Anorexia Nervosa

Overview — Highest Mortality of Any Psychiatric Disorder
DSM-5 Diagnostic Criteria
Subtypes and Severity Specifiers
Medical Complications
Refeeding Syndrome
Differential Diagnosis — ARFID
Pharmacological Treatment
Psychotherapeutic Treatment
Levels of Care and Prognosis
Research Papers
Connections
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Overview — Highest Mortality of Any Psychiatric Disorder

Anorexia nervosa is a serious eating disorder characterized by self-imposed food restriction, intense fear of weight gain, and a distorted perception of body image. It carries the highest mortality rate of any psychiatric disorder, making early recognition and treatment critically important.

Mortality and Epidemiology

All-cause mortality rate: approximately 5–10% (roughly 5% per decade of illness)
Standardized mortality ratio (SMR): 5.86 — meaning individuals with anorexia nervosa die at nearly 6 times the expected rate (Arcelus et al., 2011 meta-analysis)
Suicide mortality: approximately 1% die by suicide; suicide risk is elevated 30–50 times that of the general population
Causes of death: medical complications (cardiac, electrolyte, organ failure) and suicide are the two leading causes
Onset: bimodal peak — adolescence (ages 14–18) and young adulthood; a smaller peak occurs in the mid-20s
Sex distribution: predominantly female, with approximately a 9:1 female-to-male ratio, although male cases are underdiagnosed
Lifetime prevalence: approximately 0.9% in women and 0.3% in men (DSM-5)
Onset trigger: often follows a period of dieting, a stressful life event, or puberty; perfectionism, anxiety, and obsessive-compulsive traits are common premorbid features

DSM-5 Diagnostic Criteria

All three criteria (A, B, and C) must be present for a diagnosis of anorexia nervosa:

Criterion A — Restricted Energy Intake

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" is defined as a weight that is less than minimally normal or, for children and adolescents, less than minimally expected.

Criterion B — Intense Fear of Weight Gain

Intense fear of gaining weight or of becoming fat, or persistent behavior that interferes with weight gain, even at a significantly low weight. This fear often does not diminish as weight is lost — it may intensify.

Criterion C — Disturbance in Body Image

Disturbance in the way 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. Patients may feel "fat" even when objectively emaciated.

Subtypes and Severity Specifiers

Restricting Type (AN-R)

During the past 3 months, the person has not engaged in recurrent episodes of binge eating or purging. Weight loss is accomplished primarily through dieting, fasting, and/or excessive exercise. This is the classic presentation most people associate with anorexia nervosa.

Binge-Purge Type (AN-BP)

During the past 3 months, the person has engaged in recurrent episodes of binge eating or purging behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics, or enemas). Crucially, these patients are still at significantly low body weight — this distinguishes AN-BP from bulimia nervosa (BN), where patients are typically at normal or above-normal weight.

DSM-5 Severity Specifiers (Based on BMI)

Mild: BMI ≥17.0 kg/m²
Moderate: BMI 16.0–16.99 kg/m²
Severe: BMI 15.0–15.99 kg/m²
Extreme: BMI <15.0 kg/m²

Severity can be increased above BMI-based levels to reflect clinical symptoms, degree of functional disability, and need for supervision.

Medical Complications

Anorexia nervosa causes widespread medical complications due to starvation, malnutrition, and purging behaviors. Every organ system can be affected.

Cardiovascular

Bradycardia: most common cardiovascular finding; the most frequent cause of sudden cardiac death in anorexia nervosa
Hypotension and orthostatic hypotension: due to volume depletion and autonomic dysfunction
Prolonged QTc interval: increases risk of ventricular arrhythmia (torsades de pointes)
Mitral valve prolapse: occurs in a subset due to loss of supporting cardiac tissue
Pericardial effusion: can develop in severe malnutrition

Dermatological

Lanugo: fine, downy body hair that grows as a thermoregulatory response to loss of subcutaneous fat
Dry skin (xerosis) and brittle nails
Telogen effluvium: diffuse hair thinning and loss caused by nutritional deficiency and physiological stress
Russell's sign: calluses or scarring on the dorsal surface of the knuckles, caused by repeated trauma from self-induced vomiting (shared with bulimia nervosa)
Carotenemia: yellowish skin discoloration from elevated carotene (common in restrictive AN)

Endocrine and Metabolic

Hypothermia: impaired thermoregulation due to loss of fat insulation and reduced metabolic rate
Amenorrhea: functional hypothalamic amenorrhea caused by suppressed GnRH pulsatility → low LH and FSH → low estrogen; historically required for diagnosis (removed from DSM-5 to allow male/pre-pubertal inclusion)
Euthyroid sick syndrome (low T3 syndrome): body conserves energy by converting less T4 to active T3; TSH is usually normal — this is adaptive, not primary thyroid disease
Low IGF-1: growth hormone resistance; impairs bone and muscle maintenance
Hypoglycemia: depleted glycogen stores; can cause altered mental status
Low cortisol reserve: relative adrenal insufficiency can occur in extreme cases

Bone

Osteopenia and osteoporosis: one of the most serious long-term complications, driven by estrogen deficiency, low IGF-1, malnutrition, and cortisol elevation
Fracture risk: significantly elevated, including stress fractures during exercise
Peak bone mass: because anorexia often begins in adolescence (the critical window for peak bone accrual), bone loss may be irreversible even after full weight restoration

Renal and Electrolyte

Dehydration: from restriction and/or purging
Hypokalemia: particularly with vomiting or laxative use; causes muscle weakness, arrhythmias
Hyponatremia: from excessive water intake (psychogenic polydipsia) to suppress hunger
Metabolic alkalosis: from vomiting (loss of HCl)
Metabolic acidosis: from laxative abuse (bicarbonate loss)
Renal impairment: chronic dehydration can cause pre-renal azotemia and, in severe cases, chronic kidney disease

Neurological

Cerebral atrophy: both gray and white matter loss visible on MRI; largely reversible with sustained weight restoration
Peripheral neuropathy: from B-vitamin deficiencies (especially B1 and B12)
Cognitive impairment: executive function, attention, and processing speed are all affected; partially related to starvation-induced cerebral changes
Wernicke's encephalopathy risk: thiamine (B1) deficiency, especially during aggressive refeeding

Refeeding Syndrome

Refeeding syndrome is a potentially fatal metabolic complication that occurs when severely malnourished patients receive rapid nutritional replenishment — whether via oral feeding, enteral tube feeding, or parenteral nutrition. It is a critical safety concern in the inpatient management of anorexia nervosa.

Mechanism

During starvation, the body shifts from carbohydrate to fat metabolism, and total body stores of phosphate, potassium, and magnesium become severely depleted (although serum levels may appear normal). When carbohydrates are reintroduced, insulin surges, driving rapid cellular uptake of these electrolytes:

Hypophosphatemia is the hallmark finding — phosphate is essential for ATP synthesis
ATP depletion causes: cardiac arrhythmia (potentially fatal), respiratory muscle failure, hemolytic anemia, seizures, rhabdomyolysis, and altered mental status
Hypokalemia and hypomagnesemia potentiate cardiac and neuromuscular effects

Prevention Protocol

"Start low, go slow": NICE guidelines recommend beginning at 5–10 kcal/kg/day in patients with BMI <14 or after prolonged starvation; increase gradually over 4–7 days; maximum weight gain rate of 0.5–1.0 kg/week (inpatient) or 0.5 kg/week (outpatient)
Electrolyte supplementation before and during refeeding: correct phosphate, potassium, and magnesium prophylactically; monitor electrolytes daily for the first 2 weeks
Thiamine (Vitamin B1) BEFORE refeeding: administer 200–300 mg/day IV or IM thiamine for at least 30 minutes before any glucose/carbohydrate is given to prevent Wernicke's encephalopathy
Monitor closely: daily weight, fluid balance, electrolytes, glucose, phosphate, magnesium, potassium; ECG monitoring in high-risk patients
NICE 2017 and MARSIPAN (UK Royal Colleges) guidelines both identify hypophosphatemia as the primary refeeding danger and mandate pre-emptive supplementation

Differential Diagnosis — ARFID

Several conditions can present with significant food restriction and low weight. The most important differential is Avoidant/Restrictive Food Intake Disorder (ARFID):

ARFID vs. Anorexia Nervosa

ARFID: restriction based on sensory properties of food (texture, color, smell), fear of aversive consequences (choking, vomiting), or apparent lack of interest in eating — there is no body image disturbance and no fear of weight gain
AN: restriction is driven by fear of weight gain and distorted body image — the "why" is fundamentally different
ARFID is common in autism spectrum disorder and ADHD; AN peaks in adolescent girls without autism
ARFID is not better explained by cultural or religious food practices

Other Differentials

Bulimia nervosa (BN): binge-purge pattern at normal or above-normal weight (vs. AN-BP which is at significantly low weight)
Major depressive disorder: appetite loss without body image disturbance or fear of weight gain
Celiac disease / IBD: weight loss and food avoidance from GI symptoms — rule out with labs
OCD: food rituals can overlap; the cognitive content distinguishes (contamination/symmetry vs. weight/shape)
Somatic symptom disorder: food avoidance from vague physical complaints

Pharmacological Treatment

Pharmacotherapy for anorexia nervosa has limited evidence compared to bulimia nervosa, and no medication is FDA-approved specifically for anorexia nervosa.

Olanzapine

The antipsychotic olanzapine has the most supporting evidence for AN, specifically for modest weight gain and reduction in obsessional thinking about food and weight:

OLANZAN trial (Attia et al., 2019, NEJM): multicenter RCT (N=152) found olanzapine produced significantly greater weight gain than placebo (BMI increase of 0.259 vs. 0.095 per month) but did not significantly improve psychological features of AN
Typical dose: 2.5–10 mg/day; start low given sedation and metabolic sensitivity in underweight patients
Monitoring: QTc interval, fasting glucose, lipids, extrapyramidal symptoms
Considered in treatment-resistant AN, particularly when weight gain is the primary goal and obsessional features are prominent; not recommended as first-line

SSRIs

SSRIs (particularly fluoxetine) are NOT effective for weight restoration in underweight AN patients — serotonin synthesis is impaired by starvation, so serotonergic agents have minimal effect
SSRIs may reduce relapse risk and help manage comorbid OCD, anxiety, or depression after weight restoration to a healthy range

Medications to Avoid

Bupropion: lowers seizure threshold; the risk is amplified by malnutrition and purging-induced electrolyte disturbances — contraindicated in AN
High-dose antipsychotics: avoid medications with significant QTc-prolonging potential in the context of existing cardiac vulnerability

Psychotherapeutic Treatment

Psychotherapy is the foundation of treatment for anorexia nervosa. The choice of modality depends primarily on patient age and level of care.

Family-Based Treatment (FBT) — Maudsley Approach

FBT is the gold standard for adolescents with anorexia nervosa. It consists of three phases:

Phase 1 — Externalization and parental control: parents take full control of all food decisions and refeeding; the eating disorder is "externalized" — treated as a separate entity that has hijacked the adolescent, not the adolescent's fault
Phase 2 — Gradual return of autonomy: as weight is restored, food control is gradually returned to the adolescent
Phase 3 — Healthy adolescent identity: establishing identity and developmental trajectory independent of the eating disorder

Lock et al. (2010, Arch Gen Psychiatry) RCT demonstrated FBT superiority over individual therapy in adolescents at 1-year follow-up.

CBT-E (Enhanced Cognitive-Behavioural Therapy, Fairburn)

For adults, CBT-E is an extended, individualized form of CBT adapted specifically for eating disorders. It addresses not just eating, weight, and shape concerns, but also "transdiagnostic" maintaining factors including perfectionism, low self-esteem, and interpersonal difficulties. Standard duration is 40 sessions over approximately 40 weeks. Fairburn's CBT-E manual (2008) is the canonical reference.

MANTRA (Maudsley Anorexia Nervosa Treatment for Adults)

MANTRA is a cognitive-interpersonal model developed by Schmidt et al. at King's College London. It explicitly addresses maintaining factors specific to AN: obsessive-compulsive traits, rigid thinking, avoidant emotional processing, and close-others' responses to the illness. Schmidt et al. (2015, Lancet Psychiatry) RCT showed MANTRA was non-inferior to SSCM and both were superior to specialist supportive therapy.

Specialist Supportive Clinical Management (SSCM)

SSCM combines clinical management focused on weight restoration with elements of supportive therapy. It is direct, focuses on the link between eating and symptoms, and is less cognitively demanding than CBT-E or MANTRA. Used particularly in outpatient settings for adults with moderate illness.

Comparative Efficacy

Adolescents: FBT > individual therapy (CBT or supportive) at 1 year
Adults: MANTRA ≈ SSCM > specialist supportive therapy; CBT-E shows comparable outcomes; no single modality clearly dominant; weight restoration goal is universal
Long-term recovery: psychotherapy benefits persist; pharmacotherapy effects are modest and adjunctive

Levels of Care and Prognosis

Stepped Care Model

Treatment intensity is matched to clinical severity and response to lower levels of care:

Outpatient (OP): weekly or twice-weekly appointments; appropriate for medically stable patients with adequate motivation and social support
Intensive Outpatient Program (IOP): 3–4 days/week, several hours per day; structured meal support and therapy
Partial Hospitalization Program (PHP): 5–7 days/week, 6–8 hours/day; daily meal support, medical monitoring, and intensive therapy without overnight stays
Residential: 24-hour care in a specialized eating disorder facility; for patients who cannot progress in lower levels
Inpatient medical stabilization: acute hospital admission for medical emergencies

Medical Indications for Inpatient Admission

Heart rate <50 beats/minute
Blood pressure <90/60 mmHg
Potassium (K+) <3.0 mEq/L
Rapid or uncontrolled weight loss
Syncopal (fainting) episodes
QTc >500 ms on ECG
Blood glucose <60 mg/dL
BMI <13–14 with physiological compromise

Prognosis

Full recovery: approximately 50% achieve full recovery at 10-year follow-up (Eddy et al., 2017)
Partial recovery: approximately 30% have persistent symptoms but improved function
Chronic course: approximately 20% develop a chronic, treatment-resistant illness
Mortality: 5–10% over the long term; cardiac complications and suicide are the leading causes
Predictors of worse outcome: longer duration of illness before treatment, older age at onset, binge-purge subtype, comorbid depression, and previous hospitalizations
Predictors of better outcome: earlier age of onset, shorter illness duration at presentation, good family support, absence of comorbid substance use

Research Papers

Key Research Papers

Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders: a meta-analysis of 36 studies. Arch Gen Psychiatry. 2011;68(7):724–731. PMID 21727255.
Treasure J, Claudino AM, Zucker N. Anorexia nervosa. Lancet. 2010;375(9714):583–593. PMID 19931176.
Attia E, Kaplan AS, Walsh BT, et al. Olanzapine versus placebo for out-patients with anorexia nervosa: a randomised controlled trial (OLANZAN). N Engl J Med. 2019;381(2):111–120. PMID 31322296.
Lock J, Le Grange D, Agras WS, Moye A, Bryson SW, Jo B. Randomized clinical trial comparing family-based treatment with adolescent-focused individual therapy for adolescents with anorexia nervosa. Arch Gen Psychiatry. 2010;67(10):1025–1032. PMID 21041647.
Schmidt U, Magill N, Renwick B, et al. The Maudsley outpatient study of treatments for anorexia nervosa and related conditions (MOSAIC): comparison of the Maudsley model of anorexia nervosa treatment for adults (MANTRA) with specialist supportive clinical management (SSCM) in outpatients with broadly defined anorexia nervosa. Lancet Psychiatry. 2015;2(4):340–347. PMID 26360243.
Mehler PS, Brown C. Anorexia nervosa — medical complications. J Eat Disord. 2015;3:11. PMID 26034579.
National Institute for Health and Care Excellence (NICE). Eating disorders: recognition and treatment. NICE guideline NG69. Published May 2017.
Eddy KT, Tabri N, Thomas JJ, et al. Recovery from anorexia nervosa and bulimia nervosa at 22-year follow-up. J Clin Psychiatry. 2017;78(2):184–189. PMID 28068462.
Keski-Rahkonen A, Mustelin L. Epidemiology of eating disorders in Europe: prevalence, incidence, comorbidity, course, consequences, and risk factors. Curr Opin Psychiatry. 2016;29(6):340–345. PMID 27662598.
Fairburn CG. Cognitive Behavior Therapy and Eating Disorders. New York: Guilford Press; 2008. PubMed search: Fairburn CBT eating disorders.
Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it is, and how to prevent and treat it. BMJ. 2008;336(7659):1495–1498. PMID 18460540.
Strober M, Freeman R, Morrell W. The long-term course of severe anorexia nervosa in adolescents: survival analysis of recovery, relapse, and outcome predictors over 10–15 years in a prospective study. Int J Eat Disord. 1997;22(4):339–360. PMID 9284860.

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