Anorexia Nervosa

Anorexia nervosa is an eating disorder characterized by the inability to maintain a minimally normal weight, a devastating fear of weight gain, relentless dietary habits that prevent weight gain, and a disturbance in the way in which body weight and shape are perceived. This condition has potentially life-threatening physiologic effects and causes enduring psychological disturbance. (See Prognosis and Clinical Presentation.)[11, 12]

With the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), changes have occurred in the definition of anorexia nervosa, namely in Criterion A there is a focus on behaviors including restricting calorie intake, and the word “refusal” is no longer included related to weight maintenance because of the incorrect and possibly stigmatizing implication of intention on the part of the patient and because this aspect may be not something that can accurately be assessed.[13]

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Criterion D requiring amenorrhea, or the absence of at least three menstrual cycles, has been deleted as that criterion cannot be applied to males or premenarchal females, females taking oral contraceptives, and postmenopausal females. In some cases, individuals exhibit all other symptoms and signs of anorexia nervosa but still report some menstrual activity.[13]

Anorexia nervosa may be divided into 2 subtypes:

• Restricting, in which severe limitation of food intake is the primary means to weight loss

• Binge-eating/purging type, in which there are periods of food intake that are compensated by self-induced vomiting, laxative or diuretic abuse, and/or excessive exercise

Although the DSM-5 separates anorexia nervosa and bulimia nervosa as two separate disorders, there continues to be consideration that these two disorders may be part of a unified eating disorder. Recent research at the University of Chicago with children and adolescents who met criteria for DSM-5 restrictive type (AN) or binge eating/purging type AN (AN-BE/P) differed in their eating patterns as youths with AN-R consumed meals and snacks more regularly relative to youths with AN-BE/P; youths with AN-BE/P who skipped dinner were associated with a greater number of binge eating episodes, and skipping breakfast was associated with a greater number of purging episodes. Thus, it appeared that youths with AN-R followed a more regular pattern but consumed insufficient amounts of food during meals and youth with AN-BE/P tended to have more irregular eating patterns.[14]

Patients with anorexia nervosa often display such traits as a desire for perfection and academic success, a lack of age-appropriate sexual activity, and a denial of hunger in the face of starvation. Psychiatric characteristics include excessive dependency, developmental immaturity, social isolation, obsessive-compulsive behavior, and constriction of affect. Many patients also have comorbid mood disorders, with depression and dysthymic disorder being most prevalent.(See Clinical Presentation, Workup, Treatment, and Medication.)[15, 16, 17]

Diagnostic criteria (DSM-5)

Diagnostic criteria for anorexia nervosa in the DSM-5 include the following:[13]

• Restriction of energy intake relative to requirements, leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health; significantly low weight is defined as a weight that is less than minimally normal or, for children and adolescents, less than that minimally expected

• Intense fear of gaining weight or of becoming fat, or persistent behavior that interferes with weight gain, even though the patient’s weight is already significantly low

• 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 persistent lack of recognition of the seriousness of the current low body weight

The DSM-5, which was published in May 2013, revised the definition of anorexia from the DSM-IV to focus more on behaviors, such as calorie restricting, and removed the qualification of low weight being less than 85% ideal body weight. Additionally, the criterion of amenorrhea in postmenarchal females was completely removed from the definition. (See Clinical Presentation.)

The prevalence of subthreshold eating conditions supports the notion that eating disorders tend to exist along a spectrum and that, if defined by a broader range of symptoms, might be better recognized by doctors. (See Workup, Treatment, and Medication.)[18]

A typical case of anorexia nervosa involves a young person (teenager or young adult) who is mildly overweight or of normal weight and who begins a diet and exercise plan to lose weight. As he or she loses weight and receives initial positive reinforcement for this behavior (eg, compliments by peers on his or her appearance), the reward is high and causes an inability to stop this behavior once an ideal weight is achieved.

Anorexia nervosa may be difficult to resolve due to persistent starvation from abnormal eating behavior resulting in treatment resistance due to the neuroadaptive changes causing increases in angiopoetin-like protein 6 (ANGPTL6) that cause anorexia nervosa to more likely become chronic and persistent.[19, 4]

Malnutrition subsequent to self-starvation leads to protein deficiency and disruption of multiple organ systems, including the cardiovascular, renal, gastrointestinal, neurologic, endocrine, integumentary, hematologic, and reproductive systems.

The impact of anorexia nervosa on neuropsychological functioning has been found to include what are likely estrogen-mediated impairments in learning and memory tasks, such as cognitive inflexibility (poor set shifting), weak central coherence, and social-emotional processing difficulties that may in part be due to low energy intake causing lack of available energy.[20] New research horizons include an upcoming double blind placebo controlled study looking at hormonal supplementation in females with anorexia nervosa to help restore normal neuropsychological functioning.[21]

Cardiovascular complications

Cardiac complications are the most common cause of death; the mortality rate is about 10%. Cardiac effects from anorexia nervosa include profound bradycardia, hypotension, decreased size of the cardiac silhouette, and decreased left ventricular mass associated with abnormal systolic function. Patients with anorexia report fatigue and have an attenuated blood pressure response to exercise and reduction in maximal work capacity. An increased incidence of mitral valve prolapse without significant mitral regurgitation is also observed. Low potassium-dependent QT prolongation increases the risk of ventricular arrhythmia.[22]

The patient's vital signs reflect hypotension with systolic pressures as low as 70 mm Hg and sinus bradycardia with heart rates as low as 30-40 beats per minute. These changes are a response to a decrease in the basal metabolic rate. The mechanism may be due to an autonomic imbalance in heart rate regulation, with increases in vagal activity and a reduction in sympathetic activity. These changes are physiologic cardiovascular responses, and treatment is unnecessary, unless negative clinical sequelae are present.

If electrocardiography (ECG) is performed, evidence of sinus bradycardia, ST-segment elevation, T-wave flattening, low voltage, and rightward QRS axis is apparent. All the aforementioned changes are clinically insignificant; however, the frequency of rhythm disturbances is most concerning, especially QT-interval prolongation that may be an indication for those at risk of cardiac arrhythmias and sudden death.

Cardiac decompensation is greatest during the initial 2 weeks of refeeding, when the myocardium cannot withstand the stress of an increased metabolic demand. However, if the daily weight gain is 0.2-0.4 kg, then complications are limited.

Endocrinologic and metabolic complications

Foremost in the gamut of endocrinologic complications is amenorrhea, although, as previously mentioned, the DSM-5 no longer includes this condition as part of the diagnostic criteria of anorexia nervosa.[23] Amenorrhea results from disorders in the hypothalamic-pituitary-ovarian axis in which levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are low despite low levels of estrogen. Reversion to the prepubertal state occurs; the LH response to gonadotropin-releasing hormone (GnRH) is blunted. This blunted response is insufficient to maintain menstrual integrity, and amenorrhea results.

Weight loss and emotional instability play a role in amenorrhea, although amenorrhea persists in 5-44% of patients in whom weight gain has been documented. The explanation for this wide range has not been elucidated.

Other changes related to endocrine function include a reduction in fertility, multiple small follicles in the ovaries, and decreased uterine volume and atrophy.

Thyroid function is also affected in patients with anorexia nervosa, with laboratory data revealing a decrease in triiodothyronine (T3) and thyroxine (T4) and an increase in reverse T3. These changes are characteristic of the euthyroid sick syndrome and, similar to the cardiac changes, represent an adaptive mechanism; hormonal replacement is not necessary.

An associated impaired release of vasopressin consistent with diabetes insipidus is present. This defect is of the neurogenic type; concentration of urine is observed after administering vasopressin. This condition affects 40% of persons with anorexia nervosa and is reversible with weight gain.

Osteopenia is a serious complication. Cortical and trabecular bone are affected, and osteopenia persists despite estrogen therapy. Low levels of progesterone (accelerates remodeling) formation and decreased insulinlike growth factor-1 (IGF-1) levels, which stimulate type 1 collagen biosynthesis, contribute to bone loss.

Treatment of osteopenia with bisphosphonates is not routinely indicated in adolescents, because of concerns about osteonecrosis of the jaw; however, if this therapy is used, close monitoring is critical.[23, 24] Supplementation with 1000-1500 mg/d of dietary calcium and 400 IU of vitamin D is recommended to prevent further bone loss and to maximize peak bone mass. Although exercise and hormonal replacement therapy have some benefit in perimenopausal women, exercise may be deleterious in patients with anorexia nervosa who have amenorrhea, and hormonal replacement may induce premature closure of bone epiphysis.[23]

Gastrointestinal complications

Patients with anorexia nervosa have fewer gastrointestinal complications than those with bulimia nervosa. Constipation is common. In addition, these patients still have prolonged gastrointestinal transit, alterations in antral motility, and gastric atrophy. Prokinetic agents may accelerate gastric emptying, and the relief from gastric bloating can accelerate resumption of normal eating habits.

Neurologic, integumentary, and renal complications

Cerebral atrophy and loss of brain volume may be observed in patients with anorexia nervosa. Generalized muscle weakness is the most common neurologic symptom.

Patients with anorexia nervosa typically have dry, scaly skin; brittle hair and nails; and increased lanugo-type body hair.

An increase in blood urea nitrogen (BUN) levels, which reflects a level of dehydration and a decreased glomerular filtration rate (GFR), is present. Electrolyte imbalances are secondary to vomiting, and potassium is most often affected. Other abnormalities include disturbances of calcium, magnesium, and phosphorus.

Anorexia nervosa results from a complex interplay between biologic, psychological, and social factors; it tends to affect women more than men, and adolescents more than older women.

Prepubescent patients who subsequently develop anorexia nervosa have a high incidence of premorbid anxiety disorders. The onset of anorexia nervosa during puberty has led to the theory that, by exerting control over food intake and body weight, adolescents are attempting to compensate for a lack of autonomy and selfhood.

Modern preoccupation with slenderness and beauty in the Western world may contribute to the mindset of thinness as a valued quality in adolescents; however, this link has not been proven. A subset of adolescents who are temperamentally incapable of dealing with age-appropriate challenges without extreme reward-seeking behavior (thinness) may be susceptible to anorexia nervosa.[25]

Recognizing the predisposing, precipitating, and perpetuating factors in the disease is important to better facilitate early intervention, especially since nutritional rehabilitation performed simultaneously with family-based treatment (FBT) and the Maudsley method is crucial to recovery.[11, 26, 7]

Predisposing factors

Predisposing factors in eating disorders include the following:

• Female sex

• Family history of eating disorders[27]

• Perfectionistic personality

• Difficulty communicating negative emotions

• Difficulty resolving conflict

• Low self-esteem

Maternal psychopathology (negative expressed emotion, maternal encouragement of weight loss) can also be a risk factor for anorexia nervosa, especially for childhood-onset of this disorder.[28]

Genetic factors

Reported cases of anorexia nervosa in twins and triplets suggest the possibility of an increased genetic predisposition.[29, 30] Indeed, there is evidence from twin studies to suggest that the genetic contribution to the disease is as high as 50–80%, a heritability estimate similar to that for bipolar disorder and schizophrenia.[31, 32]

There may be variations of the 5HTT (serotonin transporter gene) genome (eg, biallelic, triallelic) that are associated with subtypes of eating disorders and that interact with life-history factors.[33, 34, 35]

There is also evidence that an area on band 1p at the DF1153721 locus may be related to a 7% increased incidence of anorexia nervosa in first-degree relatives.[36] Genetic risk factors may also be predictive of specific complications in anorexia nervosa, such as bone loss.[37]

Biochemical factors

Individuals with anorexia nervosa maintain a lifelong increased incidence of anxiety, depressive disorders, and obsessive-compulsive disorder. Neurobiologists hypothesize that disruption of both serotonergic and dopaminergic pathways in the brain mediate the development of anorexia nervosa and may account for the frequent coexistence of other psychological disturbances.[38, 39]

Anorexia nervosa is often heralded by a patient’s desire to lose an insignificant amount of weight through dieting. Once the weight loss is in progress, immunologic and hormonal factors, including leptins (involved with signaling satiety) and alpha-melanocyte–stimulating hormone, may play a role in the downward spiraling and maintenance of anorexia nervosa.[40, 12]

During prolonged food restriction in genetically vulnerable individuals, the ensuing malnutrition perpetuated by the biochemical changes induced by weight loss (ie, ketosis) further magnifies the impact of the malnutrition on the brain, owing to it being in a starvation-illness mode. Thus, it is helpful to conceptualize anorexia nervosa as a developmental condition rather than as a purely mental one. Persistent states of starvation may result in biochemically based treatment resistance due to neuroadaptive changes including increases in angiopoetin-like protein 6 (ANGPTL6) that occur that increase the likelihood that anorexia nervosa will become chronic and persistent.[4]

Age-related factors

Precipitating factors relate most often to developmental tasks that cause intense intrapsychic conflict and unconscious feelings of anxiety, which in turn interact with physiologic and biologic ones.

In individuals aged 10–14 years, such precipitating factors are related to sexual development and menarche, which are associated with a spurt in weight gain. Societal influences, such as a peer group that comments in a rejecting fashion, intensify the fear of becoming "fat." Affected individuals often diet and receive peer acceptance for weight loss; this emotional reinforcement, combined with the physiologic response of the body to the sudden loss of weight (when >5 lb), increases the likelihood of continued weight loss.

Sudden weight loss with loss of fat causes a decrease in body temperature, which physiologically causes a subjective feeling of chills; this discomfort is relieved by increased physical activity, which causes further weight loss. The continuous downward spiraling of weight loss then causes secondary amenorrhea and loss of secondary sexual characteristics, further worsening weight loss.

In adolescents aged 15–16 years, precipitating factors stem from struggles with independence and autonomy. Individuals in this age group with anorexia nervosa typically feel ambivalent about growing up and will transition from dependence to interdependence rather than to independence.

In individuals aged 17–18 years, identity conflicts are more common. These patients do not make healthy transitions from leaving home to going to college or getting married.

Associated diseases

Disorders associated with anorexia nervosa include congenital adrenal hyperplasia[41] and systemic lupus erythematosus.[42]

One study showed that a low resting heart rate (below 50) and very low treatment goal weight were associated with persons reclassified as having anorexia nervosa instead of Avoidant-Restrictive Food Intake Disorder (ARFID).[43]

Anorexia nervosa is found in all developed countries and in all socioeconomic classes, occurring around the world at similar rates (0.3-1% in women, 0.1–0.3% in men). It is also found in developing countries such as China and Brazil.[17, 44]

According to Mehler et al, certain groups are especially at risk for anorexia nervosa, including dancers, long-distance runners, skaters, models, actors, wrestlers, gymnasts, flight attendants, college sorority members, and others for whom thinness is emphasized and overly rewarded.[45]

In a European study, a 0.48% lifetime incidence of anorexia nervosa was reported among 21,425 respondents.[46]

The lifetime prevalence of anorexia nervosa in the United States is estimated to be 0.3–1%; however, some studies have shown rates as high as 4% among women. The rates among men are estimated at 0.1–0.3%. As many as 5% of young women exhibit symptoms of anorexia but do not meet the full diagnostic criteria, and some studies show disordered eating behavior in 13% of adolescent girls in the United States.[15, 16, 17, 44]

Using nationally representative, face-to-face interview surveys of 10,123 adolescents in the continental United States, Swanson et al found the following 12-month prevalence rates for eating disorders[18] :

• Anorexia nervosa (0.2%)

• Bulimia nervosa (0.6%)

• Binge-eating disorder (1.6%)

• Subthreshold anorexia nervosa (0.9%)

• Subthreshold binge-eating disorder (1.1%)

Race-related demographics

Anorexia nervosa is diagnosed more often in the white (>95%) adolescent (>75%) populations[47, 48] of the middle and upper socioeconomic classes, although it can be observed in either sex and in people of any race, age, or social stratum. A study of adults in the United States found that, after adjusting for income, lifetime rates of anorexia nervosa were lower for non-Hispanic black and Hispanic respondents than for white respondents.[49]  This disorder is probably underdiagnosed in black individuals and males because of a lower index of suspicion.[50, 51, 52]

Sex-related demographics

Anorexia nervosa is more common in women than in men, with a female-to-male ratio of 10-20:1 in developed countries. In some professions, however, the frequency is much higher among men (wrestling, running, modeling) than it is in the general male population. Treatment plans remain the same for both sexes. Gay and bisexual males are more likely to have an eating disorder than heterosexual males, but they are also more likely to have bulimia than anorexia.[53, 54]

Age-related demographics

Anorexia nervosa has been observed in both the very young and very old, but the disorder is primarily a phenomenon of puberty and early adulthood. Eighty-five percent of patients have onset of the disorder between the ages of 13 and 18 years (although a survey of adolescents by Swanson et al found a median age of onset of 12.3 y).[18, 15, 55] Patients who are older at the time of onset of the disorder have a worse prognosis, as do patients with an onset before age 11 years.[56]

The prognosis of anorexia nervosa is guarded. Morbidity rates range from 10-20%, with only 50% of patients making a complete recovery. Of the remaining 50%, 20% remain emaciated and 25% remain thin.[57, 58]

The remaining 10% become overweight or die of starvation. However, mortality from the complications of starvation is less frequent in patients with anorexia nervosa than is death from suicide.[59, 60, 61, 58, 62] A history of previous suicide attempts, physical pain, drug use, and laxative use may correlate with a higher likelihood of suicide attempts.[59, 60, 63] Metacognition plays a role in predicting adverse outcomes or suicide, as does alexithymia.[64]

Recovery from anorexia nervosa generally is accompanied by resumption in growth, although there may be residual loss of height that is linear in nature.[65]

Prognostic factors

Onset of anorexia nervosa before adulthood predicts a more favorable outcome, although onset at too young an age, before 11 years, is a poor prognostic factor.[56]

The outcome of anorexia nervosa also depends on the patient’s body mass index (BMI) and his or her weight loss at presentation, as well as the duration of symptoms, duration of inpatient care, and state of family relationships.[66] In addition, patients with the restricting subtype of anorexia nervosa tend to be more refractory to treatment and are at high risk of death.[67]

Body weight and symptom duration

Although the degree of weight loss at the clinically noted onset of the involvement of the patient's organic systems is not predictive of outcome, lower weight (less than 75% of mean body weight [MBW]) and longer duration (more than 19 months) of symptoms were predictors of poorer outcomes in a review of 267 adolescents from 11 different eating disorder programs.[68]

A shorter duration of involvement of the patient's organic systems before admission and a short inpatient treatment period have been associated with a favorable outcome in some studies.

Mental health

Using nationally representative, face-to-face interview surveys of 10,123 adolescents in the continental United States, Swanson et al found that the majority of those with an eating disorder met the criteria for at least 1 other lifetime DSM-4 disorder, as follows[18] :

• Anorexia nervosa (55.2%)

• Bulimia nervosa (88%)

• Binge-eating disorder (83.5%)

• Subthreshold anorexia nervosa (69.8%)

• Subthreshold binge-eating disorder (70.1 %)

Psychiatric and somatic comorbidities have been found to worsen the outcome of patients with eating disorders. Psychiatric comorbidities are common with anorexia nervosa, with the following lifetime incidences[69] :

• Depression (15-60%)

• Anxiety disorders (20-60%)

• Substance abuse (12-21%)

• Personality disorders (20-80%)

Obsessionality and impulsivity in individuals with anorexia nervosa correlate with a lower lifetime BMI, reflecting poorer long-term outcomes, and can be measured with the Yale-Brown-Cornell Eating Disorder Scale (YBC-EDS).[70]

Family involvement

A good relationship between the parent and child tends toward a more favorable outcome. There may be a poorer prognosis among patients from single-parent families, from families in which parents have been married before, and from families in which several generations live together, possibly owing to greater expression of negative emotions in the household.[47, 71] Indeed, joint family therapy is not as effective as separated family therapy if there is a high level of negative emotional expressivity (eg, high levels of maternal criticism).[5]

Mortality

Mortality rates were significantly higher in a well-done 25-year longitudinal study with a standarized mortality ratio (SMR) elevated at 34.5 for females and 16.0 for males with comorbid cluster B personality disorder.[72]

A recent study found that mortality was higher if psychiatric comorbifities such as substance abuse were present. This may be due to the co-occuring shame and isolation that substance abuse disorders engender.[73, 74]

A meta-analysis by Arcelus et al found a weighted annual mortality incidence for anorexia nervosa of 5.1 deaths per 1000 person-years; a lower mortality rate—1.74 deaths per 1000 person-years—was noted in individuals with bulimia nervosa.[75] However, it is possible that because this study was a meta-analysis, individuals with crossover between anorexia and bulimia could not be correctly tracked, causing loss of data in this study.[75]

Patients who misused alcohol, had a low BMI at presentation, or were of older age at first presentation were found to have a higher likelihood of poor outcomes, including death. Comorbid disorders, such as affective disorder or suicidal behavior or self-harm, or a history of mental-health hospitalization for these problems, also strongly predicted patient mortality.[75]

A 25-year study of patients diagnosed with co-morbid substance abuse[73] and with cluster B personality disorders[72] appeared to have much higher rates of mortality with a standardized mortality raio of 34.5 for females and 16.0 for males. 

Suicide

The presence of an eating disorder has been associated with increased levels of suicidal thinking. Using nationally representative, face-to-face interview surveys of 10,123 adolescents in the continental United States, Swanson et al found the incidence of suicidal ideation and behavior in anorexia nervosa to be as follows[18] :

• Suicidal ideation: Anorexia nervosa (31.4%); subacute anorexia nervosa (30%)

• Suicide planning: Anorexia nervosa (2.3%); subacute anorexia nervosa (14.2%)

• Suicide attempts: Anorexia nervosa (8.2%); subacute anorexia nervosa (12.4%)

According to the meta-analysis by Arcelus et al, 1 in 5 individuals with anorexia nervosa who died had committed suicide.[75]

Most complications of anorexia nervosa are secondary effects from starvation. Malnutrition subsequent to self-starvation leads to protein deficiency and disruption of multiple organ systems, including the cardiovascular, renal, gastrointestinal, neurologic, endocrine, integumentary, hematologic, and reproductive systems. Endocrine and metabolic disturbances, for example, result in the following[76] :

• Delayed puberty

• Amenorrhea

• Anovulation

• Low estrogen states

• Increased growth hormone

• Decreased antidiuretic hormone

• Hypercarotenemia

• Hypothermia

• Hypokalemia

• Hyponatremia

• Hypoglycemia

• Euthyroid sick syndrome

• Hypercortisolism

• Arrested growth

• Osteoporosis

In addition, decreased gonadotropin levels and hypogonadism may occur among males who are affected.

Cardiovascular effects of anorexia nervosa include the following[77, 25, 78] :

• Cardiomyopathy

• Mitral valve prolapse

• Supraventricular and ventricular dysrhythmias

• Long QT syndrome

• Bradycardia

• Orthostatic hypotension

• Shock due to congestive heart failure

Renal disturbances include the following:

• Decreased glomerular filtration rate (GFR)

• Elevated BUN

• Edema

• Acidosis with dehydration

• Hypokalemia

• Hypochloremic alkalosis with vomiting

• Hyperaldosteronism

• Renal calculi

Gastrointestinal findings in anorexia nervosa include the following:

• Constipation

• Decreased intestinal mobility

• Delayed gastric emptying

• Gastric dilation and rupture: From binge eating and purging; gastric rupture can lead to pneumothorax and pneumoperitoneum[79, 80]

Neurologic disturbances include the following:

• Peripheral neuropathy

• Ventricular enlargement

Integumentary findings include the following:

• Dry skin and hair

• Hair loss

• Lanugo body hair

Hematologic findings include the following:

• Anemia

• Leukopenia

• Thrombocytopenia

Reproductive disturbances include the following:

• Infertility

• Low ̶ birth-weight infant

Patients who induce vomiting develop dental enamel erosion, palatal trauma, enlarged parotids, esophagitis, Mallory-Weiss lesions, elevated transaminase levels, and, in extreme cases, seizures (due to electrolyte disturbances). Cases of superior mesenteric artery (SMA) syndrome from loss of intraperitoneal fat in anorexia nervosa have been reported.[79, 80]

Impairment

In the Swanson study, 97.1% of adolescents with anorexia nervosa reporting suffering from some form of impairment (most commonly, social impairment) in the previous 12 months, with 24.2% reporting severe impairment; 11.6% reported a complete inability to carry out normal activities for at least 1 day.[18]

According to Becker et al, for adequate weight gain, the patient or family requires some "education on nutrition, adjustment of caloric and nutritional intake, and limitations on exercise and other modifications of behavior,” with enteral or parenteral nutrition being used only in patients with severe undernutrition who have not responded to these other methods.

In the moderate stage of anorexia nervosa, in addition to the above recommendations, providing structure to daily activities is necessary. This includes eating 3 meals a day. Also, parents should ensure that healthy food is available, but the patient should assume all responsibility for eating.

For patient education information, see the Women's Health Center, as well as Anorexia Nervosa, Bulimia, and Amenorrhea. Other useful sources of patient information include the following:

• National Association of Anorexia Nervosa and Associated Disorders (ANAD)

• National Eating Disorders Association (NEDA)

Obtain the patient's history with the goal of developing a treatment plan rather than with the objective of merely ruling out an eating disorder.

A study by Nicholls et al found that about 21% of individuals with a childhood eating disorder had early feeding difficulties that predated the disorder’s diagnosis. In the study, the incidence of eating disorders was 3 per 100,000 youth; of that group, the criteria for anorexia nervosa, bulimia nervosa, and eating disorder not otherwise specified were met by 37%, 1.4%, and 43% of individuals, respectively.[81]

A psychological profile for a patient with anorexia nervosa often demonstrates premorbid anxiety disorders, as well as more severe affective disorders, such as major depression and dysthymic disorder. Patients may also have symptoms of obsessive-compulsive disorder, with rigid and ritualistic eating behaviors. The study by Nicholls and colleagues found that of 208 individuals who met the criteria for an eating disorder, 41% had significant comorbidity (other psychiatric diagnoses) and 44% had a family history of psychiatric disorders.[81, 59, 60, 82, 83, 84, 85]

Pay careful attention to the patient's self-image and self-esteem, even if the patient identifies that he or she has an eating disorder. This may help to stratify the risk of mortality, which is 18 times higher when anorexia nervosa is comorbid with significant psychiatric disorders such as major depressive disorder. Patients should be asked about early morning awakening, tearfulness, and thoughts of suicide or a plan for it.

It is also important to focus on self-image in the treatment of anorexia nervosa because control-submission interactions between patient and therapist must be handled with care.[47, 86]

This interview can also help to identify an increased risk of dropping out from inpatient treatment. For example, the presence of anxiety or other mental health conditions can help to predict a response to treatment and assess motivation for changing behavior.

With medical assessment, focus on the medical complications of altered nutrition. Seek a careful history detailing weight changes, dietary patterns, and excessive exercise. Determine weight and height.[86] Low body mass index (BMI) often relates to preexisting body dysmorphic disorder.[87, 88] The presence or absence of self-induced vomiting/binge eating and laxative use should also be ascertained.

A review of systems may reveal many positive responses. The following symptoms are commonly observed in patients with anorexia nervosa:

• Physical health and mental health concerns (including depression[89] )

• Amenorrhea

• Concentration and decision-making concerns

• Headaches

• Irritability

• Cold hands or feet

• Constipation

• Dry skin or hair loss

• Social withdrawal

• Fainting or dizziness

• Obsessiveness (food)

• Lethargy

SCOFF questionnaire

The SCOFF questionnaire, as follows, is a screening tool for eating disorders, with 1 point awarded for every positive reply and a score greater than 2 indicating likely anorexia nervosa or bulimia[90] :

• Do you make yourself Sick because you feel uncomfortably full?

• Do you worry you have lost Control over how much you eat?

• Have you lost more than One stone* in a 3-month period?

• Do you believe yourself to be Fat when others say you are too thin?

• Would you say that Food dominates your life?

* One stone is approximately 14 lb, or 6.35 kg.

Although patients with anorexia nervosa may show obvious emaciation, they can present anywhere along the spectrum of weight loss. Moreover, they may attempt to hide their weight loss by wearing bulky clothing or many layers.

Focus the physical examination on the changes commonly observed in anorexia nervosa. Vital sign changes include hypotension, bradycardia, and hypothermia. Other changes include the following[1] :

• Dry skin

• Hypercarotenemia

• Lanugo body hair

• Acrocyanosis

• Atrophy of the breasts

• Swelling of the parotid and submandibular glands

• Peripheral edema

• Thinning hair

Patients with purging behavior may have callouses to the dorsum of their dominant hand and dental enamel erosion.

Characteristic signs of inadequate energy (caloric) intake observed in patients with anorexia nervosa that are due to starvation-induced changes are summarized below. Positive signs include the following:

• Hypothermia

• Acrocyanosis

• Resting bradycardia (resting heart rate often 40-49 beats per minute)

• Hypotension

• Orthostatic lowered blood pressure or pulse

• Loss of muscle mass

• Low blood glucose (impaired insulin clearance)

• Low parathyroid hormone levels

• Elevated liver function

• Low white blood cell (WBC) count

Negative signs include the following:

• Normal fundi or visual fields

• No organomegaly

• No lymphadenopathy

Behaviorally, a patient may demonstrate a flat affect and display psychomotor retardation, especially in the later stages of the disease. Cases of acute psychosis in anorexia nervosa from Wernicke-Korsakoff syndrome due to severe thiamine deficiency have been reported.[91]

Diagnosis of anorexia nervosa continues to include an early (or mild) stage, when there has not yet been any treatment initiated and the patient has significant signs and symptoms involving fear and disturbance of perception regarding normal body weight status, including dietary habits to prevent weight gain. Additional significant criteria include the presence of a body mass index (BMI) less than the third percentile and an established/severe stage (sometimes labelled stage 6 by some investigators) in which end-organ complications that involve the cardiac, renal, and endocrine systems can place the person at risk of death or significant morbidity.[92, 93, 94]

Early stage is defined by the following:

• Mildly distorted body image

• Weight 90% or less of average weight for height

• No symptoms or signs of excessive weight loss

• Use of potentially harmful weight-control methods or a strong drive to lose weight

Established or moderate stage features include the following:

• Definitely distorted body image that has not diminished with weight loss

• Weight goal less than 85% of average weight for height associated with a refusal to gain weight

• Symptoms or signs of excessive weight loss associated with a denial that any problems are present

• Unhealthy means of losing weight, such as eating fewer than 1000 calories per day, purging, or excessive exercise

There has been a case report of a patient with anorexia nervosa presenting with pancytopenia mimicking aplastic anemia.[95]

Because an eating disorder is a clinical diagnosis, no definitive diagnostic tests are available for anorexia nervosa. However, given the multi-organ system effects of starvation, a thorough medical evaluation is warranted. Basic tests include the following:

• Physical and mental status evaluation

• Complete blood count (CBC)

• Metabolic panel

• Urinalysis

• Pregnancy test (in females of childbearing age)

Gastrointestinal signs include intestinal dilation from constipation and diminished intestinal motility.

Fecal occult blood may be indicative of esophagitis, gastritis, or repetitive colonic trauma from laxative abuse. Thyroid function tests, prolactin, and serum follicle-stimulating hormone (FSH) levels can differentiate anorexia nervosa from alternative causes of primary amenorrhea

Obtain a CBC with erythrocyte sedimentation rate (ESR). The hemoglobin levels are typically normal, although elevations are observed in states of dehydration. If anemia is observed, it is not due to menstrual blood loss, as these patients are usually amenorrheic. In such cases, further investigation is warranted.

The white blood cell (WBC) count is typically low due to increased margination, and thrombocytopenia is also observed. The leukopenia is not a sign that the patient is at an increased risk for infection.

The ESR is normal in anorexia nervosa. Therefore, elevations should prompt a search for an organic etiology, such as neuropsychiatric involvement including affective disorders, psychosis, cognitive dysfunction, and steroid-induced anorexia nervosa in adolescents with systemic lupus erythematosus (SLE), which may be triggered by steroid-induced changes in weight and body shape. Anorexia nervosa may be a presentation of neuropsychiatric SLE; thus, patients with anorexia nervosa who have joint symptoms, a positive antinuclear antibody, or lymphopenia should be investigated and followed for possible SLE, especially as treatment of the SLE may be associated with recovery from anorexia nervosa.[99]

Results can include the following:

• Hyponatremia: Reflects excess water intake or the inappropriate secretion of antidiuretic hormone (ADH)

• Hypokalemia: Results from diuretic or laxative use

• Hypoglycemia: Results from the lack of glucose precursors in the diet or low glycogen stores; low blood glucose may also be due to impaired insulin clearance

• Elevated blood urea nitrogen (BUN): Renal function is generally normal except in patients with dehydration, in whom the BUN level may be elevated (also perform a urinalysis)

• Hypokalemic hypochloremic metabolic alkalosis: Observed with vomiting

• Acidosis: Observed in cases of laxative abuse

Serum vitamin D and calcium levels may be helpful, especially if osteoporosis is suspected, and should always be obtained if a trial of bisphosphonates is attempted for confirmation of osteoporosis.[47, 100]

Liver function test results are minimally elevated, but levels encountered in patients with active hepatitis are not observed. Albumin and protein levels are usually normal, because although the amount of food intake is restricted, it usually contains high-quality proteins.

A dramatic elevation in cholesterol is observed in cases of starvation and may be secondary to the following: (1) a decrease in triiodothyronine (T3) levels, (2) low cholesterol-binding globulin levels, and (3) leakage of intrahepatic cholesterol.

A chest radiograph may reveal rib fractures or pneumomediastinum in the presence of other examination and laboratory findings to suggest repetitive vomiting. Patients may also show evidence of osteopenia.

Radiographic evidence of emphysematous changes may be present on chest computed tomography (CT) scans of patients with anorexia nervosa[101] ; however, these changes resolve with refeeding and weight normalization, unlike those seen in chronic obstructive pulmonary disease. Echocardiography can reveal a decreased ventricular mass and mitral valve prolapse.

Cardiovascular complications account for most of the morbidity and mortality associated with anorexia nervosa. Electrocardiography (ECG) can reveal evidence of sinus bradycardia, ST-segment elevation, T-wave flattening, low voltage, and rightward QRS axis, although these changes are clinically insignificant. A finding of QT-interval prolongation, however, may indicate that the patient is at risk for cardiac arrhythmias and sudden death.[102, 78, 1]

The use of scales such as the MacArthur Competence Assessment Tool for Treatment (MacCAT-T) can be helpful in the assessment of mental capacity to refuse treatment.[103]

Anorexia nervosa is difficult to treat because of the shame, denial, and lack of insight concomitant with the disorder.[104] Medical management is directed toward correcting and preventing the disease’s complications. Reestablishing normal eating patterns is crucial to restoring the patient’s health.[105]

Hospital admission may be indicated for patients who are extremely ill, have cardiac dysrhythmias, or have severe metabolic abnormalities. Most patients will be admitted to medical facilities for refeeding, referred to psychiatric facilities and counseling if medically stable, or be managed on an outpatient basis.[106, 107]

Outpatient treatment should be undertaken only with very close monitoring, such as weekly weight measurement with the patient wearing only a gown.

As with all psychiatric and behavioral emergencies, care must be taken to prove and document competency upon discharge. Many patients with anorexia nervosa may have additional psychopathology, which may leave them incapacitated during an anorexic crisis. If doubt remains, the patient must be admitted for more thorough psychiatric and physiologic monitoring or be discharged in the care of a competent caretaker.[103]

Transfer to an inpatient psychiatric facility may be the disposition for patients who are medically safe for discharge but who require aggressive inpatient psychiatric treatment of their disorder.

Research has found a correlation between low BMI in anorexia nervosa and altered physical activity patterns providing an implication that restriction on physical activity might help restore a healthy BMI.[108]

Acute pharmacologic treatment of anorexia nervosa is rarely required. However, vitamin supplementation with calcium should be started in patients, and although estrogen has no established effect on bone density in patients with anorexia nervosa, estrogen replacement (ie, oral contraceptives) has been recommended for the treatment of osteopenia; the benefits and minimal effective dose of the hormone are being explored.[109]

Various psychological therapies have proven helpful in treating patients with anorexia nervosa, including the following[5, 6] :

• Individual therapy (insight-oriented)

• Cognitive analytic therapy

• Cognitive behavioral therapy (CBT)

• Enhanced cognitive-behavioral therapy (CBT-E)

• Cognitive remediation therapy (CRT)

• Interpersonal therapy (IPT)

• Motivational enhancement therapy

• Dynamically informed therapies

• Group therapy

• Family-based therapy (FBT)

• Specialist supportive clinical management (SSCM)

• Conjoint family therapy

• Separated family therapy

• Multifamily groups

• Relatives and caregiver support groups

• Attention bias modification training

Younger individuals with anorexia nervosa, especially adolescents, may respond best to family-based treatment (FBT), which appeared superior to individual therapy.[7] The recovery rate for adults appeared higher with CBT, however other treatments such as SSCM and the Maudsley method (MANTRA) showed an outpatient recovery rate of 15% in maintaining remission from anorexia nervosa. FBT also appeared superior to CBT although the rate of recovery from CBT-E was slightly improved over CBT.[110, 7, 111]

A modification of CBT called CRT (cognitive remediation therapy) may be more effective in helping the patient to gain better cognitive flexibility,  and is a manual-based program especially effective for motivated persons.[111]

Caregivers' interactions are most helpful when stigma is lessened and collusion, avoidance, accommodation to the illness, and negative expressed emotion such as overprotection and hostility were avoided.[74]

A review by Mercado et al. found that Attention Bias Modification Training (ABMT) has the potential to modify maladaptive eating behaviors related to anxiety around food and eating and propose two mechanistic models: (1) ABMT increases general attentional control (which will improve control over disorder-relevant thoughts) or (2) ABMT promotes stimulus re-evaluation possibly via changes in the subjective value of food stimuli (i.e., reward processing) or via habituation, with both resulting in a reduced threat response.[112]

Nutrition is an important part of the treatment for the individual with anorexia nervosa. A nutritionist or dietitian should be an integral part of the treatment plan, because the well-recognized refeeding syndrome can occur during the early stages of refeeding the patient with anorexia. This syndrome encompasses cardiovascular collapse, starvation-induced hypophosphatemia, and dangerous fluctuations in potassium, sodium, and magnesium levels.

The process of refeeding must therefore be undertaken slowly, with modest increases in metabolic demands. Assessment of vitamin D and calcium intake is helpful in the design of a successful refeeding plan.[24]

Assessment of linolenic acid, retinol, vitamin A, vitamin D, and pantothenic acid levels can also be helpful, because early in anorexia, levels of vitamin A can be elevated, causing symptoms such as dizziness, cerebral edema, and nausea, as well as bone mineral loss. This tends to exacerbate worsening of the anorexia, thereby worsening the patient’s nutritional and general medical status.[113]

Tube feeding must often be initiated on an inpatient basis when the patient's weight is less than or at 85% of expected weight and/or less than the third percentile for BMI,[114] as outpatient refeeding can be too uncomfortable, and the weight gain can be too rapid for the patient to tolerate, resulting in the patient sabotaging treatment. Tube refeeding does not impair efficacy of any psychological therapies.[115]

Rio et al (2013) and Mehler et al (2010) have proposed the following strategies to avoid the refeeding syndrome:[116, 114]

• Identify patients at risk.

• Measure serum electrolyte levels and correct abnormalities before refeeding, as low levels of potassium, magnesium, and phosphate may be a risk factor for refeeding syndrome

• Obtain serum chemistry values every 3 days for the first 7 days and then weekly during the rest of the refeeding period

• Attempt to increase daily caloric intake slowly from 1000 to 1900 kcal/day by 200-300 kcal every 3-5 days until a sustained weight gain of 1-2 pounds (0.45-0.9 kg) per week is achieved (rapid refeeding can lead to excessive bloating, edema, and, rarely, congestive heart failure)

• Monitor the patient carefully for development of tachycardia[117] or edema

• Monitor for pellagra and administer niacin supplementation if needed[118]

A small, but well-done, study by Garber et al of 35 hospitalized patients with anorexia nervosa found that increased fluid output and less-dilute specific gravity at the start of refeeding may be causally related to the common finding that initial weight loss occurs at the start of treatment and continues until day 8. Thus, it may be better to refeed anorexic patients with a higher caloric intake (average, 1966 kcal) than has been recommended by the American Psychiatric Association and the American Dietetic Association, which generally results in a low weight gain (1 kg/wk maximum on an initial 1200-kcal/day diet) following initial weight loss.[119]

In the Garber study, refeeding more aggressively did not result in refeeding syndrome, as phosphorus levels did not decrease to an unacceptable level. The result was a reduction in the duration of hospital stay by almost 1 day, without increased risk of medical complications.[119]

Psychological issues encompass the coping strategies engendered by eating disorders. According to Kreipe and Birndorf, the treating clinician may threaten the homeostatic balance that has been achieved within the family system secondary to dealing with the patient with anorexia; negative emotions, such as anger and denial, may be directed at the clinician.[92]

Individuals with anorexia nervosa may respond best to family-based treatment, also known as the Maudsley method, an established therapeutic modality for achieving and maintaining remission from anorexia nervosa.[110, 26]

This treatment modality should take into account the level of negative expressed emotion in the patient’s family and be performed conjointly only if that level is not excessive.[48, 5, 120] Simultaneous sessions can be more productive because, if patients feel intense negative emotions from their families, they are more likely to be noncompliant with treatment.

A large, randomized, controlled study of 121 adolescents and young adult subjects found that although family-based therapy was equally as effective as adolescent-focused therapy,[121] family-based therapy resulted in more successful maintenance of improvement after 12 months, as measured by superior outcomes at 6 months and 12 months posttreatment.

For some adolescents with more severe anorexia nervosa, extending family-based treatment beyond 20 weeks' duration may be needed. One study of 69 medically unstable adolescents found that continuing family-based treatment beyond 20 weeks' duration improved outcomes.[122]

Although an earlier meta-analysis/review did not find a difference in outcome between family-based therapy and educational interventions, that review incorrectly grouped several studies together that were different in approach.[123] Specifically, some of those studies did not have a standardized approach and had an insufficient number of subjects.

Psychodynamic psychotherapy in combination with behavioral strategies is indispensable in patients with anorexia nervosa. Randomized, controlled trials show that CBT is very effective, especially in the setting of tube feeding.[124]

A flexible approach to the use of CBT or IPT is important and should be tailored to the individual, whenever possible, especially taking into account expressed emotion.[125] Successful CBT can yield better results than community-based treatment, especially in the presence of specific issues (eg, sexual abuse, traumatic events) more likely to respond to specific subtypes of CBT, such as trauma-focused CBT or exposure therapy with response prevention.[47, 126, 127, 128]

IPT and CBT versus nonspecific therapy

In a study by McIntosh et al, some patients with anorexia nervosa who received nonspecific management (in which clinical management was combined with supportive psychotherapy) appeared to have outcomes as good as or better than those of patients who received IPT or CBT.[129] The reason for this may be that in the nonspecific approach, the therapy was provided by experienced clinicians, was practiced according to a detailed treatment manual, and instituted psychoeducation with a strong focus on normalizing eating (with approaches such as smart food selection and quantities needed to gain weight).[129]

Family group psychoeducation versus family therapy

A study by Geist et al of 25 adolescent females with anorexia nervosa suggested that family group psychoeducation is as useful as family therapy (as measured by weight gain in patients) in newly diagnosed, medically compromised patients, while being more cost-effective.[130]

Psychopharmacologic treatment in anorexia nervosa is generally unhelpful, although fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI), may stabilize recovery in patients who have already attained 85% of their weight. If SSRIs are used, however, patients should be carefully monitored for hypomanic or manic adverse effects.

Evidence-based studies show that pharmacotherapy is more effective when combined with CBT and should not be used alone.

Psychotherapy with adjunctive low-dose olanzapine may be useful for anorexia nervosa during inpatient treatment, especially in the context of anxiety, obsessive eating-related ruminations, and treatment resistance due to failure to engage.[10]

Individuals with anorexia nervosa who are at risk medically or psychiatrically require inpatient treatment. Indications for hospital admission include the following:

• Low weight (85% or less of expected weight and/or less than the third percentile for BMI)[114]

• Lack of any weight gain

• Significant edema

• Physiologic decompensation including, but not limited to, the following: (1) severe electrolyte imbalance (life-threatening risks created by sodium and potassium derangements), (2) cardiac disturbances or other acute medical disorders, (3) altered mental status or other signs of severe malnutrition, and (4) orthostatic differential greater than 30/min

• Temperature less than 36°C

• Pulse below 45 beats per minute

• Psychosis or a high risk of suicide

• Symptoms refractory to outpatient treatment

In order to preserve his or her self-esteem and to prevent suicidality and feelings of hopelessness, inpatient management should be approached in such a way as not to seem like punishment to the patient. The goals of inpatient therapy should be fully discussed with the family and the patient, including elements such as developing a healthy meal plan, addressing underlying conflicts (such as low self-esteem) and planning new coping strategies, and enhancing communication skills.

It is essential to monitor the patient's weight, vital signs, and serum electrolyte levels. Although weight gain is a primary goal of treatment, the weight gain should not be excessive, because rapid refeeding can lead to refeeding syndrome: excessive bloating, edema, and, rarely, congestive heart failure (CHF). Leptin and cortisol levels may be helpful in predicting the time to weight recovery.[131]

Limited physical activity (eg, sports, exercise classes) is recommended. By limiting activity, energy expenditure is limited, thus assuring a balanced weight. Moreover, without structure, patients may exercise in potentially harmful ways and at very high intensities. Limitation of activity may also motivate the patient to maintain healthy eating habits in order to ensure a rapid return to favorite activities. Note that the disadvantage of curtailing activity is the removal of the patient's coping mechanism to deal with stress.

Anorexia nervosa is based on caloric restriction and increased caloric expenditure that leads to excess exercise to control weight. Previous studies have described the use of exercise programs for hospitalized inpatients in which exercise was exchanged for weight gain and compliance. However, no guidelines were set forth in terms of type, intensity, and duration of exercise.

Thien et al looked at a standard program designed for outpatient use, graduated in type of exercise, duration, and level of activity, and demonstrated that both the exercise and the control groups in the study achieved increases in BMI and body fat percentage. However, quality of life was increased in the exercise group, whereas the control group showed a decrease in all aspects of quality-of-life measures, although the difference was not statistically significant.[132]

The approach to the treatment of individuals with anorexia nervosa is multidisciplinary. Consultations with specialists in adolescent medicine, nutrition, psychiatry or behavioral-developmental pediatrics, and psychology may be required.

Most cases of anorexia nervosa encountered in the emergency department (ED) will be appropriate for outpatient management if close, planned follow-up is arranged prior to discharge. Consultation with the pediatrician or primary care physician is necessary to arrange follow-up. Urgency of follow-up depends on the patient's condition and how soon the laboratory study results will need to be reevaluated.

Psychiatric consultation in the ED should be considered for patients expressing suicidality, psychosis, or severely disordered thinking. Outpatient psychiatric follow-up is necessary and may be arranged either from the ED or by the primary care provider.

For patients with the mild stage of anorexia nervosa, reevaluate in 1-2 months to check that the weight is not decreasing, that health is maintained, and that the patient has not developed bad eating habits. Surveillance is required to ensure that the patient has not progressed to the moderate stage.

Complications of weight-control habits include the inability to break the cycle of disordered eating as an outpatient and the inability to initiate effective outpatient psychotherapy.[92]

American Psychiatric Association

The American Psychiatric Association (APA) published guidelines for the treatment of eating disorders in February 2023.[133, 134] The guidelines recommend that screening for the presence of an eating disorder should be part of an initial psychiatric evaluation. The initial evaluation of a patient with a possible eating disorder should include assessment of multiple factors, including but not limited to, patient’s history of height and weight, eating-related behaviors, food repertoire, weight control behaviors, and family history. The evaluation should also identify co-occurring health conditions and psychiatric disorders.

Patients with anorexia nervosa (AN) who require nutritional rehabilitation and weight restoration should have individualized goals for weekly weight gain and target weight. Adults with AN should be treated with an eating disorder-focused psychotherapy.

The Royal Australian and New Zealand College of Psychiatrists

The Royal Australian and New Zealand College of Psychiatrists released the first set of eating disorder guidelines that incorporate recommendations from the DSM-5. The guidelines focus on anorexia nervosa, but also cover bulimia nervosa, binge eating disorder, and the new disorder of avoidant-restrictive food intake disorder.[135]

Recommendations include the following:

• Most patients with anorexia nervosa should be treated as outpatients or day patients.

• A multi-disciplinary treatment approach incorporating consideration of nutritional, medical and psychological aspects, family-based therapies in younger patients, and specialist therapist-led manual-based psychological therapy with long-term follow-up in all age groups should be used.

• In chronic anorexia nervosa, a harm minimization approach should be used.

• The approach to diagnosis and treatment should be culturally informed.

Canadian practice guidelines

Canadian practice guidelines for treating children and adolescents with eating disorders were published in 2020.[136] Recommendations include the following:

• Family-based treatment (FBT) is strongly recommended for children and adolescents with anorexia nervosa or bulimia nervosa.

• Multi-family therapy (MFT) is a reasonable treatment option for children and adolescents with anorexia nervosa.

• Cognitive-behavioral therapy (CBT) is a reasonable treatment option for children and adolescents with anorexia nervosa or bulimia nervosa.

• Adolescent-focused therapy (AFP) is a reasonable treatment option for children and adolescents with anorexia nervosa.

• Yoga, in addition to standard treatments, is a reasonable treatment option for medically stable children and adolescents with anorexia nervosa, bulimia nervosa, and other specified feeding and eating disorders.

• Olanzapine or aripiprazole may be reasonable treatment options for certain populations of children and adolescents with anorexia nervosa if monitored carefully.

• It is strongly recommended that the least intensive treatment environment be provided, especially for those children and adolescents with anorexia nervosa requiring a first admission to hospital and/or with a duration of illness less than 3 years.

The use of medication in individuals with anorexia nervosa is limited to the treatment of medical complications, and the treatment of comorbid psychiatric conditions such as anxiety and depression that may impede psychosocial and behavioral treatments. To treat osteopenia and to prevent further bone loss, daily dietary intake of calcium 1000-1500 mg and vitamin D 400 IU are recommended. Estrogen replacement (ie, oral contraceptives) has also been recommended for the treatment of osteopenia, although the benefits and minimal effective dose is being explored.[109] Bisphosphonate therapy can be effective, but the patient should be closely monitored for osteonecrosis of the mandible.[100]

Evidence regarding the efficacy of medication treatment for eating disorders has tended to be weak or moderate, especially as side effects tend to limit long-term compliance compared with the time devoted to psychotherapeutic treatments. However, randomized, controlled trials have shown benefits from the use of medication in combination with cognitive behavioral therapy (CBT).[8, 9, 137]

Fluoxetine was found to be generally helpful in patients with anorexia nervosa who had been stabilized with weight restoration. Psychotherapy with adjunctive low-dose olanzapine may be useful for anorexia nervosa during inpatient treatment, especially in the context of anxiety, obsessive eating-related ruminations, and treatment resistance due to failure to engage. Higher-dose fluoxetine and/or topiramate may be helpful in bulimia nervosa. At this time, however, medication for weight loss in bulimia nervosa is not recommended, due to significant adverse effects such as pulmonary hypertension and heart failure.[8, 9]

In a meta-analysis of 8 studies involving 221 patients with anorexia nervosa, antipsychotics failed to show efficacy for body weight or other anorexia-related outcomes.[138]

Pharmacotherapy should not be the only line of treatment and should be used with caution in suspected bipolar disorder, but it may be helpful for depression.[139] Most patients who recover from anorexia nervosa will have been treated with a multidisciplinary approach that includes medication, psychotherapy, nutritional counseling, and frequent medical evaluations.

Antidepressive agents

Antidepressive and neuroleptic agents, although not reported to be effective, have a limited use in patients who have adequate nutrition and mood changes associated with anorexia nervosa. Prolongation of the QT interval is a contraindication to tricyclic antidepressants because a prolonged QT may increase the risk of ventricular tachycardia and death.

SSRIs and SNRIs

Selective serotonin reuptake inhibitors (SSRIs) have been shown to be beneficial in patients with bulimia nervosa but not anorexia. However, since many patients with anorexia have concurrent mood disorders, medication may be of benefit.

In patients with anorexia nervosa who have attained 85% of their expected weight, the SSRI fluoxetine has been used to stabilize recovery. Zinc and cyproheptadine have not been useful. SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may be more helpful for addressing concurrent obsessive-compulsive issues and, owing to their relative neutral effect on weight, may be more easily accepted by the patient.

SSRIs are greatly preferred over the other classes of antidepressants.[140] Because the adverse effect profile of SSRIs is less prominent, improved compliance is promoted. SSRIs do not have the cardiac arrhythmia risk associated with tricyclic antidepressants. Arrhythmia risk is especially pertinent in overdose, and suicide risk must always be considered in the treatment of a child or adolescent with a mood disorder.

Precautions in the pediatric population

Use appropriate caution when considering treatment with SSRIs in the pediatric population. In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of "depressive illness." After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except fluoxetine, which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

In October 2003, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality (ideation and attempts) in pediatric patients being treated with antidepressant medications for major depressive disorder and other conditions. The FDA asked, however, that additional studies be performed because suicidality occurred in treated and untreated patients with major depression and thus could not be definitively linked to drug treatment.

In 2005, the FDA proposed that manufacturers change antidepressant labeling by adding a black-box warning regarding the increased suicidality risk in children and adolescents who use antidepressants. The labeling change also emphasized the need for appropriate monitoring and patient awareness via medication guides. Two years later, the FDA also recommended updates on the black-box labeling of antidepressants regarding increased risk of suicidality in young adults aged 18-24 during initial treatment (generally the first 1-2 months).

A cohort study looked at suicide risk for youths younger than 24 years in the context of use of SSRIs and SNRIs and the current “Black Box” warning regarding increased risk of suicidal ideation in this population.[141] This retrospective cohort study included 36,842 children aged 6-18 years enrolled in Tennessee Medicaid from 1995-2006 who were new users of 1 of the antidepressant medications of interest (defined as filling no prescriptions for antidepressants in the preceding 365 days). It found that there was increased risk for suicide attempts among users of multiple antidepressants concomitantly; however, there was no evidence that risk of suicide attempts increased when one medication was prescribed and the adjusted rate of suicide attempts did not differ significantly among current users of SSRI and SNRI antidepressants compared with current users of fluoxetine.

The current evidence does not support an increased risk of suicide in patients with obsessive-compulsive disorder or other anxiety disorders who are treated with SSRIs.

Atypical antipsychotics

The atypical antipsychotics (eg, olanzapine, quetiapine, risperidone) have shown some benefit in the treatment of anorexia nervosa. This is thought likely to be from their effects on depression, anxiety, and core eating disordered psychopathology. However, there are significant safety concerns surrounding these drugs due to the high likelihood of cardiac conduction abnormalities in patients with anorexia.[139, 142]

Gastrointestinal prokinetic agents

Part of the pathophysiology of anorexia nervosa is a delay in gastric emptying, which can perpetuate the disorder by limiting the quantity of food that can be eaten. Although a study of cisapride (Propulsid) did not show gastric-emptying enhancement, participants reported a greater improvement in subjective symptoms during a meal.[143]

In 2000, however, cisapride use in patients with anorexia nervosa or bulimia was discouraged after cisapride was found to be associated with serious cardiac events (ie, serious arrhythmias associated with prolonged QTc) and the risk of cardiovascular-related events in patients with eating disorders.

Class Summary

Electrolyte repletion is necessary in patients with profound malnutrition, dehydration, and purging behaviors. Repletion may be done orally or parenterally, depending on the patient’s clinical state.

Calcium carbonate (Tums, Oysco, Os-Cal, Maalox)

Calcium moderates nerve and muscle performance by regulating the action potential excitation threshold. It also improves bone density.

Potassium chloride (K-Lor, Klor-Con, Micro-K)

Potassium is essential for the transmission of nerve impulses, contraction of cardiac muscle, maintenance of intracellular tonicity, skeletal and smooth muscle contraction, and maintenance of normal renal function. Gradual potassium depletion occurs via renal excretion or gastrointestinal loss or because of low intake. Depletion usually results from diuretic therapy, primary or secondary hyperaldosteronism, diabetic ketoacidosis, severe diarrhea (if associated with vomiting), or inadequate replacement during prolonged parenteral nutrition.

Potassium depletion sufficient to cause 1 mEq/L drop in the serum potassium level requires a loss of approximately 100-200 mEq of potassium from the total body store.

Calcium gluconate (Cal-Glu)

Calcium gluconate moderates nerve and muscle performance and facilitates normal cardiac function. It can initially be given intravenously, and then calcium levels can be maintained with a high-calcium diet. Some patients require oral calcium supplementation. The 10% intravenous (IV) solution provides 100 mg/mL of calcium gluconate, equaling 9 mg/mL (0.46 mEq/mL) of elemental calcium. One 10-mL ampule contains 93 mg of elemental calcium.

Potassium phosphates, IV

For severe hypophosphatemia (< 1 mg/dL), parenteral preparations of phosphate should be used for repletion. IV preparations are available as sodium or potassium phosphate (K2PO4). Response to IV serum phosphorus supplementation is highly variable and is associated with hyperphosphatemia and hypocalcemia. The rate of infusion and choice of initial dosage should be based on the severity of hypophosphatemia and the presence of symptoms. Serum phosphate and calcium should be monitored closely.

For less severe hypophosphatemia (1-2 mg/dL), oral phosphate salt preparations can be used. Oral preparations are available as sodium or potassium phosphate in capsule or liquid form. Neutra-Phos packets each contain 250 mg of phosphorus; tablets contain 250, 125.6, or 114 mg. Liquid preparations are available as 250 mg/75 mL.

Class Summary

Vitamins are used to meet necessary dietary requirements. They are utilized in metabolic pathways, as well as in deoxyribonucleic acid (DNA) and protein synthesis.

Ergocalciferol (Calciferol, Drisdol, Calcidol)

This is a vitamin D-2 analogue that is converted in the liver to an active intermediate and then further converted to its most active form in the kidneys. It stimulates the absorption of calcium and phosphate from the small intestine and promotes the release of calcium from bone into blood. Because it is a precursor, a significant delay between dose administration and effect exists. The liver must be intact for the intermediate to be formed (calcidiol, 25-hydroxy vitamin D). Many drugs may affect this step.

Ergocalciferol is stored in fat, so when there is a lack of fat (due to weight loss), the potential exists for overdose of ergocalciferol. It has lipid storage, so overdoses may cause prolonged hypercalcemia.

Ergocalciferol is used as a replacement therapy. To measure of its efficacy, assess the serum calcium concentration.

Class Summary

These agents have been reported to reduce binge eating, vomiting, and depression and to improve eating habits, although their impact on body dissatisfaction remains unclear.

Fluoxetine (Prozac)

Fluoxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on the reuptake of norepinephrine or dopamine. It may cause more adverse gastrointestinal effects than other currently available SSRIs, which is the reason it is not recommended as a first choice.

Fluoxetine can be administered as a liquid or a capsule and can be given in single or divided doses. The presence of food does not appreciably alter levels of the medication. It may take up to 4-6 weeks to achieve steady-state levels of the medication because it has a long half-life (72 h). The long half-life is both an advantage and a drawback. If fluoxetine works well, an occasional missed dose is not a problem; if fluoxetine-related problems occur, however, eliminating all active metabolites takes a long time.

The choice to use fluoxetine depends on adverse effects and drug interactions. Adverse effects of SSRIs seem to be quite idiosyncratic; thus, relatively few reasons exist to prefer one over another at this point if dosing is started at a conservative level and advanced as tolerated.

Fluoxetine is indicated for the treatment of binge eating and self-induced vomiting in patients with moderate to severe bulimia nervosa. The drug's antidepressant, anti–obsessive-compulsive, and antibulimic actions are presumed to be linked to inhibition of the central nervous system's uptake of serotonin.