Article published online: 2022-12-21

THIEME
Review Article 3

A Clinical Overview of Anorexia Nervosa and

Overcoming Treatment Resistance
Hassan Nagy1 Tanya Paul1 Esha Jain1 Hanyou Loh1 Syeda Hafsa Kazmi1 Rishbha Dua1
Ricardo Rodriguez1 Syed Ali Abbas Naqvi1 Metu Chiamaka U.1 Erjola Bidika1

1 Division of Research & Academic Affairs, Larkin Health System, Address for correspondence Hassan Nagy, MD, MBA, Division of
South, Miami, Florida, United States Research & Academic Affairs, Larkin Health System, South, Miami, FL
6342, United States (e-mail: hassmnagy@gmail.com).
Avicenna J Med 2023;13:3–14.

Abstract Anorexia nervosa (AN) is a type of eating disorder that has been increasing in incidence
and has been encountered more commonly by physicians in their daily practice. Both
environmental and genetic risk factors paired along with a more susceptible neurobi-
ology are at play in the emerging resistance to treatment in AN. Preoccupations with
intense fear of weight gain, dietary restrictions, excessive exercise, and how the
individual is perceived by society mixed with underlying psychopathology all further
add to the issue. Many patients who fall into this cycle of obsessive and restrictive
Keywords patterns refuse to get treatment. As clinicians, it is essential we recognize the early
► anorexia nervosa signs of both eating disorders during the initial primary care appointments.
► treatment-resistant To review the literature on the etiology of AN, possible misdiagnosis leading to
anorexia inappropriate management of this condition, and understand the treatment-resistant
► eating disorders AN and its management. Additionally, it will explore possible reasons that contribute to
► psychiatric disorders the resistance to treatment, the underlying psychopathology of anorexics, its genetic
► managing chronic predisposition, psychiatric comorbidities, identification of the early signs and symp-
anorexia toms, and timely prevention.
► psychosocial Early recognition by a physician includes a thorough history and physical examination,
treatments of pertinent laboratory, and electrolyte studies, and identifying comorbid psychiatric
anorexia conditions. The treatment of AN is intricate and requires a holistic approach. Treatment
► deep brain includes multiple modalities such as nutritional rehabilitation and psychosocial and
stimulation in pharmacological therapies. An interdisciplinary team of medical professionals for
anorexics managing chronic AN is recommended.

Introduction from another observational study conducted by Petkova et al

between February 1, 2015 and September 10, 2015, across
Anorexia nervosa (AN) is a condition increasingly encoun- the United Kingdom and Ireland.2 Through this study, it was
tered by physicians in their daily practice. It was reported by estimated that 37 new cases of AN were reported annually
Hoek that there has been an increase in the incidence of AN for every 100,000 females aged between 10 and 19 years,
up to the early 2000s, with females aged between 15 and while only 3 new cases were reported for every 100,000
24 years accounting for majority of the cases.1 This disorder males of the same age.2 Majority of these cases again
was also found to be more common among Caucasians than involved Caucasians (92%) and prevalence was estimated
African Americans.1 Similar results for AN were obtained to range between 0.3% and 0.6%.2

article published online DOI https://doi.org/ © 2022. The Author(s).

December 21, 2022 10.1055/s-0042-1758859. This is an open access article published by Thieme under the terms of the
ISSN 2231-0770. Creative Commons Attribution License, permitting unrestricted use,
distribution, and reproduction so long as the original work is properly cited.
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4 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al.

A meta-analysis of 36 studies published between Janu- personality traits, perfectionism, and sensitivity. There is strong
ary 1966 and September 2010 was performed by Arcelus evidence that individuals with first-degree relatives with AN are
et al. This study concluded that individuals with eating at increased risk of developing this condition.5 Precipitating
disorders have significantly elevated mortality rates with factors include dieting, weight loss, as well as stressors from life
the highest occurring in those with AN.3 Moreover, they events.6 Dieting and weight loss are major factors that predis-
reported that the cause of death was suicide for every one in pose to AN, by directly influencing mood changes, brain func-
five individuals who died from AN.3 This could possibly be tion, and the further decrease in appetite. Stressors from life
related to the psychiatric comorbidities associated with AN. events including new school, job, or home; death of a loved one;
Salbach-Andrae et al conducted a study on 101 female or any sudden transitions increase emotional stress significantly
adolescents who were being treated at a psychiatric unit and put individuals at increased risk for developing AN. The risk
primarily for AN.4 About 73.3% of these patients were diag- is reported to be higher in females.7 Previous studies have
nosed with comorbidities, with mood disorders being the indicated that the serotonin receptor HTR2A and serotonin
most common at 60.4%.4 Anxiety disorders were next in-line molecule (5-HTT) are implicated in the pathogenesis of AN.8
at 25.7%, followed by obsessive-compulsive disorder (OCD) at Moreover, different studies that have been performed in twins
16.8%, and substance use disorder at 7.9%.4 suggest a shared genetic factor between AN and major depres-
Given the increased incidence of this condition and high sion, suicide attempts, OCD, and eating disorders.9–11
mortality rate, the purpose of this paper is to review the Ghrelin resistance also plays an important role in the
literature on the etiology of AN, possible misdiagnosis lead- pathogenesis of AN.12 Ghrelin is a 28 amino-acid peptide
ing to inappropriate management of this condition and hormone produced by the oxyntic glands in the stomach in
understand the treatment resistance AN and its manage- the fasting state. As shown in ►Fig. 1, the release of Ghrelin
ment. Using this article, we seek both to guide future stimulates the ventromedial hypothalamus by binding and
research on AN and inform fellow physicians on the best activating the growth hormone secretagogue receptor
forms of management for the condition. (GHSR), leading to phosphorylation of the 5′ adenosine
monophosphate-activated protein kinase (AMPK), resulting
in an increase in gastric motility and appetite (►Fig. 2).12
Etiology of Anorexia Nervosa
AN is a multifactorial eating disorder involving a combination of
Complications of Anorexia Nervosa
predisposing and precipitating factors. Predisposing factors can
be biological, psychological, or environmental and include Medical complications of AN can vary in the degree of
genetics, pregnancy-related factors, childhood life-events and severity and often they can be systemically widespread.13,14
eating behaviors, teasing and criticism or bullying from peers, Common complications associated with AN include second-
personality traits, and psychiatric comorbidities. Although there ary amenorrhea and the presence of lanugo (thin, fine body
is no proven involvement of genes in anorexia, some people may hair). Life-threatening complications may also occur, such as
have a genetic tendency toward obsessive-compulsive and other those of the endocrine and cardiovascular systems, namely

Fig. 1 Mechanism of ghrelin in the regulation of food intake. 12 AMPK, 5′ adenosine monophosphate-activated protein kinase; GHSR, growth
hormone secretagogue receptor; pAMPK, phosphorylated 5′ adenosine monophosphate-activated protein kinase.

Avicenna Journal of Medicine Vol. 13 No. 1/2023 © 2022. The Author(s).

 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al. 5

Fig. 2 Mechanism of ghrelin resistance in the pathogenesis of anorexia nervosa. 12 (Designed by research team). AMPK, 5′ adenosine
monophosphate-activated protein kinase; GHSR, growth hormone secretagogue receptor; pAMPK, phosphorylated 5′ adenosine mono-
phosphate-activated protein kinase.

hypoglycemia and sudden cardiac death respectively. Addi- RS, and it is recommended that supplemental phosphorus
tionally, other complications that may be encountered in- be commenced early to maintain serum levels above 3.0-
clude those of the pulmonary, gastrointestinal, hematologic, mg/dL.15,16 Cardiac and neurological events associated with
dermatologic, and nervous system.14,15 Reduced pulmonary refeeding were most frequently noted to occur within the
function, aspiration pneumonia, emphysema, and spontane- first weeks of refeeding, making it important to closely
ous pneumothorax are potential pulmonary complications monitor a patient’s electrolyte and cardiac status during
of AN. Superior mesenteric artery syndrome and gastro- this period.16
paresis with constipation are gastrointestinal complications
that have been found to be associated with AN.15 Gelatinous
History and Physical Examination of AN
bone marrow transformation, sarcopenia, and reduced bone
Patients
mass are also observed.15 Depending on the severity of AN,
anemia, leukopenia, and thrombocytopenia may also be In order for a prompt diagnosis and successful treatment, it is
present to varying degrees. Patients could also present crucial to recognize the clinical signs and symptoms along
with xerosis and acrocyanosis. Imaging studies of the brain with the physical presentation of AN. Studies have shown
have also shown evidence of atrophy, with secondary cogni- that the severity of the illness AN is equivalent to lower body
tive impairment manifesting clinically.13,14 Additional com- weights—mild: body mass index (BMI) more than or equal to
plications of the endocrine system include reduced leptin 17 kg/m2, moderate: BMI 16 to 16.99 kg/m2, severe: BMI 15
levels, euthyroid sick syndrome, elevated cortisol serum to 15.99 kg/m2, extreme: BMI less than 15 kg/m2.17 Accord-
levels, as well as resistance to growth hormone. Structural ing to the Diagnostic and Statistical Manual of Mental Dis-
changes to the left ventricle and mitral valve prolapse may orders (DSM)-IV diagnostic criteria, if a patient consistently
also be encountered.13,14 refuses to keep their body weight equivalent to or above 85%
In addition to the above medical complications of AN, of what is normal for their age and height, one must consider
complications associated with the treatment may also arise AN.18 Concern is raised when low body weight is associated
such as a refeeding syndrome (RS).15 RS is a serious with worsened bradycardia and hypotension.18 The combi-
complication that can occur during the treatment of AN. nation of low body weight and inability to remain hemody-
This complication occurs when nutritional therapy admin- namically stable leads the patient to severe complications
istered to the anorexic patient is introduced in excess and and an overall poorer prognosis. These patients are subse-
can also be fatal if not managed appropriately. Hormonal quently at a higher risk of pathologies such as refeeding
and metabolic changes can occur during the refeeding of hypophosphatemia, low bone mineral density, and abnor-
chronically malnourished patients, via either oral or paren- mally increased liver enzymes.18
teral methods.15 Electrolyte derangements that may occur Typically, patients that deal with eating disorders often
include hypophosphatemia, hypokalemia, hyponatremia, fixate on their appearance, especially encompassing an
hypomagnesemia, and metabolic acidosis.15 Of these, hypo- extreme dislike for their body shape and weight. Because
phosphatemia is the most important diagnostic marker for these patients hide their weight loss with extra layers of

Avicenna Journal of Medicine Vol. 13 No. 1/2023 © 2022. The Author(s).

6 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al.

clothing, AN can go unnoticed.19 It is important that physi- just a hospital gown and underwear may be warranted.17
cians recognize the physical presentation of AN patients so Laboratory studies should include a complete metabolic
that it can facilitate prompt treatment and recovery. Patients panel, complete blood count, toxicology screen, thyroid
have been found to take many measures to reduce their body levels, liver function tests, and pancreatic enzyme levels.
weight, including restricting and skipping meals, and certain These laboratory measures should be obtained and evaluated
rituals before mealtime such as cutting their food into very to note any electrolyte imbalances or other underlying con-
small portions, or spreading the food around the plate as if ditions or complications.17 A healthcare provider may assess
more food had been consumed.19 Important questions a the patient’s psychological status by completing comprehen-
physician should ask which can help lead to a certain sive neuropsychological tests, which are additional measures
differential diagnosis include “what have you eaten since that comprise evaluating an individual’s attention span,
yesterday?” and “have you ever eaten more than you wanted psychomotor speed, visuospatial capacity, immediate and
to (binge-eating) or used any diet pills or laxatives?”19. Being long-term memories, recall ability, reaction time, decision-
vigilant on the way a patient describes their body weight can making capacity, etc. There are significant findings of AN
help lead the clinician to diagnosing AN. For example, a such as attentional disengagement, shorter reaction times in
patient may express extreme dislike for the shape of their copying tasks, poor reaction time, fewer words recalled,
body or constantly be analyzing areas of their body in the worse visuospatial, and immediate memory as well as def-
mirror. Keeping this in mind, a detailed history and physical icits in decision-making.21 Patients with chronic AN can
examination are paramount to detect the unnoticed signs present with menstrual irregularities such as amenorrhea.18
and symptoms of AN.19 Regularly assessing follicle-stimulating hormone, luteinizing
Parameters of nutritional status in anorexia are signifi- hormone, thyroid-stimulating hormone and prolactin levels
cantly lower levels of BMI, ideal body weight, lean body, and can be quite helpful in evaluation of abnormalities and areas
fat mass. Additionally, AN patients display lower heart rates, to target for management. Furthermore, an electrocardio-
blood pressure, body temperatures, and red blood cell and gram is crucial as AN patients’ binge-eating and purging
white blood cell count.17 Taking all this into account, consis- habits can have metabolic changes leading to potentially
tent monitoring, and regular follow-up of the AN patient can fatal arrhythmias. Also assessing neuropsychological status
mitigate harmful or fatal complications of AN. can give insight into understanding the possible decline in
cognitive function seen in patients enduring AN.22 Lastly, it is
important to acquire bone densitometry so that physicians
Evaluation of AN
can evaluate the severity of bone loss in these patients.18 By
When evaluating a patient for AN, physicians must first rule being meticulous with evaluation of the AN patient, this can
out any emergency medical sequelae that necessitate hospi- lead to timely diagnosis and treatment, and improved
talization and stabilization.17 It is necessary to obtain a outcomes.
thorough history and physical examination to rule out any
neurological or psychiatric comorbidities through compre-
Differential Diagnosis of Anorexia Nervosa
hensive evaluation.20 Many diagnoses can present with
similar symptoms to AN; these include hyperthyroidism, To improve the outcomes of patients suffering with AN, early
malabsorption disorders, diabetes, inflammatory bowel dis- and prompt diagnosis, especially at an earlier age, has been
ease, immunodeficiencies, Addison’s disease, and some shown to be correlated with improved health outcomes. The
chronic infections.20 These diagnoses need to be ruled out American Academy of Family Physicians states that patients
before confirming the diagnosis of AN. Many psychiatric suffering with AN typically restrict calories or involve them-
disorders can coincide with AN, like major depressive disor- selves in excessive exercise to control their emotional needs.
der (MDD) or OCD. All patients must be screened during their These patients demonstrate an unhealthy and extreme fear
office visits to rule out other psychiatric comorbidities when of gaining weight.20 The DSM-V has described two main
diagnosing AN. Patient history is the most important tool in subtypes of AN: 1) the binge-eating and purging type, and 2)
diagnosis of AN, as laboratory and physical examination can the restrictive type. The person with the former subtype
be normal in the earlier stages of this disorder.20 A common usually demonstrates actions like self-induced vomiting, and
screening tool used in the primary care setting is the SCOFF laxative or diuretic abuse. The latter subtype is considered in
questionnaire; although this has a 12.5% false positive rate, it a patient that abstains from the regular binge eating and/or
is used as an appropriate screening measure, but not for AN purging for a minimum of 3 months.23
diagnosis.20 Prior to obtaining the patient’s weight, one Majority of times, patients suffering with AN are noticed
should assess the patient’s hydration status via urinalysis first by primary care providers.24 Lebow et al conducted a
and evaluate their specific gravity, ketone levels, and kidney retrospective clinical cohort study and exemplified the role
functions. Recording all initial vital signs such as blood that primary care physicians can play in the treatment of
pressure, temperature, pulse, height, weight, and BMI is adolescents trying to recover from restrictive eating disor-
necessary for evaluating the patients’ clinical progression ders, along with facilitating weight gain.24 This study placed
or regression.17 It is possible that patients may try to falsely emphasis on the pertinent role that physicians’ play in helping
raise their weight by wearing multiple layers or hide objects to restore AN patients’ body weight and improve their overall
on their person; therefore, the need to obtain their weight in clinical status by focusing on family-based treatment (FBT) for

Avicenna Journal of Medicine Vol. 13 No. 1/2023 © 2022. The Author(s).

 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al. 7

AN. They found a significant improvement in adolescents’ BMI like hypothyroidisms. Fatigue, constipation, menstrual irreg-
following FBT by primary care physicians.24 While AN patients ularities, edema, hypothermia, bradycardia, and low thyroid
may not present to their family physician to help treat their hormones (T3 and T4) are also often discovered in both
anorexia, patients often present to their family physician conditions.17,26,32 Lastly, AN and BDD are severe psychiatric
for secondary complaints such as amenorrhea or extreme conditions with comparable personality characteristics.
fatigues. Thus, family physicians can potentially combine the Prevalent features include negative body image, ritualistic
treatment of secondary symptoms with FBT, while also focus- behaviors, compulsive mirror checking, and a high value
ing on restoring weight .24 placed on attractiveness. In addition, suicidal ideation is
AN is a multidimensional disorder that shares significant constant in both diagnoses.27,33,34
signs and symptoms with multiple medical conditions. Avoidant/restrictive food intake disorder (ARFID) is an-
Bulimia nervosa (BN), MDD, body dysmorphic disorder other differential diagnosis that should be considered when
(BDD), and hypothyroidism should be on the differential assessing patients with a history of restrictive eating. These
diagnostic radar due to their shared similarities with patients have either a sensory issue with the appearance,
AN.17,25–27 ►Fig. 3 depicts the resemblances between these odor, or feel of a specific type of food or they may associate
four disorders.17,25–34 Eating-disorder symptoms and psy- certain types of food to a past traumatic event such as
chosis symptoms may coexist. Psychosis may also be consid- choking or vomiting and avoid whole food groups or avoid
ered a severity marker for an eating disorder; on the other eating altogether. Patients who suffer from ARFID may
hand, varying eating patterns may also be observed as a severely restrict the 202 volume of food they consume due
severity marker for psychosis. There is no consistent se- to a lack of interest in eating or decreased appetite.36 While
quence in the cooccurrence of the two, and hence, it is both disorders will cause nutritional deficiencies, decreased
essential to look out for these overlapping dimensions of body mass, physical and psychosocial disturbances, the
illnesses.35 reasons for the food aversion are different. ARFID can be
Eating disorders such as BN and AN manifest with nega- differentiated from AN because the food intolerance in
tive body image, episodes of food binging followed by patients with ARFID is not due to the fear of gaining weight
purging, Russell’s sign (calluses on the dorsum of the hand, or because of the pressure on oneself to be aesthetically
formed by induced vomiting), and the potential of laxative pleasing, like in AN.37 Keen history taking and evaluation ate
and diuretic abuse. They also share more life-threatening crucial to tell both disorders apart because of the overlapping
symptoms such as electrolyte abnormalities, severe dehy- similarities.
dration, and arrhythmias.17,30 The most consistent features
present in MDD and AN are depressed moods, sleep pattern
Treatment of Anorexia Nervosa
changes, decreased energy, loss of interest, low self-esteem,
cognitive impairment, and suicidal 190 ideations.17,25,31 AN According to the American Psychiatric Association, there are
shares signs and symptoms with endocrinological disorders three approaches to treating 210 AN: nutritional

Fig. 3 Key similarities between anorexia nervosa and its differential diagnosis. 17,25–34

Avicenna Journal of Medicine Vol. 13 No. 1/2023 © 2022. The Author(s).

8 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al.

rehabilitation, psychosocial treatments, and medications. equal amount of placebo for 28 days every day. This study
Although the first line of treatment is psychotherapy, a also showed no significant difference in admission weight,
combined approach is superior to either one alone.38 BMI, or caloric intake between the two groups by the end of
the study.48
Nutritional Rehabilitation
Nutritional rehabilitation is when a patient is given the Psychosocial Treatments
proper nutrition and calories to help them regain their When it comes to psychosocial treatments, the supporting
healthy weight.39 This initially leads to an increase in lean evidence on efficacy of factors such as psychoeducation,
body mass and eventually increased adipose tissue deposi- individual and family therapies, and group therapies is
tion as the target weight is achieved.39 Some studies have inadequate. However, the conclusion that such treatments
shown that when hospitalized patients are discharged with- can be beneficial comes from patient self-reporting and vast
out reaching their target weight, they relapse and are clinical experience.49 In a review of 23 surveys, it was
readmitted to hospitals at a higher rate than their counter- reported that the psychological interventions as well as
parts who attain target weight before discharge.40 The target providing support to the AN patient, understanding their
weight gain in outpatient scenarios is 0.5 to 1.0 lbs/week, condition, and fostering empathetic relationships were more
while the step-down programs in which patients are hospi- helpful than the pharmacological therapies focused on
talized for 12 hours a day, 7 days a week have reported a 2 weight gain for the treatment of AN.38 Behavioral programs
lbs/week weight gain.41 The most common side effect of such that focus on individual psychotherapy, family psychothera-
rehabilitation includes RS. RS is defined as an imbalance in py, compassionate nursing approaches, nutritional counsel-
the fluid and electrolytes concentration in a patient’s body. ing, and therapies to improve a patient’s knowledge and
This results because in a state of starvation the body loses its attitude about eating, exercise, and body image have shown
carbohydrate reserves. Upon reintroduction of carbohy- good short-term improvements.50 A review comparing the
drates, there is an insulin spike that results in potassium benefits of behavioral psychotherapy alone versus pharma-
moving intracellularly.42 This complication is much more cological treatment alone found that behavioral psychother-
common in severely malnourished patients and can be apy results in shorter hospital stays as well as more
avoided with slower feeding, and monitoring of heart rate consistent weight gain among patients with AN, while the
and rhythm, body weight, and electrolytes especially phos- same results were not observed with patients treated with
phorus.39 A study done on 100 adolescent Caucasian females medication alone.50 The strong risk factors for hospital
suggested that voluntary supplemental nasogastric noctur- readmission in patients with AN are young age (<15 years),
nal feeding produced greater and quicker weight gain than eating attitudes that were markedly abnormal, and a low rate
oral feedings alone.43 Rapid weight gain was also observed of weight gain while hospitalized.51 Cognitive behavioral
with high-calorie intake.44 Therapies such as warming and therapy (CBT) has also shown significant efficacy when
growth hormone injections have been routinely used for the compared to nutritional counseling in patients with AN.52
treatment of patients with AN. However, such therapies have One such study that depicts this was done by Pike et al with
shown no evidence of significant weight gain in these 33 patients in the Department of Psychiatry at Columbia
patients.45 The idea behind warming was based on the fact University who were either assigned to 1 year of CBT or 1 year
that AN patients undergoing warming treatment showed a of nutritional counseling.52 The patients assigned to the
reduction in anxiety, depression, and hyperactivity; hence, it nutritional counseling group relapsed much earlier and at
was predicted that decreasing these symptoms would help higher rates than those receiving CBT. The Morgan Russell
with weight gain.45 Warming is usually provided via one of criteria for “good outcome” were also met by 44% of patients
three methods: exposing the patient to a continuous warm receiving CBT, while only 7% of those receiving nutritional
environment, using a thermal waistcoat, and/or a sauna counseling met such criteria.52 The Morgan Russell criteria
bath.46 A randomized clinical trial done by Birmingham are relatively subjective, and patients are either put into
et al involved 21 females with AN who were admitted to good, intermediate, and poor outcome groups. The two main
the hospital for RS. They were either put into the control arm variables that these criteria take into consideration are body
that received warming via a vest or the treatment arm in weight and the presence or absence of menstruation.53
which the patients wore the vest, but they were never turned When children are diagnosed with AN, the sensitivity of
on. This was done to assess if the warming would lead to an this illness should also take into account the familial beliefs
increase in the rate of weight gain. Ten patients were and views as this can be a major setback in their treatment.54
allocated to the treatment arm and eleven were allocated In adolescents with AN for less than 3 years, family psycho-
to the control arm and followed for 13.6
6.7 years. Both therapy showed more benefits than individual psychothera-
groups wore a heating vest for 3 hours a day for 21 days, but py.54 Individual therapy is when the therapist mainly focuses
only the experimental group’s vests were turned on for that on the patient dealing with AN. Family psychotherapy
time. The results did not show any significant increase in the involves the family as a whole, along with education and
rate of weight gain in patients of the treatment group as counseling of the family members of the patient suffering
compared to the controlled group.47 In a separate double- with AN. In a follow-up study 5 years later, this observation
blind study conducted by de Vos et al, patients were either was reiterated by the results which showed that patients
injected with recombinant human growth hormone or an with AN that had an earlier onset in life and a shorter history

Avicenna Journal of Medicine Vol. 13 No. 1/2023 © 2022. The Author(s).

 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al. 9

showed much more benefit with family therapy than that controlled trial treated with estrogen who weighed less than
with the individual therapy.55 70% of their healthy body weight showed a 4.0% increase in
mean bone density. The matched subjects with comparable
Pharmacological Treatment body weights (<70% of their healthy body weight) who were
AN was formally recognized as an illness over a century ago.56 not treated with estrogen showed a 20.1% further decrease in
Even though much time has passed since that time, the their bone density.66
treatment of this condition is as challenging today as it was In conclusion, it is imperative that more research be
a century ago.55 Since patients presenting with AN exhibit conducted to create better guidelines for patients diagnosed
symptoms of mood disturbance and OCD, the use of antide- with AN so that gold standard treatments can be curated and
pressants has shown some utility in the treatment of AN.56 The employed rather than physicians basing treatment on their
studies on the use of antidepressants in patients with AN for- clinical judgment.
weight restoration are limited. One such study looked at the
addition of fluoxetine with nutritional and psychosocial treat-
Understanding Treatment Resistance of AN
ments and found no benefits in respect to rate and the amount
of weight gain.56,57 A 7-week randomized, placebo-controlled, Both environmental and genetic risk factors paired along
double-blind study of 60 mg of fluoxetine daily in 31 women with a more susceptible neurobiology are at play in the
with AN showed no significant changes in their body weight, emerging resistance to treatment in AN and bulimia.67
measures of eating behavior, or a change in psychological state Preoccupations with intense fear of weight gain, dietary
in patients taking the fluoxetine as opposed to those not on restrictions, excessive exercise, and how the individual is
it.56 A double-blind, placebo-controlled trial done by Kaye et al perceived by society mixed with underlying psychopatholo-
showed that patients who were put on fluoxetine after weight gy all further add to this issue. Many patients who fall into
gain and then followed up after 1 year showed maintenance of this cycle of obsessive and restrictive patterns refuse to get
weight and lower rates of relapse versus the control arm that treatment.67 As clinicians, it is essential we recognize the
was put on placebo.58 Hence, it can be concluded that fluoxe- early signs of both eating disorders during the initial primary
tine has not shown significant results in weight gain; however, care appointments. The purpose of this article is to explore
it has shown results of weight maintenance in patients who possible reasons that contribute to the resistance to treat-
were put on the medication after weight restoration had ment in anorexics, including their genetic predisposition,
already been achieved. A separate 5-year two-site study and coexisting psychiatric disorders.
favored CBT over fluoxetine for relapse prevention of AN.59 Resistance to the treatment of AN is characterized in a few
An outpatient study observing the weights of underweight ways but has no set definition. Treatment-resistant anorexia
adolescent patients treated with psychotherapy plus citalo- is identified as a persisting illness of anorexia greater than 7
pram versus psychotherapy alone elicited that the weight loss to 10 years. A study conducted by Broomfield et al classified
in patients undergoing dual therapy was worse (several kilo- repeated failed treatments as the second most common
grams) when compared with psychotherapy alone.60 The criteria as per the published definitions of severe and endur-
studies on tricyclic antidepressants are very limited. A dou- ing anorexia nervosa (SE-AN).68 The DSM-V classifies treat-
ble-blind controlled study revealed no significant beneficial ment-resistant anorexia in relation to BMI, symptom
effects of adding clomipramine to the baseline treatment of severity, additional supervision, and inability to perform
patients with AN.61 daily functions.68 DSM-V considers a severe BMI to be 15
Antipsychotics have shown benefits in patients with AN to 15.99 kg/m2 and an extreme BMI to be less than 15
when open label trials were conducted. A study showed that kg/m2.17 DSM-V criteria for inpatient hospitalization for
17 hospitalized patients at Western Psychiatric Institute and AN are the following: a heart rate of less than 50 beats
Clinic in Pittsburg with AN were subject to an open-label per minute during the day and less than 45 beats per minute
treatment for 6 weeks with olanzapine. These patients during the night, a systolic blood pressure less than 90 mm
showed a reduction in depression, anxiety, core eating Hg, orthostatic changes in pulse greater than 20 beats
disorder symptoms, and a significant weight gain.62 Thirteen per minute, a body temperature less than 96 F, body fat
severely ill patients at University of Pisa in Italy with restrict- less than 10%, a less than 75% ideal body weight, arrhythmia,
ing type AN, which is when the patients exercise rigorously declining food intake, and unsuccessful outpatient therapy.17
and restrict food intake, treated with low-dose haloperidol In-patient treatment programs have shown to be more
along with standard therapy revealed significant weight gain beneficial and are the best form of treatment available to
and better insight.63 anorexia patients who have been unsuccessful in outpatient
In regard to managing the complications of AN, supple- treatment programs. These programs use integrative prac-
ments such as estrogen–progestins, calcium, and vitamin D tices that emphasize the importance of developing a healthy
are used in practice to reduce osteopenia or osteoporosis but relationship with food, proper eating patterns, and weight
have not shown clinical benefits such as preventing, limiting, gain.69 In-patient programs also have plans in place to
or reversing skeletal deterioration.64 Rather, adequate nutri- encourage psychological change by educating patients on
tional rehabilitation during the period of bone growth is the the benefits of nutritional value, individual as well as group
only viable option to possibly reverse bone loss.65 Six out of psychotherapy, and regulated meals.69 Previous studies have
forty-four AN patient at Massachusetts General Hospital in a categorized readmissions to hospitals and eating disorder

Avicenna Journal of Medicine Vol. 13 No. 1/2023 © 2022. The Author(s).

10 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al.

clinics to be another basis of identification for treatment ogy that develops from an interaction between nature versus
resistance among in-patient anorexics.68 These in-patient nurture, making it vital to assess genetic traits along with
programs have a dropout rate ranging from 20 to 51% and a environmental risks.67
readmission rate ranging from 27 to 42%.68
Resistance to treatment is a common ordeal among
Management of the Treatment-Resistant AN
patients with AN. Many anorexics have expressed that
they do not want to physically mature into an adult female AN is complex and difficult to treat. Many people with AN are
body in order to avoid separation from their parents and hesitant about seeking help, leading to avoidance and no
responsibilities.67 Many of these patients do not have the treatments, even when AN is potentially life-threatening.
experience to develop a sense of autonomy, which can lead to Their desire to recover from AN may coexist with hesitancy
low self-esteem, poor personal, and social efficacy. This will to behavioral change.70 AN has highly egosyntonic features
often cause anorexic patients to become distressed when that make it run a chronic course with an impact on a
faced with life challenges.67 One theory is that the intense person’s quality of life. Moreover, a large proportion of
fear of weight gain, dietary restrictions, excessive exercise, people do not have access to a specialized AN treatment
distorted perception of oneself distracts the anorexic’s mind and for those who do, treatment dropout rates are notably
from life’s worrisome events. It is also thought that the cycle high.70 Until now AN treatment intervention has focused on
of obsessive and restrictive patterns gives anorexics a sense addressing weight and changing eating behavior with mea-
of control and heightens their self-worth.67 The physical suring the outcomes on these variables or the presence or
effects of starvation and cognitive decline further add to absence of other psychiatric comorbidities. However, people
their treatment resistance.67 who deal with chronic AN consider quality of life as a more
Studies have shown that the function of serotonin and important goal. Hence, one-sized treatment may not fit all in
dopamine has been changed in both anorexia and bulimia, AN.70 Management of AN requires balance between inter-
which interfere with emotional and behavioral character- ventions that focus on physical safety (eating behavior and
istics, and this adds to the mounting resistance to treat- weight restoration), and those that address psychological
ment.67 These changes in serotonin and dopamine are distress. There is a discrepancy in what a successful treat-
related to increased harm avoidance, which is a count of ment looks like for a person receiving the treatment and the
anxiety and inhibition of behavior.70 Gamma aminobutyric person delivering treatment for AN. Treatment that priori-
acid (GABA) is the primary inhibitory neurotransmitter in tized both physical safety as well as assisted an individual to
the brain. Gamma 376 aminobutyric acid receptor subunit grow and develop their identity was positively perceived.
gamma-1 (GABRG1) belongs to the family of ligand-gated Doctors should always address individual differences and
ionic channels and in part, is what forms the GABA-A determine what works best from person to person.67
receptors. GABA’s inhibitory effect is regulated by GABA-A Managing AN, or treatment-resistant AN, also depends on
receptors or metabotropic GABA-B receptors.71 In a study whether weight gain is considered as fear stimulus/cue or an
performed by Bloss et al on 1,878 women, the researchers outcome/ consequence. It has been proposed that individu-
tested 5,151 single-nucleotide polymorphisms (SNPs) in 350 alized exposure exercises based on patient-specific configu-
genes for possibly retarding recovery from eating disorders. ration will promote better treatment outcomes. The
An intronic SNP in GABRG1 showed strongest statistical application of exposure therapy without defining which
evidence of association with retarding 382 recovery (p ¼ 4.57 fear-based expectancy one is attempting to violate is non-
 10  6, false discovery rate ¼ 0.0049, odds ratio ¼ 0.55). specific or contraindicated.70 Exposure therapy involves
The same intronic SNP was found to be associated with the approaching the individual with a fear, that is, conditioned
anxiety trait (p ¼ 0.049), suggesting a possible genetic mech- stimulus (CS) without the occurrence of the feared outcome,
anism through which this variant may influence the outcome that is, unconditioned stimulus. Over time, the fear (CS) no
or recovery from eating disorders.71 Individuals who have longer results in fear or anxiety. Inhibitory learning theory
SNP on GABRG1 gene, rs17536211, showed decreased chan- suggests that exposure therapy aims to create a new, non-
ces of developing anxiety, which is one of the most common threat association with the CS, which serves to reduce
psychiatric illnesses linked to the treatment resistance in AN. anxiety and disconfirm the expectation of the feared out-
The SNP, rs17536211, also exhibited strong correlation of come. In the inhibitory learning model, exposure is designed
recovery from eating disorders.71 to maximize the newly learned nonthreat association when
Psychiatric comorbidity is another issue that contributes the feared stimulus is presented. Exposure therapy may be
to anorexia treatment noncompliance.67 According to the U.S. utilized to inhibit or cease the association between the feared
National Survey Replication, 56.2% of anorexics had at least stimulus and the feared outcome.72
one psychiatric comorbidity. Out of all participants, the most One of the goals of managing a patient with treatment-
common mental illness was an anxiety related problem, OCD resistant AN is to provide a treatment of carefully measured
(41%) followed by social phobia (20%.) The anxiety disorders intensity along with palliative care. A number of interven-
of many of these patients were reported to have started in tions employed by therapists are as follows68:
their youth, long before the onset of their eating disorders.67
Treatment resistance for eating disorders is generally antici- a. Giving assurance that weight is not the objective of the
pated by the severity of focal eating disorder psychopathol- management and that the patient can negotiate and

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 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al. 11

collaborate with the whole team to prevent panic and brain.73 The cingulate plays a role in processing and reward-
regression. ing value to external stimuli that is affected in AN. The study
b. Encouraging the patient to explore intellectual pursuits or mentioned above showed that the activity within and adja-
hobbies that stimulate pleasure and mastery along with cent to DBS target, that is, the subcallosal and anterior
cognitive function. cingulate was reduced and there was an increase in parietal
c. Encouraging patients to have some kind of social activity activity (which is decreased in anorexics). Therefore, DBS can
to prevent isolation. This can include spending time with a have a broad effect on neural circuits downstream from the
supportive family member or a friend, attending a reli- DBS target.73 Additionally, the temporal region responsible
gious gathering or a support group, or spending time at a for social cognitive behavior also showed increased glucose
favorite place. metabolism. All the above data collected emphasizes that
d. Doing regular physical examination so that the physician modulation of activity within subcallosal cingulate might
and the whole team along with the patient are kept lead to long-term changes in cortical circuits that in turn is
informed about the medical status of the patient, thus, significant for interpersonal behaviors beneficial in treating
making an informed decision about the supportive steps anorexics.73 Another randomized controlled trial (RCT) of
to be taken further. DBS of nucleus accumbens and subcallosal cingulate with a
e. Improving the nutrition in such a way that does not cause 6-month follow-up showed improvement in quality of life
weight gain in the patient and the changes sought will be (regardless of increase in BMI). This was calculated by the
measured against the tolerance of the anxiety that may be Short-Form 36 questionnaire, increase in BMI, and improve-
triggered. ment in AN behavior (reduced use of laxatives, diuretics and
f. Educating the family and relevant others about the psy- decrease in physical activity).74
chopathology of patients with AN and provide them solace
and support and warn them to not show overt displays of Electroconvulsive Therapy
anger or irritation against the patient.68 A systematic review of use of electroconvulsive (ECT)
therapy showed that it can be used in refractory AN,
Deep Brain Stimulation particularly those individuals who are having a high-risk
Deep brain stimulation (DBS) is a surgical procedure involv- behavior or are refusing to eat or drink.75 Fourteen patients
ing implantation of typically bilateral electrodes in key between the ages of 12 and 94 who have eating disorders
structures that are believed to drive the pathological activity were included in the study. Of those patients, 13 patients
in AN.73 Nucleus accumbens has been considered to play a were diagnosed with AN and 1 patient with binge eating
significant role in reward circuitry.71 A long-term (2-year) disorder. All these patients showed an improvement in
follow-up study of DBS of nucleus accumbens in treatment eating disorders following ECT. Following the treatment,
refractory AN patients showed that this procedure is safe and the median increase in BMI was 3.36. Additionally, 50% of
effective in improving BMI as well as psychiatric symptoms. the individuals had normal BMI after ECT as compared 0%
BMI consistently increased over a 6-month follow-up and 2- before the ECT.75 In conclusion, ECT can be used in patients
year follow-up period. Moreover, 12 patients out of the 29 as an alternative to forced feeding or forced medicine
female patients who underwent the procedure achieved a administration in acute cases or as a supportive treatment
normal BMI (>18.5 kg/m2) by the end of the 2-year follow- along with psychotherapies.
up period and 5 patients had more than 30% increase in BMI
achieving a lower threshold in a normal range of BMI. Eleven Psychosocial Therapies in Treatment-Resistant AN
patients had lower than normal BMI at 2-year follow-up An RCT was performed to evaluate the efficacy of CBT and
period. Cognitive ability evaluated by Mini-Mental State Specialist Supportive Clinical Management (SSCM) in
Exam at 6-month and 2-year follow-up was intact.71 patients with SE-AN. SSCM involves combining principles
DBS of subcallosal cingulate in treatment-resistant AN of clinical management and supportive psychotherapy.76,77
(total patients in the study (n)¼ 16), with a 1-year follow-up Clinical management consists of the assessment of the
period showed significant improvement in mood, anxiety, patients, educating them about the disorder, its outcome
affective regulation, and BMI. This study also demonstrated with and without treatment. The discussion should be two-
how DBS of subcallosal cingulate affects the natural history way so that we can understand patients’ fears and prejudice
of chronic AN.73 Positron emission tomography imaging if any. Supportive psychotherapy consists of demonstration
showed significant changes in glucose metabolism in brain of support, affection, acceptance towards the patient. Ac-
structures implicated in AN at 6 and 12 months compared knowledgment of the patient’s strength and respecting their
with baseline indicating that DBS directly affects anorexia- defenses allows the clinicians to explore their point of
related brain circulatory.73 view.77 There were no differences at the end of treatment
Insula, a part of the brain responsible for homeostasis and between both the treatment groups. However, in patients
interoception and the parietal part of the brain, which is with CBT group, a 6-month follow-up showed they have
responsible for perception of the body, showed changes in better social adjustment. A 12-month follow-up revealed
glucose metabolism. A number of studies showed that the that individuals with CBT have lower eating disorder symp-
patients with AN have structural and functional disturbances toms and a readiness for recovery when compared to SSCM
in anterior cingulate and hypometabolism of the parietal group.76

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12 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al.

A study showed that enhanced CBT is a transdiagnostic One of the obstacles in providing early intervention to
approach. This means that this approach seeks to identify patients with AN is the fact that the patients deny anything is
core cognitive-behavioral processes hypothesized to be sig- wrong with them. We need to minimize the time of untreat-
nificant across a range of disorders (AN, BN, and eating ed symptoms early in the disease to improve the outcome.
disorders not specified) and to develop a treatment that There should be education in schools and families to recog-
targets these in contrast to CBT which is disorder-specific.78 nize early symptoms and prevent delay of treatment. We
In this study, two samples of AN population (n ¼ 99) were have to work with families and overcome the barriers of help
given enhanced CBT and results were recorded before the seeking.81 Body image programs have been conducted in
treatment, after the treatment and at 60 weeks of follow-up schools that include activities to improve self-esteem, peer
period. The first step in this study was to increase the influence, pubertal development, education on maintaining
patient’s motivation to change. This was followed by tackling a healthy weight, psychoeducation on eating disorders. A
their eating disorder psychopathology that includes their systematic review showed that body image programs con-
extreme response to weight and shape, with simultaneous ducted in secondary schools have been effective in improving
regaining of the weight if the patient is willing to. The last body image and secondary factors relating to body dissatis-
step was to educate the patient to identify the setbacks and faction. Effective programs targeted adolescents aged be-
develop strategies to overcome them. The result of this study tween 12 and 13 years.82
demonstrated an increase in weight along with decrease in
the eating disorder psychopathology and other psychiatric
Conclusion
features. Two-thirds of both sample populations completed
the study and showed high compliance.78 AN is a complex and rapidly progressive illness that can
FBT focuses on educating parents that they are not present in various ways. Recognition by a physician includes
responsible for AN in their children along with developing a thorough history and physical examination, along with
strategies to regain weight. Later, parents are guided on how pertinent laboratory studies to evaluate any life-threaten-
to transition eating and weight control to the adolescent.79 ing electrolyte abnormalities. Physicians must be aware of
FBT helps in focusing a healthy relationship between parents the overlap of pathologies that can occur with AN for
and adolescents, whereas adolescent-focused individual successful and holistic management, and prevention of fatal
therapy (AFT) is based on the fact that patients with AN complications. The treatment of AN is intricate and requires
confuse self-control with their biological needs. It focuses on attention to details. Treatment includes multiple modalities
identifying the patient’s emotions and tackling them rather such as nutritional rehabilitation along with psychosocial
than numbing themselves with starvation. The patients are and pharmacological therapies. An astute clinician under-
taught to distinguish their emotional state from their bodily stands that sometimes multiple treatment modalities can
needs and accept their responsibility with food related be met with resistance in the patient. An interdisciplinary
issues.79 Another RCT showed efficacy of FBT over AFT in team of medical professionals should always manage cases
adolescents with AN. FBT was superior in the follow-up of treatment resistance in AN. Not only psychiatrists are
period and there was less hospitalization with adolescents mandated to provide quality healthcare to AN treatment
who underwent FBT. AFT is a good alternative for patients resistance, but also mental health counselors, mental health
and families who prefer individualized treatment.79 therapists, psychologists, social workers, dietitians, nursing
team, and technicians. All the efforts of the collaborated
Early Intervention to Prevent Treatment-Resistant AN medical team should be coordinated in the support of
Early diagnosis and intervention are significant to prevent SE- delivering quality healthcare to help the transition of AN
AN. AN, if diagnosed early in adolescents and treated with patient to a healthy lifestyle. Achieving a balance between
family therapy, shows improved outcomes. A RCT comparing a interventions is crucial for a successful outcome of the AN
group of patients with AN who had early intervention versus patient.
the late intervention showed that family therapy was superior
to individual supportive therapy in terms of remission, weight,
Limitations and Recommendations
and cognitive function in the early intervention group.80
Another trial at a 4-year follow-up showed a better outcome A clinical approach to management of the AN patients with
of family therapy given early in the course of the illness.80 particular focus on the treatment resistance encounters few
Single-family therapy is an intervention in which the patient limitations including the paucity of reliable double-blinded
and their family both visit the therapist together. Multifamily randomized clinical trials that can provide in-depth detailed
therapy works on the same principles as single-family therapy strategy for the management of AN treatment resistance.
but involves the support of other families that are going Besides, most of the studies collected and analyzed lacked
through the same situation to overcome the isolation, stigma the deliberation of the cultural component that may influ-
and maximize the resources at hand. Single-family therapy ence the responsiveness of AN patients toward therapy
and multifamily therapy were studied in adolescents with AN. options. More randomized clinical trials with larger sample
Multifamily therapy showed how bringing families together is size that contemplate the cultural difference among patients
potentially powerful for managing AN.81 and providers are recommended.

Avicenna Journal of Medicine Vol. 13 No. 1/2023 © 2022. The Author(s).

 A Clinical Overview of Anorexia Nervosa and Overcoming Treatment Resistance Nagy et al. 13

Conflict of Interest 20 Pritts SD, Susman J. Diagnosis of eating disorders in primary care.
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21 Jáuregui-Lobera I. Neuropsychology of eating disorders: 1995-
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22 Broomfield C, Stedal K, Touyz S. The neuropsychological profile of
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