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Recent advances in understanding anorexia nervosa

Guido k.w. frank.

1 Department of Psychiatry, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA

2 Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA

Megan E. Shott

Marisa c. deguzman.

Anorexia nervosa is a complex psychiatric illness associated with food restriction and high mortality. Recent brain research in adolescents and adults with anorexia nervosa has used larger sample sizes compared with earlier studies and tasks that test specific brain circuits. Those studies have produced more robust results and advanced our knowledge of underlying biological mechanisms that may contribute to the development and maintenance of anorexia nervosa. It is now recognized that malnutrition and dehydration lead to dynamic changes in brain structure across the brain, which normalize with weight restoration. Some structural alterations could be trait factors but require replication. Functional brain imaging and behavioral studies have implicated learning-related brain circuits that may contribute to food restriction in anorexia nervosa. Most notably, those circuits involve striatal, insular, and frontal cortical regions that drive learning from reward and punishment, as well as habit learning. Disturbances in those circuits may lead to a vicious cycle that hampers recovery. Other studies have started to explore the neurobiology of interoception or social interaction and whether the connectivity between brain regions is altered in anorexia nervosa. All together, these studies build upon earlier research that indicated neurotransmitter abnormalities in anorexia nervosa and help us develop models of a distinct neurobiology that underlies anorexia nervosa.

Anorexia nervosa (AN) is characterized by a persistent restriction of energy intake and leads to a body weight that is significantly lower than what is expected for height and age 1 . There is either an intense fear of gaining weight or becoming fat or persistent behavior that interferes with weight gain (even though at significantly low weight). Individuals with AN experience a disturbance in the way one’s body weight or shape is experienced, undue influence of body shape and weight on self-evaluation, or persistent lack of recognition of the seriousness of the current low body weight. A restricting type has been distinguished from a binge eating/purging type; individuals in the latter group may intermittently have binge eating episodes or may use self-induced vomiting to avoid weight gain. AN shows a complex interplay between neurobiological, psychological, and environmental factors 2 and is a chronic disorder with frequent relapse, high treatment costs, and severe disease burden 3 , 4 . AN has a mortality rate 12 times higher than the death rate for all causes of death for females 15 to 24 years old 5 – 7 . Treatment success is modest, and no medication has been approved for AN treatment 8 .

Various psychological or psychodynamic theories have been developed in the past to explain the causes of AN but their underlying theories have been difficult to test 9 . On the contrary, neurobiological research using techniques such as human brain imaging leads to more directly testable hypotheses and holds promise to help us tease apart mechanisms that contribute to the onset of the illness, maintenance of AN behavior, and recovery from AN. This article will review recent advances in our understanding of the neurobiology of AN. Neurobiology is a branch of the life sciences, which deals with the anatomy, physiology, and pathology of the nervous system 10 . Neurobiology is closely associated with the field of neuroscience, a branch of biology, which tries to understand brain function, from gross anatomy to neural circuits and cells that comprise them 11 . The goal of neurobiological research in AN is to develop a medical model perspective to reduce stigma and help develop better treatments 12 . At the earlier stages of brain research in AN, study samples tended to be quite small, which made replication difficult 13 . Most frequently, altered serotonin function was associated with AN and anxiety in the disorder 14 . More recent brain research has built upon those studies and increased sample sizes in structural studies and introduced studying brain function in relation to specific tasks that are thought be related to food restriction, anxiety, and body image distortion. Most studies have been carried out in adults, although there is a growing body of literature that investigated youth with AN.

The most frequently applied brain imaging study design in the past studied brain volume in AN, and more recent research now allows cortical thickness of the brain to be investigated. For a long time, there was the notion that gray matter volume and cortical thickness are lower in patients with AN (when ill and after recovery) than in controls. This research was pioneered by Katzman et al . in adolescents with AN 15 , 16 . However, recent research by Bernardoni et al . 17 and King et al . 18 in adolescents and young adults indicated that such abnormalities are rather short-lived and that both lower volume and cortical thickness normalize with weight recovery. Animal studies suggest that those changes may be due to the effects of malnutrition and dehydration on astrocytes within the brain connective tissue 19 . Two studies from our group have found larger orbitofrontal cortex and insula volume in adults and adolescents with AN after 1 to 2 weeks of normalization of food intake or in individuals after recovery, and orbitofrontal cortex volume was related to taste pleasantness 20 , 21 . Those results were intriguing as they implicated taste perception in relation to brain volume but they need replication. New data from our group in healthy first-degree relatives of patients with AN also show larger orbitofrontal cortex volume, supporting a trait abnormality (unpublished data). Studies by Bernardoni et al . in young adults have found abnormalities in gray matter gyrification in AN, and nutritional rehabilitation seems to normalize altered cortical folding 22 . A valuable lesson from those studies is that food intake can have dramatic effects on brain structure. Whether lower or higher brain volume in AN has implications on illness behavior or is instead an effect of malnutrition without effects on behavior is still unclear and needs further research 23 , 24 .

Functional brain imaging provides the opportunity to tie behavior to brain activation and thus to distinct brain neurobiology, which could become a treatment target. Several aspects of behavior in AN stand out. One is the ability to restrict food intake to the point of emaciation while the typical mechanisms to maintain a healthy body weight are inefficient. Another is how the body can maintain this behavior even when AN patients in therapy are trying to break that behavior pattern.

Relevant to food avoidance behavior is the brain reward system, which processes the motivation to eat and hedonic experience after food intake, and also calculates and updates how valuable a specific food is to us 25 . This circuitry includes the insula, which contains the primary taste cortex, the ventral striatum that comprises dopamine terminals to drive food approach, and the orbitofrontal cortex that calculates a value, while the hypothalamus integrates body signals on hunger and satiety for higher-order decision making and food approach. Many studies have used visual food cues but it has been difficult to draw conclusions on the pathophysiology of AN from those studies 26 .

Several studies from our group using sugar taste stimuli have found that brain activation in adolescent and adult AN was elevated compared with controls in response to unexpected receipt or omission of sweet taste in the insula and striatum 27 , 28 . This so-called “prediction error” response has been associated with brain dopamine circuitry and serves as a learning signal to drive approach or avoidance of salient stimuli in the environment in the future. In addition, orbitofrontal cortex prediction error response correlated positively with anxiety measures in AN 28 , 29 . We found a similar pattern of elevated brain activation in AN to unexpected receipt or omission of monetary stimuli, suggesting a food-independent alteration of brain dopamine circuitry. Importantly, those studies have also shown that brain response was predictive of weight gain during treatment and that brain dopamine function could have an important role in weight recovery in AN. This was supported by a retrospective chart review in adolescents with AN that suggested that the dopamine D 2 receptor partial agonist aripiprazole was associated with higher weight gain in a structured treatment program in comparison with patients not on that medication 30 . Mechanistically, it was hypothesized that dopamine D 2 receptor stimulation might be desensitizing those receptors and normalize behavior response. This, however, is speculative and controlled studies are lacking.

Other lines of research on the pathophysiology of AN are directed toward feedback learning, and several studies have found that AN is associated with alterations, behaviorally or in brain response. A study by Foerde and Steinglass, who investigated learning using a picture association task in patients with AN before and after weight restoration, indicated deficits in feedback learning and generalization of learned information in comparison with controls 31 . Such alterations could translate directly into difficulties in behavior modification toward recovery. Studies from Ehrlich’s group found normal feedback learning in ill, but reduced performance on reversal learning in recovered AN, which made the impact of learning in ill AN less clear 32 , 33 . Furthermore, Bernardoni et al ., using a different study design, found that individuals with AN had an increased learning rate and elevated medial frontal cortex response following punishment 34 . That result supports previous findings of elevated sensitivity to punishment in AN as a possible biological trait 35 . Another very interesting study by Foerde et al . tested brain response to food choice presenting images of food and that research implicated the dorsal striatum in this process in AN 36 . The authors also found that the strength of connectivity between striatum and frontal cortex activation correlated inversely with actual caloric food intake in a test meal after the brain scan. The authors interpreted the findings to mean that this frontostriatal involvement in AN could contribute to habit formation of food restriction behavior. Behavioral research has provided evidence that habit formation or habit strength could be necessary for the perpetuation of AN behaviors and this concept is important to study further 37 – 39 .

The self-perception of being fat despite being underweight is another aspect of AN that the field continues to struggle with in finding its underlying pathophysiology. Some studies have found a specific brain response related to altered processing of visual information or tasks that tested interoception. For instance, Kerr et al . 40 found elevated insula activation during an abdomen perception task, and Xu et al . 41 found that a frontal and cingulate cortex response during a social evaluation task correlated with body shape concerns. A study by Hagman et al ., however, indicated a strong cognitive and emotional influence on body image distortion, and the intersection between altered perception and fear-driven self-perception needs further study 42 . Social interaction and its brain biology constitute another area that was hypothesized to be related to AN behaviors and some research is emerging on this topic. For instance, a study by McAdams et al . showed that the quality of the social relationship or social reciprocity tested in a trust game showed lower occipito-parietal brain response in patients with AN in comparison with a control group 43 . This research suggests altered reward experience from interpersonal contact in AN, which could impact emotional well-being and interfere with recovery. Oxytocin, a peptide hormone related to social behavior, could play a role but this requires more detailed research 44 .

Studies on brain connectivity can test either what brain regions work in concert during a specific task (functional connectivity) or what the hierarchical organization is between areas in the brain (that is, what region drives another) (effective connectivity). Several studies in the past have shown that resting-state functional connectivity is altered in patients with AN compared with control groups. Those studies repeatedly found altered connectivity that involved the insula, a region associated with taste perception, prediction error processing, and integration of body perception, as reviewed by Gaudio et al . 45 . More recent studies found higher or lower resting-state activation in AN across various networks and during rest or task conditions 39 , 46 – 49 . Longitudinal studies will need to test what might be the best resting-state network to focus on to predict, for instance, illness outcome or whether functional connectivity during specific tasks such as taste processing could be more informative. One study by Boehm et al . found normalization of functional connectivity in the default mode but continued abnormal frontoparietal network connectivity in recovered AN 50 . It remains to be seen whether functional connectivity will normalize with recovery or can identify long-lasting or maybe trait alterations.

Effective connectivity studies indicated that while viewing fearful faces, a group with AN had deficits of brain connectivity between prefrontal cortex and the amygdala, which correlated with measures for anxiety and eating behaviors in a study by Rangaprakash et al . 51 . Studies from our group that assessed effective connectivity during the tasting of sucrose solution found that, whereas in controls the hypothalamus drove ventral striatum response, in patients with AN, effective connectivity was directed from the ventral striatum to the hypothalamus 28 , 52 . Previously, a dopamine-dependent pathway from the ventral striatum to the hypothalamus that mediates fear was described and we hypothesized that this circuitry might be activated in AN to override appetitive hypothalamic signals 53 .

In summary, brain research has started to make inroads into the pathophysiology of AN. We have learned that malnutrition has significant effects on brain structure, changes that can recover with weight restoration, but whether those alterations have an impact on illness behavior remains unclear 23 . Research into the function of brain circuits has implicated reward pathways and malnutrition-driven alterations of dopamine responsiveness together with neuroendocrine changes, and high anxiety may interfere with normal mechanisms that drive eating behavior 54 . Habit learning and associated striatal-frontal brain connectivity could provide another mechanism of how brain function and interaction of cortical and sub-cortical regions may perpetuate illness behavior that is difficult to overcome. Those advances are promising to establish that AN is associated with a distinct brain pathophysiology. This will help researchers develop effective biological treatments that improve recovery and help prevent relapse. A significant challenge to overcome will be to integrate the differing brain research studies and develop a unified model 13 . Critical in this effort will be well-powered and comparable study designs across research groups, which take into account confounding factors such as comorbidity and medication use and which use rigorous standards for data analysis.

[version 1; peer review: 2 approved]

Funding Statement

This work was supported by National Institute of Mental Health grants MH096777 and MH103436 (both to GKWF) and by T32HD041697 (University of Colorado Neuroscience Program) and National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards grant TL1 TR001081 (both to MCD).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

  • Carrie J McAdams , Department of Psychiatry, University of Texas at Southwestern Medical Center, Dallas, TX, USA No competing interests were disclosed.
  • Janet Treasure , Section of Eating Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK No competing interests were disclosed.

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Eating Disorders: Current Knowledge and Treatment Update

  • B. Timothy Walsh , M.D.

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Although relatively uncommon, eating disorders remain an important concern for clinicians and researchers as well as the general public, as highlighted by the recent depiction of Princess Diana’s struggles with bulimia in “The Crown.” This brief review will examine recent findings regarding the diagnosis, epidemiology, neurobiology, and treatment of eating disorders.

Photo: B. Timothy Walsh, M.D.

Eight years ago, DSM-5 made major changes to the diagnostic criteria for eating disorders. A major problem in DSM-IV ’s criteria was that only two eating disorders, anorexia nervosa and bulimia nervosa, were officially recognized. Therefore, many patients presenting for treatment received the nonspecific diagnostic label of eating disorder not otherwise specified (EDNOS), which provided little information about the nature of the patient’s difficulties. This problem was addressed in several ways in DSM-5 (see DSM-5 Feeding and Eating Disorder list). The diagnostic criteria for anorexia nervosa and bulimia nervosa were slightly expanded to capture a few more patients in each category. But two other changes had a greater impact in reducing the use of nonspecific diagnoses.

The first of these was the addition of binge eating disorder (BED), which had previously been described in an appendix of DSM-IV . BED is the most common eating disorder in the United States, so its official recognition in DSM-5 led to a substantial reduction in the need for nonspecific diagnoses.

DSM-5 Feeding and Eating Disorder

Rumination Disorder

Avoidant/restrictive food intake disorder

Anorexia nervosa

Bulimia nervosa

Binge-eating disorder

Other specified feeding or eating disorder

Unspecified feeding or eating disorder

The second important change was the combination of the DSM-IV section titled “Feeding and Eating Disorders of Infancy or Early Childhood” with “Eating Disorders” to form an expanded section, “Feeding and Eating Disorders.” This change thereby included three diagnostic categories: pica, rumination disorder, and feeding disorder of infancy or early childhood. Pica and rumination disorder are infrequently diagnosed.

The other category, feeding disorder of infancy or early childhood, was rarely used and had been the subject of virtually no research since its inclusion in DSM-IV . The Eating Disorders Work Group responsible for reviewing the criteria for eating disorders for DSM-5 realized that there was a substantial number of individuals, many of them children, who severely restricted their food intake but did not have anorexia nervosa. For example, after a severe bout of vomiting after eating, some individuals attempt to prevent a recurrence by no longer eating at all, leading to potentially serious nutritional disturbances. No diagnostic category in DSM-IV existed for such individuals. Therefore, the DSM-IV category, feeding disorder of infancy or early childhood, was expanded and retitled “avoidant/restrictive food intake disorder” (ARFID). Combined, these changes led to a substantial reduction in the need for nonspecific diagnostic categories for eating disorders.

In the course of assessing the impact of the recommended changes in the diagnostic criteria for eating disorders, the Eating Disorders Work Group became aware of another group of individuals presenting for clinical care whose symptoms did not quite fit any of the existing or proposed categories. These were individuals, many of them previously overweight or obese, who had lost a substantial amount of weight and developed many of the signs and symptoms characteristic of anorexia nervosa. However, at the time of presentation, their weights remained within or above the normal range, therefore not satisfying the first diagnostic criterion for anorexia nervosa. The work group recommended that a brief description of such individuals be included in the DSM-5 diagnostic category that replaced DSM-IV ’s EDNOS: “other specified feeding and eating disorders” (OSFED); this description was labeled atypical anorexia nervosa. The degree to which the symptoms, complications, and course of individuals with atypical anorexia nervosa resemble and differ from those of individuals with typical anorexia nervosa remains an important focus of current research.

Epidemiology

Although eating disorders contribute significantly to the global burden of disease, they remain relatively uncommon. A study published in September 2018 by Tomoko Udo, Ph.D., and Carlos M. Grilo, Ph.D., in Biological Psychiatry examined data from a large, nationally representative sample of over 36,000 U.S. adults 18 years of age and older surveyed using a lay-administered diagnostic interview in 2012-2013. The 12-month prevalence estimates for anorexia nervosa, bulimia nervosa, and BED were 0.05%, 0.14%, and 0.44%, respectively. Although the relative frequencies of these disorders were similar to those described in prior studies, the absolute estimates were somewhat lower for unclear reasons. Consistent with clinical experience and prior reports, the eating disorders, especially anorexia nervosa and bulimia nervosa, were more prevalent among women (though men are also affected). Although eating disorders occurred across all ethnic and racial groups, there were fewer cases of anorexia nervosa among non-Hispanic and Hispanic Black respondents than among non-Hispanic White respondents. Consistent with long-standing clinical impression, individuals with lifetime anorexia nervosa reported higher incomes.

Finally, when BED was under consideration for official recognition in DSM-5 , some critics suggested that, since virtually everyone occasionally overeats, BED was an example of the misguided tendency of DSM to pathologize normal behavior. The low prevalence of BED reported in the study by Udo and Grilo documents that, when carefully assessed, BED affects only a minority of individuals and is therefore distinct from normality.

A subject of some debate and substantial uncertainty is whether the incidence of eating disorders (the number of new cases a year) is increasing. Some studies, such as that of Udo and Grilo, have found that the lifetime rates of eating disorders among older individuals are lower than those among younger individuals, suggesting that the frequency of eating disorders may be increasing. However, this might also reflect more recent awareness and knowledge of eating disorders. Other studies that conducted multiple examinations of the frequency of eating disorders in the same settings over time appear to suggest that, in the last several decades, the incidence of anorexia nervosa has remained roughly stable, whereas the incidence of bulimia nervosa has decreased. Presumably, this reflects changes in the sociocultural environment such as an increased acceptance of being overweight and reduced pressure to engage in inappropriate compensatory measures such as self-induced vomiting after binge eating.

The COVID-19 pandemic has impacted virtually every facet of life across the world and has produced severe financial, medical, and psychological stresses. Preliminary research suggests that such stresses have exacerbated the symptoms of individuals with preexisting eating disorders and have led to increased binge eating in the general population. Hopefully, these trends will improve with successful control of the pandemic.

Neurobiology

Much recent research on the mechanisms underlying the development and persistence of eating disorders has focused on the processing of rewarding and nonrewarding/punishing stimuli. Several studies have suggested that individuals with anorexia nervosa are less able to distinguish among stimuli with varying probabilities of obtaining a reward. Other studies suggest that, when viewing images of food during MRI scanning, individuals with anorexia nervosa tend to show less activation of brain reward areas than do controls. Such deficits may be related to disturbances in dopamine function in areas of the brain known to be involved in reward processing. Research based on emerging methods in computational psychiatry suggests that individuals with anorexia nervosa may be particularly sensitive to learning from punishment; for example, they may be very quick to learn what stimuli lead to a decrease in the amount of a reward. Conceivably, they may learn that eating high-fat foods prevents weight loss and produces undesirable weight gain, and they begin to avoid such foods. These studies, and a range of others, focus on probing basic brain mechanisms and how they may be disrupted in anorexia nervosa. A challenge for this “bottom-up” approach is to determine how exactly disturbances in such mechanisms are related to the eating disturbances characteristic of anorexia nervosa.

Other recent studies take a “top-down” approach, focusing on the neural circuitry underlying the persistent maladaptive choices made by individuals with anorexia nervosa when they decide what foods to eat. Such research successfully captures the well-established avoidance of high-fat foods by individuals with anorexia nervosa and has documented that such individuals utilize different neural circuits in making decisions about what to eat than do healthy individuals. These results are consistent with suggestions that the impressive persistence of anorexia nervosa in many individuals may be due to the establishment of automatic, stereotyped, and habitual behavior surrounding food choice. A challenge for such top-down research strategies is to determine how these maladaptive patterns develop so rapidly and become so ingrained.

Research on the neurobiology underlying bulimia nervosa is broadly similar. Although the results are complex, individuals with bulimia nervosa appear to find food stimuli more rewarding, and there are indications of disturbances in reward responsiveness to sweet tastes. Several studies have documented impairments in impulse control assessed using behavioral paradigms such as the Stroop Task. In this task, individuals are presented with a word naming a color (for example, “red”) but asked to name the color of the letters spelling the word (for example, the letters r, e, and d are green). Increased difficulties in performing such tasks have been described in individuals with bulimia nervosa and linked to reduced prefrontal cortical thickness.

It has long been known that eating disorders tend to run in families, and there has been strong evidence that this in part reflects the genes that individuals inherit from their parents. In recent decades, it has become clear that the risk of developing most complex human diseases, including obesity, hypertension, and eating disorders is related to many genes, each one of which contributes a small amount to the risk. Because the contribution of a single gene is so small, the DNA from a very large number of individuals with and without the disorder needs to be examined. For instance, genomewide association studies (GWAS) in schizophrenia have examined tens of thousands of individuals with schizophrenia and over 100,000 controls and identified well over 100 genetic loci that contribute to the risk of developing schizophrenia.

GWAS examining the genetic risk for eating disorders are under way but to date have focused primarily on anorexia nervosa. The Psychiatric Genetics Consortium has collected information from 10,000 to 20,000 individuals with anorexia nervosa and over 50,000 controls and has, so far, identified eight loci that contribute to the genetic risk for this disorder. In addition, this work has identified genetic correlations between anorexia nervosa and a range of other disorders known to be comorbid with anorexia nervosa such as anxiety disorders as well as a negative genetic correlation with obesity. These data suggest that the genetic risk for anorexia nervosa is based on a complex interplay between loci associated with a range of psychological and metabolic/anthropometric traits.

Although there have been no dramatic developments in our knowledge of how best to treat individuals with eating disorders, there have been some significant and useful advances in recent years.

For anorexia nervosa, arguably the most significant advance in treatment in the last quarter century has been family-based treatment for adolescents. In this approach, sometimes referred to as the “Maudsley method,” the family, guided by the therapist, becomes the primary agent of change and responsible for ensuring that eating behavior normalizes and weight increases. This approach differs markedly from prior treatment strategies that assumed parental involvement was not helpful or even detrimental. Family-based treatment is now widely viewed as a treatment of first choice for adolescents with anorexia nervosa and has also been adapted to treat bulimia nervosa.

Family-based treatment can be quite challenging for parents. The entire family is asked to attend treatment sessions, and one session early in treatment includes a family meal during which the parents are charged with the difficult task of persuading the adolescent to consume more food than he/she had intended. An alternative but related model, termed “parent-focused treatment,” has recently been explored in a few studies. In this approach, parents meet with a therapist without the affected adolescent or other members of the family and receive guidance regarding how to help the adolescent to alter his or her behavior following techniques virtually identical to those provided in traditional family-based treatment. Several small studies have examined this approach, and results suggest similar effectiveness. Although more research is needed, these findings suggest that parent-focused treatment may be an attractive alternative to family-based treatment for many parents and practitioners.

The COVID-19 pandemic has led to a dramatic acceleration in the provision of psychiatric care remotely, including family-based treatment. Work on providing family-based treatment via videoconference had begun prior to the arrival of COVID-19, as this specialized form of care is not widely available, and its provision via HIPAA-compliant video links would offer a substantial increase in accessibility. Several small studies suggested that remote provision of family-based treatment is feasible and likely to be efficacious. The restrictions imposed by COVID-19 on face-to-face contact have accelerated the remote delivery of family-based treatment; hopefully, new research will document its effectiveness. It should be noted, however, that, in most cases, local contact with a medical professional who can directly measure weight and oversee the patient’s physical state is required.

The treatment of adults with anorexia nervosa, who typically developed the disorder as teenagers and have been ill for five or more years, remains challenging. Structured behavioral interventions, such as those available in specialized inpatient, day program, or residential centers, typically lead to significant weight restoration and psychological and physiological improvement. However, the rate of relapse following acute care remains substantial. Furthermore, most adult patients with anorexia nervosa are very reluctant to accept treatment in such structured programs. A recent helpful development is evidence that olanzapine, at a dose of 5 mg/day to 10 mg/day, assists modestly with weight gain in adult outpatients with anorexia nervosa and is associated with few significant side effects. Unfortunately, it does not address core psychological symptoms and must be viewed as adjunctive to standard care.

There have been fewer recent developments in the treatment of patients with bulimia nervosa and of BED. For bulimia nervosa, cognitive-behavioral therapy remains the mainstay psychological treatment, and SSRIs continue to be the first-choice class of medication. For BED, multiple forms of psychological treatment are associated with substantial improvement in binge eating, and, in 2015, the FDA approved the use of the stimulant lisdexamfetamine (Vyvanse) for individuals with BED. Unlike most psychological treatments, lisdexamfetamine is associated with modest weight loss but has effects on pulse and blood pressure that may be of concern, especially for older individuals.

Also noteworthy are the development and application of new forms of psychological treatment for individuals with eating disorders. These include dialectical behavior therapy (DBT), acceptance and commitment therapy (ACT), and integrative cognitive-affective therapy (ICAT). Although only a few controlled studies have examined the effectiveness of these treatments, anecdotal information and the results of these studies suggest that such methods may be useful alternatives to more established interventions.

Conclusions

Eating disorders remain uncommon but clinically important problems characterized by persistent disturbances in eating or eating-related behavior. Cutting-edge research focuses on neurobiology and genetics, utilizing novel and rapidly evolving methodology. There have been modest advances in treatment approaches, including the COVID-19 pandemic’s acceleration of treatment delivery via video-link. Future studies will hopefully clarify the nature of ARFID and of atypical anorexia nervosa and lead to the development of more effective interventions, especially for individuals with long-standing eating disorders. ■

Additional Resources

Walsh BT. Diagnostic Categories for Eating Disorders: Current Status and What Lies Ahead. Psychiatr Clin North Am . 2019; 42(1):1-10.

Udo T, Grilo CM. Prevalence and Correlates of DSM-5 -Defined Eating Disorders in a Nationally Representative Sample of U.S. Adults. Biol Psychiatry . 2018; 84(5):345-354.

Van Hoeken D, Hoek HW. Review of the Burden of Eating Disorders: Mortality, Disability, Costs, Quality of Life, and Family Burden. Curr Opin Psychiatry . 2020; 33(6):521-527.

Bernardoni F, Geisler D, King JA, et al. Altered Medial Frontal Feedback Learning Signals in Anorexia Nervosa. Biol Psychiatry . 2018; 83(3):235-243.

Frank GKW, Shott ME, DeGuzman MC. The Neurobiology of Eating Disorders. Child Adolesc Psychiatr Clin N Am . 2019; 28(4):629-640.

Steinglass JE, Berner LA, Attia E. Cognitive Neuroscience of Eating Disorders. Psychiatr Clin North Am . 2019; 42(1):75-91.

Bulik CM, Blake L, Austin J. Genetics of Eating Disorders: What the Clinician Needs to Know. Psychiatr Clin North Am . 2019; 42(1):59-73.

Attia E, Steinglass JE, Walsh BT, et al. Olanzapine Versus Placebo in Adult Outpatients With Anorexia Nervosa: A Randomized Clinical Trial. Am J Psychiatry . 2019; 176(6):449-456.

Le Grange D, Hughes EK, Court A, et al. Randomized Clinical Trial of Parent-Focused Treatment and Family-Based Treatment for Adolescent Anorexia Nervosa. J Am Acad Child Adolesc Psychiatry . 2016; 55(8):683-92.

Pisetsky EM, Schaefer LM, Wonderlich SA, et al. Emerging Psychological Treatments in Eating Disorders. Psychiatr Clin North Am . 2019; 42:219-229.

B. Timothy Walsh, M.D., is a professor of psychiatry at the Columbia University Irving Medical Center and the founding director of the Columbia Center for Eating Disorders at the New York State Psychiatric Institute. He is the co-editor of the Handbook of Assessment and Treatment of Eating Disorders from APA Publishing.

Dr. Walsh reports receiving royalties or honoraria from UpToDate, McGraw-Hill, the Oxford University Press, the British Medical Journal, the Johns Hopkins Press, and Guidepoint Global

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  • Case report
  • Open access
  • Published: 15 February 2022

Terminal anorexia nervosa: three cases and proposed clinical characteristics

  • Jennifer L. Gaudiani   ORCID: orcid.org/0000-0002-2035-9390 1 ,
  • Alyssa Bogetz 2 &
  • Joel Yager 2  

Journal of Eating Disorders volume  10 , Article number:  23 ( 2022 ) Cite this article

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Most individuals with eating disorders will either recover, settle into an unrecovered but self-defined acceptable quality of life, or continue to cycle from crisis to relative stability over time. However, a minority of those with severe and enduring eating disorders recognize after years of trying that recovery remains elusive, and further treatment seems both futile and harmful. No level of harm reduction proves achievable or adequately ameliorates their suffering. In this subgroup, many of those with anorexia nervosa will experience the medical consequences of malnutrition as their future cause of death. Whereas anyone who wishes to keep striving for recovery despite exhaustion and depletion should wholeheartedly be supported in doing so, some patients simply cannot continue to fight. They recognize that death from anorexia nervosa, while perhaps not welcome, will be inevitable. Unfortunately, these patients and their carers often receive minimal support from eating disorders health professionals who are conflicted about terminal care, and who are hampered and limited by the paucity of literature on end-of-life care for those with anorexia nervosa.

  • Case presentation

Three case studies elucidate this condition. One patient was so passionate about this topic that she asked to be a posthumous co-author of this paper.

Conclusions

Consistent with literature on managing terminal illness, this article proposes clinical characteristics of patients who may be considered to have a terminal eating disorder: diagnosis of anorexia nervosa, older age (e.g. age over 30), previous participation in high quality care, and clear and consistent determination by a patient who possesses decision-making capacity that additional treatment would be futile, knowing their actions will result in death. By proposing the clinical characteristics of terminal anorexia nervosa, we hope to educate, inspire compassion, and help providers properly assess these patients and provide appropriate care. We hope that this proposal stimulates further expert consensus definitions and clinical guidelines for management of this population. In our view, these patients deserve the same attendant care and rights as all other patients with terminal illness, up to and including medical aid in dying in jurisdictions where such care is legal.

As a patient with severe and enduring anorexia nervosa advocating for my legal right to MAID (medical aid in dying), I confronted numerous obstacles and challenges from the medical profession, related not just to the question of whether I should have access to MAID generally, but more so, how my anorexia, a psychiatric condition frequently misunderstood by the medical community, interacted with my decision making capacity and desire to pursue MAID as one potential option knowing that my illness was indeed terminal. –Alyssa

The vast majority of potentially terminal illnesses carry with them thoughtfully considered and evidence-based staging criteria. These criteria allow patients and clinicians to distinguish mild and likely curable presentations of the disease from irreversible, pre-terminal and terminal stages. Medical specialties treating cancer, organ failure, or various infectious diseases have dedicated considerable attention and resources to delineating levels of severity. While preliminary suggestions for labeling severe and enduring anorexia nervosa (SE-AN) [ 1 ] and for staging the disorder have been proposed [ 2 ], generally accepted staging criteria for anorexia nervosa (AN) have not yet been developed. Remarkably, the same diagnostic label (“AN”) and treatment criteria that apply to teenagers only a few months into their disorder are also used for patients who are decades older, who have lived through innumerable admissions to inpatient and residential care facilities, and whose quality of life has been irrevocably damaged by persistent, severe mental and physical illness. The field acknowledges SE-AN as a somewhat distinct clinical condition, but despite thoughtful clinical and research efforts [ 3 , 4 ] the designation has not been formalized as a diagnosis, and consensus regarding criteria for SE-AN remains elusive [ 5 ].

AN carries the second highest mortality rate in the DSM-5 after opioid use disorder, with a death rate estimated at 5–16 times that of the general population. [ 6 , 7 ] Several important recent studies confirm and expand upon these data. A specialized medical inpatient unit in France for those with severe anorexia nervosa evaluated 384 patients admitted over 17 years, with a mean age at admission of 29.4 years old. The standardized mortality ratio (SMR) was 15.9 for women and 22.4 for men, where older age was determined to be a major predictor of mortality. The mean age at death was 41.3 (± 15.3) years, on average two years after hospital admission. The SMR was maximally increased for patients whose first admission to the unit took place while they were between 25 and 35 years old. Specifically, those admitted between 30–34 years old had the highest SMR of 26. Somatic (medical) causes accounted for 43% of deaths, while 11.5% of deaths were caused by suicide. [ 6 ] In a registry-based observational epidemiological study encompassing the entire population of Denmark over 44 years, the SMR for all-cause mortality reached a maximum of about 6 in the age group 20–34 years, and the SMR for suicide in those with AN was 11. Natural causes accounted for two-thirds of death in those with AN. [ 8 ] Finally, a retrospective cohort study evaluated 19,041 individuals with an eating disorder in Ontario, Canada, using administrative healthcare data. The entire cohort, not comprised only of those with AN, had an SMR of 5; they found that potential years of life lost were 6 times higher than expected compared with the Ontario population. Similar to the other studies, peak values for SMRs were observed among adults between 30 and 44 years old, and again the SMRs observed in males were almost two-fold higher than in females. [ 9 ] Importantly, the profound suffering inherent in AN drives the high suicide rate noted in multiple studies, where up to 20% of patients who die prematurely do so by suicide [ 10 ]. Compared with gender- and age-matched groups, patients with AN are 18 times more likely to die by suicide [ 11 ].

Based on these data, AN can unquestionably prove fatal. Despite this fact, the field lacks clinical roadmaps for compassionate, appropriate care for those who will not be able to survive. This does great disservice to patients and their families. By comparison, we do not expect individuals with metastatic lung cancer who have disease progression despite past treatments, which often come with negative sequelae, to keep presenting for those same ineffective treatments. Rather, they are more likely to receive the psychological preparation, connection, and medical and emotional support offered to patients with terminal conditions. Although current laboratory measures and imaging studies by themselves are unable to help us stage patients with AN, based primarily on clinical histories and patients’ narratives we can better understand the clinical course of this illness and the subset of patients with AN who may seek palliative care [ 12 , 13 , 14 ].

There is growing recognition that palliative care may be appropriate for some patients, but the clinical characteristics for terminal anorexia nervosa have not been proposed. Delineating and validating this stage would greatly assist patients, families, and clinicians across disciplines, especially those in palliative and hospice care. Designating terminal AN may more readily enable patients to receive palliative care, hospice care, and emotional and practical resources for loved ones, as well as access to medical aid in dying (MAID) where legal. Therapeutic goals in these situations are to ameliorate suffering and honor the life lived. Of note, MAID is offered to individuals whose death is inevitable within six months from an underlying disease process; it provides patients a choice in how they die, not whether they die. It is not a means of suicide.

In this paper, we describe three cases of exceptional people whose AN was terminal, and who died peacefully with family around them. All three were patients of a private practice outpatient medical clinic specializing in eating disorders in Denver, Colorado. One patient, who had been a medical researcher herself, was so passionate about the topic that she asked to join as a posthumous author on this paper so her voice could be heard. The other two patients’ parents consented to share their son’s/daughter’s stories and reviewed, and all three families edited the relevant story prior to manuscript submission. All families agreed that first names should be used instead of a pseudonym or initials in order to emphasize the truly personal, real-life origin of these stories. Based on these experiences and others [ 12 , 14 ], we conclude by proposing a set of clinical characteristics of those who can be identified as having terminal AN.

Case presentations

Case 1: aaron.

Aaron was a 33-year-old man with a long history of restrictive AN, severe obsessive compulsive disorder (OCD), recurrent major depression, and chronic suicidality. He had been a sensitive child with low self-esteem and perfectionism from a young age. His parents noticed OCD traits from early childhood, but he did not receive this formal diagnosis until years later.

During his freshman year in high school, a health class warned about the risks of “eating junk food.” Aaron began to run regularly and played hours of basketball daily. One by one, he eliminated dietary fats and created food rules. His parents thought this was just a stage, an assessment they came to understand very differently over time, but they eventually recognized his serious problems and established a treatment team. Later in high school, Aaron was hospitalized several times for AN, participated in family therapy, and required his mother’s presence, even at school, to complete meals. Despite graduating as valedictorian of his high school class, he was initially too ill to start college. Later, his attempt to begin college was thwarted by his need for constant supervision of food intake. Aaron’s perfectionism and self-criticism ultimately ended his college career.

Over the next two decades, Aaron spent countless months in medical hospitals and in inpatient and residential eating disorder settings. He repeatedly gained the weight required for discharge so that he could return home, only to inevitably relapse. He felt mortified and guilty about the amount of money his family spent on his treatment, and he was acutely aware of life passing him by.

In his early 30 s, following a long and serious downward spiral during which he refused a higher level of care, his family finally threatened to call 911 if he did not enter treatment. Consequently, he was admitted to an inpatient eating disorder program. After first spending time in a hospital setting for stabilization where he refused to eat, a feeding tube was placed. A court mandate to ensure ongoing treatment was requested and granted on grounds of grave disability from his mental illness, and he spent the next 10 months against his will in inpatient and residential eating disorder care. He cut off communication with his parents but allowed the treatment team to talk with them. Eventually his therapist convinced him to have family sessions over the phone; it was the only time his parents could talk to him.

Aaron’s persistent resistance to treatment throughout his stay at the eating disorder program caused difficulty in maintaining his nutritional stability. He underwent in-depth exposure and response prevention therapy around food as he continued to be tube fed, and he was finally able to sustain his weight with oral food. At that time, he only agreed to eat to avoid the prospect of being administered olanzapine against his will, as he feared this medication would cause him to gain weight.

After Aaron had been fully weight restored for several months, he was stepped down to a partial hospital program (PHP). He immediately restricted intake and proceeded to lose nearly a pound a day, resulting in readmission to residential treatment where, after intensive efforts, he once again achieved his target weight. Aaron struggled with basic activities of daily living due to his OCD. For instance, he resisted using lotion or lip balm as he feared they might be absorbed into his skin as calories. He completed a course of intranasal ketamine in hopes of alleviating his OCD, depression, and suicidality, but ketamine treatments had no meaningful impact.

Author JG (hereafter referred to as “Dr. G”) first met Aaron for an outpatient medical consultation after he had completed this most recent residential treatment and was once again about to step down to PHP. This consultation constituted one component of an organized, comprehensive future discharge plan. In this initial medical visit, after a year of residential treatment, Aaron was medically stable. He desperately missed his eating disorder behaviors, fantasized about eating less and losing weight, and wished his AN would have already taken his life. Aaron mused that his all-or-nothing, perfectionistic temperament made the unknown terrifying, but he felt proud of how rigidly he had previously adhered to his eating disorder rituals, as he believed that few others could achieve a similar degree of calorie restriction. Despite his long history of treatments, including his year of suffering through the long court-mandated treatment, Aaron had never meaningfully changed his eating related attitudes, thoughts, or behaviors. He had absolutely no motivation for recovery.

During the initial consultation, Dr. G informed both Aaron and his emotionally supportive and highly invested parents that she could offer ongoing outpatient medical care along one of two pathways. In one, Aaron would complete PHP, be discharged to home (where he lived with his parents), see a therapist and dietitian regularly, and work on whatever degree of recovery he could bear, aiming toward a quality of life that he called “living productively.” Should he decide that he required a higher level of care, the team would promptly support that choice. On the second pathway, if Aaron relapsed and declined readmission, the outpatient team would no longer battle with him to seek a higher level of care, given the futility of his most recent, autonomy-depriving treatment course. Rather, the family and team would support and comfort him until such time as he required home palliative care and eventually hospice support. Aaron initially felt that these two choices were needlessly stark and binary, and he settled back into PHP.

Two months after the initial consultation, Aaron continued to endure PHP, primarily to honor his commitment to his residential treatment team that he would see through his course of treatment. But he felt no better. He received a course of intravenous ketamine to supplement the intranasal ketamine treatment initiated in the residential program, but he experienced no improvements in mood, hopelessness, or OCD. Just before discharge to his parents’ home, he still hadn’t decided which treatment pathway to choose. He would not accept psychiatric medications, and a team consisting of a physician, therapist, and dietitian was established to care for him at home.

However, starting on the day of his discharge from PHP, Aaron stopped eating altogether, a course of behavior that is rare even in those with severe AN. He drank only water, stating, “I don’t want to die, but my eating disorder is in charge.” A week later, he met with his longstanding outpatient therapist. She was very apprehensive about his ability to remain in the community, and she felt ambivalent concerning what her role might be if he insisted on remaining at home. Aaron told her, “I wish I could eat, but I won't eat; I don't want to die, but I feel hopeless that there's any other pathway.” The therapist worried that she would be forced to have Aaron detained against his will in his home state. A formal decision-making evaluation was performed by a local psychiatrist, and Aaron was found to possess decisional capacity. Consulting with his home therapist, Dr. G proposed that Aaron’s refusal to eat was less about “wanting to die” than simply accepting that he could not live—he was not “attracted to life” [ 17 ]. Dr. G suggested that the proper course at this point would be to proceed with a home palliative care consultation and shift treatment goals to supporting comfort and dignity, as Aaron clearly declined a return to treatment.

During a telemedicine meeting with Dr. G a week later, Aaron asserted, “I don't want to do this for anybody else anymore. It's time to do things only if I want them.” At about this time, Aaron also sought comfort from his therapist and his religious leader, as the prospect of death frightened him, and he was unsure what dying would mean. But he described that being given the choice of what would happen next was empowering – “different, scary, relieving, and right” – in great contrast to repeatedly feeling powerless and demeaned by his many prior chaotic relapses followed by intense pressures to return to treatment. Aaron signed a Do Not Resuscitate (DNR) order and within the next few days was referred to a home palliative and hospice care organization. Dr. G spoke with the organization’s medical director to explain why this brilliant 33-year-old man who was refusing to eat was being referred for palliative care. Aaron hoped that the home palliative care service would help him and his family “process this sorrow and fear.”

Two weeks later, after more than a month of eating nothing and drinking only water, Aaron’s OCD and insomnia were heightened; he worried that by simply smelling his mother’s cooking he might be ingesting those calories. He believed that he might absorb calories from the grocery cart of the person ahead of him at the store. Always reluctant to take medications, he began to consider accepting anxiolytics from the hospice staff, whom he thought were extremely kind.

Aaron noted that by spending no energy forcing himself to eat, he was able to direct energy toward engaging in his faith. His siblings came to visit, and as they talked and laughed, he realized it had been years since they had connected positively. Throughout the course of his eating disorder, every family connection had felt fraught. He summarized his collective family’s response to this pre-terminal phase as, “They were very supportive. They recognize the gravity of this situation. They aren't angry, sad but not fearful.” As he chose to spend his days talking with his parents and sleeping, he noted that he was thinking about others "rather than being so self-absorbed." Imagining his parents’ distress made him sad, and he wanted his parents to keep getting support after his death. "This is one of the hardest things they've had to deal with in their lives."

Even as he rapidly lost weight, Aaron’s body distortions grew worse, and he kept wishing his weight would fall even faster. After almost six weeks without food, Aaron began accepting anxiolytics and antiemetics. He obsessed that someone might have injected his water bottles with calories. When Dr. G asked if he had any words to share for posterity, he expressed words of warning for those who might find themselves in his situation: “OCD will amplify,” “Be prepared for an annoying obsessive brain that might drive you crazy,” and “Just because you aren’t eating doesn’t mean it’s all good now.” He expressed how vital it was to “have people in your life [doctor, parents, family, close friends] whom you trust and can seek reassurance from, who love you unconditionally,” whose comforting words can be “life-saving in terms of giving you peace.” He connected deeply with a feeling that peace comes from God.

After about eight and a half weeks without any food, Aaron was spontaneously vomiting daily and feeling much weaker. Beautifully cared for by home hospice, he began to take low dose morphine for pain and distress. When Aaron’s parents wondered what his death certificate would say about cause of death, Dr. G reassured them that the cause would be anorexia nervosa and malnutrition, not suicide. Often speaking through tears, Aaron’s parents described how they were enjoying a deep loving sweetness with their son that they hadn’t experienced in years, and how they would miss him when he died. They felt compassion for those who lose a loved one abruptly without having time for love, connection, and closure. Often, they saw glimpses of the boy they hadn’t seen in years, as when he looked at photos that made him laugh.

Two weeks later, Aaron passed away with his family surrounding him. Even as they were exhausted and grieving deeply, his parents expressed enormous gratitude for the care he received and for the way they had been able to reconnect with him.

Case 2: Jessica

Jessica was a 36-year-old woman with a history of OCD and AN, purging subtype (laxatives) that began during her junior year of high school, when she tried to lose weight prior to a vacation. This started a pattern of restricting, binge eating, and then overexercising that persisted into college. When her weight, which had remained normal for some time, did eventually drop, she left college for intensive outpatient eating disorder treatment. It was such a difficult experience that from this time on, she mistrusted eating disorders providers. She lamented that she lost most of the fun of college to her eating disorder.

Due to progressive constipation, Jessica began using laxatives, which led to laxative abuse. She soon found that every time she stopped taking laxatives, her weight skyrocketed (due to rehydration and rebound edema). Ultimately, her AN caused her to drop out of nursing school. Jessica experienced her first hip fracture from severe osteoporosis when she was critically emaciated at age 27, requiring her to move home with her parents; the following month she incurred a stress fracture of her shoulder from using crutches. Her parents pursued guardianship as Jessica was refusing a higher level of care, but her medical team refused to release records to the family’s attorney due to HIPAA. Without the option to pursue guardianship with mandated longer-term residential treatment, her parents came to believe this was the critical juncture where recovery might have been possible, but instead her disease became more entrenched. Over the next 7 months, working with her outpatient primary care provider, dietitian, and therapist, she slowly gained a meaningful amount of weight, although she remained very underweight. Following this, she got an excellent job and once again lived independently from her parents, working productively for three years. However, at age 29, her increased anxiety, the side effects of laxative abuse, and the shame of her anorexia caused her to separate herself from her family and to work from home, increasing her isolation. She checked herself into an expert inpatient medical center to stop using laxatives and then spent a week in inpatient eating disorder treatment before leaving against medical advice. Jessica did manage to stay off laxatives for a year but was plagued by edema. Repeatedly, restriction and overexercise would recur, usually accompanied by laxative abuse, which at its worst consisted of taking 100 tablets a day.

During her initial consultation with Dr. G, Jessica memorably stated, “The eating disorder keeps me out of integrity with my values. It doesn't feel good. You believe something but aren't living it. This is the biggest motivation for wanting to change. I really want to live in alignment with my values, honoring my body, feeling things, stopping being unkind to my body.” Although very kind and compassionate towards others, she struggled to show herself the same grace.

Jessica met criteria for immediate admission back to the inpatient medical service, but given her prior negative experiences with treatment, she wanted to attempt to keep working and live near her parents. She agreed to outpatient care with a multidisciplinary team, focusing on harm-reduction goals. Initially, Jessica was able to follow medical and nutritional recommendations faithfully. Then, within three months of initiating outpatient medical care she fell and sustained a pelvic fracture. This was frightening, disabling, and prevented her from taking her calming (and to her, calorie-burning) nature walks. Overcome by managing the challenges of a rapidly changing body on her own and worried about her fracture and bone health, Jessica readmitted herself to specialized inpatient medical care for medical stabilization. Following stabilization, she agreed to transfer to residential care to attempt a full course of eating disorder treatment. However, after two weeks in the residential care program she left against clinical advice, unable to follow the meal plan consistently and feeling extremely distressed by her bodily changes (even though her weight had barely changed).

At home, Jessica again tried hard to follow treatment recommendations at a harm-reduction level (no laxatives, low caloric intake, gentle movement in the outdoors), but once more the distress of bodily changes was too much for her to bear. About a month after leaving the residential program, Jessica first talked about the possibility of palliative care and began talking with her mom about suicidal thoughts. Most nights she would say she hoped she didn’t wake up the next morning. In order to help Jessica resist the laxatives that gave her such severe abdominal pain and nausea, and still hoping to support her in finding an acceptable degree of harm reduction, Dr. G worked with Jessica to use diuretics to manage fluid weight changes. (Notably, this approach would rarely if ever be offered in a more typical eating disorders treatment plan.) Jessica operated within these guidelines and constraints for the next five months, at times thinking she might be able to persist, but more often lamenting that this strategy was still too difficult and painful. By this point, she had been granted indefinite leave from work and moved in with her parents.

About nine months after initial consultation, Jessica acknowledged that it was time for a palliative approach, confessing, “I’m just ready. It's been a long fight. I'm eating so little, and I'm back on the laxatives every couple of days.” She declined intranasal or intravenous ketamine which might have ameliorated her depression, OCD symptoms, and hopelessness. As she felt progressively miserable physically and psychologically, her suicidality increased. She purchased a gun, and one night she drove to a bridge with thoughts of jumping off, but then decided to return home. She had difficulty finding a therapist who understood terminal AN and who could accept her treatment trajectory, but she found and worked with a kind naturopathic doctor who specialized in mental health, and she did experience some benefit from psychiatric medications.

At this point, fearful of suffering a long, drawn-out death from starvation and unwilling to put her parents through the agony of witnessing this decline, Jessica requested referral to a palliative care specialist who assessed patients for medical aid in dying (MAID). Dr. G spoke with Jessica’s parents repeatedly, assuring them that guardianship and forced treatment were likely now to be futile. The parents had done everything possible to help their daughter find an acceptable quality of life. Jessica signed a DNR order. After speaking with the palliative care physician by phone to discuss the case and advocate for Jessica, Dr. G completed the MAID forms as consulting physician, given that Jessica’s prognosis was presumed to be 6 months or less. The palliative care physician prescribed the MAID medications.

About a year after the initial consultation, and about three months after the MAID consultation, Dr. G saw Jessica for the last time via telemedicine. Jessica wrote to Dr. G in an e-mail, “I’ve been back in a place the last several weeks where the emotional pain and the physical and emotional exhaustion of living like this are just too much for me. I’m trying to make it to the end of May, maybe through June to meet my brother’s upcoming baby before I go.” Jessica described her life as filled with unbearable pain and anxiety. Watching people walking around the neighborhood making future plans felt devastating, because she’d “give anything to be in anybody else’s shoes.” Yet when she thought about stopping diuretics, eating enough food, and gaining weight so she could physically live that life, she said, “it feels impossible.”

Jessica waited several weeks to fill the MAID prescription. She then set multiple dates to use it over a couple of months and changed her mind as that date got closer. A month before her death, she started to receive home hospice services. During this time period, she had long conversations with her parents, brother, and friends, noting that she had many happy memories over her life, apologizing for what she had put them all through over the years, and stating that she hated her eating disorder. She told them she realized that, while her eating disorder behaviors made it seem like she hadn’t loved or trusted them at times, she loved them all very much. She repeatedly told her family that she didn’t want to die, that she didn’t want to miss out on future time with her family, friends, and niece and nephew, but she just couldn’t continue to exist this way. The emotional pain and anxiety were unbearable. She couldn’t live a normal life, and she felt her body was too destroyed to recover. Her parents believe that in her last month she was trying to die naturally by barely eating, reducing her fluid intake, and walking for hours daily, even when she had to sit down often to catch her breath. She stopped driving and carried identification in case she collapsed on a walk. She fainted at home several times in the week before her death, including the night before she died. On the day she took the MAID prescription, she stayed in bed, was at peace, and spent time talking with each parent and her brother. Together as a family, they reminisced, laughed, cried, had their “hug circle” as they had called it since her childhood, and felt surrounded by love. Her parents each held a hand, and her brother sat right next to her. During the three doses of the medicine taken over an hour, she was comfortable and conscious. Within ten minutes of taking the final dose, Jessica closed her eyes, and her breathing slowed.

Jessica didn’t choose to live with anorexia. For all the years she endured living within its prison and myriad complications, her parents ultimately felt strongly that she deserved to choose the time, place, and way of her release. They felt that an unexpected blessing of MAID was that it allowed Jessica to live several months longer than she otherwise would have. Knowing she didn’t have to die a violent death by suicide, that she would have a peaceful way out when the pain and anxiety became unbearable, and that she would be able to die with dignity surrounded by loving family, allowed her to hold on longer. As a dying wish to her mother, she shared, “Mom, I'd like you to do something that will help others not go through what I went through."

Case 3: Alyssa

Alyssa, the posthumous author on this paper, was a 36-year-old woman with OCD, depression, and restrictive AN who described herself as having “a type A, neurotic personality: a sensitive, compassionate, loving person who's incredibly self-critical and has wanted to do things 0% or 110% with no gray area.” She first felt suicidal at age 13, when she realized that her body was too large to fit into standard dress sizes for her upcoming Bat Mitzvah. She started therapy at that time and was continually in therapy thereafter. After going through high school at a higher weight, the summer before college she vowed to change her body and began exercising in earnest. In college it was easy to restrict. By the time she returned home for Thanksgiving she had lost a substantial amount of weight. Everyone praised her, and she experienced “a deluge of external validation that was irresistible,” firmly establishing her eating disorder by age 18. Alyssa wrestled with AN throughout the rest of her education and career. A brilliant academic, she became the only non-physician Assistant Director of a major academic medical center residency department, mentoring residents and students, doing research, and publishing in major journals.

After struggling with AN for 15 years, during which she received intermittent outpatient support, Alyssa moved in with her parents and reduced her workload. She was extremely helpful in her mother’s struggle with a cancer diagnosis and often underplayed the significance of her own illness. At age 33, to correct severe hypercalcemia she was admitted to the teaching hospital in which she had previously worked. The family felt that her AN was hardly addressed during that hospitalization, in part due to the fact that institutional expertise for AN was confined to a pediatric program. To them, this felt like a vital missed opportunity to attempt changing her disease trajectory, in particular as the only recommendation on discharge was to seek residential eating disorder care.

Alyssa worked for 7 months to obtain insurance authorization for care in a residential eating disorders program, and to gain enough weight to meet their admission criteria. However, upon admission to that program she was deemed still too underweight (by one pound) and was referred to a specialized inpatient medical program. Being rejected for care after so much work also felt like a missed therapeutic opportunity. After a delay, Alyssa spent several weeks in the specialized hospital program and met the minimal criteria for discharge, departing with the understanding that she would immediately enroll in another residential program. However, after discharge from the hospital she refused to do so and could never accept going to an eating disorders program thereafter.

In the years prior to initial consultation with Dr. G, Alyssa’s outpatient treatment team included a local primary care physician with whom she was very close, a therapist she had been seeing regularly in recent years, and an expert eating disorders therapist who had worked with her and the family over the years. Over a period of three years, Alyssa had intermittently thought about and even phoned Dr. G’s outpatient medical clinic, but she never booked an appointment, indicating that she felt very ambivalent about recovery and was considering a palliative care approach. When she finally presented for an initial consultation, Alyssa identified her goals as follows: “I really want a life, to use my Masters in Social Work degree to help others heal, to find a partner, and to experience pleasure, laughter, joy, and freedom, including from my own brain.” As her main barrier she cited the chronic, longstanding shame and body disgust that persistently kept her from meeting her own needs.

At the time of initial consultation, Alyssa met criteria for inpatient medical hospitalization, although she experienced remarkably few physical symptoms, which reinforced her view that she must be “fine.” She declined a higher level of care. Nonetheless, she saw herself as shamefully thin, more keenly felt given her extended family’s experience of the Holocaust. She wanted to be able to walk down the street without turning heads due to being so emaciated, but concurrently struggled to balance this desire against her strong resistance to gaining weight.

Alyssa agreed to ongoing care with the clinic and accepted referral to an expert registered dietitian. She committed to at least attempt a harm reduction approach in which she would slowly restore weight to a point where she could be more physically, mentally, and professionally functional, and where she could resume her yoga practice. However, she stipulated that she would halt weight restoration if and when her AN thinking could no longer bear it. Over the course of the next year or so, she valiantly succeeded in increasing her caloric intake considerably above her previous severely restrictive baseline. But due to the hypermetabolic state often seen in malnourished patients who increase their caloric intake, she experienced no meaningful weight gain.

Nine months after initial consultation, Alyssa emphatically reflected that her goals had not changed, but she had grave doubts about her ability to achieve them. She described feeling “utterly exhausted” and could no longer muster the strength to keep fighting. She vividly described her daily internal battles, struggling every minute of the day to eat enough of her meal plan and constantly fighting against the extreme headwinds of her AN’s resistance. Once she had eaten, she would bitterly berate and punish herself for having done so. At this point she was not certain that her AN was terminal, but she was moving strongly in that direction and wanted to understand her options.

Dr. G clarified that at any time, Alyssa could choose to pursue full recovery and a higher level of care, could continue fighting as she was, or could consider two options that did not focus on recovery. The first option would be choosing palliative care. This would acknowledge that she would likely not survive and also allow her to consider a "bucket list" of experiences for the time she had left. Palliative care would mean that she could eat what appealed to her, with no pressure applied by the team. The treatment focus would be on finding joy and comfort as much as possible. Dr. G emphasized the value of signing a DNR document to protect Alyssa from the mandates of the healthcare system in the event that she experienced an abrupt decline and/or cardiac arrest. Alyssa was also advised that a home palliative care/hospice evaluation would be useful to oversee her treatment as desired during this stage, for emotional and practical support if needed and to protect her parents from any potential legal repercussions should she pass away at home as an emaciated adult. Dr. G noted that for some patients, this stage can last a long time, and that some can “reset” when pressures to gain weight and threats of mandated treatment are removed. In some cases, this state of reduced external pressure might even lead to renewed ability to engage in meaningful harm reduction and even recovery work.

The second option would be to seek hospice care. Hospice care would be suitable if the torments of her AN and the extraordinary difficulties of moving about the world in a skeletal body were beyond being helped by a palliative care approach. Given her faster metabolism, if Alyssa abandoned her attempts to consume a higher meal plan, she would clearly have a less than six-month prognosis and qualify for hospice care. With this option, Dr. G would refer Alyssa to a home hospice service, anticipating that she would become increasingly frail. The home hospice staff would establish warm relationships with Alyssa and her parents, make sure that anxiety, insomnia, nausea, and/or pain were managed, and provide them all access to psychological and spiritual support as desired. During this time, Alyssa could live her life as she chose. As she became less independent, hospice would provide assistive aids such as a shower chair, bedside commode, and hospital bed. The overall goals would be to maximize Alyssa’s comfort, dignity, and time to connect with family.

During this conversation, Dr. G also noted that Alyssa lived in a location where MAID was legal. If she chose the hospice route—and had interest—a referral for the option of MAID was also possible. Alyssa was informed that she herself would have to administer the MAID medications if she chose to use them; no one else could administer them to her. After completing the required regulatory processes and filling the prescription, MAID medications could be used or not as desired. But, as the human body can be exceptionally resilient even with terminal malnutrition, having the medications at hand would give Alyssa the opportunity, while still having an intact brain, to choose not to suffer through additional weeks of extreme physical discomfort and weakness.

A week after these options were reviewed, Alyssa wrote Dr. G:

After deep reflection and discussion with my parents, I’ve decided it makes sense to initiate the Hospice process (Ie evaluation, etc.) now so my family and I are prepared for what may come. I would value your guidance and help with this….I do not know if they have ever worked with patients like myself… I would love for you to be the PCP overseeing this process regardless of the Hospice we select if, and only if, you are comfortable with this. I want to be clear that my priority is to obtain access to the medications that would support my legal right to die should I wind up choosing this path in the future. I feel strongly that based on our thorough discussion, I am aware of my options and their risks and benefits in light of the trajectory of my illness. Please do let me know what I can do to help facilitate initiation of this process. I am available and happy to help.

In a family meeting the following week, Alyssa’s father, a physician, tearfully shared the principles he and Alyssa’s mother had come to accept during intense conversations with their daughter: She had the right to choose care or no care after having been ill for 18 years. There would be no ultimatums. This disease would probably be the reason that "we lose you." They knew how much she had suffered and continued to suffer, and they understood that at some point the psychological anguish would become unbearable for her. They respected that this could be as bad as physical pain. They accepted that when the anguish became unbearable, Alyssa would have the right to end her life by taking medical aid in dying medications. They agreed that financial planning and end of life planning were worthy tasks. To Dr. G and to Alyssa, these words conveyed deeply reassuring love, compassion, and support.

Alyssa’s parents asked whether any treatments remained that might yet change the outcome of her course, specifically noting that Alyssa had not completed a full residential eating disorder program, never fully restored weight, never tried newer psychedelic options such as ketamine, psilocybin, or MDMA, and hadn’t had a feeding tube. Dr. G acknowledged that all but the feeding tube might ordinarily be undertaken prior to someone’s seeking end of life care for AN. Yet, she had been suffering for so long, and despite many conversations about all these treatment possibilities, Alyssa would not consent to any of them. Therefore, given her clarity of understanding around these issues and her sense that she could not fight anymore, everyone had to accept that they weren’t meaningful options. With regards to a surgical feeding tube in the context of AN rather than due an anatomical impediment, Dr. G noted that if someone restricts the “tube God gave them,” i.e. their esophagus, they would also be very likely to restrict through a surgical feeding tube, so that would not be a long term solution.

An excellent home hospice agency agreed to work with Alyssa and her family, and Dr. G placed a referral for a MAID consultation. The palliative care physician met with Alyssa about MAID. Since the idea of requesting MAID for a patient with AN was so foreign and unnerving to him, he asked Alyssa to be assessed formally for decision-making capacity. After a local psychiatrist confirmed that Alyssa clearly possessed decision-making capacity, the palliative care doctor fully accepted Alyssa’s right to enter home hospice care and could understand the rationale for MAID provision. However, even as he and his team provided empathetic support, he ultimately felt personally unable to write the MAID medication prescription due to his discomfort with the unique presentation. Clarification with the state’s Medical Board and other regulatory entities determined that Dr. G, licensed in this state although based in another state, could serve as prescribing physician, and that Alyssa’s longstanding primary care physician could serve as consulting physician. Dr. G prescribed the MAID medications about six weeks after Alyssa entered hospice care. Four days before her death, eager to contribute to this article, Alyssa sent Dr. G the following (unedited) notes about her thoughts on this complicated topic:

Below I share the considerations I made as I weighed the potential benefits and risks of pursing MAID. I share my experience in hopes of offering a first-hand perspective that may help other patients and physicians as they consider and weigh the option of utilizing MAID, rather than offering a prescriptive decision-making tool or recommending that all patients with terminal SEAN have access to such medication.

Personal considerations:

MAID not pursued in isolation, but rather in the context of being in Hospice care following a terminal dx of anorexia (i.e., estimated 6 months or left to live). I would not have qualified for Hospice care unless my illness was terminal (i.e., not reversible for me in light of physical, mental, emotional damage to my body).

In my individual case, death was inevitable. I clearly understood my prognosis and accepted this. I saw MAID as an opportunity to select a specified time and circumstances for my death. Death itself is fraught with fear, ambiguity, a sense of powerlessness and tremendous anguish, not just for the patient who is dying, but for that patient’s family. Upon deep reflection, I came to see MAID as an opportunity to relieve my suffering and minimize at least some of my family’s suffering related to my death by choosing the when and how of my death, rather than “wait” for sudden death from cardiac arrest or other outcome of my illness or experience a slow and protracted death as my family and I watch my body and mind degrade over days and maybe even weeks of time

I had to ask important questions about my quality of life and whether for me, the quality of my life was more important than the quantity of days I remained alive. I was experiencing extreme physical pain, was unable to walk, could not sit without discomfort, I couldn’t swallow my food, my breath was labored, and I had frequent chest pain. I was not living. I felt like “dead girl barely walking.” For me personally, a longer life spent in bed feeling ill and suffering and dependent on others to provide most of my care was not how I wanted to live. My concerns about this suffering trumped any fear of selecting the route of my death (again, knowing that death was inevitable). Knowing that I could utilize MAID if the suffering became so severe offered me a sense of ease and peace of mind in my final stage of life that I would not have had otherwise

One question that I needed to answer for myself honestly was whether I understood the impact use of MAID would have on my family. I had to confront that my use of MAID would be difficult for them, not just the idea of my using it but how their presence at the end of my death, watching me administer my own medications to die, would be ingrained in their memories of me as their daughter and their sister, and how this story of my passing would affect my family throughout the generations to come (i.e., what stories would they tell about my life and death, how could this be traumatizing or perhaps seen as healing?). Such questions could only be answered through ongoing involvement and discussion with my family members, which we had with my physicians and amongst ourselves

Another important question I asked was how would I want a family member to die if I knew their illness was terminal and death was imminent. Would I see their use of MAID as a compassionate act towards themselves? How would I tell their story? Would I extend the compassion I was asking for from them to them if the situation were reversed? I also asked them individually how they would want to die if they could have the option of choosing?

All in all, a voluntary decision, not made in haste, thoughtful, careful, meticulous. Decision made as arrangements were made for my passing including burial arrangements, financial and family orders.

Decision also heavily considered with spiritual advisors (chaplain, Rabbi, etc.)

Challenges faced:

MAID in general is highly controversial and its use is RARE – even for patients who do receive it, many do not end up using it. Only a handful of physicians who support using it. Makes it unknown and scary for physicians and patients alike; limited research

Makes acceptance of its use more difficult for family members, too

Prescribing MAID (for some physicians) may feel counter to physician identity as healer & fixer; may spark deep internal/ethical/moral debate for individual physicians as they weigh the option of whether to prescribe

Do they see this as an act of compassion for patients who wish to relieve their suffering?

Do they see this as prescribing a means of suicide?

Anorexia specific – for me, a big issue that caused most ethical debate was whether my case of anorexia nervosa was “reversible.” Many physicians misunderstand SEAN (not even an official DSM diagnosis) and that while anorexia nervosa is a psychiatric illness, it comes with severe medical complications that ultimately are the reason for death. Some of the physicians I worked with could not believe my illness was indeed terminal, but rather felt that there would be something that could be done to reverse the physical damage done to my body that would somehow lengthen my life (even if not for very long – i.e., 1 year).

Yes, perhaps I could stay alive for a few months while in the hospital, but I would have to live in the hospital (MDs might see the benefit of this, but could I? NO! This is where my own reflection around quality of life came in)

My personal belief that this is what makes having such an extreme form of AN so agonizing – mental and emotional suffering is compounded by painful physical complications

Gross misunderstanding about anorexia nervosa in general.

Just over a day before she died, Alyssa wrote to Dr. G, “Thank you with all of my heart for helping to make this possible. I view it as a tremendous act of love.” With family and spiritual support surrounding her, Alyssa became unresponsive in the natural course of her malnutrition. Shortly thereafter, she passed away peacefully. She never actually ingested the MAID medication she had at her disposal.

By presenting these three cases, we have intended to convey some of the emotional, moral, and ethical challenges and dilemmas that patients with SE-AN, their families, and their professional caregivers may face at the end of life. Suffering from unrelenting and irredeemable disorders, these patients made difficult choices, ultimately deciding “enough is enough” [ 18 ]. The anguish endured by these patients and their families resulted in part from lack of professional understanding and consensus regarding terminal care for patients with AN. Neither the fields of palliative and hospice care nor eating disorders have provided definitions or guidance regarding what constitutes a terminal condition in AN or proper ways to address patients and their families grappling with this condition.

Accordingly, we present the following proposed clinical characteristics of those with terminal AN for consideration by both fields (Table 1 ). As illustrated by our cases, no set of criteria will apply perfectly to every patient who identifies with having a terminal case of AN. However, based on prior literature on criteria for clinical terminality [ 15 ], high SMR in those who have previously received inpatient care, are older, and have a history of more severely medically compromised presentations [ 6 , 7 , 8 , 9 , 10 , 11 ], and clinical expertise, the authors propose these clinical characteristics. Some deviation within the second and third characteristics is to be expected and must be individualized to the patient situation. However, the first and fourth must be met in full.

Proposed clinical characteristics of patients with terminal anorexia nervosa

A diagnosis of anorexia nervosa . Anorexia nervosa is the only eating disorder that carries a guaranteed medical cause of death from malnutrition should weight loss continue unabated. As a result, consistent with literature on duration of life during hunger strikes resulting in death [ 16 ], a prognosis of less than 6 months can fairly be established when the patient acknowledges further treatment to be futile and stops engaging in active recovery work. A less than six-month prognosis is congruent with current practice around determination of terminal diagnoses. We fully recognize that patients with SE-AN are likely to have other psychiatric conditions as well.

Age of 30 or older . This criterion accommodates for what is clinically seen as a potential “late maturation phase” in which even those who have been sick for a long time may discover a shift in values and desires that motivates recovery as they enter their late 20 s. Every effort should be made to promote full recovery and continuation of life in those younger than 30. However, the SMR data of multiple recent studies showing the highest death rates in those with a history of inpatient admissions, longer duration of AN, and age over 30 years old [ 6 , 7 , 8 , 9 ], taken alongside what functionally has often been a decade or two of exhaustive, ultimately unsuccessful eating disorder treatment, indicates that the age of around 30 as a minimum for terminal AN is reasonable.

Prior persistent engagement in high-quality, multidisciplinary eating disorder care. Worldwide access to expert eating disorder care varies widely, as does the availability of access to expert inpatient, residential, and full day treatment programs for those with eating disorders. Thus, the definition of care identified here must remain somewhat broad. Before someone can decide they cannot recover, they must have participated in high-quality, expert care to the maximum extent that this is available. This provision should motivate policies that allow for transfers of patients out of designated “networks” that lack expertise, with funding coverage provided at a center of excellence. Ideally, at least some of this treatment will have been undertaken at a sufficiently high level of care to provide extensive structure and support, preferably to the point of full weight restoration at least once in the relatively recent past. Congruent with receipt of such care, qualified health care professionals on the team must support the patient in their decision to stop fighting. We acknowledge that many factors may impact patients’ ability to participate in such care, including lack of access to eating disorders expertise, limitations of the healthcare system, and a personal sense—often based on prior treatment experiences—that admission to certain care settings would cause more harm than good.

Consistent, clear expression by an individual who possesses decision-making capacity that they understand further treatment to be futile, they choose to stop trying to prolong their lives, and they accept that death will be the natural outcome. Careful determination of decisional capacity is required in each case [ 19 ]. An individual who wavers in their conviction or expresses different goals to different people is not yet ready to receive the appellation of terminal AN.

Most eating disorders providers have cared for patients with AN who, despite suffering for decades, continue to show extraordinary determination and resilience. These patients still want help, at least with a harm-avoidance strategy if not with outright full recovery. In these cases, every effort must be made to support the patient’s wishes and provide appropriate resources for recovery. There must be no “giving up” on those who still seek to get better. Indeed, the drive to live and ability to find aspects of life worth fighting for can be seen vividly in the majority of those with AN, even in the face of years or decades of illness and suffering. The psychological imperatives of AN that often lead patients to resist or refuse clinically appropriate care, hazarding medical and psychological risk and deterioration, may seem to conflict with a stated desire to keep trying for recovery. However, in honoring patient autonomy, responsive care must always be offered as long as an individual states that this is their wish.

Patients in their earlier and younger years of AN may say they would rather die than gain weight or nourish themselves properly, a characteristic indicating that AN may present as an ego-syntonic mental illness. Nonetheless, the majority of patients with AN ultimately recover, and such expressions of anguish can be met with compassion and appropriate multidisciplinary care. We would not condone accepting a terminal diagnosis in younger patients. Of note, there are no explicit physiologic markers or measurables (weight, degree of weight loss, presence of or degree of organ failure, vital signs) which delineate someone with terminal AN. Even individuals with extreme medical malnutrition may recover fully if they so choose and have access to expert care. By contrast, if all criteria for terminal AN are met, as in the case of Aaron, individuals should not be obliged to demonstrate extreme medical instability before having the right to choose to stop fighting. Furthermore, while the obsessional ruminations of individuals with AN can be perplexing, clinicians should not regard the presence of body distortions and food fears as proof that these patients are unable to understand personal options and make reasoned health care decisions.

How can we determine that patients with severe anorexia nervosa possess the clinical decision-making capacity necessary to permit them to withdraw from treatment? With respect to decision-making capacity, four traditional criteria are usually applied: understanding, appreciation, ability to reason, and communication of decision [ 20 ]. In Dr. G’s estimation, confirmed in the two cases where formal independent assessment by a psychiatrist was performed, each of the patients met these criteria and was therefore capable of deciding to withdraw from conventional treatment. Alyssa’s clear, incisive writing just days before her death beautifully illustrates the insight and cognitive capacity that many patients with AN possess right up to the end of their life.

Clinical, legal, and ethical commentators in the field concur that withdrawal from treatment may be appropriate when further treatment, whether voluntary of involuntary, will provide only brief improvement, and is unlikely to offer sustained quality of life [ 21 , 22 ]. A formal assessment of decision-making capacity may help ameliorate family member fears that such an important decision is being made in an appropriate and ethical manner, especially when AN fears and distortions can seem so irrational. In addition, a formal bioethics evaluation might be valuable, but consideration of this must be balanced against most bioethicists’ lack of experience with patients who have AN, with the risk that their own innate and misguided reaction that “this patient just has to eat” could undermine a qualified patient’s decisions that are supported by their longstanding care team and family. Even medical ethicists must be wary about how their own cognitive and affective biases might influence their recommendations. [ 23 ]

Family members and carers play an immensely important role in the lives of those with AN. They bear witness to the suffering and challenges experienced by those with AN and are usually directly involved in the recovery process in multiple ways (financial/material support/behavioral support/engagement in the therapeutic work, among others). Many dread the day their child legally becomes an adult and can choose to exclude them from the details of recovery work, such that they become the financial supporters of care they are no longer privy to. The exhaustion, fear, love, and hope experienced by family members cannot be overstated. In any case where a patient meets the criteria for terminal AN, it is always preferable to include family members in the discussions and ideally come to a consensus. There may be dissent within a family about whether their loved one should be allowed to make the decision to stop fighting. These three cases illustrated how each family was meaningfully involved in the clinical discussions in the months before each patient’s death. Each family’s ultimate acceptance (through deep grief) of their son or daughter’s prognosis and choice contributed to a heightened sense of connection and love prior to death.

Acknowledging the considerable controversies surrounding MAID for patients with mental disorders [ 24 , 25 , 26 ], we also submit that patients with terminal AN who are severely physiologically compromised, and whose end-of life suffering results from both psychological and physical pain, should be afforded access to medical aid in dying in locations where such assistance has been legalized—just like other patients with terminal conditions.

AN confers an exceptionally high death rate. The lack of acceptance of terminality in AN and the absence of professionally condoned protocols and standard procedures for supporting patients and families through these phases further complicates end-of-life stages for the adults with AN who cannot keep fighting. These represent a small fraction even of the population of those with SE-AN. Per our proposed clinical characteristics, patients must not only decline further recovery-oriented treatment (which is not uncommon at times for those with AN), but also must explicitly and consistently choose to stop trying to prolong their lives, accepting that death will be the natural outcome. When a patient begins talking about the possibility of not being able to survive, every effort should be made to validate such a serious perspective and to offer an individualized and thoughtful series of harm reduction strategies and treatment options that might make life bearable. However, the process of seeking alternatives to death must not be so exhaustive as to disrespect limits the patient sets; while a family might be desperate for their loved one to try an experimental treatment or “just try going to treatment one more time,” they must ultimately accept the patient’s lack of consent for these.

Our proposed clinical characteristics of patients with terminal AN have no bearing on those who wish to keep fighting despite very long-standing and severe disease, even when their eating disorder behaviors seem incongruent with survival. Very specifically, to move toward a designation of terminal AN, an individual must express consistently that they can no longer live with their disease and will no longer maintain a minimum nutritional intake needed to support life. To be clear, each patient is unique and requires careful individual assessment and consideration as to the best approach going forward. Consistent with calls from others regarding the need for better definition and agreement regarding labeling and staging for SE-AN in general [1,2,3,4 5], the authors hope that these cases and characteristics of those with terminal AN will provide a starting point for identification, care, and further discussion. We would strongly encourage the development of expert consensus criteria and clinical guidelines endorsed by both the fields of palliative and hospice care and eating disorders. These brave, suffering individuals deserve no less.

Availability of data and materials

All narrative data and record of e-mails exchanged with patients and families throughout and after their care with the clinic are available.

Abbreviations

  • Anorexia nervosa

Dr. Jennifer Gaudiani

Medical Aid in Dying

Obsessive Compulsive Disorder

  • Severe and enduring anorexia nervosa

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Acknowledgements

Dr. Gaudiani would like to acknowledge the Gaudiani Clinic’s nurse, Abby Brockman, RN, for her excellent clinical care of these patients and their families.

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Dr. Gaudiani was the internist for the three patients, drafted the article, and reviewed and approved revisions. Ms. Bogetz (deceased patient) contributed to the text and proposed criteria. Dr. Yager consulted with Alyssa and her family, contributed to the text, and provided extensive editing.

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Correspondence to Jennifer L. Gaudiani .

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Consent for publication of these cases was provided by all of the deceased patients’ families and by Alyssa prior to her death, and all families asked that patients’ first names be used in lieu of initials. This case report did not require further ethical approval.

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Gaudiani, J.L., Bogetz, A. & Yager, J. Terminal anorexia nervosa: three cases and proposed clinical characteristics. J Eat Disord 10 , 23 (2022). https://doi.org/10.1186/s40337-022-00548-3

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  • Published: 26 November 2015

Anorexia nervosa

  • Janet Treasure 1 ,
  • Stephan Zipfel 2 ,
  • Nadia Micali 3 , 4 ,
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  • Angélica Claudino 7 ,
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  • Feeding behaviour
  • Nutrition disorders
  • Psychiatric disorders

Anorexia nervosa (AN) is a psychiatric condition characterized by severe weight loss and secondary problems associated with malnutrition. AN predominantly develops in adolescence in the peripubertal period. Without early effective treatment, the course is protracted with physical, psychological and social morbidity and high mortality. Despite these effects, patients are noted to value the beliefs and behaviours that contribute to their illness rather than regarding them as problematic, which interferes with screening, prevention and early intervention. Involving the family to support interventions early in the course of the illness can produce sustained changes; however, those with a severe and/or protracted illness might require inpatient nursing support and/or outpatient psychotherapy. Prevention programmes aim to moderate the overvaluation of ‘thinness’ and body dissatisfaction as one of the proximal risk factors. The low prevalence of AN limits the ability to identify risk factors and to study the timing and sex distribution of the condition. However, genetic profiles, premorbid features, and brain structures and functions of patients with AN show similarities with other psychiatric disorders and contrast with obesity and metabolic disorders. Such studies are informing approaches to address the neuroadaptation to starvation and the other various physical and psychosocial deficits associated with AN. This Primer describes the epidemiology, diagnosis, screening and prevention, aetiology, treatment and quality of life of patients with AN.

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anorexia nervosa research studies

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W. Timothy Garvey, Rachel L. Batterham, … the STEP 5 Study Group

Micali, N., Hagberg, K. W., Petersen, I. & Treasure, J. L. The incidence of eating disorders in the UK in 2000–2009: findings from the General Practice Research Database. BMJ Open 3 , e002646 (2013).

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Treasure, J., Stein, D. & Maguire, S. Has the time come for a staging model to map the course of eating disorders from high risk to severe enduring illness? An examination of the evidence. Early Interv. Psychiatry 9 , 173–184 (2015).

Treasure, J. & Schmidt, U. The cognitive–interpersonal maintenance model of anorexia nervosa revisited: a summary of the evidence for cognitive, socio-emotional and interpersonal predisposing and perpetuating factors. J. Eat. Disord. 1 , 13 (2013).

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van Son, G. E., van Hoeken, D., Bartelds, A. I., van Furth, E. F. & Hoek, H. W. Time trends in the incidence of eating disorders: a primary care study in the Netherlands. Int. J. Eat. Disord. 39 , 565–569 (2006).

Zerwas, S. et al . The incidence of eating disorders in a Danish register study: associations with suicide risk and mortality. J. Psychiatr. Res. 65 , 16–22 (2015).

Currin, L., Schmidt, U., Treasure, J. & Jick, H. Time trends in eating disorder incidence. Br. J. Psychiatry 186 , 132–135 (2005).

Smink, F. R., van Hoeken, D. & Hoek, H. W. Epidemiology of eating disorders: incidence, prevalence and mortality rates. Curr. Psychiatry Rep. 14 , 406–414 (2012). This meta-analysis and review provides an overview of the epidemiology of eating disorders over time, as well as mortality rates across all eating disorders.

Hoek, H. W. et al . The incidence of anorexia nervosa on Curaçao. Am. J. Psychiatry 162 , 748–752 (2005).

Nicholls, D. E., Lynn, R. & Viner, R. M. Childhood eating disorders: British national surveillance study. Br. J. Psychiatry 198 , 295–301 (2011).

Madden, S., Morris, A., Zurynski, Y. A., Kohn, M. & Elliot, E. J. Burden of eating disorders in 5–13-year-old children in Australia. Med. J. Aust. 190 , 410–414 (2009).

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Bulik, C. M. et al . Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch. Gen. Psychiatry 63 , 305–312 (2006).

Preti, A. et al . The epidemiology of eating disorders in six European countries: results of the ESEMeD-WMH project. J. Psychiatr. Res. 43 , 1125–1132 (2009).

Hudson, J. I., Hiripi, E., Pope, H. G. & Kessler, R. C. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol. Psychiatry 61 , 348–358 (2007).

Wade, T. D., Bergin, J. L., Tiggemann, M., Bulik, C. M. & Fairburn, C. G. Prevalence and long-term course of lifetime eating disorders in an adult Australian twin cohort. Aust. N. Z. J. Psychiatry 40 , 121–128 (2006).

Swanson, S. A., Crow, S. J., Le Grange, D., Swendsen, J. & Merikangas, K. R. Prevalence and correlates of eating disorders in adolescents: results from the national comorbidity survey replication adolescent supplement. Arch. Gen. Psychiatry 68 , 714–723 (2011).

Stice, E., Marti, C. N., Shaw, H. & Jaconis, M. An 8-year longitudinal study of the natural history of threshold, subthreshold, and partial eating disorders from a community sample of adolescents. J. Abnorm. Psychol. 118 , 587–597 (2009).

Nobakht, M. & Dezhkam, M. An epidemiological study of eating disorders in Iran. Int. J. Eat. Disord. 28 , 265–271 (2000).

Kjelsås, E., Bjørnstrøm, C. & Götestam, K. G. Prevalence of eating disorders in female and male adolescents (14–15 years). Eat. Behav. 5 , 13–25 (2004).

Smink, F. R., van Hoeken, D., Oldehinkel, A. J. & Hoek, H. W. Prevalence and severity of DSM-5 eating disorders in a community cohort of adolescents. Int. J. Eat. Disord. 47 , 610–619 (2014).

Bennett, D., Sharpe, M., Freeman, C. & Carson, A. Anorexia nervosa among female secondary school students in Ghana. Br. J. Psychiatry 185 , 312–317 (2004).

Steinhausen, H.-C., Jakobsen, H., Helenius, D., Munk-Jørgensen, P. & Strober, M. A nation-wide study of the family aggregation and risk factors in anorexia nervosa over three generations. Int. J. Eat. Disord. 48 , 1–8 (2015).

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Boraska, V. et al . A genome-wide association study of anorexia nervosa. Mol. Psychiatry 19 , 1085–1094 (2014). This paper provides statistical evidence that larger sample sizes will yield significant findings.

Ripke, S. et al . Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45 , 1150–1159 (2013).

Bulik-Sullivan, B. K. et al . LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47 , 291–295 (2015).

Bulik-Sullivan, B. et al . An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47 , 1236–1241(2015).

Anttila, V. et al . The Brainstorm project; a cross-phenotype analysis of 14 brain disorders by heritability-, constraint- and pathway-based methods, using genome-wide association data from 500,000 samples. ASHG [online] , (2014).

Cederlöf, M. et al . Etiological overlap between obsessive-compulsive disorder and anorexia nervosa: a longitudinal cohort, family and twin study. World Psychiatry 14 , 333–338 (2015).

Scott-Van Zeeland, A. A. et al . Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol. Psychiatry 19 , 724–732 (2014).

Cui, H. et al . Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. J. Clin. Invest. 123 , 4706–4713 (2013).

Frank, G. K. What causes eating disorders, and what do they cause? Biol. Psychiatry 77 , 602–603 (2015).

Lawson, E. A. & Klibanski, A. Endocrine abnormalities in anorexia nervosa. Nat. Clin. Pract. Endocrinol. Metab. 4 , 407–414 (2008).

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Van den Eynde, F. et al . Structural magnetic resonance imaging in eating disorders: a systematic review of voxel-based morphometry studies. Eur. Eat. Disord. Rev. 20 , 94–105 (2012).

Rolls, E. T. Functions of the orbitofrontal and pregenual cingulate cortex in taste, olfaction, appetite and emotion. Acta Physiol. Hung. 95 , 131–164 (2008).

Critchley, H. D., Wiens, S., Rotshtein, P., Ohman, A. & Dolan, R. J. Neural systems supporting interoceptive awareness. Nat. Neurosci. 7 , 189–195 (2004).

King, J. A. et al . Global cortical thinning in acute anorexia nervosa normalizes following long-term weight restoration. Biol. Psychiatry 77 , 624–632 (2015).

Frank, G. K., Shott, M. E., Hagman, J. O. & Mittal, V. A. Alterations in brain structures related to taste reward circuitry in ill and recovered anorexia nervosa and in bulimia nervosa. Am. J. Psychiatry 170 , 1152–1160 (2013). This is the first structural brain imaging study that compared women who were ill with or had recovered from AN, who were studied in a highly nutritionally controlled environment and controlled for co-morbidity and medication use. This study found specific orbitofrontal and insula cortical alterations across stages of the illness.

Frank, G. K., Shott, M. E., Hagman, J. O. & Yang, T. T. Localized brain volume and white matter integrity alterations in adolescent anorexia nervosa. J. Am. Acad. Child Adolesc. Psychiatry 52 , 1066–1075.e5 (2013).

Frank, G. K. Recent advances in neuroimaging to model eating disorder neurobiology. Curr. Psychiatry Rep. 17 , 559 (2015).

Kaye, W. H., Wierenga, C. E., Bailer, U. F., Simmons, A. N. & Bischoff-Grethe, A. Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa. Trends Neurosci. 36 , 110–120 (2013). This paper provides the reader with a good ‘feel’ for the phenotype of AN, in terms of behaviour, temperament and neurobiology, explaining why patients are skewed towards aversive or inhibitory responses rather than reward and motivation.

Manuel-Apolinar, L., Rocha, L., Damasio, L., Tesoro-Cruz, E. & Zarate, A. Role of prenatal undernutrition in the expression of serotonin, dopamine and leptin receptors in adult mice: implications of food intake. Mol. Med. Rep. 9 , 407–412 (2014).

García-García, I. et al . Neural responses to visual food cues: insights from functional magnetic resonance imaging. Eur. Eat. Disord. Rev. 21 , 89–98 (2013).

Vocks, S., Herpertz, S., Rosenberger, C., Senf, W. & Gizewski, E. R. Effects of gustatory stimulation on brain activity during hunger and satiety in females with restricting-type anorexia nervosa: an fMRI study. J. Psychiatr. Res. 45 , 395–403 (2011).

Cowdrey, F. A., Park, R. J., Harmer, C. J. & McCabe, C. Increased neural processing of rewarding and aversive food stimuli in recovered anorexia nervosa. Biol. Psychiatry 70 , 736–743 (2011).

Oberndorfer, T. A. et al . Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa. Am. J. Psychiatry 170 , 1143–1151 (2013).

Wagner, A. et al . Altered insula response to taste stimuli in individuals recovered from restricting-type anorexia nervosa. Neuropsychopharmacology 33 , 513–523 (2008).

Bischoff-Grethe, A. et al . Altered brain response to reward and punishment in adolescents with Anorexia nervosa. Psychiatry Res. 214 , 331–340 (2013).

Decker, J. H., Figner, B. & Steinglass, J. E. On weight and waiting: delay discounting in anorexia nervosa pretreatment and posttreatment. Biol. Psychiatry 78 , 606–614 (2014).

Ehrlich, S. et al . Elevated cognitive control over reward processing in recovered female patients with anorexia nervosa. J. Psychiatry Neurosci. 40 , 307–315 (2015).

Wagner, A. et al . Altered reward processing in women recovered from anorexia nervosa. Am. J. Psychiatry 164 , 1842–1849 (2007).

Frank, G. K. W. et al . Anorexia nervosa and obesity are associated with opposite brain reward response. Neuropsychopharmacology 37 , 2031–2046 (2012). This is the first study that used a neuroscience-based model of reward system function across high and low body weight and applied it to humans. The study suggested that BMI and eating behaviour have a substantial effect on brain reward function.

Frank, G. K. W., Reynolds, J. R., Shott, M. E. & O'Reilly, R. C. Altered temporal difference learning in bulimia nervosa. Biol. Psychiatry 70 , 728–735 (2011).

Avena, N. M., Rada, P. & Hoebel, B. G. Underweight rats have enhanced dopamine release and blunted acetylcholine response in the nucleus accumbens while bingeing on sucrose. Neuroscience 156 , 865–871 (2008).

Johnson, P. M. & Kenny, P. J. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat. Neurosci. 13 , 635–641 (2010).

Kim, K. R., Ku, J., Lee, J.-H., Lee, H. & Jung, Y.-C. Functional and effective connectivity of anterior insula in anorexia nervosa and bulimia nervosa. Neurosci. Lett. 521 , 152–157 (2012).

McFadden, K. L., Tregellas, J. R., Shott, M. E. & Frank, G. K. Reduced salience and default mode network activity in women with anorexia nervosa. J. Psychiatry Neurosci. 39 , 178–188 (2014).

Gaudio, S. & Quattrocchi, C. C. Neural basis of a multidimensional model of body image distortion in anorexia nervosa. Neurosci. Biobehav. Rev. 36 , 1839–1847 (2012).

Call, C., Walsh, B. T. & Attia, E. From DSM-IV to DSM-5: changes to eating disorder diagnoses. Curr. Opin. Psychiatry 26 , 532–536 (2013).

Garfinkel, P. E. et al . Should amenorrhoea be necessary for the diagnosis of anorexia nervosa? Evidence from a Canadian community sample. Br. J. Psychiatry 168 , 500–506 (1996).

Attia, E. & Roberto, C. A. Should amenorrhea be a diagnostic criterion for anorexia nervosa? Int. J. Eat. Disord. 42 , 581–589 (2009).

Fairburn, C. G. & Harrison, P. J. Eating disorders. Lancet 361 , 407–416 (2003).

Treasure, J., Claudino, A. M. & Zucker, N. Eating disorders. Lancet 375 , 583–593 (2010).

Pisetsky, E. M., Thornton, L. M., Lichtenstein, P., Pedersen, N. L. & Bulik, C. M. Suicide attempts in women with eating disorders. J. Abnorm. Psychol. 122 , 1042–1056 (2013).

Allen, K. L., Byrne, S. M., Oddy, W. H. & Crosby, R. D. DSM-IV-TR and DSM-5 eating disorders in adolescents: prevalence, stability, and psychosocial correlates in a population-based sample of male and female adolescents. J. Abnorm. Psychol. 122 , 720–732 (2013).

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Kaye, W. H., Bulik, C. M., Thornton, L., Barbarich, N. & Masters, K. Comorbidity of anxiety disorders with anorexia and bulimia nervosa. Am. J. Psychiatry 161 , 2215–2221 (2004).

Nilsson, E. W., Gillberg, C., Gillberg, I. C. & Råstam, M. Ten-year follow-up of adolescent-onset anorexia nervosa: personality disorders. J. Am. Acad. Child Adolesc. Psychiatry 38 , 1389–1395 (1999).

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Atkinson, M. J. & Wade, T. D. Does mindfulness have potential in eating disorders prevention? A preliminary controlled trial with young adult women. Early Interv. Psychiatry http://dx.doi.org/10.1111/eip.12160 (2014).

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Stice, E., Rohde, P., Shaw, H. & Gau, J. An effectiveness trial of a selected dissonance-based eating disorder prevention program for female high school students: long-term effects. J. Consult. Clin. Psychol. 79 , 500–508 (2011).

Green, M., Scott, N., Diyankova, I. & Gasser, C. Eating disorder prevention: an experimental comparison of high level dissonance, low level dissonance, and no-treatment control. Eat. Disord. 13 , 157–169 (2005). This trial provided a creative and rigorous test of the role of dissonance induction in producing reductions in eating disorder symptoms and clearly delineated factors that maximize dissonance induction, which provided guidance for the design of more-effective second-generation dissonance-based eating disorder prevention programmes.

McMillan, W., Stice, E. & Rohde, P. High- and low-level dissonance-based eating disorder prevention programs with young women with body image concerns: an experimental trial. J. Consult. Clin. Psychol. 79 , 129–134 (2011).

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Janet Treasure & Ulrike Schmidt

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Introduction (J.T.); Epidemiology (N.M.); Mechanisms/pathophysiology (C.M.B. and G.K.F.); Diagnosis, screening and prevention (T.W. and E.S.); Management (J.T., S.Z. and A.C.); Quality of Life (E.W.); Outlook (U.S.); Overview of the Primer (J.T.).

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J.T. has received royalties from authored books, and an honorarium from Lilly for a presentation at the Diabetes Meeting 2015. She has received research grants from the National Institute for Health Research (NIHR) under the Research for Patient Benefit (RfPB) programme, Mental Health Biomedical Research Centre at South London, the Maudsley NHS Foundation Trust, King's College London, the Swiss Anorexia Nervosa Foundation, Guy's and St Thomas' Charity and the Psychiatry Research Trust. E.S. has received research grants funding from the World Association of Girl Guides and Girl Scouts. A.C. has received a travel grant from Eli Lilly in the past 5 years and won a prize for her work in 2010 at the VI Congresso Brasileiro de Cérebro, Comportamento e Emoções, RS, Brazil, which included support for attending an international conference (registration and travel expenses) by Lundbeck. C.M.B. has received a research grant from Shire Pharmaceuticals and royalties from Walker and Pearson, and acknowledges funding from the Swedish Research Council (VR Dnr: 538-2013-8864). All other authors declare no competing interests.

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anorexia nervosa research studies

Factors predicting long-term weight maintenance in anorexia nervosa: a systematic review

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Eating disorder recovery is a poorly defined concept, with large variations among researchers’ definitions. Weight maintenance is a key aspect of recovery that remains relatively underexplored in the literature. Understanding the role of weight maintenance may help guide the development of treatments. This paper aims to address this by (1) investigating the factors predicting long-term weight maintenance in anorexia nervosa (AN) patients; (2) exploring differences in predictive factors between adolescent and adult populations; and (3) exploring how weight maintenance is conceptualised in the literature. Methods: We conducted a systematic review following PRISMA guidelines to address our research questions. Five databases were searched and filtered according to our exclusion criteria.

From the search, 1059 studies were yielded, and 13 studies were included for review. A range of weight, biological and psychological factors were found to predict weight maintenance among these papers. BMI at admission and discharge from inpatient treatment was the most common predictor among the papers. Few studies investigated biological factors and mixed evidence was found for psychological factors. We found no observable differences between adult and adolescent populations. Finally, weight maintenance was defined and measured differently across studies.

This review’s findings can help contribute to a well-rounded understanding of weight maintenance, and ultimately, of recovery. This can help support clinicians in tailoring interventions to improve long-term outcomes in AN. Future research should aim to replicate studies to better understand the relationship between the factors identified and weight maintenance.

Systematic review.

Avoid common mistakes on your manuscript.

Introduction

Eating disorders are severe mental health conditions that negatively impact an individual’s physical, psychological and social functioning [ 1 ]. The prevalence and severity of eating disorder presentations have increased significantly over the last few years, with hospital admissions in the UK increasing by 84% in the last five years [ 2 ]. The recent COVID-19 pandemic further contributed, in part, to this increase, whereby individuals with eating disorders faced significant challenges such as increased social isolation, a reduced sense of control, and limited access to healthcare services [ 3 , 4 ]. Taken together, these pressures have meant that eating disorder services have struggled to meet demand and healthcare providers face the ongoing need to develop and adapt treatments accordingly.

Clinicians have highlighted concerns around long-term outcomes for patients following eating disorder treatment, in particular relapse. For example, relapse rates of 31% have been reported in anorexia nervosa (AN) [ 5 ], highlighting the importance of understanding contributing factors. Studies have explored possible mechanisms behind AN relapse and have found a wide range of possible factors. Frostad et al. [ 6 ] found BMI at discharge was a significant predictor of relapse in adults and adolescents. This lies in contrast to other studies that have found factors such as weight and shape concerns [ 5 ] having the binge–purge subtype of AN, having more motivation to recover at different points in treatment, and the severity of pre-treatment checking behaviour [ 7 ] to be significant predictors of relapse. Whilst these findings may support the adaptations of future treatments, a drawback of focusing on relapse is the heavy emphasis on preventing negative outcomes, rather than promoting positive change. These are two separate facets of long-term AN outcomes, and a substantial focus on preventing relapse may disempower an individual in their journey.

The promotion of positive outcomes in AN can be viewed through a recovery-focused lens. Numerous factors have been identified as predictors of recovery or positive outcomes, including personality traits [ 8 , 9 ], family relations [ 10 ], impulsivity [ 9 ], selflessness [ 11 ], and self-esteem [ 12 , 13 ]. As the aim for patients, families and clinicians is full recovery from AN, this has led to a comprehensive literature base on factors impacting AN recovery, and subsequently, a vast landscape of possible definitions of recovery [ 14 ]. Many researchers have attempted to operationalise ‘recovery’, with a widely accepted modern view that this should include a combination of biological, physical, and cognitive constructs [ 15 ], as well as measures of psychological and social wellbeing [ 16 ]. However, the concept of recovery remains somewhat abstract due to the variability in the individual’s experience and the personal nature of recovery for each person, which together have led to difficulties with measuring recovery, its predictors and with producing replicable studies [ 8 ].

An important aspect of recovery is weight maintenance, which refers to the sustained management of weight within a healthy range over time. Underweight individuals with AN have a twofold challenge when it comes to weight: weight gain and weight maintenance. Research has investigated factors that contribute to weight gain in various clinical settings [ 17 , 18 ]. Byrne et al. [ 17 ] found that parental self-efficacy was a significant predictor of weight gain for adolescents undergoing family-based treatment for AN. Nyman-Carlsson et al. [ 18 ] investigated pre-treatment factors predicting weight gain in a sample of young adult women and found that different predictors were significant depending on the type of treatment received. These factors included levels of emotion dysregulation and deficits in one’s ability to understand and cope with emotions. Research has also demonstrated early weight gain during treatment is a strong predictor of overall weight gain, as well as full recovery [ 19 , 20 ]. Whilst studies have investigated weight gain, there is little research on factors that impact weight maintenance. This is surprising given weight maintenance is a primary aim of AN treatments. Furthermore, research has found that weight maintenance is an essential part of full recovery outcomes [ 21 , 22 ]; for example, Rigaud et al. [ 22 ] found in a sample of adult inpatients with AN that more years spent relapse-free increased the probability of reaching full recovery with each year.

Better understanding the factors that impact weight maintenance can provide a focus on the positive aspects of AN trajectories and may support services to sustain existing improvement, including maximising current successful aspects of treatment. Furthermore, this perspective would allow us to focus on weight as an important aspect of positive change, whilst acknowledging that there are other relevant factors within recovery. This specific focus prevents researchers from becoming lost in an abstract world of ‘recovery’. In this context, recovery lacks a clear conceptualisation due to the wide number of relevant factors and its personal nature. Investigating weight maintenance in more depth can contribute to establishing a better understanding of recovery, and at the same time, the specificity of weight maintenance may allow findings to be more effectively applied in clinical settings.

This study reviews the current literature on factors associated with long-term weight maintenance in AN specifically, rather than eating disorders as a whole, given the heterogeneity of eating disorders and the likelihood of different factors affecting weight maintenance. Long-term weight maintenance is considered as defined by the papers included in the review and its definition will be further discussed in this paper.

This study further aims to investigate whether any identified factors vary between adult and adolescent populations. AN impacts adolescents and adults differently due to differences across developmental stages; for example, younger patients may have poorer medical outcomes as compared with adults [ 23 ]. Furthermore, therapeutic approaches differ according to age [ 24 ]. It is therefore possible that the factors maintaining long-term weight maintenance may also differ for each population. Another important reason to investigate differences between adults and adolescents is their differences in treatment outcome. Despite poorer morbidity, research suggests that adolescents have overall better outcomes after treatment for their eating disorder, and that the effect of factors such as early weight gain is larger for children than for adults [ 25 , 26 ]. This suggests that it is important to investigate patterns in factors that predict aspects of recovery, such as weight maintenance, as this may help explain overall differences in recovery rates for each group.

This paper aims to answer the following questions:

What are the factors associated with long-term weight maintenance following weight restoration in AN?

What are the similarities and differences in the factors associated with long-term weight maintenance between adult and adolescent AN populations?

How is long-term weight maintenance conceptualised in AN literature?

Search strategy

A systematic search of the literature was conducted by one reviewer, following PRISMA guidelines, between February and August 2022 using PubMed, MEDLINE, PsycINFO, Cochrane Library and Wiley Online Library. A pre-defined list of search terms was used to generate the literature search, including a combination of: “eating disorders”; “long term weight restoration”; “long term weight maintenance”; “anorexia nervosa”; “weight maintenance” and “restrictive eating disorder”.

Eligibility criteria and selection process

Due to the lack of available studies in this research area, no limits were placed on the patient demographics, type of intervention or study design. Studies were excluded using the following primary criteria:

Measuring weight maintenance after weight loss, in obesity and binge eating populations;

Examining factors that predict poor outcomes;

Examining factors that predict global outcomes, including psychological improvement; and

Measuring factors that predict long-term improvements in weight as a continuous variable.

Inclusion criteria included:

Studies measuring factors associated with and/or predicting weight maintenance in AN populations; and

English language studies.

For the purpose of this paper, studies met the condition of weight maintenance if they identified a weight or weight range to be sustained over a period of time. No limits were placed on the defined length of time required for a participant’s weight to be considered maintained, and patterns in these definitions will be discussed in the results.

The reviewer screened abstracts and retrieved full-texts of appropriate studies using the eligibility criteria above. Reference lists of reports that were assessed for eligibility were also searched for any appropriate studies. Reference lists were searched at this point in the retrieval process as the reports retrieved thus far were likely to be the most appropriate and may refer to other studies that contribute to their reports on weight maintenance. Figure  1 outlines the selection process for the studies included in this review, including full exclusion criteria. The third author was consulted regarding any studies that required further consultation to determine if they met inclusion or exclusion criteria.

figure 1

PRISMA 2020 flow diagram

A data extraction sheet was used by two reviewers to independently gather data on study purpose and design, intervention details, participant characteristics, definition of weight maintenance, any other measures and results/outcomes were sought from the retrieved full-text studies. These studies were then examined by the third author for clarification on study details and outcomes where needed.

The quality of the included studies was evaluated using the Quality Assessment Tool (QAT) [ 25 ].

The initial search yielded 1059 studies which were then screened for eligibility. Eighty-eight studies remained, and their abstracts were reviewed, with any papers that did not investigate factors associated with weight maintenance in AN being excluded at this stage. Thirteen studies remained, and the full texts were retrieved and assessed for eligibility. In addition, the reference lists of these 13 studies were reviewed, alongside any papers that had cited them, yielding a total of 21 additional studies. Combined, this resulted in the retrieval of full-texts for 34 studies. Twenty-one studies were excluded because they met the exclusion criteria, resulting in 13 studies for review in this paper. The process of selecting studies for review, following PRISMA guidelines, is depicted in Fig.  1 .

Sample characteristics of all included studies, as well as results from the quality assessment, are presented in Table  1 . All studies examined factors that influence long-term weight maintenance in individuals with AN as part of their research, although some studies did not investigate this as a primary aim. All the included studies were published between 2007 – 2021. In all 13 studies, the samples consisted of patients who had been admitted to inpatient or day patient programmes [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ] and in 6 of these studies, patients had been discharged to outpatient programmes [ 26 , 27 , 28 , 29 , 30 , 38 ].

The mean age of participants across all studies ranged from 14.40 to 32.55 years. Data from studies show that the average weight maintenance rate for the participants ranged from 32.10% to 62.50%. Six studies included only adults [ 26 , 28 , 33 , 35 , 37 , 38 ], two studies included only adolescents [ 29 , 32 ], and five studies included both adults and adolescents [ 27 , 30 , 31 , 34 , 36 ]. The combined sample size across all the studies was 1689. Significant findings and p-values from the included papers are presented in Table  2 .

Definition of weight maintenance

There was a range of weight maintenance definitions across the studies, with different definitions for both adult and adolescent samples. Eleven studies used a measure of between BMI ≥18 and 19.5 [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 ], whilst Forman [ 34 ] used > 85% median BMI (%mBMI).

All studies took measures at three or more time points: admission, discharge and one or more follow-up points. Follow-up ranged from 6 months to 5 years. Six studies provided measures of weight between discharge and follow-up to ensure weight maintenance was sustained during the given time period [ 27 , 28 , 30 , 31 , 35 , 38 ]. From these, two studies used only in-person measures [ 27 , 30 ], two studies used only online/phone measures [ 31 , 35 ], and two studies used a combination of both [ 28 , 38 ]. Furthermore, three studies defined the time in weight maintenance needed for a patient to be considered in ‘maintenance’, specifying a requirement ranging from 4 to 8 consecutive weeks [ 27 , 28 , 30 ].

After reviewing the included articles, our findings can be grouped into three themes: BMI/weight variables; biological markers; and psychological markers.

Weight variables—BMI

Overall, BMI was most commonly investigated as a predictor of weight maintenance across the studies [ 26 , 29 , 30 , 31 , 32 , 35 , 37 ].

The most common finding was that BMI at discharge from inpatient treatment significantly predicted weight maintenance at follow-up [ 26 , 30 , 31 , 35 , 37 ]. Kaplan [ 30 ] found that women with a higher BMI at discharge from intensive treatment (inpatient or day patient) were more likely to maintain their weight at 6- and 12-month follow-up. El Ghoch [ 26 ] found discharge BMI significantly predicted weight maintenance at 12-month follow-up in a sample of inpatient women. Redgrave [ 37 ] also found similar results using a more stringent measure of maintenance (BMI ≥ 19 kg/m 2 ) at 6-month follow-up, and two studies found similar findings at longer term follow-up, namely up to 5 years [ 31 , 35 ]. These five studies reported that participants had a discharge BMI between 19.0 ± 3.3 kg/m 2 and 20.3 ± 0.5 kg/m 2 .

Alternatively, only two studies found that a higher BMI at admission to inpatient treatment significantly predicted weight maintenance up to 1-year follow-up [ 29 , 31 ]. Castro-Fornieles [ 29 ] found that admission BMI predicted weight maintenance at 9-month follow-up. Glasofer [ 31 ] found that BMI at admission predicted weight maintenance at 18.5 kg/m 2 , but not at a more stringent cut off at 19.5 kg/m 2 , whereas discharge BMI predicted maintenance in both maintenance at 18.5 kg/m 2 and at 19.5 kg/m 2 . These studies reported a BMI at admission between 15.5 ± 1.4 kg/m 2 and 16.0 ± 1.86 kg/m 2 .

However, not all studies found BMI to be a significant predictor. Boehm [ 32 ] used a different measure of BMI and found that increases in BMI standard deviation scores did not significantly predict weight maintenance at follow-up, which was a mean of 3.7 years after the start of inpatient treatment.

Other weight variables

Some studies investigated the predictive value of other weight-related variables on long-term weight maintenance. Forman [ 34 ] found that %MBMI was a significant predictor of weight maintenance at 1-year follow-up in a sample of adolescents and young adults, such that for each 5% increase in baseline %MBMI, patients were 1.69 times more likely to reach weight maintenance.

Uniacke [ 27 ] investigated the impact of weight suppression using data from Kaplan’s [ 30 ] study. Weight suppression refers to the difference between a person’s previous highest weight and their current weight [ 40 ]. Whilst previous research has found that weight suppression predicts weight gain outcomes [ 40 ], Uniacke [ 27 ] found neither weight suppression, nor the interaction between weight suppression and BMI (measured at start of outpatient treatment), significantly predicted weight maintenance at follow-up.

One study investigated the predictive value of early weight gain on long-term outcomes. Kaplan [ 30 ] found that the rate of weight change, namely a lower rate of weekly weight loss, in the first 28 days of outpatient CBT treatment was a significant predictor of weight maintenance.

Biological markers

Three studies investigated the impact of biological factors related to weight [ 26 , 28 , 38 ]. Two studies found that body fat percentage, measured using a whole-body DXA scan and MRI imaging, did not significantly predict weight maintenance at 12-month follow-up [ 26 , 38 ]. However, Kim [ 28 ] found that both body fat percentage and higher levels of leptin (fat-adjusted) pre-discharge from inpatient treatment, measured using whole-body MRI imaging, significantly predicted weight maintenance at 12-month follow-up.

Psychological markers

The identified studies in this paper investigated a range of psychological markers with mixed findings. Some studies found significant findings for predictors related to motivation and belief in oneself to change [ 29 , 36 ]. Castro-Fornieles [ 29 ] found that readiness to recover significantly predicted weight maintenance at 9-month follow-up in a sample of adolescents. Cooper [ 36 ] found that normative eating self-efficacy at admission was significantly associated with long-term weight maintenance, with participants 4.65 times more likely to have maintained weight at 6-month follow-up for each one-unit increase in normative eating self-efficacy scores from admission to follow-up.

Three studies investigated the impact of body image concern components on weight maintenance outcomes namely: ‘fear of weight gain’, ‘preoccupation with weight or shape’, ‘feeling fat’, body image distortion, and body image self-efficacy [ 32 , 33 , 36 ]. Calugi [ 33 ] explored a range of variables, measured by using items taken from the Eating Disorder Examination 12.0D at the end of treatment, and found that lower scores for ‘fear of weight gain’ at baseline were associated with a higher likelihood of maintaining weight at 6- and 12-month follow-up in a sample of young women. Calugi [ 33 ] also found that lower scores of ‘preoccupation with shape or weight’, and ‘feeling fat’ predicted weight maintenance at 6-month follow-up, but not at 12-month follow-up. However, the authors did not include significance values in their findings therefore it is unclear whether these measures are significant predictors. In contrast, Boehm [ 32 ] investigated a separate facet of body image, specifically perceptual body image distortion, referring to the accuracy of comparison between one’s perceived and actual body size [ 41 ], and found this did not significantly predict weight maintenance, although it was a significant predictor of long-term global outcome (including psychological outcomes). In line with this, Cooper [ 36 ] found that improvements in body dissatisfaction and body image self-efficacy from admission to follow-up, namely the belief in oneself to complete everyday tasks without being held back by body image concerns [ 42 ], did not significantly predict long-term weight maintenance either.

Other studies found that psychological variables, including anxiety symptoms, depression symptoms, eating disorder psychopathology, expectations for recovery, personality traits and quality of life did not significantly predict long-term weight maintenance [ 30 , 35 , 36 ].

Difference between adult and adolescent samples

The studies were reviewed to examine whether any predictors differentiated the adult and adolescent patient groups. None of the studies with both adolescent and adult samples analysed differences in predictors between these two groups. Studies looking at biological markers used only adult samples. Otherwise, there were no observable patterns in the data to suggest that any variable has been found to predict weight maintenance more consistently in adult or adolescent samples.

The overarching aim of this review was to explore the factors predicting long-term weight maintenance in adults and adolescents with AN, and then compare any differences between adults and adolescents. Another aim was to evaluate how weight maintenance is defined and measured among these papers. A literature review was conducted following the PRISMA framework, resulting in 13 studies. The review identified a range of weight, biological and psychological factors investigated in relation to weight maintenance, but also found that the concept of weight maintenance varied among the studies.

BMI at admission and discharge

The most common significant finding across studies was that BMI at admission and discharge from inpatient treatment significantly predicted weight maintenance across both adult and adolescent samples.

Our finding that admission BMI predicts weight maintenance is mirrored in the literature on recovery, as admission BMI has been found to significantly predict treatment outcome and recovery [ 43 , 44 ]. However, we found that BMI at discharge from treatment was a more common significant predictor of weight maintenance than admission BMI among the included studies. This finding is important as there is little research on the predictive value of discharge BMI in the recovery and relapse literature. A possible reason for this finding is that patients with a higher discharge BMI would have a wider margin for some weight loss to remain in the ‘maintenance’ category as compared to those with a lower discharge BMI, making maintenance easier from a weight perspective. It is also possible that higher BMI at discharge correlates with increased cognitive function recovery, which is linked to increased cognitive flexibility [ 45 ]. This may support individuals in their efforts to maintain their weight after treatment, although further research is needed to investigate these relationships.

Research on recovery has investigated changes in BMI during inpatient treatment, rather than BMI before or after treatment, and found that larger changes in BMI between admission and discharge were a significant predictor of remission at follow-up, whereas admission BMI was not a significant predictor [ 46 ]. It would be interesting to investigate this construct further in relation to long-term weight maintenance, in order to better understand the predictive value and relationships between admission BMI, discharge BMI and weight gain during treatment.

Some papers included in this review investigated the predictive value of other weight-related variables, such as weight suppression and rate of weight change in treatment [ 27 , 28 ]. Whilst some findings are significant, given that there has been little replication of any significant findings on these weight variables, future research is needed.

Biological factors

This review also identified studies that investigated biological factors predicting weight maintenance, namely body fat and leptin levels. Whilst studies investigating body fat found this was not a significant predictor of weight maintenance [ 26 , 38 ], one study found that body fat percentage and leptin levels at discharge significantly predicted weight maintenance at follow-up [ 28 ]. This may correlate with our finding that discharge BMI predicts weight maintenance, as identified in this review. Given the relationship between body fat percentage and leptin levels with a person’s weight for height, these findings may be linked [ 6 ].

Psychological factors

The present study found a range of psychological factors affecting weight maintenance among the literature. Some studies found that factors related to self-efficacy and motivation to change significantly predicted weight maintenance [ 36 , 39 ]. Research suggests that increased self-efficacy predicts end-of-treatment outcomes in eating disorder populations [ 12 , 47 ], and it is possible that this may help to support individuals with AN in maintaining their weight after treatment, helping them cope with difficulties and challenges they may face during this process [ 48 ]. However, the other studies looking at body image constructs in this review found mixed results [ 32 , 33 , 36 ]. Research suggests that psychological factors tend to take longer than physical factors to improve [ 49 ], and body image disturbance is suggested to shift in the later stages of recovery [ 12 ]. This may explain these inconsistent findings in the present review, though this should be interpreted with caution.

Adult vs adolescent samples

Our second aim was to explore whether there were any differences between adult and adolescent samples in factors that predict weight maintenance. We found no observable patterns in results from the included studies between age groups. This may be due to the limited number of studies in this review, which will have impacted our ability to observe patterns; it would be important for future research to investigate this further. An understanding of the role of different factors in weight maintenance may help clinicians to tailor interventions according to age group, as adolescents and adults face different challenges when overcoming eating disorders. [ 50 ].

Conceptualisation of weight maintenance

We found that many studies used different definitions of weight maintenance, including different weight cut-offs and time periods required for weight restoration to be considered maintenance. This makes it difficult to compare findings across studies because different factors may have varying predictive value. For example, one study using a different measure of BMI, namely BMI-SDS, found this did not predict weight maintenance [ 32 ], which may suggest that the measurements used may impact findings. Further, one study with a notably longer-term follow-up period [ 32 ] had non-significant findings regarding a range of variables. This highlights the need for more consistent measurements and follow-up periods, to gain a better understanding of predictive variables in weight maintenance.

Despite this, many studies used the weight criterion from the Morgan–Russell scale [ 51 ]. These studies also included menstrual recovery as part of their weight maintenance definition. This dilutes the definition of weight maintenance, which cannot be used across wider samples, including men.

Furthermore, most studies took one measure of weight at follow-up and used a weight cut off to establish whether participants had maintained their weight throughout this time period, instead of taking multiple measurements to ascertain sustained weight maintenance. This approach does not necessarily represent a true measure of ‘maintenance’, as it is possible that participants may have lost weight in between follow-up measures.

Taken together, there is a lack of consensus between researchers in the definition of weight maintenance, as well as a need for more robust and consistent measurement methods. We hope this paper stimulates the debate. It is important to improve this before trying to explore more complex concepts, such as recovery.

Strengths and limits

This study gives voice to the lack of clarity around the concept of eating disorders recovery, alongside the impact that this could have on treatment. To our knowledge this is the first systematic review on papers looking at factors affecting weight maintenance.

The present study has several limitations. Findings should be treated with caution given the small number of available studies, as well as the heterogeneity in their design, intervention and follow-up durations. The differences make it difficult to make comparisons between studies and find patterns in results, highlighting the need for a common definition of weight maintenance across studies [ 45 ]. We included studies that included menstruation as part of their criteria. It is possible that this may have skewed findings, for having an additional criterion for maintenance may reduce the likelihood that certain predictors are found significant, or alternatively, other factors may hold more importance. In addition, most studies had primarily white female samples, particularly so in the studies that included menstruation resumption as part of their criteria. Men and non-white samples are more likely to have poorer outcomes [ 44 ], therefore significant predictors identified in this review may not apply to those populations.

Implications

Future research must focus on developing a clear concept of weight maintenance as it pertains to the eating disorders and particularly AN. Research and common clinical observation suggests that weight maintenance is the first step to full psychological recovery [ 19 ]. In addition, there lacks a clear consensus on the definitions of recovery and relapse, and better understanding weight maintenance may help contribute to rectifying this. Understanding the factors that predict weight maintenance can help clinicians adapt existing treatments to focus on targeting these factors, with the aim of supporting patients to maintain their weight after treatment and work towards full recovery.

Avenues that may be explored by future research include replicating studies looking at BMI throughout treatment, in order to increase reliability in the findings around weight variables. Future research should also investigate further the relationship between body image and long-term weight maintenance, given this review’s mixed findings.

The present study aimed to scope the literature on the factors predicting weight maintenance after acknowledging that this is a critical factor for recovery, and the inconsistent findings and definitions of recovery.

The current literature on weight maintenance suggests that a higher BMI at admission and discharge are the strongest predictors of long-term weight maintenance. Mixed findings have been found for biological and psychological factors. It is important for readers to interpret these findings with care, and to combine this with a wider understanding of what is important for AN patients, rather than using these results in isolation to promote a purely medical model of recovery. The findings provide important implications for future research as they highlight the need for a common definition of weight maintenance, as well as the need to compare differences between adult and adolescent samples so we can ensure that treatments are tailored to their individual needs. Further research should aim to develop a clear definition of weight maintenance and investigate predictive factors, including how BMI and weight gain processes account for weight maintenance, and elucidate the role of psychological processes in weight maintenance.

What is already known on this subject?

There exists extensive research on eating disorder recovery, but there are different views on how this should be defined and measured. Several factors have been suggested to predict long-term recovery, yet the recovery landscape remains unclear due to the lack of consensus on the definition of recovery and on the factors deemed to predict recovery.

What this study adds?

This study adds an understanding of how weight maintenance is conceptualised in eating disorder research and an initial understanding of factors predicting weight maintenance, upon which future research can build.

Data availability

The datasets used in this study are available from the corresponding author on reasonable request.

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Maurel, L., MacKean, M. & Lacey, J.H. Factors predicting long-term weight maintenance in anorexia nervosa: a systematic review. Eat Weight Disord 29 , 24 (2024). https://doi.org/10.1007/s40519-024-01649-5

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Study protocol of comprehensive risk evaluation for anorexia nervosa in twins (CREAT): a study of discordant monozygotic twins with anorexia nervosa

  • Maria Seidel 1 , 2   na1 ,
  • Stefan Ehrlich 1   na1 ,
  • Lauren Breithaupt 3 , 4 ,
  • Elisabeth Welch 5 , 6 ,
  • Camilla Wiklund 2 ,
  • Christopher Hübel 2 , 7 , 8 , 9 ,
  • Laura M. Thornton 10 ,
  • Androula Savva 2 ,
  • Bengt T. Fundin 2 ,
  • Jessica Pege 2 ,
  • Annelie Billger 2 ,
  • Afrouz Abbaspour 2 ,
  • Martin Schaefer 10 ,
  • Ilka Boehm 1 ,
  • Johan Zvrskovec 2 , 7 ,
  • Emilie Vangsgaard Rosager 11 ,
  • Katharina Collin Hasselbalch 11 ,
  • Virpi Leppä 2 ,
  • Magnus Sjögren 11 , 12 ,
  • Ricard Nergårdh 13 ,
  • Jamie D. Feusner 14 ,
  • Ata Ghaderi 7 , 10 &
  • Cynthia M. Bulik 2 , 15 , 16  

BMC Psychiatry volume  20 , Article number:  507 ( 2020 ) Cite this article

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Anorexia nervosa (AN) is a severe disorder, for which genetic evidence suggests psychiatric as well as metabolic origins. AN has high somatic and psychiatric comorbidities, broad impact on quality of life, and elevated mortality. Risk factor studies of AN have focused on differences between acutely ill and recovered individuals. Such comparisons often yield ambiguous conclusions, as alterations could reflect different effects depending on the comparison. Whereas differences found in acutely ill patients could reflect state effects that are due to acute starvation or acute disease-specific factors, they could also reflect underlying traits. Observations in recovered individuals could reflect either an underlying trait or a “scar” due to lasting effects of sustained undernutrition and illness. The co-twin control design (i.e., monozygotic [MZ] twins who are discordant for AN and MZ concordant control twin pairs) affords at least partial disambiguation of these effects.

Comprehensive Risk Evaluation for Anorexia nervosa in Twins (CREAT) will be the largest and most comprehensive investigation of twins who are discordant for AN to date. CREAT utilizes a co-twin control design that includes endocrinological, neurocognitive, neuroimaging, genomic, and multi-omic approaches coupled with an experimental component that explores the impact of an overnight fast on most measured parameters.

The multimodal longitudinal twin assessment of the CREAT study will help to disambiguate state, trait, and “scar” effects, and thereby enable a deeper understanding of the contribution of genetics, epigenetics, cognitive functions, brain structure and function, metabolism, endocrinology, microbiology, and immunology to the etiology and maintenance of AN.

Peer Review reports

We present the study protocol for the Comprehensive Risk Evaluation for Anorexia nervosa in Twins (CREAT): A study of monozygotic (MZ) twins who are discordant for anorexia nervosa (AN). AN is a complex and serious disorder characterized by prolonged undernutrition, low weight, weight/shape concerns [ 3 ] and is often accompanied by pathologically elevated physical activity. Individuals with AN present with considerable somatic and psychiatric comorbidity [ 130 ]. Mortality associated with AN is significantly elevated [ 2 ] and higher than in other serious psychiatric disorders, such as schizophrenia, bipolar disorder, and major depression [ 21 ]. Rates of relapse and hospital readmission are high [ 34 , 116 , 130 ]. Consequently, the disorder places a major social and financial burden on patients, family members, and the health care system [ 112 ]. No medications are effective in the treatment of the core symptoms of AN [ 130 ] and drug development has been hindered by a lack of understanding of the (neuro) biology of the disorder and a systematic integration of those biological factors with environmental components [ 88 ]. Until we gain a deeper understanding of the biology of the illness, we will be unable to determine which factors place individuals, or more nuanced questions such as which factors enable individuals with AN who do not die from the disorder to maintain dangerously low body mass indices (BMI), often for prolonged periods of time, without succumbing to medical complications of severe starvation or other opportunistic illnesses [ 16 ].

Study overview

To address these aforementioned knowledge gaps and to inform treatment development, we employ a co-twin control design—an investigation of discordant MZ twins (i.e., twin pairs in which one twin has a target disorder and the other remains unaffected, despite being past the age at risk of onset for the illness). We are recruiting ~ 50 pairs of female MZ twins in which one has or has had AN, and ~ 50 pairs of age matched female control MZ twins in which neither twin has any history of eating disorders symptoms.

The study is made possible by the existence of the Swedish [ 69 , 75 ] and Danish [ 107 , 108 ] twin registers and the rich national health registers in both countries [ 29 , 72 , 73 , 84 ]. This will allow us to identify all twins in each country in which one twin has an identified diagnosis of AN.

As discordant MZ twins are both rare and highly valuable to health research, we have assembled an experienced interdisciplinary team to design a comprehensive investigation that will thoroughly explicate the role of genetic, epigenetic, neurocognitive, neural, endocrinological, metabolic, microbial, immunological, and environmental factors associated with AN. We employ a longitudinal, multimodal co-twin control design that includes an experimental component, namely an 18-h overnight fast. This experimental component affords us the opportunity to observe differential response to fasting across a range of biological and psychological outcome domains.

The value of co-twin control designs

The study of discordant MZ twins represents a powerful research strategy to explore factors that influence differences between individuals who are fundamentally genetically identical. Discordant MZ twins are a natural experiment in which appropriate matching occurs. The validity of twin research also rests on the assumption that environmental factors are also shared equally between MZ twins (during early life). As one can therefore assume background genetic matching, observed differences in the relevant traits can be due to differential exposures, consequences of the illness, epigenetic processes, or the state of recovery of the affected twin. Due to the prevalence of AN, co-twin control studies in this field have been rare and small [ 54 , 93 , 114 , 119 ]. Below we describe each component of CREAT including a concise background, relevance, and expected outcomes.

Study aims and protocol overview

Previous studies on risk factors for AN have often focused on differences between acutely ill and recovered individuals. However, this design lends itself to some ambiguity in interpretation. Differences observed in acutely ill patients could reflect state effects due to acute starvation or acute disease-specific factors, or could represent underlying traits. Alternatively, observations in recovered individuals could reflect either an underlying trait or a “scar”, due to lasting effects of sustained undernutrition and illness [ 89 ]. We anticipate that approximately half of the participating twins with AN will be recovered. Recovery criteria in the current study follow a modified version of Bardone-Cone et al. [ 6 ] and include 1) physical recovery: BMI ≥ 18.5 kg/m2; 2) behavioral recovery: no binge eating, purging, or fasting in the past year, and 3) psychological recovery: all Eating Disorder Examination-Questionnaire (EDE-Q; [ 30 ]) subscales within 1 SD of age-matched community norms. Further, we anticipate that about 25% will be actively ill (i.e., meet threshold diagnostic criteria), and 25% will be partially recovered, falling between ill and recovered on either physical, behavioral, or psychological parameters. Using a discordant MZ twin design as well as different recovery states the current study will help to disentangle not only state and trait effects, but also “scar” effects (comparisons as outlined in Fig.  1 ) across several different investigational domains. Briefly, in a two-day study, all participating twins undergo blood sampling, neuroimaging, neurocognitive testing, body composition measurement via dual X-ray absorptiometry (DXA), accelerometer-based activity monitoring, microdialysis, self-report questionnaires, and structured interviews over a 28–30 h period with standardized food intake and a monitored overnight fast (Fig.  2 ).

figure 1

Overview of possible comparisons between twins to investigate whether effects constitute state, trait, or “scar” markers. Lines indicate comparisons where observed differences would imply state, trait, or “scar” effects respectively

figure 2

Overview of the study schedule. Participants undergo a 30 h protocol, starting at 8:30 am in the morning of day 1 until approximately 1:00 pm of day 2. Study components flow as per Fig. 3 . Individuals wear an accelerometer for 29 h of the study. The fasting period commences at 18:30 following dinner on day 1 and continues until 12:30 on day 2. Neurocognitive testing, neuroimaging, biological sampling, and microdialysis are conducted before (T1) and after (T2) the experimental fast

Experimental overnight fast

Appetite regulation and, therefore, the motivation to eat reflects a complex integration of several physiological signals influencing hunger, satiety, physical activity, and cognitive processes that affect the subjective value of food [ 60 , 120 ]. The relentless and pervasive caloric restriction during periods of extreme low body weight and hallmark endocrine disturbances that accompany eating behavior [ 101 ] suggest disrupted homeostatic influences on reward processing [ 33 , 85 ]. The majority of studies in acute AN to date are unable to disaggregate the effects of fasting from confounding effects of long-term mal- or undernutrition. However, altered responses to short-term fasting persist even after weight restoration [ 44 , 124 ], suggesting persistent traits underlying the AN phenotype and associated pathological eating behavior. Our experimental overnight fast allows us to document differences between affected twins and their unaffected co-twins, as well as between discordant affected MZ case twins and concordant unaffected MZ control twins in neuronal, neurocognitive, metabolic, endocrinological, and psychological response to short-term food restriction by repeating assessments across a number of domains pre- and post-fast while holding other variables constant.

Genomics & Epigenetics

AN is highly familial. Twin studies estimate between 28 and 74% of the variance in liability is attributable to genetic factors [ 127 ]. The most recent genome-wide association study (GWAS) identified eight genomic loci associated with AN, with genetic correlations suggesting both metabolic and psychiatric risk factors for the illness. These recent findings advance previous notions of a re-conceptualization of the illness as a metabo-psychiatric condition [ 42 , 58 , 121 ]. In addition to genetic risk, the AN phenotype and disease course could also be shaped by epigenetic mechanisms. Epigenetics refers broadly to the regulation of gene expression without a change in the DNA coding sequence. Unlike the genome sequence, epigenetic marks can be subject to environmental stimuli starting immediately after conception [ 79 ], which play a role in AN, including hormones, nutrition, lifestyle, and intestinal microbiota [ 2 , 79 , 91 ]. Epigenetic studies to date have focused solely on the role of DNA methylation [ 45 , 46 ]. We expect that affected twins will differ in their epigenetic signature, including DNA modifications, histone modifications, and non-coding RNAs, and that differences between discordant twins, especially the recovery status of the affected twin, may aid identifying illness-related (state) effects (Fig. 1 A) versus “scar” effects from chronic undernutrition (see Fig. 1 C).

Neuropsychology

Several neurocognitive functions such as set-shifting, value-based decision making, and central coherence have been reported to be altered in AN [ 1 , 115 , 123 ]. The extent to which these alterations are trait or state markers remains unclear. Observations in individuals with acute AN, recovered AN, and unaffected sisters or mothers suggest that deficiencies in set shifting may be a trait marker in AN [ 61 , 63 , 71 , 97 , 123 ]. On the other hand studies in adolescent patients have not replicated impairments in set-shifting, suggesting that chronic illness might have contributed to positive findings [ 62 ].

Consistent with the clinical presentation of elevated self-control in AN [ 53 ], delay discounting (i.e., the depreciation of the value of a reward related to the time of retrieval), and probability discounting have been reported to be altered in AN patients [ 8 , 26 , 110 , 111 ]. Some studies suggest that AN patients have a preference for larger delayed rewards when compared to healthy individuals whereas studies in younger AN patients did not find differences in discounting behavior [ 56 , 96 ]. Multiple studies have also observed weak central coherence - reduced global and integrated processing and enhanced focus on detail [ 35 ] - in underweight individuals with AN, and in some studies in unaffected relatives [ 37 , 61 , 63 , 98 ], yet there are conflicting reports about whether this persists in weight-restored or recovered states [ 61 , 63 , 122 ]. Preliminary evidence in healthy individuals suggests that short term fasting affects both set-shifting and central coherence [ 7 , 13 , 87 ]. The experimental overnight fast allows us to observe whether short term food deprivation differentially modifies cognitive functioning in affected versus unaffected twins, and in comparison to concordant unaffected MZ control twins.

  • Neuroimaging

Structural brain changes, i.e., the reduction of gray matter (GM) and white matter (WM), are most pronounced in acutely underweight patients with AN [ 55 , 57 , 104 ] with normalization occurring quite rapidly after short-term recovery [ 9 , 10 , 118 ]. Standard designs have been unable to differentiate state (due to undernutrition, even after recovery) and trait effects. The co-twin control design has the potential to aid in disaggregating these effects and potentially identifying trait effects in structural changes in AN.

Accumulating evidence of functional MRI (fMRI) data further points to alterations within established resting state networks [ 11 , 12 , 24 , 77 , 100 ] as well as during specific tasks. Domains reported to be altered in AN include reward processing [ 85 ], food-cue reactivity [ 129 ], emotion recognition and processing [ 95 , 103 , 129 ], and general visual processing [ 66 , 67 ]. The relative contribution of trait, state, or “scar” factors of these alterations will be visible in the difference between a) the affected and currently ill and the unaffected discordant twin (state), b) the unaffected discordant twin and twin controls (trait), and c) the affected now recovered and unaffected discordant twin (“scar”) respectively (see Fig. 1 ). Reward processing and food cue reactivity are expected to be modulated by the nutritional status of the patients, i.e., whether patients are acutely ill or weight-restored and whether patients are scanned after a period of fasting or after a meal [ 64 , 124 ].

Endocrinology & Metabolism

AN has far reaching effects on most endocrine systems [ 47 , 101 ]. This is unsurprising as the endocrine system plays a major role in adaptation to an ever-changing environment with varying demands on how to eat, use, and store energy. Being able to adapt to periods of food restriction, negative energy balance, and even starvation is essential for most animals and, not surprisingly, starvation has broad impact on metabolism, reproduction, and behavior. In the CREAT study we will compare endocrine and metabolic responses to food restriction between discordant MZ twins. Early metabolic changes in response to the overnight fast will be captured by microdialysis. The microdialysis technique, described in detail elsewhere [ 52 ], places a probe in subcutaneous fat, allowing observation of how glucose homeostasis is maintained via different metabolic pathways, e.g., activation of lipolysis and gluconeogenesis. We will also measure key metabolic hormones such as cortisol, ghrelin, and thyroid hormones. Our experimental design will enable us to differentiate between early differences in response to fasting from secondary effects of starvation as well as separate biomarkers of negative energy balance from biomarkers of the disorder. We hypothesize that an identifiable metabolic/endocrine response to negative energy balance is associated with an increased risk of developing AN.

Intestinal microbiome

The human intestinal microbiota is a complex and dynamic community of microorganisms that plays a fundamental role in many host processes including energy metabolism [ 18 ] and immunity [ 36 ], as well as broad regulation of mood [ 27 ] and behavior [ 83 ]. Dysbiosis of the intestinal microbiota has been associated with a diverse range of health deficits [ 48 ]. Several studies have confirmed differences in the diversity and composition of the intestinal microbiota in individuals with AN and controls, and across the course of therapeutic renourishment [ 4 , 14 , 59 , 74 , 81 , 82 , 102 ]. It is possible that alterations in the intestinal microbiota are adaptive responses to an extreme intestinal environment during acute stages of AN, allowing survival during periods of starvation. Another possibility is that the gut microbiota plays a co-causal role in AN, although the mechanism for this requires further explication. Although the aforementioned studies provide valuable findings that give us an outlook for future investigations, their study designs do not allow elaborating beyond associations nor do they disambiguate state, trait, or “scar” effects. We will compare fecal microbiota (as a proxy to study intestinal microbiota) in affected versus discordant unaffected co-twins (to identify state-related alterations), unaffected discordant twins and twin controls (to pinpoint trait-related changes), and affected recovered twins versus unaffected discordant co-twins (to assess “scar”-related alterations). Relating the microbiota data to dietary and metabolic data will help explicate the role of microbial variability in the availability and absorption of nutrients from the gut and, potentially, in modulating host factors. As epigenetic regulation is a potential mechanism through which gut microbiota and microbial metabolites can affect host factors, we will also investigate the associations between epigenetic data and microbiota data in our study groups.

The blood-brain barrier and the blood-cerebrospinal fluid barrier separate the neuroimmune system from the peripheral immune system. However, the communication between them is possible via cytokines that can influence a variety of brain functions relevant to behaviour including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, anxiety, and motivation [ 19 ]. Higher concentrations of the cytokines tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) have been reported in AN compared with healthy controls but may not be specific for AN [ 25 ]. Longitudinal investigations of cytokines have not yet been conducted, therefore, it is difficult to judge whether these alterations are trait-related or a sequelae of AN [ 25 ], but initial evidence suggests that individuals with AN seem to carry genetic variants predisposing them to lower C-reactive protein (CRP) concentrations [ 70 ]. Additionally, a bidirectional relationship between AN and autoimmune diseases, such as ulcerative colitis and Crohn’s disease, and an increased risk for AN after a preceding diagnosis of type 1 diabetes has been reported and replicated [ 43 , 92 , 126 , 128 ]. The co-occurrence is not yet fully understood, but no shared genetic liability between autoimmune diseases and AN has been detected so far [ 117 ]. The existing findings encourage the exploration of other factors, such as infections, medication [ 15 ], insulin, diet or starvation effects as potential candidates to explain the relationship between AN and abnormalities of the immune system and/or autoimmune diseases. We also aim to understand whether the effects of either ongoing subtle cell damage or an unusual pattern of inflammation are exacerbated by a lack of adipose tissue which alters the expected production of mediators and the interrelationship of cytokines.

Basic characteristics and diagnosis

Participants.

We are recruiting female MZ twins rigorously discordant for AN and healthy non-dieting age- matched female concordant unaffected MZ twin controls. The twins are identified and recruited from the Swedish Twin Registry (STR) [ 69 ] and the Danish Twin Registry (DTR) [ 107 , 108 ]. The STR was first established in the late 1950s and includes about 200,000 twins, providing an invaluable and unique resource for scientific studies such as CREAT. The Danish Twin Register (DTR) was initiated in 1954 and covers all twin cohorts established in Denmark since 1870. The DTR contains more than 85,000 twin pairs and a similarly valuable resource for health research.

We intend to enroll 50 MZ discordant twin pairs and 50 MZ concordant unaffected control pairs (N total  = 200). Participants are reimbursed for participation with a fixed amount of 4000 Swedish kronor, which they receive after completion of the study.

Inclusion-exclusion criteria

Stage 1 Initial screen: The Stage 1 review determines preliminary eligibility (females only, aged between 18 and 50 Fig.  3 ). Twins who appear to be MZ and discordant for AN based on diagnostic information obtained via participation in the STR [ 68 ] are sent an invitation to participate in Stage 1. Danish twins are identified by selecting a cohort of all MZ female twins, age 18–50 from the DTR ( n  = 1617 pairs, where both twins are alive per 1st of October 2018) or via social media or contacts with healthcare providers. Via the Danish National Patient Register [ 73 ] and Psychiatric Central Research Register [ 84 ], this cohort will be matched for the diagnosis of AN and contact information obtained via the Civil Registration System. After giving informed consent, each twin pair is genotyped to verify monozygosity (for details see Supplementary Material 1.1, Additional file  1 ). In addition to the saliva kits for the monozygosity screening, participants are also provided with a link to a validated diagnostic online questionnaire, ED100K [ 113 ] which captures lifetime DSM-5 eating disorder diagnoses. This is a second stage of verifying that affected twins did indeed have AN and that co-twins and control twins are unaffected.

figure 3

Inclusion (↓)/Exclusion (→) procedures for recruitment. Pre-screening begins at Stage 1. Individuals are screened with the ED100K online questionnaire [ 113 ] for lifetime eating disorder symptoms as well as genetic testing. Participants are excluded if screening reveals them to be dizygotic or if the unaffected co-twin is discovered to be affected. Screening at Stage 2 is more intensive and includes telephone interviews by trained interviewers conducting the Eating Disorder Examination [EDE [ 23 ]], Mini-International-Neuropsychiatric-Interview [MINI, [ 106 ]], and the Eating Disorders section of the Structured Clinical Interview for DSM-5 [SCID-5 [ 32 ]]. If all criteria fulfilled and participants remain interested in participating, they are invited to participate in the 30 h study protocol

Stage 2 Pre-visit evaluations: MZ twins who are confirmed to be MZ via genotyping and who appear to meet eligibility criteria after Stage 1 undergo a phone-based interview including the complete Eating Disorder Examination (EDE [ 23 ]) for assessing current diagnosis of eating disorder, and eating disorder-specific psychopathology. For control twins, a short version of the EDE (only diagnostic questions) is used. The EDE is a reliable, valid, and widely used instrument for diagnosing eating disorders, and has been translated into Swedish and Danish. In both twin groups, the Eating Disorders module of the SCID-5 [ 32 ] is used to assess the lifetime illness course and recovery status. The assessments are performed by clinically trained research staff who are experienced in psychiatric diagnostic assessments in general and eating disorders in particular.

Our definition of rigorous discordance is that the affected twin should meet or have met modified DSM-5 criteria for AN at some point in their life, and the unaffected twin should not meet any current or past criteria for AN or any other eating disorder. In addition, the unaffected twin should have been unaffected for at least five years after the onset of their co-twin’s AN, have a lifetime minimum adult BMI above the underweight cut off (18.5 kg/m 2 ), and not suffer from other metabolic conditions that could influence body weight or appetite.

After evaluating all inclusion and exclusion criteria, all twin pairs undergo a second phone-based interview using the MINI International Neuropsychiatric Interview 7.0 [MINI, [ 106 ]]. The MINI is a structured clinical interview for diagnosing psychiatric disorders.

Control twins (unaffected MZ twins) must both meet the same criteria as the unaffected co-twins of the discordant pairs. Additional exclusion criteria for healthy MZ control twin pairs are: history of psychiatric illness such as recurrent major depression, psychosis, bipolar disorder, or generalized anxiety disorder screened by the MINI International Neuropsychiatric Interview (2015), and ongoing psychotropic medication use. All participants are excluded if they report being pregnant (invited to participate at a later date), are breastfeeding (invited to participate at a later date), have a neurological disease, had brain surgery, or have magnetic materials in the body (contraindicating MRI). MZ twins who are rigorously discordant and unaffected MZ control twins who meet all of these criteria are then invited for further participation.

Materials and measures

Questionnaires.

Participants will complete a battery of questionnaires developed to capture a range of relevant behavioral, cognitive, personality, and psychological factors hypothesized to be relevant to risk for eating disorders (Table  1 , Supplementary Material 1.2, Additional file 1 ).

Anthropometric measures, diet, and physical activity

Central to our investigation is the exploration of differences in anthropometric measures and body composition, diet, and physical activity among unaffected and affected twins and healthy controls. BMI is calculated from measured height (via fixed stadiometer) and weight (via calibrated digital scale). Percent body fat and lean muscle mass are measured by DXA. Physical activity is measured by the Active-Q Questionnaire (see subsection Questionnaires for more detail). Additionally, participants wear GENEActive Original accelerometers (Activinsights Ltd., UK) for a six-day period on their non-dominant wrist prior to the on-site phase of the study and during the entire stay during the study. We sample vertical, anteroposterior, and mediolateral movement at a rate of 40 Hz to maintain accuracy at an informative level.

Blood DNA samples from all participants will be genotyped on an appropriate chip at the time of study commencement and after standard quality control [ 22 ]. The genomic information will be used to estimate the polygenic loading for different phenotypes, including metabolic, behavioral, and psychiatric traits. The polygenic loading will be estimated by polygenic scores [ 65 ] or summary data-based best linear unbiased predictors (SBLUPs) [ 99 ] and we will investigate differences in the association of these predictors with other outcome measures. Potentially, these polygenic scores will be combined with the classical twin design [ 80 ]. For selected samples, we will consider whole genome or exome sequencing to identify de novo alterations.

Epigenetics

As monozygotic twins are nearly 100% genetically identical, the majority of genomic effects influencing differences between each twin of a twin pair will be due to epigenetic changes between the twins. To investigate these epigenetic differences between twins, we will conduct epigenome-wide association studies examining differential methylation and histone modifications [ 79 ]. We will correct for potential differences in cell type composition between the four groups by appropriate statistical models [ 51 ] and take eating disorder-specific confounders, including diet composition, medication, hormone concentrations, and underlying DNA sequence into account [ 45 ].

  • Cognitive functions

Participants complete a battery of neurocognitive tests both online on a laptop and by paper and pencil (Table  2 ). The neurocognitive battery is administered twice using alternate forms, once before (T1) and once after (T2) the 18 h fasting period. For more detailed description of each task, please see Supplementary Material (1.3, Additional file 1 ).

Participants complete a protocol of structural (T1-weighted (T1W) and diffusion tensor imaging (DTI)) and functional neuroimaging sequences (resting state and four task-based scans) twice, once before (T1) and once at the end of the 18 h fasting period (T2, Table  3 ). The MRI acquisition is performed on a 3-Tesla whole body scanner (GE 750) with a 32-channel head coil. We also assess heart rate and breathing rate continuously during scanning to better control for possible artifacts during preprocessing of functional data. For more detailed description of acquisition parameters and the single tasks please refer to Supplementary Material (1.4, Additional file 1 ).

Endocrinology and metabolism

For assessment of the endocrine and metabolic response to fasting, blood samples are taken once prior to the 18-h fast (Sample 1) and twice during the 18-h fast on the second day (Sample 2, Sample 3 Table  4 ).

Microdialysis

The direct metabolic response in subcutaneous adipose tissue to fasting is addressed in situ by microdialysis. A probe with a tubular semipermeable membrane is placed subcutaneously in the abdominal fat after Neuroimaging T1 (hour 9 day 1) [ 5 , 49 ]. A sterile Ringer’s solution is continuously pumped through the dialysis tube at a flow rate of 0.5 μl/min. The dialysate samples are collected in microvials that are changed every 30 min. Overnight, one cumulative sample is collected between 23:00 and 6:00 to avoid disturbing the participant during sleep. The probe remains in place until after the last blood sampling on the second day. From the dialysate metabolites, including glucose, lactate pyruvate, and glycerol are analyzed for each participant repeatedly (CMA 600 Microdialysis Analyzer, CMA Microdialysis AB, Stockholm, Sweden). The data will provide us with information about glycolysis, gluconeogenesis, lipolysis with a high temporal resolution and their contribution to generate energy during the fasting period [ 5 ].

Intestinal microbiota

The stool samples are collected after the study visit at home, using OMNIgeneGut (OM-200, DNA Genotek) self-collection kits. Dietary intake for the 24 h before the stool sample collection is assessed via the Online 24-Hour Recall Log Book (Table 1 ). The samples are mailed to the laboratory to extract microbial genomic DNA. In order to obtain high-resolution taxonomic and functional microbiome data, we will perform whole genome shotgun sequencing. Raw sequence data will be quality filtered and trimmed to remove bases with Phred quality scores less than 20. Downstream bioinformatics analysis will consist of: i) taxonomic composition; ii) functional composition; iii) alpha diversity (as measured by Shannon index) and beta diversity (quantified by Bray Curtis and UniFrac metrics); and iv) computing descriptive statistics and identifying groups within the data, as well as performing statistical analyses between subgroups using additional metadata, where available [ 86 ]. Since the sequencing technology and bioinformatics tools are rapidly advancing, we will utilize the most suitable methods and tools available at the time of analysis. For more detail see Supplementary Material 1.6, Additional file 1 .

We measure concentrations of immune-related cytokines, cell injury, and cell death markers at three different timepoints (Table 4 ) in plasma or serum depending on the assay (Table  5 ). The cytokines are representative of the function of various immune cell populations and have been previously used in studies of psychiatric disorders, including depression, bipolar disorder, and schizophrenia [ 41 ]. We also gather information on cell injury and death by measuring concentrations of nuclear molecules and general cell loss markers, such as lactate dehydrogenase (LDH).

Data management

General data security.

All network communication between IT systems, including between participant or study operator devices, used in the study is encrypted by cryptographically strong methods as standard, if not otherwise specified. The hosting department provides central university network security services such as a central firewall and perimeter protection for the used networks. For more detail on data management please refer to Supplementary Material 1.6, Additional file 1 .

Data storage and business logic

To handle administrative and research data during the collection phase of the study, we have implemented Karolinska Institutet Biobank IT, which is organizationally part of the core facility Karolinska Institutet Biobank. Data in file form are placed on the study research data disk area and indexed in a Central Research Database by an automated Study Data Management Application. The Central Research Database uses MS SQL Server technology, is only accessible by pre-specified users from selected department networks and has its own authentication scheme in addition to the department centralized directory service in the form of MS Active Directory.

All datasets will be stored in Sweden within in the described systems. All project investigators will be given access to their respective data sets and will have access to other sites data by request. To ensure confidentiality, data dispersed to project team members will be blinded of any identifying participant information.

Web survey platform

Confirmit is an online web survey platform service for study operators to implement and publish online web surveys and to perform data management for survey data collection. Confirmit allows us to implement surveys with advanced logical action flow, question filters, and scripted survey events. Study specific resources and collected survey data are only accessible by selected study operators. Additional PGP encryption, using a user-specific encryption key, is applied.

On the study website participants are authenticated with strong authentication methods for access to personal areas where they consent electronically to the study and access the web surveys. We use national electronic identity technology: Swedish BankID, or technology of similar capacity to perform authentication. The visual layout of the web site is made to illustrate progress through the study and the online web surveys to the participant.

Online 24-h recall web tool

The 24-h dietary recall logbook is introduced in the study through an online service by Nutrition Data Sweden AB. The 24-h recall logbook is a tool where the study participant can log nutrition intake before stool sample collection. The tool provides basic data quality protection of data entries made by the participants. Since being an online web tool, it is accessible through the internet. Study specific resources and collected survey data are only accessible by selected study operators.

Statistical analyses

The MZ co-twin-control design is a method to evaluate the effect of non-shared factors on risk for AN, in the present study. Because MZ twins within a pair share, for all intents and purposes, 100% of their segregating genes, comparing twins discordant for AN controls for genetic and shared environmental factors. Thus, associations found between AN and other variables of interest suggest either a causal relationship, e.g., the variable of interest is a risk factor for AN or is a result of having AN, or a third variable indicative of an individual-specific factor that influences both AN and the variable of interest.

We will first contrast twins from discordant pairs (affected vs unaffected) on the wide array of variables evaluated in this study, which assesses state factors. Given that some of the outcomes for the present study are ordinal and some are repeated measures, and we anticipate using appropriate covariates in our models, we will apply mixed models. These models account for the clustered nature of twin data (i.e., non-independence of observations) and can incorporate fixed and random effects. In addition, the distribution of the outcome variables can be specified, and covariates can be added.

Second, the concordant unaffected MZ control twins will be included in the above models to evaluate whether having an affected co-twin influences the outcome variables. Results from these analyses may provide evidence that the co-twin’s affection status (an indication of familial influences of either environmental or possibly also epigenetic nature) is associated with the outcome if, e.g., the concordant unaffected twins have values or risk lower than those for the unaffected discordant twins, and these, in turn are lower than those for the affected discordant twins. Thus, these expanded models will be able to evaluate whether factors are state or trait in nature.

Those variables in which the discordant unaffected co-twins are significantly different than the affected twins will be further evaluated. In this case, the affected twins will be subdivided into those who are currently ill (state factors) and those who are recovered (“scar” effects). Pairwise comparisons will be made across the three groups: unaffected, recovered, and currently ill. “Scar” effects will be considered to be present if all three groups differ from one another (see Fig. 1 ; Table  6 ). While pairwise comparisons seem the right approach if subgroups constitute of equal (high) number of study participants, one also has to take into consideration that it might not be possible to clearly separate the group of affected twins into ill and recovered. In this case we propose a working model of using recovery status as continuous variable that can be controlled for as covariate in subsequent analyses. General covariates (e.g., illness duration, or nationality) appropriate to each domain will be entered into models. Analyses that will be across different domains (e.g., neuroimaging and endocrinology) will be handled with caution and covariates for both domains accounted for. Corrections for multiple testing will be considered within each domain to determine significance (e.g., for fMRI we will use the false discovery rate (FDR) or non-parametric permutation based approaches). Effect sizes and clinical relevance will be discussed based on the previous literature and current clinical practice.

CREAT is one of the first studies of AN that will allow us to parse unique environmental, genetic, and medical contributions (e.g., sequelae of undernutrition) of the disorder and therefore advances the debate of identifying underlying risk factors across different domains [ 88 ]. The comprehensive investigation optimizes the natural experiment of MZ twins who are discordant for AN. This design allows us to address several key questions related to AN risk and recovery across a broad range of relevant domains. In the following section we discuss both advantages and limitations of the current research protocol.

Adequate sample sizes are only attainable in locations with extensive twin registries, such as Sweden or Denmark. The study is demanding for participants and we have implemented a number of measures to ensure comfort and to express our deep appreciation of all participants. In addition to monetary incentives, twins are accompanied throughout the study by a dedicated research nurse and at night by specially trained nursing assistants. We have built in digital incentives and progress markers as participants work their way through questionnaires, and we are working to create a CREAT community through study branding, staying in contact with participants, and sharing results. In so doing, we hope to be able to return to twins in the future should additional research questions arise.

The specific research methods in each of the areas of the study were chosen by a panel of experts to maximize the utility of this specific data set. For example in the area of brain imaging well-validated paradigms [ 20 , 28 , 31 , 66 , 95 ] as well as state of the art statistical methods were chosen in order to ensure comparability with existing neuroimaging studies and excellent data quality. As a result of overly simplistic descriptions of the brain connectome in previous resting state research [ 38 ], we intend to apply multivariate techniques [ 17 ], graph theoretical approaches [ 109 ], and dynamic effective connectivity analyses [ 95 ], all of which offer promising tools to ask questions that go beyond simple connectivity analyses with resting state data [ 11 , 39 , 40 ] and integrate results from the other study domains, e.g. metabolic and endocrinological data.

Previous neurocognitive studies have often investigated the subcomponents of (value-based) decision making within single tasks (e.g., Wisconsin card sorting task, Iowa gambling task) that are unable to further differentiate between more specific concepts such as risk aversion and loss avoidance. Hence, the task battery employed for this project [ 90 ] also provides measures for risk aversion (for gains), risk seeking (for losses), as well as loss aversion. In a similar vein, other neurocognitive abilities as well as body image distortion (i.e., Somatomap [ 94 ]) are assessed using validated state-of-the-art task batteries. We are aware of the problem of learning effects when applying these tasks repeatedly. Since the neurocognitive domain includes established and validated tasks, there is no easy solution to this problem, without possibly changing the difficulty or complexity of the task, or extending the protocol beyond what is feasible in one session. However, since the learning effects will also be visible in the HC twins, we will focus only on the relative differences (e.g., between the AN discordant twins accounting for differences that were also observable in HC twins).

Methods in the field of genetics, epigenetics, microbiome research, and immunology develop rapidly. Analytic strategies will be finalized considering the latest technologies and methodologies available at completion of data collection. However, we have taken great care to assess all potential confounds and to store and preprocess the biological materials under conditions that ensure the integrity of the materials. New publicly available databases and computational methods will help us to enrich our findings, control for population-specific effects, and identify relevant metabolic and immunological pathways [ 50 ]. Furthermore, given the deep phenotyping of CREAT, we will be able to test for associations and interactions between genetic and immunological markers, hormones, and alterations of the microbiome and potentially answer the current questions regarding the gut-brain axis [ 105 ].

CREAT does pose logistical challenges and results will have limitations. Firstly, our strict inclusion criteria (i.e., requiring rigorous discordance) will probably lengthen the recruitment process to ascertain eligible pairs. Secondly, although the study itself will be conducted at a single site, participant recruitment covers both Sweden and Denmark, possibly introducing subtle differences in recruitment procedures, interviewing, and translations and wordings that might affect the comparability of the data (which we will control for statistically). In long-running studies, above all at different recruitment sites, it is essential to ensure that all staff are highly trained, and procedures remain consistent across the study period (i.e., do not evidence drift). Thirdly, the targeted sample size is relatively small. Although we have power to detect relatively small effect sizes, other clinical variables may have an adverse effect on power. For example, it is not possible to predict in advance the exact proportion of participants who are actively ill versus recovered. Depending on the distribution, we may be underpowered to detect differences between these two subgroups. Furthermore, duration of illness might moderate some of the expected differences (and will therefore be treated as a covariate in statistical models). Also, including only females within a specified age range, might yield a limited picture of the disorder. This decision is practical as we were unable to identify discordant MZ male twins in the register and it is essential that we only study twins who have passed through the age of risk to ensure unaffected status. Lastly, similar to other complex studies [ 76 ], planned analyses represent a mixture of hypothesis-driven and exploratory research questions. The exploratory aims emerge from findings in the literature regarding where differences may lie in affected versus unaffected individuals.

With these challenges and limitations in mind, we have instituted multiple checks including extensive standard operating procedures (SOPs) and detailed protocols to ensure the longevity of the project and maximize the utility of the rich data that will be captured from these highly valuable sets of twins.

The twin design employed in the current study offers the opportunity to deliver a comprehensive understanding of possible alterations within genetics, epigenetics, neurocognitive function, neuroimaging, metabolism, endocrinology, microbiology, and immunology in AN by disaggregating genetic and environmental factors influencing risk for the disorder.

Availability of data and materials

Not applicable.

Abbreviations

Adrenocorticotropic hormone

Adiponectin

α-fetoprotein

Alanine transaminase

  • Anorexia nervosa

Autism spectrum disorder

Aspartate transaminase

Big five inventory

Behavioral inhibition and behavioural activation system

Body-mass index

Blood oxygenation level-dependent

Chemokine (C-C motif) ligand

Creatine kinase

Comprehensive risk evaluation for anorexia nervosa in twins

C-reactive protein

Dehydroepiandrosterone

Double stranded deoxyribonucleic acid

Diagnostic and Statistical Manual of Mental Disorders

Diffusion tensor imaging

Danish twin registry

Dual X-ray absorptiometry

Eating disorder

Eating disorder diagnostic online questionnaire

Eating Disorder Examination

Eating Disorder Examination Questionnaire

Functional magnetic resonance imaging

Follicle stimulating hormone

Free triiodothyronine

Free thyroxine

General anxiety disorder questionnaire

Glutamate dehydrogenase

Grey matter

Genome-wide association study

High mobility group

Hormonal, menstrual and reproductive history

Insulin-like growth factor

Insulin-like growth factor-binding protein

Interleukin

Interleukin-1 receptor antagonist

Intelligence quotient

Lactate dehydrogenase

Luteinizing hormone

Monocyte chemoattractant protein

Mini International Neuropsychiatric Interview

Multidimensional perfectionism scale

Magnetic resonance (imaging)

Monozygotic

Obsessive compulsive inventory – revised

Positive and negative affect scale

Patient health questionnaire

Perception of teasing scale

Quality of life inventory

Raven’s progressive matrices und vocabulary scales

Region of interest

summary data-based best linear unbiased predictors

Structured Clinical Interview for DSM-5

Standard Deviation

Sex hormone-binding globulin

Statistical parametric mapping software

Swedish twin registry

Impulsive behaviour scale

Timepoint 1

Timepoint 2

Tumor necrosis factor α

Thyroid-stimulating hormone

Visual analogue scale

Value based decision making

White matter

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Acknowledgements

We would like to thank all the participants for their willingness to help in this study. We would further like to express our gratitude to all junior researchers and student workers for their assistance with diagnostic interviews, data collection, and quality checks. We acknowledge The Swedish and Danish Twin Registry for access to data. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council (VR Dnr: 2017-00641), and the Danish Twin Registry is managed by the University of South Denmark.

This work is funded by the Swedish Research Council (VR Dnr: 538–2013-8864) as well as the German Research Society (DFG: EH 367/7–1). The funding body was not involved in the design of the study, data collection, analysis and interpretation of data, as well as in writing the manuscript. Open Access funding enabled and organized by Projekt DEAL.

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Maria Seidel and Stefan Ehrlich are joint first authors.

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Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany

Maria Seidel, Stefan Ehrlich & Ilka Boehm

Department of Medical Epidemiology and Biostatistics, Karolinska Institutetet, Nobels väg 12A, 17165, Stockholm, Solna, Sweden

Maria Seidel, Camilla Wiklund, Christopher Hübel, Androula Savva, Bengt T. Fundin, Jessica Pege, Annelie Billger, Afrouz Abbaspour, Johan Zvrskovec, Virpi Leppä & Cynthia M. Bulik

Department of Psychiatry, Harvard Medical School, Boston, MA, USA

Lauren Breithaupt

Eating Disorders Clinical and Research Program, Massachusetts General Hospital, Boston, MA, USA

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Elisabeth Welch

Stockholm Health Care Services, Region Stockholm, Stockholm Centre for Eating Disorders, Stockholm, Sweden

Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Christopher Hübel, Johan Zvrskovec & Ata Ghaderi

UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust, London, UK

Christopher Hübel

National Centre for Register-based Research, Aarhus Business and Social Sciences, Aarhus University, Aarhus, Denmark

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Laura M. Thornton, Martin Schaefer & Ata Ghaderi

Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Emilie Vangsgaard Rosager, Katharina Collin Hasselbalch & Magnus Sjögren

Eating Disorder Research Unit, Mental Health Center Ballerup, Ballerup, Denmark

Magnus Sjögren

Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

Ricard Nergårdh

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA

Jamie D. Feusner

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Cynthia M. Bulik

Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

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Contributions

AG, CB, EW, LMT were responsible for conceptualization and design of the study. CB, JMS were responsible for funding in Sweden and Denmark. CB, AG, EW, LB (and others) created and piloted the study protocol. AG, MS, SE, LB, IB, EW, JDF were responsible for the setup and analysis plans of the neuroimaging component of the study. MS, LB, MSch, AS helped with data acquisition of the neuroimaging data. AG, SE, MS, JDF designed the neurocognitive test battery. CW, AA, CB, RN designed the microbiome component of the study. CH, RN, CB conceptualized the setup of the microdialysis and endocrinological investigations. AB, JP, RN helped with the data acquisition of the microdialysis section. BF, CH, VL, SE, CB helped with the design of genetics and epigenetics and immunological components of the study. AG, BF, SE, EW, AB, JP, LMT, CB helped with designing the recruitment procedures, clinical diagnostics, interviews, and scheduling of participants. AG, LMT, EW, CB designed the format of the questionnaire battery for the current study. JZ, AS implemented the data storage and analysis pipelines for the current project. JMS, EVR, KCH were responsible for recruitment, coordination, conducting diagnostic interviews and translations in Denmark. MS, SE, CH, AA, AS, CB, LMT, AG made substantial contributions to the manuscript. All authors reviewed and approved the current manuscript.

Corresponding authors

Correspondence to Stefan Ehrlich or Cynthia M. Bulik .

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Ethical approvals were granted by the Regional Ethical Review Board in Stockholm (Dnr 2015/1479–31/2) and in Denmark, by the Regional Ethics Review Board in Hillerod (H-17004363, 24 August 2017). All Changes to the protocol are sent as amendments to the respective Ethical Review Board for approval. Consent to participate is given in written form (Denmark) and electronically (Sweden, see Data Management section) from all participants after initial contact.

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CM Bulik reports: Shire (grant recipient, Scientific Advisory Board member); Idorsia (consultant) Pearson (author, royalty recipient). Other authors report no competing interests.

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Supplementary information about diagnostics and measured parameters in the study.

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Seidel, M., Ehrlich, S., Breithaupt, L. et al. Study protocol of comprehensive risk evaluation for anorexia nervosa in twins (CREAT): a study of discordant monozygotic twins with anorexia nervosa. BMC Psychiatry 20 , 507 (2020). https://doi.org/10.1186/s12888-020-02903-7

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Published : 14 October 2020

DOI : https://doi.org/10.1186/s12888-020-02903-7

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Anorexia Nervosa

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At the suggestion of her pediatrician, “Rachel,” a 19-year-old college freshman at a competitive liberal arts college, was brought by her parents for psychiatric evaluation during spring break. According to her parents, Rachel had lost 16 lb since her precollege physical the previous August, falling to a weight of 104 lb at a height of 5 feet, 5 inches. Rachel’s chief complaint was that “everyone thinks I have an eating disorder.” She explained that she had been a successful student and field hockey player in high school. Having decided not to play field hockey in college, she began running several mornings each week during the summer and “cut out junk food” to protect herself from gaining “that freshman 10.” Rachel lost a few pounds that summer and received compliments from friends and family for looking so “fit.” She reported feeling more confident and ready for college than she had expected as the summer drew to a close. Once she began school, Rachel increased her running to daily, often skipped breakfast in order to get to class on time, and selected from the salad bar for her lunch and dinner. She worked hard in school, made the dean’s list the first semester, and announced to her family that she had decided to pursue a premed program. When Rachel returned home for Christmas vacation, her family noticed that she looked thin and tired. Despite encouragement to catch up on rest, she awoke early each morning to maintain her running schedule. She displayed a newfound interest in cooking and spent much of the day planning, shopping, and preparing dinner for her family. Rachel returned to school in January and thought she might be developing depression. Courses seemed less interesting, and she wondered whether the college she attended was right for her after all. She was sleeping less well and felt cold much of the day. Rachel’s parents asked her to step on the bathroom scale the night she returned home for spring break. Rachel was surprised to learn that her weight had fallen to 104 lb, and she agreed to a visit to her pediatrician, who found no evidence of a general medical illness and recommended a psychiatric consultation. Does Rachel have anorexia nervosa? If so, how should she be treated?

Anorexia nervosa is a serious mental illness characterized by the maintenance of an inappropriately low body weight, a relentless pursuit of thinness, and distorted cognitions about body shape and weight. Anorexia nervosa commonly begins during middle to late adolescence, although onsets in both prepubertal children and older adults have been described. Anorexia nervosa has a mortality rate as high as that seen in any psychiatric illness (1) and is associated with physiological alterations in virtually every organ system, although routine laboratory test results are often normal and physical examination may reveal only marked thinness.

Current Definition

DSM-IV (2) lists four criteria for the diagnosis of anorexia nervosa:

1. Refusal to maintain body weight at or above a minimally normal weight for age and height

2. Intense fear of gaining weight or becoming fat, even though underweight

3. Disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight

4. In postmenarchal females, amenorrhea (i.e., the absence of at least three consecutive menstrual cycles)

DSM-IV describes two subtypes of anorexia nervosa—the restricting subtype, consisting of those individuals whose eating behavior is characterized by restriction of type and quantity of food without binge eating or purging behaviors, and the binge-purge subtype, consisting of those who also exhibit binge eating and/or purging behaviors, such as vomiting or misuse of laxatives.

Diagnostic Challenges

The DSM-IV criteria are most easily applied when patients are both sufficiently ill to fulfill all four diagnostic criteria and able to describe their ideation and behavior accurately. However, because ambivalence and denial frequently lead those with anorexia nervosa to minimize their symptoms, the clinician must make inferences about mental state and behavior.

An additional problem in diagnosis is that many individuals meet some but not all of the formal diagnostic criteria. For example, some women who meet all other criteria for anorexia nervosa continue to report some spontaneous menstrual activity. In a community-based sample of 84 female patients with full- or partial-syndrome anorexia nervosa, those with amenorrhea were not statistically different from those without across a number of clinical variables (3) , which raises questions about the utility of this diagnostic criterion (4 , 5) .

Differential Diagnosis

Proper diagnosis of any condition that includes low weight and restrictive eating must include consideration of other psychiatric and medical conditions that include these problems. Psychotic disorders, including schizophrenia and schizoaffective and delusional disorders, as well as anxiety disorders, such as obsessive-compulsive disorder, can include symptoms of food avoidance and distorted beliefs about one’s body. Medical conditions, including endocrine disturbances (such as thyroid disease and diabetes mellitus), gastrointestinal disturbances (such as inflammatory bowel and celiac disease), infections (such as hepatitis), and neoplastic processes may present with weight loss and should be considered when evaluating a patient for a possible eating disorder.

Anorexia nervosa has been recognized for centuries. Sir William Gull coined the term anorexia nervosa in 1873, but Richard Morton likely offered the first medical description of the condition in 1689 (6 , 7) . Despite its long-standing recognition, remarkably little is known about the etiology of, and effective treatment for, anorexia nervosa. A 2002 review in the American Journal of Psychiatry concluded that little progress was made during the second half of the 20th century in understanding the etiology, prognosis, or treatment of the disorder (8) .

Epidemiology

Prevalence rates for anorexia nervosa are generally described as ranging from 0.5% to 1.0% among females (9 , 10) , with males being affected about one-tenth as frequently (10 , 11) . A recent study describing a large population-based cohort of Swedish twins born between 1935 and 1958 found the overall prevalence of anorexia nervosa among the 31,406 study participants to be 1.20% and 0.29% for females and males, respectively; the prevalence of anorexia nervosa in both sexes was greater among those born after 1945 (12) .

Risk Factors

The identification of risk factors for anorexia nervosa is challenging because the low incidence of the disorder makes the conduct of prospective studies of sufficient size very difficult. A variety of possible risk factors have been identified, including early feeding difficulties, symptoms of anxiety, perfectionistic traits, and parenting style, but none can be considered to have been conclusively demonstrated (13 , 14) . Similarly, cultural factors undoubtedly play some role in the development of anorexia nervosa, although the disorder’s long history and its presence in regions around the globe (15 – 18) suggest that factors other than culture provide central contributions to the development of the disorder. In fact, one review that considers historical reports of eating disorders, data regarding changing incidence rates of eating disorders over time, and the prevalence of eating disorders in non-Western cultures concludes that anorexia nervosa is not a culture-bound syndrome (19) . Genetic factors are increasingly accepted as important contributors to the risk of anorexia nervosa. Twin studies of eating disorders have consistently found that a significant fraction of the variability in the occurrence of anorexia nervosa can be attributed to genetic factors, with heritability estimates ranging from 33% to 84% (20) .

Course of Illness

The course of anorexia nervosa is highly variable, with individual outcomes ranging from full recovery to a chronic and severe psychosocial disability accompanied by physical complications and death. Intervention early in the course of illness and full weight restoration appear to be associated with the best outcomes. Adolescent patients have a better prognosis than do adults. One-year relapse rates after initial weight restoration approach 50% (21) . Intermediate and long-term follow-up studies examining clinical samples find that while a significant fraction of patients achieve full psychological and physical recovery, at least 20% continue to meet full criteria for anorexia nervosa on follow-up assessment, with many others reporting significant residual eating disorder symptoms, even if they do not meet full criteria for anorexia nervosa (22) .

Physiological Disturbances

A multitude of biological disturbances may occur in underweight patients, but most appear to be normal physiological responses to starvation. Clinically significant abnormalities may develop in the cardiovascular, gastrointestinal, reproductive, and fluid and electrolyte systems (23) . These abnormalities usually do not require specific treatment beyond refeeding, and they return to normal on weight restoration. A worrisome possible exception is reduced bone density; since peak bone density is normally achieved during young adulthood, a prolonged episode of anorexia nervosa during this development stage may have a long-term impact on the risk of osteoporosis.

Neurobiological Hypotheses

The striking physical and behavioral characteristics of anorexia nervosa have prompted the development of a variety of neurobiological hypotheses over the years. Recently, results of several investigations have suggested that abnormalities in CNS serotonin function may play a role in the development and persistence of the disorder (24 , 25) . Notably, studies of long-term weight-recovered patients have described indications of increased serotonin activity, such as elevated levels of the serotonin metabolite 5-hydroxyindoleacetic acid in the CSF (26) and reduced binding potential of 5-HT 2A receptors, suggestive of higher levels of circulating CNS serotonin, in several brain regions (27) .

Kaye and colleagues (28) hypothesize that individuals with anorexia nervosa may have a trait disturbance characterized by high levels of CNS serotoninergic activity leading to symptoms of anxiety that are relieved by dieting, which leads to a reduction in serotonin production. However, this provocative hypothesis is based on assessments conducted after the onset of illness, which therefore cannot distinguish a predisposing trait from a long-lasting consequence of anorexia nervosa.

Another recent line of inquiry into the biological underpinnings of anorexia nervosa focuses on the perfectionistic and rigid behavioral style, including repetitive and stereotyped behaviors, characteristic of the syndrome. Investigators have hypothesized that these behaviors may result from a propensity to extreme fear conditioning and resistance to fear extinction (29) , suggesting that abnormalities may be present in limbic structures known to be involved in the acquisition of conditioned fear behavior. Other investigators have proposed that difficulties of individuals with anorexia nervosa in changing maladaptive behavior may relate to problems with set shifting, a function mediated by corticostriatothalamocortical neural circuits (30 , 31) .

Engaging a patient with anorexia nervosa to participate fully in the psychiatric evaluation may present a greater challenge than would be the case for patients with other disorders, including other eating disorders such as bulimia nervosa or binge eating disorder. Patients with anorexia nervosa often present for evaluation not because of their own interest in symptom relief but because of the concerns of family, friends, or health care providers. It may be necessary to obtain additional information from family members or others who know the patient well.

In addition, during the evaluation, it may be helpful to identify symptoms of the illness that are most likely to be ego-dystonic for the particular patient. Patients commonly minimize their concerns about low weight, but they may be more concerned, and therefore more likely to participate in the evaluation, if they recognize poor concentration, increased irritability, low bone density, hair loss, or feeling cold as developments associated with their restrictive eating pattern.

Medical issues should be reviewed, including weight and menstrual history. A complete review of systems is indicated, as anorexia nervosa can manifest a multitude of disturbances, including cardiovascular symptoms (e.g., bradycardia and other arrhythmias, including QTc prolongation, and hypotension), gastrointestinal symptoms (e.g., slow motility, esophageal inflammation associated with purging), endocrinologic symptoms (low estrogen in females, low testosterone in males, osteopenia, and osteoporosis), and dermatologic changes, such as the development of a layer of fine hair (lanugo) on the face and extremities.

The evaluation should include specific questions about eating behaviors, including the number and content of all meals and snacks on a recent day. The clinician should inquire about 1) restricting behaviors, including limiting permissible foods, as well as decreasing caloric amounts; 2) binge eating; 3) purging behaviors, including vomiting and misuse of laxatives and diuretics; and 4) exercise and hyperactive behaviors, including preferential walking and standing.

Given patients’ reluctance to endorse all of the diagnostic symptoms of anorexia nervosa on first meeting, the clinician may do well to identify the problem as “low weight” and explain that the treatment needs to include weight restoration, whether or not the patient meets full criteria for anorexia nervosa. Patients and their families are generally very interested in data from the World War II Minnesota study of semistarvation that documented the association between starvation and the development of psychological symptoms frequently identified with anorexia nervosa, such as depression, anxiety, obsessionality about food, and rigidity about eating behaviors (32) . The clinician may have better results engaging the patient with the identification of symptoms that are commonly associated with the state of starvation and that the patient has likely found troubling (such as thinking constantly about food) and therefore worth resolving.

Treatment Guidelines

All current treatment guidelines for anorexia nervosa emphasize weight restoration. There is no clearly defined algorithm for how to accomplish this goal, although common practice includes the selection of the least restrictive treatment setting that is likely to be effective. The APA practice guideline on treatment of eating disorders suggests that highly structured treatments are often needed to achieve weight gain for patients at weights <85% ideal body weight (33) . Hospital-based treatments may be used when weight is significantly low (e.g., <75% of ideal body weight) or when there has been rapid weight loss or medical signs of malnutrition, including significant bradycardia, hypotension, hypothermia, and so on.

Generally, outpatient treatments rely on a team of professionals. Medical monitoring, including weight and laboratory assessment, may be provided by an internist or pediatrician; psychological support is offered by a psychiatrist or other therapist; and nutritional counseling from a dietitian or nutritionist is often included. The team is generally led by the medical or psychiatric clinician—typically the one with the greatest expertise in the management of eating disorders.

Effective treatments generally assess outcome by weight and behavioral change. Nonspecific support needs to be paired with expectation of progress in measurable medical, behavioral, and psychological symptoms. Weight restoration is generally associated with improvement in a variety of psychological areas, including mood and anxiety symptoms (34 , 35) . In contrast, psychological improvement without accompanying changes in weight and eating behavior is of limited value. Patients and families should be informed about the physiology of weight gain, including the substantial number of calories required daily.

A family-based outpatient treatment for anorexia nervosa, also called the “Maudsley method,” may be helpful for younger patients (36) . This approach empowers the parents of a patient with anorexia nervosa to refeed their child, renegotiate the relationship between child and parents to involve issues other than food, and help their child resume normal adolescent development without an eating disorder. Several preliminary studies have shown promising results for family therapy with adolescent patients (37 , 38) .

For patients with anorexia nervosa who do not respond to outpatient treatments or those who do not have specialized outpatient treatments available in their vicinity, more structured treatments such as inpatient or partial hospital (day treatment) programs may be necessary. Structured treatments generally include observation during and after meals together with a consistently applied behavioral program that reinforces weight gain and normal eating behaviors. In recent years, the length of hospital stay for anorexia nervosa has decreased substantially because of economic limitations imposed by third-party payers; nonetheless, hospital programs can achieve a rate of weight gain of 2–4 pounds per week during active treatment (39) .

Controlled Treatment Trials

While structured settings have been used successfully for weight restoration treatments, there is little empirical support for a specific level of care or a particular psychosocial treatment for anorexia nervosa. As mentioned, a family-based approach appears promising for children and adolescents with anorexia nervosa; family therapy has been reported to be superior to individual therapy in two randomized controlled trials for adolescents with anorexia nervosa (40 , 41) . For adults with anorexia nervosa, a small study by Pike and colleagues (42) found cognitive behavior therapy superior to nutritional counseling in preventing relapse after hospital-based weight restoration. A recent study by McIntosh et al. (43) provocatively suggested that a patient-centered nonspecific supportive therapy may have been more helpful than cognitive behavior therapy or interpersonal therapy, as measured by a global rating of anorexia nervosa symptoms, in a sample of 56 underweight women with anorexia nervosa receiving treatment over a minimum of 20 weeks; unfortunately, the amount of weight gain was modest and not significantly different among the three study treatments.

Randomized controlled trials of medications for patients with anorexia nervosa have consistently reported disappointing results. Several psychopharmacologic agents have been studied, without identification of clear benefit, although studies have been limited by small sample sizes and the fact that most of the trials have been conducted in hospital settings where other treatment interventions are offered in addition to study medication (44) . While it has been suggested that psychotropic medications are rendered ineffective in underweight patients by the biological impact of starvation, a recent study comparing fluoxetine and placebo in weight-restored patients notably found no significant benefit to medication during the year following nutritional rehabilitation (45) .

Summary and Recommendations

Although recognized for centuries, anorexia nervosa remains enigmatic, often difficult to treat, and potentially lethal. The current approach to treatment includes careful medical assessment, ongoing medical and weight monitoring, and behaviorally oriented treatment aimed at normalizing weight and eating behaviors. Family-based treatment appears promising for younger patients.

With Rachel, the patient in the vignette, her typical presentation, her low weight (corresponding to a body mass index of 17.3), and her reluctance to restore her weight to its previously healthy level led the evaluating psychiatrist to conclude that Rachel indeed had anorexia nervosa. The psychiatrist recommended that Rachel attempt outpatient treatment but explained to her and her family that many patients require more structured settings for successful weight restoration. The psychiatrist recommended that Rachel see an eating disorder specialist knowledgeable about the characteristics of anorexia nervosa and experienced in dealing with the challenges of its treatment. The outpatient treatment plan included weekly psychotherapy sessions, along with regular visits with her pediatrician and a nutritionist. Although Rachel had complained of “depression,” the psychiatrist elected not to prescribe antidepressant medication, as there is no evidence of its utility in anorexia nervosa, and weight gain in this disorder is known to lead to improvement in mood. In the meetings with Rachel, the psychiatrist used cognitive behavior therapy techniques to help her in reevaluating her assumptions that low weight was somehow essential to her sense of self-worth. Treatment outcome was assessed by changes in weight and eating behavior. Rachel’s family participated by helping to supervise meals at the start of treatment and offering her more autonomy around eating as she made progress. Rachel was asked to gain weight at a rate of >1 lb per week and knew that failure to meet this goal would lead to transfer of treatment to a more structured setting. Rachel reached and maintained her premorbid weight and was able to return to school 6 months after initial presentation.

Received July 19, 2007; accepted Aug. 6, 2007 (doi: 10.1176/appi.ajp.2007.07071151). From the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York; and the Eating Disorders Research Unit, New York State Psychiatric Institute, New York. Address correspondence and reprint requests to Dr. Attia, New York State Psychiatric Institute, 1051 Riverside Dr., Unit 98, New York, NY 10032; [email protected] (e-mail).

CME Disclosure: Dr. Attia has received research support from Pfizer and Eli Lilly. Dr. Walsh has received research support from Abbott Pharmaceuticals.

APA policy requires disclosure by CME authors of unapproved or investigational use of products discussed in CME programs. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by scientific literature and clinical experience.

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anorexia nervosa research studies

In our research lab, we are conducting a number of treatment studies that provide free treatment for anorexia nervosa and bulimia nervosa. Please read further for additional information.

Confirming the Effectiveness of Online Guided Self-Help Family-Based Treatment for Adolescent Anorexia Nervosa

Stanford University is conducting a study on virtual treatments for anorexia nervosa in adolescents.

Who can participate?

  • Adolescents living with their families between the ages of 12 and 18 years of age with DSM-5 AN
  • Adolescent lives with at least one family member
  • Parents are able to read and speak fluent English
  • Access to a computer with a reliable internet connection
  • Adolescent is medically stable for remote, outpatient treatment
  • Virtual family-based treatment (FBT-V) 
  • Online guided self-help family-based treatment (GSH-FBT)
  • In addition to treatment, participants will complete assessments and questionnaires throughout the course of the study  

If you have any questions, or are interested in signing up for the study, please email Hazal Gurcan at [email protected] . Alternatively, call (650) 723 - 9182.

Family-Based Treatment Training Study

Stanford University is conducting an NIH-sponsored study looking at how to best train therapists in delivering Family-Based Treatment for anorexia nervosa.

  • Therapists that have completed a masters or doctoral training in their field (psychology, psychiatry, family therapy, social work) and are licensed in their respective state
  • No reports of malpractice or loss of privileges at relevant clinical institutions
  • Have computer/web access for online training and assessments
  • No previous 2-day in-person workshop training in FBT
  • Able to submit baseline data on weight gain from week 1-4 from a previously treated adolescent with AN they have treated in the last 6 months or alternatively one that they treat within the first 3 months of completing their initial screen.

All participants are randomized to one of two trainings:

  • Online training which consists of 10 lectures that are self-paced with a maximum of three months to complete with each lecture bundle comprising of short didactic videos that discuss the treatment model and provide mock therapy session video clips (modeling FBT with a typical adolescent AN case), as well as supplementary readings and videotaped role-plays.
  • Webinar training which consists of 1-hour weekly webinar lectures over three months. There will be lectures discussing the scientific evidence supporting FBT, how therapists set up treatment for FBT, main interventions used in FBT during each phase, and recorded role-plays illustrating interventions throughout the 3 phases.

Both trainings are followed by post-online expert supervision for a minimum of 1 case and a maximum of 2 cases over the course of 3 months.

Contact information for participant inquiries:  Kyra Citron at (650) 723-9182; [email protected]

Confirming the Efficacy/Mechanism of Family Therapy for Children with Low Weight Avoidant/Restrictive Food Intake Disorder (ARFID)

Children ages 6-12 with a diagnosis of Avoidant/Restrictive Food Intake Disorder (ARFID) and their families are invited to participate in a Family-Based Treatment (FBT) vs. a manualized Non-Specific Care (NSC) research study through the Stanford Department of Psychiatry and Behavioral Sciences. The study consists of 14 one-hour telehealth sessions in either treatment arm, along with required medical management, over the course of 4 months. Treatment will be provided by doctoral-level, highly skilled therapists.

Recruitment age range:  6-12 years old 

Recruitment gender:  All 

Contact information for participant inquiries:   [email protected]

Key words:  eating disorders, ARFID, Avoidant/Restrictive Food Intake Disorder, Family-Based Treatment 

Emotion Regulation in Adolescents with Binge Eating and Purging

A study for girls 14-18 who struggle with binge/purge behaviors (no formal diagnosis is required to participate). The study involves two appointments - one interview and one fMRI scan. Participants are compensated $100.

Recruitment age range:  14-18 years old

Recruitment gender:  Female

Contact information for participant inquiries:    [email protected]

Key words:  eating disorders, binge eating, emotion regulation

For general information regarding questions, concerns, or complaints about research, research related injury or the rights of research participants, please call (650) 723-5244 or toll-free 1-866-680-2906, or write to the Administrative Panel on Human Subjects in Medical Research, Administrative Panels Office, Stanford University, Stanford, CA 94305-5401.

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COMMENTS

  1. Recent advances in understanding anorexia nervosa

    Anorexia nervosa is a complex psychiatric illness associated with food restriction and high mortality. Recent brain research in adolescents and adults with anorexia nervosa has used larger sample sizes compared with earlier studies and tasks that test specific brain circuits. Those studies have produced more robust results and advanced our ...

  2. Eating disorder outcomes: findings from a rapid review of over a decade

    Eating disorders (ED), especially Anorexia Nervosa (AN), have amongst the highest mortality and suicide rates in mental health. While there has been significant research into causal and maintaining factors, early identification efforts and evidence-based treatment approaches, global incidence rates have increased from 3.4% calculated between 2000 and 2006 to 7.8% between 2013 and 2018 [].

  3. The hidden burden of eating disorders: an extension of estimates from

    Of these 12 studies, four reported on results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), focusing only on anorexia nervosa and bulimia nervosa. The remaining studies either reported epidemiology or alternative health metrics (eg, quality of life) on a study sample or compiled these data in a review.

  4. Molecular neuroanatomy of anorexia nervosa

    Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using genome-wide methods, recent studies have associated many genes with the disorder.

  5. Anorexia nervosa treatment trials: time for new approaches

    Anorexia nervosa is a serious psychiatric illness with medical as well as behavioural health manifestations. It is associated with high rates of morbidity and a mortality rate as high as that of any other psychiatric illness.1 It is an old illness2 and a challenge to treat, especially in adults, who might have been ill for several years.3 Although outpatient treatments to target anorexia ...

  6. Genome-wide association study identifies eight risk loci and ...

    Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50 ...

  7. Anorexia nervosa and familial risk factors: a systematic review of the

    Anorexia Nervosa (AN) is a psychological disorder involving body manipulation, self-inflicted hunger, and fear of gaining weight.We performed an overview of the existing literature in the field of AN, highlighting the main intrafamilial risk factors for anorexia. We searched the PubMed database by using keywords such as "anorexia" and "risk factors" and "family". After appropriate ...

  8. Eating Disorders: Current Knowledge and Treatment Update

    Eight years ago, DSM-5 made major changes to the diagnostic criteria for eating disorders. A major problem in DSM-IV's criteria was that only two eating disorders, anorexia nervosa and bulimia nervosa, were officially recognized.Therefore, many patients presenting for treatment received the nonspecific diagnostic label of eating disorder not otherwise specified (EDNOS), which provided little ...

  9. Terminal anorexia nervosa: three cases and proposed clinical

    Severe and enduring anorexia nervosa: Update and observations about the current clinical reality. Int J Eat Disord. 2020;53(8):1303-12. Article Google Scholar Broomfield C, Noetel M, Stedal K, Hay P, Touyz S. Establishing consensus for labeling and defining the later stage of anorexia nervosa: A Delphi study.

  10. A retrospective study of pharmacological treatment in anorexia nervosa

    The transition from restrictive anorexia nervosa to binging and purging: a systematic review and meta-analysis. Eating and Weight Disorders-Studies on Anorexia, Bulimia and Obesity. 2022:27(3):857-65. Errichiello L, Iodice D, Bruzzese D, Gherghi M, Senatore I. Prognostic factors and outcome in anorexia nervosa: a follow-up study.

  11. Anorexia nervosa

    Anorexia nervosa (AN) is a disorder that predominantly affects women in early adolescence 1. The characteristic features of AN include severe weight loss and secondary problems associated with ...

  12. Factors predicting long-term weight maintenance in anorexia nervosa: a

    Future research should aim to replicate studies to better understand the relationship between the factors identified and weight maintenance. Systematic review. ... (2018) Preoccupation with shape or weight, fear of weight gain, feeling fat and treatment outcomes in patients with anorexia nervosa: a longitudinal study. Behav Res Ther 105:63-68.

  13. Incidence, prevalence and mortality of anorexia nervosa and

    Although most research has been performed in young females, some studies report incident anorexia nervosa cases in later life as well . It is noteworthy that the peri-menopausal period has been suggested as another high-risk period in female life for the onset or recurrence of eating disorders . In males, findings regarding the peak period of ...

  14. Study protocol of comprehensive risk evaluation for anorexia nervosa in

    Background Anorexia nervosa (AN) is a severe disorder, for which genetic evidence suggests psychiatric as well as metabolic origins. AN has high somatic and psychiatric comorbidities, broad impact on quality of life, and elevated mortality. Risk factor studies of AN have focused on differences between acutely ill and recovered individuals. Such comparisons often yield ambiguous conclusions, as ...

  15. Anorexia Nervosa

    A recent study describing a large population-based cohort of Swedish twins born between 1935 and 1958 found the overall prevalence of anorexia nervosa among the 31,406 study participants to be 1.20% and 0.29% for females and males, respectively; the prevalence of anorexia nervosa in both sexes was greater among those born after 1945 .

  16. Studies

    Contact information for participant inquiries: [email protected]. Key words: eating disorders, binge eating, emotion regulation. For general information regarding questions, concerns, or complaints about research, research related injury or the rights of research participants, please call (650) 723-5244 or toll-free 1-866-680-2906, or write ...

  17. Autobiographical memory following weight gain in adult patients with

    Generalised OGM (i.e., independent of word category) in patients with anorexia nervosa before weight restoration may be a general incapacity to recall autobiographical memory. BACKGROUND Patients with anorexia nervosa (AN) show overgeneralization of memory (OGM) when generating autobiographical episodes related to food and body shape. These memories are central for the construction of a ...

  18. Decision-Making Study for Individuals with Anorexia Nervosa ...

    The REPEAT Lab at Virginia Commonwealth University is currently recruiting adult participants who have symptoms of anorexia nervosa (e.g., restrictive eating, weight loss, fear of weight gain) and healthy adult participants with no history of a psychiatric disorder. for a research study. The goal of the study is to understand decision-making ...