measures in relation to use of medical interventions. These measures are crucial in preventing weight loss and relapse after significant resources that involve a high level of care have been used for nutritional rehabilitation.

A recent patient with severe AN in our program also had severe, comorbid obsessive-compulsive disorder (OCD). She had many magical thinking–related obsessions that substantially limited her will to live and contributed to overwhelming major depressive disorder with suicidality. The patient was treated with olanzapine to reduce distress and had been on various antidepressant and antianxiety medications, but she never received an adequately dosed trial of a selective serotonin reuptake inhibitor to treat OCD. During weight restoration, we initiated sertraline, which was titrated to 200 mg/d. After 4 months of treatment, the patient experienced significant relief from symptoms of OCD and could start participating in social activities. AN was still a significant struggle, but the patient experienced improvement in daily life activities and overall functioning.

While olanzapine has shown benefit for AN in RCTs, weight restoration tends to be minor, AN cognitions do not appear to improve significantly, and most patients are unaccepting of a medication known to cause weight gain. RCTs of additional atypical antipsychotics, especially those that have a somewhat different mechanism of action (eg, aripiprazole), used alone and in combination with antidepressants are needed. Research into strategies to better treat psychiatric comorbidities in patients with this disorder may reduce treatment resistance. Finally, early investigations to treat AN and its comorbidities with novel biological treatments (eg, psilocybin, ketamine, cannabinoids, and neuromodulation techniques of repetitive transcranial magnetic stimulation and deep brain stimulation) are ongoing.

 is an associate clinical professor of psychiatry at the University of California, San Diego, and medical director of the UCSD Eating Disorders Treatment and Research Program. 

 is a professor in residence of psychiatry at the University of California, San Diego. 

 is director of medical and clinical services at the USCD Eating Disorders Treatment and Research Program, and clinical professor of psychiatry at the University of California, San Diego. 

 is the founder and executive director of the UCSD Eating Disorders Treatment and Research Program, and professor of psychiatry at the University of California, San Diego.

1. Ward ZJ, Rodriguez P, Wright DR, et al. 

Estimation of eating disorders prevalence by age and associations with mortality in a simulated nationally representative US cohort

2. Arcelus J, Mitchell AJ, Wales J, Nielsen S. 

Mortality rates in patients with anorexia nervosa and other eating disorders

3. Abbate-Daga G, Amianto F, Delsedime N, et al. 

Resistance to treatment and change in anorexia nervosa [corrected]: a clinical overview

4. Wonderlich SA, Bulik CM, Schmidt U, et al. 

Severe and enduring anorexia nervosa: update and observations about the current clinical reality

Presentation of eating disorders in the news media: what are the implications for patient diagnosis and treatment?

6. Brandys MK, de Kovel CGF, Kas MJ, et al. 

Overview of genetic research in anorexia nervosa: the past, the present and the future

7. Monteleone AM, Castellini G, Volpe U, et al. 

Neuroendocrinology and brain imaging of reward in eating disorders: a possible key to the treatment of anorexia nervosa and bulimia nervosa

Prog Neuropsychopharmacol Biol Psychiatry

8. Kaye WH, Wierenga CE, Bischoff-Grethe A, et al. 

Neural insensitivity to the effects of hunger in women remitted from anorexia nervosa

9. Frank GKW, Shott ME, Stoddard J, et al. 

Association of brain reward response with body mass index and ventral striatal-hypothalamic circuitry among young women with eating disorders

The role of psychotropic medications in the management of anorexia nervosa: rationale, evidence and future prospects

Cognitive neuroscience of eating disorders

12. Attia E, Steinglass JE, Walsh BT, et al. 

Olanzapine versus placebo in adult outpatients with anorexia nervosa: a randomized clinical trial

13. Frank GKW, Shott ME, Hagman JO, et al. 

The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa

14. Tahillioğlu A, Özcan T, Yüksel G, et al. 

Is aripiprazole a key to unlock anorexia nervosa?: A case series.

15. Bailer UF, Price JC, Meltzer CC, et al. 

Dopaminergic activity and altered reward modulation in anorexia nervosa—insight from multimodal imaging

16. Hudson JI, Hiripi E, Pope HG Jr, Kessler RC. 

The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication

17. Steinhausen HC, Villumsen MD, Hørder K, et al. 

Comorbid mental disorders during long-term course in a nationwide cohort of patients with anorexia nervosa

18. Kask J, Ekselius L, Brandt L, et al. 

Mortality in women with anorexia nervosa: the role of comorbid psychiatric disorders

Is the severity of the clinical expression of anorexia nervosa influenced by an anxiety, depressive, or obsessive-compulsive comorbidity over a lifetime?

20. Alañón Pardo MDM, Ferrit Martin M, Calleja Hernández MAC, Márquez FM. 

Adherence of psychopharmacological prescriptions to clinical practice guidelines in patients with eating behavior disorders

Psychotropic usage by patients presenting to an academic eating disorders program

Depression, worry, and psychosocial functioning predict eating disorder treatment outcomes in a residential and partial hospitalization setting

23. Spriggs MJ, Douglass HM, Park RJ, et al. 

Study protocol for “Psilocybin as a treatment for anorexia nervosa: a pilot study.”

24. Schwartz T, Trunko ME, Feifel D, et al. 

A longitudinal case series of IM ketamine for patients with severe and enduring eating disorders and comorbid treatment-resistant depression

Treatment studies with cannabinoids in anorexia nervosa: a systematic review

Current therapeutic approaches to anorexia nervosa: state of the art

Articles

Only 13% to 50% of AN patients are considered recovered 1 to 2 years posttreatment, and 20% to 30% go on to develop a chronic and unremitting course of AN. How can we improve these outcomes?

Pharmacological Management of Treatment-Resistant Anorexia Nervosa

Scroll below the apple image for the quiz.

B. Complex psychosocial processes that relate to lack of early life deficits

C. Bio-psycho-social interactions that lead to dysregulation of brain circuitry

To avoid weight gain and driven by extreme anxiety, patients with anorexia eats even less, which further reduces weight and triggers more biological drive to eat and further increases anxiety. Thus, setting off a vicious cycle that is difficult to break.

Psychological and social factors involved in anorexia nervosa include anxious traits and the tendency to worry. Their 

 combined with social pressures and stress in general affect illness behaviors.

 This has made it difficult to tease apart environmental effects from brain biology that poses a vulnerability for developing or maintaining anorexia nervosa.

1. Kaye WH, Wierenga CE, Bailer UF, et al. 

Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa

Dysregulation of Brain Processing in Anorexia Nervosa

Poll

Based on our current understanding, what is the underlying etiology for anorexia nervosa? Take the quiz.

Mini Quiz: Etiology of Anorexia Nervosa

Anorexia nervosa is the third most common chronic illness among adolescent females. The mortality rate is 12-fold higher than with all other combined causes of death for females aged 15 to 24 years.

 The disorder is associated with severe emaciation from self-driven food refusal and a perception of being overweight despite very low body weight. Anorexia nervosa shows a complex interplay between neurobiological, psychological, and environmental factors, and it is a chronic disorder with frequent relapses, high treatment costs, and severe disease burden. Little is known about the pathophysiology or biomarkers that characterize anorexia nervosa brain function, treatment effectiveness is limited, and there are no FDA-approved medications.

What makes anorexia nervosa so difficult to treat is the seemingly willful food avoidance and self-driven relentless motivation to lose weight. While eating is a very normal behavior for most of us, overcoming the fear of eating and weight gain is extremely difficult for children or adults with anorexia nervosa. Humans have historically evolved to be biologically protected to survive times of food scarcity. The brain circuitry that drives food-seeking has been well defined in basic science models.

Developing neurobiological models for anorexia nervosa and existing mechanisms that disregard or override hunger signals has been much more difficult. Moreover, there are psychological and social factors involved in anorexia nervosa, including anxious traits and the tendency to worry, and their interaction combined with peer pressure and stress in general 

Related content: Mini Quiz: Etiology of Anorexia Nervosa

Recent brain research in anorexia nervosa has focused on reward pathways, with the hypothesis that these pathways might disturb food approach mechanism in anorexia nervosa. Food is a salient stimulus or natural reward, and reward pathways similar to those of substance abuse are activated when we desire, approach, or eat food.

 Important regions in this circuitry include the ventral striatum, which receives midbrain dopaminergic input and drives motivation and the reward approach; the orbitofrontal cortex responsible for reward valuation; the insula, which processes our taste sensations and provides input to the striatum; and the hypothalamus, which integrates body homeostasis.

 The circuitry between those brain regions may adapt to weight loss and instead of driving eating may reinforce food restriction in individuals vulnerable to anorexia nervosa.

A variety of studies in the past applied tasks that either showed food pictures or delivered monetary or taste rewards to stimulate the reward system. The studies repeatedly showed that the insula, orbitofrontal cortex, or striatum activated differently in persons with anorexia nervosa during those tasks compared with healthy controls.

In our laboratory, the aim is to identify chemical targets to develop better treatments for anorexia nervosa. To accomplish this, we applied reward tasks that were closely associated with brain dopamine response to find evidence of dopaminergic involvement in the pathophysiology of anorexia nervosa.

The dopamine neurotransmitter system has been intensively studied and well characterized. Its neurons’ cell bodies lie in the brain stem in the ventral tegmental area and substantia nigra and from there distribute to the cortical and subcortical brain. The basal ganglia and especially the ventral striatum that includes the nucleus accumbens receive dopamine input and have been involved in the drive to reward stimuli. The reward stimuli can be unconditioned or conditioned (learned) stimuli.

A central feature of dopamine neuron response is that it is triggered by unexpectancy, ie, a discrepancy between what one expects versus what in fact happens. After receiving an unexpected reward such as food or money, a dopamine surge is elicited in the striatum and midbrain, which is called a 

. When receiving this reward becomes a regular occurrence, the dopamine signal is triggered by the conditioned stimulus that predicts the reward. However, the dopamine system does not respond when the actual reward is received (prediction matches the outcome). If the reward is predicted but not received (there is no food or money after expecting it), there is a dip in dopamine activity in the brain, which reflects the negative prediction error (unexpected omission).

This dynamic can be studied in the living human brain with functional brain imaging during the application of a Pavlovian conditioning paradigm: participants learn to associate sugar-taste or monetary stimuli with pictures of colored shapes that become the conditioned stimulus and appear on the screen before money or sweet solution are delivered (

). Sometimes when the participants expect to get the reward, they will not get it; at other times the reward is delivered unexpectedly.

During these studies, adults and adolescents with anorexia nervosa repeatedly showed elevated response to the unexpected conditions in the insula and striatum, which suggests altered dopamine function.

 Basic science found that in the process of food restriction, the dopamine system in the brain gets sensitized to stimulate food seeking. We interpreted this elevated activation as a normal response.

This brain activation does not drive eating as it would in heathy individuals. In fact, it can often be observed in individuals with anorexia nervosa that despite weight loss, fear of weight gain worsens and there is no limit as to how low the weight will drop. In our most recent study, we propose a model of how this drive to lose weight may be perpetuated and how the elevated prediction error response fits into this behavior.

 Our findings indicate that elevated brain response correlated positively with harm avoidance-a measure of trait anxiety-but negatively with weight gain during treatment.

Harm avoidance was positively correlated with drive for thinness and body dissatisfaction. We propose that when a person who develops anorexia nervosa starts to lose weight, the dopamine system quickly gets faster or more strongly involved, ie, sensitized. Weight loss leads to low blood sugar and changes in hormonal and neuropeptide levels, which signal to the hypothalamus that the organism should eat. However, this biological motivation and drive to eat disagrees with conscious motivation to not eat and lose weight, which leads to high levels of anxiety. To avoid weight gain and driven by extreme anxiety, the person with anorexia eats even less, which further reduces weight and triggers more biological drive to eat and further increases anxiety. Thus, setting off a vicious cycle that is difficult to break (

Clinically, this has been a useful model to discuss the neurobiology of anorexia nervosa with patients or families. I draw and develop this model in a monthly seminar with parents of children with anorexia nervosa, which helps them understand the typically very difficult to comprehend ongoing drive for food restriction.

Understanding a certain mechanism does not cure the illness, but it provides opportunities to support treatment. In psychotherapy it helps to go from something inexplicable to understanding the connection between an anxious temperament with a predisposition to worry and eating problems. This is also relevant for patients who have recovered but who may be at risk for relapse.

Every year in August, around the time when school starts, I see several patients with symptom relapse in my outpatient clinic. This is due to heightened stress over grades that triggers eating problems and food restrictions. The subsequent weight loss may then set in motion the vicious biological cycle as previously described.

As do other biological studies including genetic research, such a model serves another important purpose. Psychiatric diseases are often associated with stigma and personal guilt. The more we understand the underlying neurobiology of psychiatric disorders such as eating disorders, the more we will be able to develop medical models, find more effective treatments, and reduce stigma.

Our research has helped to pose new hypotheses for potential treatment directions. In animal models, fear extinction was aided by dopamine receptor stimulation.

 A main focus of psychotherapy for anorexia nervosa is weight restoration, such as family-based therapy in youth, which requires overcoming the fears of eating. We hypothesized that dopamine receptor stimulation could be helpful in the treatment process for anorexia nervosa. We compared youth treated with the partial dopamine D2 receptor agonist aripiprazole with those who did not receive aripiprazole. The patients who received aripiprazole had better weight outcomes at the end of treatment.

 However, a controlled study is missing, and no firm conclusions can be drawn from these results. Although such a medication alone would probably not cure anorexia nervosa, it could, however, act as a catalyst in concert with psychotherapy.

The conceptualization of the neurobiology of anorexia nervosa in our model poses a dichotomy of frontal cortex cognitive-emotional and subcortical basal ganglia involving circuits. What has been very difficult to model from a biological perspective are the severe eating disorder core behaviors such as body dissatisfaction and drive for thinness. Those thoughts and drives can persist life-long in a person despite having recovered weight-wise from anorexia nervosa. It is possible that the anxious traits commonly found in anorexia nervosa-even before the onset of the disorder-come into play and perpetuate those behaviors, making “letting go” extremely difficult.

Models to test how to target the behaviors pharmacologically still need to be developed. Serotonin reuptake inhibitors can help with anxiety and depression but do not improve the core behaviors of anorexia nervosa.

 A more complex biochemical model may be needed for anorexia nervosa. Such a model would take into account the interaction between neurotransmitter systems such as dopamine and serotonin and signals from the body periphery such as gut hormones and their adaptation to food intake.

Recent data lend themselves to applying a neurobiological model when talking with patients, parents, or families about anorexia nervosa. This can reduce personal burden, shame, or guilt. Weight restoration continues to be a key aspect of treatment, and there is the possibility that this is supported by dopamine receptor agonists, although this is yet uncertain as controlled studies are lacking.

Dr Frank is Professor in Residence, University of California, San Diego, Eating Disorder Program for Treatment and Research, and Rady Children’s Hospital, San Diego, CA. He reports that he has received research funding from the NIMH, is on the Scientific Advisory Board of EDCare, and has provided expect testimony for Senter Goldfarb, & Rice.

1. Golden NH. Eating disorders in adolescence and their sequelae. 

2. Attia E. Anorexia nervosa: current status and future directions. 

3. Kessler RM, Hutson PH, Herman BK, Potenza MN. The neurobiological basis of binge-eating disorder. 

4. Kaye WH, Wierenga CE, Bailer UF, et al. 

5. Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci. 2002;22:3306-3311.

6. Haber SN, Behrens TE. The neural network underlying incentive-based learning: implications for interpreting circuit disruptions in psychiatric disorders. 

7. DeGuzman M, Shott ME, Yang TT, et al. Association of elevated reward prediction error response with weight gain in adolescent anorexia nervosa. 

8. Frank GK, Reynolds JR, Shott ME, et al. Anorexia nervosa and obesity are associated with opposite brain reward response. 

9. Frank GKW, DeGuzman MC, Shott ME, et al. Association of brain reward learning response with harm avoidance, weight gain, and hypothalamic effective connectivity in adolescent anorexia nervosa. 

10. Abraham AD, Neve KA, Lattal KM. Dopamine and extinction: a convergence of theory with fear and reward circuitry. 

11. Frank GK, Shott ME, Hagman JO, et al. The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa. 

12. Lock J, La Via MC, and the AACAP Committee on Quality I. Practice parameter for the assessment and treatment of children and adolescents with eating disorders. 

13. Frank GKW, DeGuzman MD, Shott ME. Motivation to eat and not to eat: the psychobiological conflict in anorexia nervosa. 

This article describes a model for anorexia nervosa that is useful when working with patients or families to help them understand the complexity of the illness.