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Review

Anorexia nervosa: aetiology, assessment, and treatment


Stephan Zipfel, Katrin E Giel, Cynthia M Bulik, Phillipa Hay, Ulrike Schmidt

Anorexia nervosa is an important cause of physical and psychosocial morbidity. Recent years have brought advances Lancet Psychiatry 2015
in understanding of the underlying psychobiology that contributes to illness onset and maintenance. Genetic factors Published Online
influence risk, psychosocial and interpersonal factors can trigger onset, and changes in neural networks can sustain October 27, 2015
http://dx.doi.org/10.1016/
the illness. Substantial advances in treatment, particularly for adolescent patients with anorexia nervosa, point to the
S2215-0366(15)00356-9
benefits of specialised family-based interventions. Adults with anorexia nervosa too have a realistic chance of achieving
Department of Psychosomatic
recovery or at least substantial improvement, but no specific approach has shown clear superiority, suggesting a Medicine, University of
combination of re-nourishment and anorexia nervosa-specific psychotherapy is most effective. To successfully fight Tübingen, Tübingen, Germany
this enigmatic illness, we have to enhance understanding of the underlying biological and psychosocial mechanisms, (Prof S Zipfel MD, K E Giel PhD);
Centre for Psychosocial
improve strategies for prevention and early intervention, and better target our treatments through improved
Medicine, Department for
understanding of specific disease mechanisms. General Internal Medicine and
Psychosomatics, Heidelberg
“The want of appetite is, I believe, due to a morbid based on conflicts with inclusion of male individuals, University Hospital,
mental state…I prefer---the more general term [anorexia] Heidelberg, Germany (K E Giel);
adolescents who have not yet reached menarche, and
University of North Carolina at
‘nervosa’, since the disease occurs in males as well as women who use exogenous hormones into the diagnostic Chapel Hill, Chapel Hill, NC,
females, and is probably rather central than peripheral.” criteria. This change is also based on a large body of USA (Prof C M Bulik PhD),
Sir William Gull, 1874 accumulated evidence13 showing no meaningful clinical Department of Medical
(Transactions of the Clinical Society of London 7: 22–28) Epidemiology and
differences between women with anorexia who
Biostatistics, Karolinska
menstruate and those who do not. DSM-5 also classifies Institutet, Stockholm, Sweden
Introduction an atypical anorexia nervosa, which includes restrictive (Prof C M Bulik PhD), School of
Anorexia nervosa is a highly distinctive serious mental behaviours without meeting the low weight criterion. Medicine and Centre for Health
Research Western Sydney
disorder. It can affect individuals of all ages, sexes, sexual In DSM-5, severity of anorexia nervosa is classified along
University, Penrith, NSW,
orientations, races, and ethnic origins; however, four levels by use of the individual’s BMI: extreme (BMI Australia (Prof P Hay MD); and
adolescent girls and young adult women are particularly <15 kg/m²), severe (BMI 15–15·99 kg/m²), moderate (BMI King’s College London, London,
at risk. This disorder is characterised by an intense fear of 16–16·99 kg/m²), and mild (BMI ≥17 kg/m²). A systematic UK (Prof U Schmidt MD)

weight gain and a disturbed body image, which motivate review from 201514 reported evidence for distinct illness Correspondence to:
Prof Stephan Zipfel, Centre of
severe dietary restriction or other weight loss behaviours trajectories and neurocognitive features for eating
Excellence for Eating Disorders
such as purging or excessive physical activity.1–3 disorders characterised by severe restriction (eg, Tuebingen (KOMET) University of
Additionally, cognitive and emotional functioning are inflexibility) or by overeating (eg, impulsivity and risk of Tübingen, Department of
markedly disturbed in people with this disorder. Serious substance use disorders) and evidence for effective Psychosomatic Medicine and
Psychotherapy, Tübingen,
medical morbidity and psychiatric comorbidity are the secondary prevention or early treatment. Preliminary
72076 Tübingen, Germany
norm.4,5 Anorexia nervosa in adults and older adolescents evidence also exists for a specific shift in focus of treatment stephan.zipfel@med.uni-
commonly has a relapsing or protracted course,6 and to quality of life as primary outcome in patients with long- tuebingen.de
levels of disability and mortality are high,7,8 especially standing or intractable anorexia nervosa.15
without treatment. Even partial syndromes (ie, sub-
syndromal anorexia nervosa) are associated with adverse Epidemiology
health outcomes.9 Quality of life is poor and the burden In high-income countries, the lifetime prevalence of
placed on individuals, families, and society is high.10 anorexia nervosa in the general population is reported to
This Review, like the Lancet Seminar published in be around 1% in women and less than 0·5% in men.9
2010,4 which included all eating disorders, focuses on Accurate point prevalence has been more difficult to
factors associated with anorexia nervosa that are of calculate, with studies often failing to identify any cases
particular relevance to clinicians, such as recent of DSM-IV-defined anorexia nervosa. If the broader
developments in diagnosis, epidemiology, pathogenesis, DSM-5 criteria A and C (low weight in the presence of
treatment, and prognosis. overvaluation of weight or shape) are applied, the point
prevalence is about 0·3–0·5%.16 Some studies,17 but not
Classification and diagnosis all clinical incidence studies, support an increase in
Low bodyweight or low body-mass index (BMI) is the anorexia nervosa in adolescents in the past two to three
central feature of anorexia nervosa. Tables 1 and 2 give an decades.9 Anorexia nervosa typically begins in early-to-
overview of diagnostic criteria for anorexia nervosa mid-adolescence, although it can emerge at any age.18
according to DSM2 and ICD11. Restricting and binge-purge The sex ratio in adults is 1:8, with more female individuals
subtypes and remission and severity specifiers exist. afflicted.19 In children, the sex distribution is less
Amenorrhoea is no longer required in the new DSM-5 skewed.20 Outcomes differ across age groups, with higher
diagnostic criteria and is also expected to be dropped in rates of full recovery and lower mortality in adolescents
ICD-11.12 Main reasons for eliminating this criterion are than in adults (mean mortality 2% vs 5%).21

www.thelancet.com/psychiatry Published online October 27, 2015 http://dx.doi.org/10.1016/S2215-0366(15)00356-9 1


Review

DSM-IV DSM-52
Psychiatric and physical comorbidity
Nearly three-quarters of patients with anorexia nervosa
A A refusal to maintain bodyweight at or above A Restriction of energy intake relative to report a lifetime mood disorder, most commonly major
a minimally normal weight for age and height requirements, leading to a significantly low
(eg, weight loss leading to a maintenance of bodyweight in the context of age, sex, depressive disorder.22 Between 25% and 75% of patients
bodyweight less than 85% of that expected, developmental trajectory, and physical health. with anorexia nervosa report a lifetime history of at
or failure to make expected weight gain Significantly low weight is defined as a weight least one anxiety disorder,23 which typically precedes
during period of growth, leading to that is less than minimally normal or, for
bodyweight less than 85% of that expected). children and adolescents, less than that
anorexia nervosa and starts in childhood.24 Obsessive-
minimally expected. compulsive disorder occurs in 15–29% of individuals
B Intense fear of gaining weight or becoming B Intense fear of gaining weight or of becoming with anorexia nervosa,25 with up to 79% experiencing
fat, even though underweight. fat, or persistent behaviour that interferes obsessions or compulsions at some point in their
with weight gain, even though at a lives.26 In population-based studies, the prevalence of
significantly low weight.
alcohol misuse or dependence in individuals with
C Disturbance in the way in which one’s C Disturbance in the way one’s bodyweight or
bodyweight or shape is experienced, undue shape is experienced, undue influence of body anorexia nervosa is between 9% and 25% for anorexia
influence of bodyweight or shape on self- shape and weight on self-evaluation, or nervosa and typically lower in those with the restricting
evaluation, or denial of the seriousness of the persistent lack of recognition of the subtype.27,28 Register-based studies29 confirmed
current low bodyweight. seriousness of the current low bodyweight.
aggregation of autism spectrum disorder in probands
D In postmenarcheal females, amenorrhoea— D ··
ie, the absence of at least three or more
with anorexia nervosa and in their relatives; however,
consecutive menstrual cycles. (A woman is the relation between anorexia nervosa and autism
considered to have amenorrhoea if her spectrum disorder seems to be non-specific.29
periods occur only following Advances in studies of comorbidity are emerging from
hormone—eg, oestrogen administration).
the genetic literature with intriguing significant positive
DSM criteria were taken from the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental genetic correlations emerging between anorexia nervosa
disorders. DSM-IV-TR, Fourth Edition. Reprinted with permission from the Diagnostic and Statistical Manual of Mental and schizophrenia (rg=0·19)30 and between anorexia
Disorders, Fifth Edition (Copyright ©2013). American Psychiatric Association. All Rights Reserved.
nervosa and obsessive-compulsive disorder (rg=0·55).31
Table 1: Comparison of diagnostic criteria for anorexia nervosa according to DSM-IV versus DSM-5 These methods have taken us one step beyond reporting
the frequency with underlying mechanisms of co-
ICD-1011 ICD-11 (proposed criteria)* occurrence—in this case, by identifying shared genetic
factors.
A Weight loss, or in children a lack of weight A Significantly low bodyweight for the
gain, leading to a bodyweight of at least 15% individual’s height, age, and developmental Patients with anorexia nervosa display a broad variety
below the normal or expected weight for age stage (BMI less than 18·5 kg/m² in adults and of somatic complications in several organ systems
and height. BMI-for-age under fifth percentile in children (figure) across various stages of illness.32 In the acute
and adolescents) that is not due to another
health condition or to the unavailability of
state, patients with anorexia nervosa present with many
food. common complaints such as dizziness, fatigue, or even a
B The weight loss is self-induced by avoidance B Low bodyweight is accompanied by a syncope.33 In patients with a chronic course, almost every
of “fattening foods”. persistent pattern of behaviours to prevent organ system can be affected because of malnutrition or
restoration of normal weight, which may the presence of binge-eating and purging behaviour.34
include behaviours aimed at reducing energy
intake (restricted eating), purging behaviours Although changes in multiple endocrine axes are mostly
(eg, self-induced vomiting, misuse of adaptive (ie, to optimise energy expenditure),35 up to 21%
laxatives), and behaviours aimed at increasing of patients with anorexia nervosa have osteoporosis and
energy expenditure (eg, excessive exercise),
typically associated with a fear of weight gain.
more than 54% have osteopenia of the lumbar spine.36
C A self-perception of being too fat, with an C Low bodyweight or shape is central to the
Patients with anorexia nervosa have an increased life-
intrusive dread of fatness, which leads to a person’s self-evaluation or is inaccurately time prevalence of autoimmune disease, most
self-imposed low weight threshold. perceived to be normal or even excessive. prominently type 1 diabetes.37 Type 1 diabetes often
D A widespread endocrine disorder involving the D ·· precedes the onset of anorexia nervosa, is associated with
hypothalamic-pituitary-gonadal axis, insulin purging, poor glycaemic control, diabetic
manifest in the female as amenorrhoea, and
in the male as a loss of sexual interest and complications, and very high mortality.38 In children with
potency (an apparent exception is the paediatric acute-onset neuropsychiatric syndrome (PANS)
persistence of vaginal bleeds in anorexic or paediatric autoimmune neuropsychiatric disorder
women who are on replacement hormonal
therapy, most commonly taken as a
associated with streptococcal infections (PANDAS), food
contraceptive pill). restriction also occurs and has been deemed to be a variant
E Does not meet criteria A and B of bulimia E ·· of childhood onset anorexia nervosa.39
nervosa (F50.2).

ICD criteria have been taken from the WHO International Statistical Classification of Diseases.11 *Proposed ICD-11
Prognosis
criteria have been taken from ICD-11 Beta Draft. BMI=body-mass index. Regarding the core anorexia nervosa-psychopathology,
Steinhausen and colleagues21 analysed 119 studies covering
Table 2: Comparison of diagnostic criteria for anorexia nervosa according to ICD-10 versus ICD-11
5590 patients with anorexia nervosa and reported that
(proposed criteria)
59·6% of those patients showed a weight normalisation,

2 www.thelancet.com/psychiatry Published online October 27, 2015 http://dx.doi.org/10.1016/S2215-0366(15)00356-9


Review

accompanied by a normalisation of menstrual status in Neurocognition and social cognition For the ICD-11 Beta Draft see
57·0%, and a normalisation of eating behaviour in 46·8% Neurocognitive markers of anorexia nervosa include set http://apps.who.int/
classifications/icd11/browse/l-m/
of the whole group of patients with anorexia nervosa. In shifting difficulties (ie, difficulties switching between en
general, patients with an illness onset before their different tasks or task demands)47 and poor central
17th birthday achieve a better outcome than adult onset, coherence (ie, a preference for local [detail-focused] over
whereas prepubertal onset confers a worse course.40 Long- global [bigger picture] processing).48 These impairments
term follow-up studies8,21 have confirmed two broad have also been noted in unaffected sisters of people with
outcome groups with either a good outcome or chronic anorexia nervosa and to some extent persist after
course with a high risk of premature death. Regarding the recovery.49 Evidence suggests that both illness stage or
time course, several follow-up studies have shown that at duration and severity affect performance.50 People with
least in adult patients with full syndrome anorexia nervosa, anorexia nervosa also have difficulties in socio-emotional
time to complete remission is between 5 and 6 years.6 processing, showing attentional biases, impaired
In a meta-analysis41 of excess mortality in the 1990s, emotion recognition, regulation, and expressivity, and
anorexia nervosa was associated with the highest rate of poor theory of mind.51 These difficulties are present both
mortality among all mental disorders.41 Another meta- in the ill state and in muted form after recovery.
analysis7 showed a crude mortality rate (number of deaths Prospective longitudinal studies of children with a high
within the study population over a specified period) of familial risk of eating disorders suggest that some neuro-
5·1 deaths per 1000 person-years and the standardised cognitive and social cognitive vulnerabilities are present
mortality rate of 5·9 with a mean follow-up period of from an early age.52
14·2 years. Although most deaths due to anorexia nervosa
are a direct consequence of starvation-related medical Structural neuroimaging
complications, particularly cardiac complications and Patients with acute anorexia nervosa have been reported
severe infections, one in five deaths in patients with this to have global reductions in grey and white matter,
disorder results from suicide.9 Data for the course and increased cerebrospinal fluid and regional grey matter
outcome in male patients with anorexia nervosa are scarce; decreases in the left hypothalamus, and in reward-
however, an older age and lower BMI at admission, and a related regions of the basal ganglia and the
purging subtype of anorexia nervosa led to an increased somatosensory cortex.53 Studies in patients who
risk of death in male individuals with anorexia nervosa.42 recovered from anorexia nervosa and longitudinal
studies (before and after treatment) suggest that brain
Pathogenesis tissue abnormalities might recover with weight
Genetic factors regain.54,55 Many earlier structural studies have
Anorexia nervosa is strongly familial43 and heritability methodological limitations (eg, not correcting for age or
estimates range from 28% to 74%.44 Two genome-wide
association studies (GWAS),45,46 currently understood to be Organ systems or organ Pathological findings Leading systems
underpowered in view of the presumed genetic CNS Morphological and functional Cognitive deficits
architecture of anorexia nervosa, predictably did not detect cerebral changes; volume
reduction in cerebral grey
genome-wide significant loci. Boraska and colleagues45 and white matter
conducted sign tests to compare results from the discovery Dental system and Impaired dental status, Dental caries,
sample with those from the replication sample, and 76% parotis glands dental caries, increased enlargement of the
serum amylase parotid glands
of the results from the replication sample were in the
Endocrine system and Hypothalamus-pituritary- Amenorrhoea in women,
same direction as the discovery sample, a result highly reproductive function gonadal-axis, low T3 symptoms of
unlikely to be due to chance (p=4 × 10–⁶). This observation syndrome, hypercortisol on,
hypothyroidism , depression,
elevated stress levels
strongly suggests that true findings exist and that an
Cardiovascular system Hypotension, bradycardia, Syncope
increase of the sample size will yield significant results; arrhythmia
the field is currently accruing larger samples. A study30 Gastrointestinal tract Impaired gastric emptying, Constipation, ileus, upper
reported a significant negative genetic correlation between gastric dilation, gastro- gastrointestinal bleeding
anorexia nervosa and BMI and a significant positive duodenal ulcers

genetic correlation between anorexia nervosa and Haematological and Bone marrow hypoplasia, Anaemia, (bacterial)
immune system anaemia with reduced infections, compromised
schizophrenia, encouraging a deeper exploration of leucocytes and immune competence
metabolic factors in anorexia nervosa and a new genetic immunoglobulin
association between anorexia nervosa and schizophrenia. Renal tract Hypokalaemia, Nephrolithiasis, oedema,
hypophosphataemia, syncope
hypernatraemia
Neurobiological factors Bone Reduced bone density Bone fractures and
Most neurobiological studies have been done in currently (osteopenia) concomitant pain,
ill or recovered patients, thus abnormalities might result or osteoporosis spinal compression

from state-related consequences of malnourishment or


so-called scarring. Figure: Impaired organ function in anorexia nervosa

www.thelancet.com/psychiatry Published online October 27, 2015 http://dx.doi.org/10.1016/S2215-0366(15)00356-9 3


Review

overall brain volume, not taking anorexia Neurobiological models of anorexia nervosa
nervosa-subtype or comorbidities into account; results Based on these neuroimaging findings, and integrating
being confounded by effects of dehydration or additional evidence from studies on cerebrospinal fluid
starvation). A series of studies by Frank and colleagues56,57 (CSF) measures of metabolites, PET, and SPECT brain
addressing these limitations reported increased grey imaging studies, Kaye and colleagues61,62 suggest that
matter volume of the medial orbitofrontal cortex gyrus some childhood temperamental and personality traits,
in both adolescents and adults with anorexia nervosa, such as anxiety, obsessions, and perfectionism might
which persisted into recovery. Similar changes were reflect neurobiological risk factors for the development
found in bulimia nervosa, whereas obese adults showed of anorexia nervosa. Restrictive eating thus might be a
reduced orbitofrontal cortex gyrus rectus volume. The means of reducing negative affect caused by imbalance
orbitofrontal cortex assesses quality and value of reward between serotoninergic (aversive or inhibitory) and
stimuli, such as food, and is implicated in regulating dopaminergic (reward) systems. Other neurobiologically
sensory-specific satiety. Additionally, participants with informed models of anorexia nervosa have highlighted
anorexia nervosa had increased right insula grey matter the role of stress, fear, and anxiety,63 the rewarding nature
compared with controls. The right anterior insula is of anorexia nervosa symptoms,64 and the subsequent
associated with self-recognition and interoceptive shift to compulsive or habitual behaviours65,66 as key
awareness. Longitudinal studies in at-risk populations factors in the persistence of the illness.
are needed to fully assess whether these changes are
biomarkers of the illness. Developmental factors
Several adverse experiences occurring around universal
Functional neuroimaging stages and transitions of development are associated
Studies using visual food cue models have found with an increased prevalence of anorexia nervosa. These
differences between anorexia nervosa and controls in developmental risk factors include adverse prenatal,
prefrontal areas and in limbic and paralimbic circuits, perinatal, and neonatal events, such as dysmaturity or
associated with salience and reward processes with some prematurity67,68 as well as feeding and sleeping difficulties
inconsistences between studies due to methodological in infancy.68 Throughout childhood, emerging personality
differences.58 Findings from studies56,57 using taste stimuli traits associated with anxiety, depression, perfectionism,
to assess neural processing of food reward show that and autism spectrum68 have been identified as risk
people who recovered from anorexia nervosa have a factors for anorexia nervosa. Puberty and adolescence are
reduced functional brain response to predictably given, characterised by profound changes, vulnerabilities, and
but an increased response to unpredictably given, sugar the transition to adulthood, and they represent the period
solutions with insula, striatum, or orbitofrontal cortex of first onset of anorexia nervosa. A possible explanation
response distinguishing anorexia nervosa from controls. for the crucial role of puberty for the onset of anorexia
The same authors, contrasted people with anorexia nervosa might lie in hormonal changes and
nervosa, bulimia nervosa, or obesity who underwent a dysregulations that interact with neurotransmitter
dopamine-related conditioning task (unexpected receipt functioning, brain maturity, and genetic factors.69
or omission of sweet taste) and found greater activation of
the ventral striatum, insula, and frontal cortex in patients Environmental factors
with anorexia nervosa than in healthy controls, but lower Female gender has consistently been shown to be a risk
activation in patients with bulimia nervosa and obesity, factor for anorexia nervosa.68 The increase of anorexia
suggesting that people with anorexia nervosa are highly nervosa in low-income and middle-income countries
sensitive to uncertainty (unpredictable reward). suggests that cultural transitions associated with
Neuroimaging studies of body-image disturbance in industrialisation, urbanisation, and globalisation might be
anorexia nervosa suggest that this is a multidimensional associated with environmental risk constellations for the
construct, with the posterior parietal network related to a development of anorexia nervosa.9 These constellations
perceptive component and the prefrontal cortex-insula- might include the adoption of the so-called western
amygdala network related to an affective component of lifestyle, including nutritional habits and thin ideal
body-image distortion in anorexia nervosa.59 internalisation. However, although body dissatisfaction
In summary, these symptom provocation models have has been identified as a risk factor for the development of
largely suggested aberrant functioning of subcortical any eating disorder,70 risk factors associated with thin ideal
regions promoting so-called bottom-up (stimulus-driven) internalisation and associated sociocultural pressures have
responses—ie, in parietal somatosensory regions, anxiety- not been confirmed for anorexia nervosa. Appraising the
related mesolimbic circuits, and reward-related regions potential influence of environmental factors, it has to be
(eg, striatum)—and in so-called top-down (evaluative) taken into account that the incidence of anorexia nervosa is
prefrontal regions implicated in executive control.60 These relatively low worldwide despite these pervasive
findings provide important pointers towards targets for sociocultural pressures to be thin.71 It is possible that these
neurobiologically informed treatments. western influences could simply increase the number of

4 www.thelancet.com/psychiatry Published online October 27, 2015 http://dx.doi.org/10.1016/S2215-0366(15)00356-9


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Essential Optional
Medical and psychiatric history Full examination Structured diagnostic interview (eg, SCID I and II, EDE)
Physical assessment BMI, heart rate, blood pressure, temperature In case of severe oedema: albumin, total protein, protein
electrophoresis
In patients with a long-term course: bone density (DEXA) scan
In case of seizures or differential diagnosis: EEG and neuroimaging (CT,
MRI)
In case of unclear thoracic pain or abdominal symptoms: chest
radiograph, abdominal ultrasound, gastroscopy
Blood profile Full blood count, blood sedimentation rate In severe anaemia: reticulocytes, iron, ferritin, transferring, vitamin B12
Biochemical profile Sodium, potassium, calcium, magnesium, In case of elevated creatinine: creatinine clearance
phosphate, creatinine, urea, liver enzyme profile, In case of low BMI (<12kg/m²) and in the early phase of nutritional
blood glucose rehabilitation: monitoring of sodium, potassium, phosphate (at least
weekly)
Cardiovascular assessment ECG In case of cardiovascular abnormalities: Holter ECG, echocardiography

SCID I and II=structured clinical interview for DSM axis I and II disorders. EDE=eating disorder examination interview. BMI=body-mass index. DEXA=dual-energy X-ray
absorptiometry. ECG=electrocardiograph.

Table 3: Investigations recommended at initial assessment, on admission, or at regular intervals over the course of refeeding

individuals who engage in behaviours such as strict dieting


or excessive exercise, which can then trigger eating Panel 1: Indicators of high medical risk and other reasons
disorders in genetically susceptible individuals. for considering inpatient treatment
Weight
Treatment • BMI <14 kg/m² or rapid weight loss (adults) or <75% of
Initial assessment and investigations expected bodyweight or rapid weight loss (adolescents)
Initial assessment of the patient with anorexia nervosa
includes an in-depth interview, a physical examination, Medical status
and investigations to establish severity and nature of • Heart rate <50 bpm
eating disorder symptoms and diagnosis, comorbid • Cardiac arrhythmia
psychological and physical symptoms, diagnoses and risk, • Postural tachycardia (increase >20 bpm)
past treatments, current motivation for treatment, and • Blood pressure <80/50 mm Hg
available supports. An early task is to build good rapport • Postural hypotension >20 mm Hg
with the patient, as they are often highly ambivalent about • QTc >450 ms
and fearful of treatment.72 Whenever possible, it is • Temperature <35·5°C
important to involve significant others (family, partners) • Hypokalaemia <3·0 mmol/L
in assessment and subsequent treatment. Table 3 • Neutropenia
summarises recommended physical investigations to be • Phosphate <0·5 mmol/L
done at assessment. We have also formulated indicators of Additional indicators
high risk, requiring rapid intensive specialist consultation • Severe bingeing and purging (eg, several times daily)
and intervention (panel 1). • Failure to respond to outpatient or daypatient treatment
• Severe psychiatric comorbidity
Pathways (levels) of care • Suicidality
A Finnish epidemiological study74 reported that about These indicators are only a guide and do not replace the need for individual
50% of people with anorexia nervosa in the community clinical judgement (adapted from Hay and colleagues, 2014,73 and Treasure
do not access treatment. Those who do engage in and colleagues, 20104). QTc=corrected QT.
treatment typically show varying degrees of ambivalence
about change.75 However, with treatment, at least 40% of
people with anorexia nervosa (and more in younger duration of <3 years) beyond which full recovery
samples) will make a full recovery.21 Additionally, access becomes much more difficult to achieve.77 Despite this
to care from a specialist service with expertise in anorexia critical window, there should not be therapeutic nihilism
nervosa might be associated with better outcomes.76 in those who develop severe and enduring anorexia
Thus it is important that health-care practitioners at nervosa and have a very high risk of disability or death.
all levels are competent to identify anorexia nervosa and Findings from a randomised trial of outpatient
that there is early access to secondary and tertiary levels psychotherapy15 supported the efficacy of modifying
of care. This early access is particularly important in psychological approaches in longstanding illness such
view of evidence that there is a critical window for that the focus shifts from weight regain and recovery to
effective intervention in the early stages of illness (ie, improved quality of life.

www.thelancet.com/psychiatry Published online October 27, 2015 http://dx.doi.org/10.1016/S2215-0366(15)00356-9 5


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psychotherapeutic interventions applied in randomised


Evidence Effect
(evidence level) trials since 2010.
First, the overall evidence base for the treatment of
Adolescent anorexia nervosa84
adolescent patients with anorexia nervosa is increasing.
Family-based treatment (FBT) Strong* +++ (1)
However, the number of empirically supported
Maudsley family therapy (MFT) Strong* +++ (1)
psychosocial treatments trials opposed to the number of
Family system therapy (FST) Moderate* ++ (2)
treatments for adolescent anorexia nervosa remains
Adolescent focused therapy (AFT) Moderate* ++ (2)
scarce. In total, 12 randomised trials (n=1060 patients)
Cognitive behavioural treatment (broad; CBT-b) Weak/moderate –/+ (4)
have compared different psychological treatments in
Cognitive behavioural treatment (enhanced; CBT-E) Moderate* + (4)
adolescent patients with the disorder (age <19 years).
Adult anorexia nervosa4,73,83 Lock84 concluded in a systematic review on psychological
Cognitive behavioural therapy (CBT) Weak + treatments in children and adolescents that there is clear
Cognitive behavioural therapy (enhanced; CBT-E) Moderate* ++ and growing evidence to support the efficacy of family
Behavioural therapies (BT) Weak –/+ treatment in adolescent anorexia nervosa compared with
Interpersonal psychotherapy (IPT) Weak + individually based approaches, and that there is evidence
Psychodynamic therapy (PT) Weak + that supports family-based treatment (FBT) with a focus
Cognitive analytic therapy (CAT) Weak + on eating disorder behaviour and weight gain as opposed
Focal psychodynamic psychotherapy Moderate* ++ to more general family processes.
Maudsley model of anorexia nervosa treatment for adults (MANTRA) Moderate* ++ Second, over the past 30 years, 12 randomised trials
Specialist supportive clinical management (SSCM) Moderate* + (+) (n=1157 patients) comparing different psychological
treatments in adult patients with anorexia nervosa (age
Evidence grades are weak, moderate, or strong. Effect grades are: – for no beneficial effect; -/+ for mixed result or still
inconsistent result; + for slight beneficial effect; +(+) for moderate beneficial effect; ++ for moderate and lasting >18 years) have been done in outpatient settings. Since the
beneficial effect (further improvement shown in follow-up); and +++ for strong beneficial effect (superiority 2010 review,4 several well designed and sufficiently
demonstrated in primary outcome of randomised trial). Evidence levels are: 1 for well established, 2 for probably powered treatment studies for adult patients with anorexia
efficious, and 4 for experimental. *At least one multicentre randomised trial or more than one randomised trial.
nervosa have been published, reporting substantial weight
Table 4: Behavioural treatments in adolescent and adult patients with anorexia nervosa gain and clear improvements of eating disorder and
general psychopathology at the end of treatment and at
Practice guidelines (eg, from the American Psychiatric follow-up.15,85–90 The largest of these trials (n=242) compared
Association,2 the German College for Psychosomatic three different first-line treatments: focal psychodynamic
Medicine,78 the National Institute for Health and Care psychotherapy (FPT), enhanced cognitive behaviour
Excellence,79 and the Royal Australian & New Zealand therapy (CBT-E), and an optimised treatment as usual,
College of Psychiatrist73) agree that most people with including psychotherapy as well as medical care by the
anorexia nervosa can be treated as outpatients but that family doctor.87 Weight gain was similar in all three groups.
day-patient and inpatient services are needed for those Considering a combined outcome (weight and eating
with more severe illness and those who do not improve disorder psychopathology), FPT proved advantageous in
with outpatient care. Brief inpatient care followed by terms of recovery at 12-month follow-up, whereas CBT-E
intensive outpatient care could achieve similar efficacy to was more effective with respect to speed of weight gain
that of longer hospital stays in adolescents,80 but there is and improvements in eating disorder psychopathology
a paucity of randomised trials to guide service use. than the other treatments. Results from one trial (n=56)91
In a multicentre randomised trial, Herpertz-Dahlmann showed that by the end of treatment, an intervention that
and colleagues81 reported that a stepped care approach combined supportive therapy with sound clinical
(day-patient treatment after short inpatient care) was management delivered by eating disorder specialists
equally effective and less costly than inpatient treatment (specialist supportive clinical management, SSCM) was
in patients with non-chronic adolescent anorexia nervosa superior to two specific psychotherapies (cognitive
at the end of treatment and at 1 year follow-up. behavioural therapy [CBT] and interpersonal psychotherapy
[IPT]). However, a long-term follow-up of this trial did not
Evidence-based psychological treatment in adolescent support the superiority of any treatment.92 Findings from
and adult patients another randomised trial15 (n=63) showed that patients
Based on comprehensive systematic reviews4,82,83 and with anorexia nervosa with severe and enduring course
complemented by well designed and sufficiently powered can make meaningful improvements with both CBT or
treatment studies, we have reported on the first-line SSCM.15 A novel anorexia nervosa-specific outpatient
behavioural treatments for adolescent and adult patients therapy (Maudsley model of anorexia nervosa therapy for
with anorexia nervosa separately (table 4) and have adults, MANTRA) has been compared against SSCM in
supplemented this by interventions for relapse two trials (n=214).85,86 Although overall outcome did not
prevention and aftercare as well as specific interventions differ between groups, patients preferred MANTRA to
for carers. Additionally, we have added information SSCM, and patients with a more severe illness had a
(panel 2) on the setting, structure, and content of greater weight gain in the MANTRA group than in the

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Review

Panel 2: Novel and effective psychological treatments in anorexia nervosa


Family-based treatment (FBT) therapeutic procedures. Individual tailoring of treatment arises
Family-based treatment is a three-phase treatment for adolescent from flexibility on how modules are combined and how much
patients with anorexia nervosa and their families over 16 1-h emphasis they are given. Nutrition and other symptom
sessions and a 9-month period (initially of 10 h during 6 months). management or behaviour change, information or advice is given
In the first phase, therapy is characterised by attempts to absolve if the patient is motivationally ready for this. Differences from
the parents from the responsibility of causing the disorder and by other treatments include that the model was developed specifically
complimenting them on the positive aspects of their parenting. for anorexia nervosa, it is based on biological and psychological
Families were encouraged to work out for themselves how best to research, and is tailored to characteristic temperamental traits in
help restore the weight of their child with anorexia nervosa. In this disorder. It is unique in its use of a patient workbook,
phase 2, parents were helped to transition eating and weight developed in co-production with patients and therapists. It is also
control back to the adolescent in an age-appropriate manner. The unique in its involvement of carers in both the model or
third phase focused on establishing a healthy relationship between formulation and the treatment. Separate carer materials based on
the adolescent and the parents. 24 1-h sessions were provided over the model are available (Schmidt and colleagues, 2015, appendix).
the 1-year period (Lock and colleagues, 2010 and Agras and
Enhanced cognitive behaviour therapy (CBT-E)
colleagues 2014; appendix).
According to Fairburn and colleagues CBT-E is the abbreviation for For more on CBT-E see http://
Specialist supportive clinical management (SSCM) “enhanced cognitive therapy”, and it refers to a “transdiagnostic” www.credo-oxford.com

This treatment should be delivered by therapists specialised in the personalised psychological treatment for eating disorders. It was
treatment of eating disorders and should provide a standardised developed as an outpatient treatment for adults but is an intensive
form of usual outpatient treatment. Patients with anorexia version for day patient and inpatient settings, and a version for
nervosa and a BMI of 15 kg/m² or lower receive up to younger people. As an outpatient therapy treatment CBT-E has
30 once-weekly individual therapy sessions and four monthly four stages and is available in a short (20 sessions) and longer
follow-up sessions. In those patients with a BMI >15kg/m² the version (40 sessions). In stage one, the focus is on gaining a mutual
number of sessions could be reduced to 20. It combines clinical understanding of the person’s eating problem and helping him or
management (ie, giving information, advice, and encouragement) her modify and stabilise their pattern of eating. In the brief second
with a supportive therapeutic style designed to build a positive stage progress is systematically reviewed and plans are made for
therapeutic relationship and to foster change. Therapy content the main body of treatment. Stage three focused on the processes
includes assessment, identification, and regular review of target that are maintaining the person’s eating problem (eg, addressing
symptoms; psychoeducation; monitoring of physical status; concerns about shape and eating). In the last stage the emphasis
establishment of a goal weight range; and nutritional education shifts onto the future. There is a focus on dealing with setbacks and
and advice. The aim is to help patients make a link between their maintaining the changes that have been obtained (Fairburn, 2008;
clinical symptoms and their abnormal eating behaviour and appendix).
weight, and to support patients in a gradual return to normal
Focal psychodynamic psychotherapy (FPT)
eating behaviour and weight. Additional therapy content is
The initial manualised treatment was designed as a 40 h
determined by the patient (McIntosh and colleagues 2006,
outpatient psychodynamic-oriented psychotherapy for
appendix).
moderately ill patients with anorexia nervosa (BMI >15 kg/m²).
Maudsley model of anorexia treatment for adults (MANTRA) At the beginning of focal psychodynamic therapy, the therapist
This treatment is an empirically based cognitive-interpersonal identifies psychodynamic relevant foci using a standardised
treatment, which proposes that four broad factors, linked to operationalised, psychodynamic diagnostic interview (OPD-II).
underlying obsessional and anxious (or avoidant) personality traits, The psychodynamic treatment manual can be divided roughly into
are central to the maintenance of anorexia nervosa. These are (1) a three treatment phases. The first phase focuses mainly on
thinking style characterised by inflexibility, excessive attention to therapeutic alliance, pro-anorectic behaviour and ego-syntonic
detail, and fear of making mistakes; (2) impairments in the beliefs (attitudes and behaviour viewed as acceptable), and
socio-emotional domain (eg, avoidance of emotional experience, self-esteem. In the second phase of treatment, main focus is placed
regulation, and expression); (3) positive beliefs about how on relevant relationships and the association between
anorexia nervosa helps the person in their life; and (4) unhelpful interpersonal relationships and eating (anorectic) behaviour. The
responses of close others (eg, overinvolvement, criticism, pertinent aspects of the final phase are the transfer to everyday life,
accommodation to symptoms). These factors are targeted in anticipation of treatment termination, and parting. Before every
treatment with the aim of improving weight, eating disorder and treatment session the patient’s weight is assessed and
other symptoms, and psychosocial adjustment. The treatment documented (Friederich and colleagues, 2014).
style is motivational. Treatment is centred around a patient-
This panel describes effective psychological treatments applied in randomised trials (table 4,
manual. This manual has core (eg, formulation) and optional including those treatment approaches shown the highest evidence and effectiveness for
modules (eg, module on building a so-called non-anorexic adolescents and adults and published as randomised trials since the 2010 review by Treasure
and colleagues 20104). For references see appendix.
identity). Treatment has a clear structure and hierarchy of

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Review

SSCM group. In summary, although the evidence base for literature that more, larger, and consistently positive
the treatment of adults with anorexia nervosa is advancing, trials of antipsychotics are needed before their use can be
thus far no specific approach has shown clear superiority. recommended.99,100
Across different individual psychotherapies for adults with There has been little advance in evidence for any other
anorexia nervosa there are common elements. These psychotropic medication in anorexia nervosa treatment
elements include a psychotherapeutic approach specific to since the review by Treasure and colleagues.4 Other drugs
and focused on anorexia nervosa in combination with a that are currently under investigation for a putative role
focus on weight regain and nutritional rehabilitation.73 in anorexia nervosa treatment are tumour necrosis factor,
Third, few studies have focused on relapse prevention dronabinol (a cannabinoid receptor agonist), and ghrelin
and aftercare in anorexia nervosa, and the little available agonists103 to promote appetite or antagonists to reduce
evidence suggests that patients who have a structured hyperactivity (for references on single trials see appendix).
intervention for relapse prevention—based on cognitive- These drugs do not have an evidence base for their use at
behavioural principles—after inpatient treatment have this stage.
fewer and later episodes of relapse in anorexia nervosa
during the first year after inpatient discharge than do Nutritional treatments
patients without a follow-up intervention.93–95 In moderately ill outpatients with anorexia nervosa,
Finally, in view of the burden of anorexia nervosa on nutritional counselling alone is not an adequate
families and partners, and evidence suggesting that carers’ treatment;94 however, dieticians are an important part of a
distress and behaviours might inadvertently maintain the multidisciplinary treatment team. Patients who are
illness, several randomised trials have also trialled substantially underweight and malnourished should be
interventions targeting carers of adults with anorexia admitted to a specialist inpatient or day-patient eating
nervosa. A new couple-based intervention for anorexia disorder unit for a combined programme of supervised
nervosa (Uniting Couples in the Treatment of Anorexia refeeding and anorexia nervosa-related psychotherapy.
Nervosa)96 also focuses on leveraging the support of close First, it is important to accurately assess nutritional and
others in the treatment of anorexia nervosa. These studies fluid intake and to document premorbid weight and the
show that carer outcomes (distress and unhelpful course of weight loss. Depending on the duration of
behaviours) can be improved and that this improvement in weight loss and malnutrition, age of the patient, somatic
turn might positively affect relationships with the patient comorbidity, and the severity of purging behaviour,
and patients’ clinical outcomes.97,98 recommended weight gain rates range from 500 g to
1400 g per week.73,79 Evidence exists that substantial
Pharmacological treatments weight gain is best achieved in inpatient settings,104
Systematic reviews consistently conclude that particularly in patients with increased somatic risk.
antidepressants neither improve weight gain99 nor reduce Refeeding syndrome is a serious and potentially fatal
eating disorder or other psychological symptoms in the medical complication, particularly during the early stages
re-feeding phase.99 The utility of antidepressants for of refeeding in those patients at the highest risk, who
relapse prevention in the post-weight restoration phase have been malnourished and emaciated for a long
remains uncertain.99 This mixed evidence is based on time.27,79 Due to a switch from fasting gluconeogenesis to
two trials, one smaller positive trial and a second larger carbohydrate-induced insulin release, there is a rapid
trial that tested the efficacy of adding fluoxetine to CBT intracellular uptake of potassium, phosphate, and
on post-weight restoration and found no added benefit in magnesium with the consequence of a rapid onset of
preventing relapse at 1 year (for references on single hypophosphataemia, hypomagnesia, and hypo-
See Online for appendix trials see appendix). A pooled meta-analysis of kalaemia.105 In accordance with the RANZP protocol
four placebo-controlled randomised trials on (2014),73 adult patients with anorexia nervosa should start
antidepressants (two on a tricyclic and two of fluoxetine) with a refeeding of 6000 kJ/day, increased by 2000 kJ/day
and a relapse prevention trial also failed to find a every 3 days, until an adequate intake to meet the
significant effect on weight gain.100 As a consequence, person’s needs for weight restoration is reached. As a
treatment guidelines73 are cautious in recommending consequence, particularly in the early phase of refeeding,
use even for comorbid features such as depression until electrolytes should be regularly monitored and this diet
it is established that these features are not due to the should be supplemented by phosphate at 500 mg twice
starvation state and remit with weight restoration. daily and thiamine at least 100 mg daily for the first week,
The review on eating disorders by Treasure and and thereafter as clinically indicated for people at high
colleagues4 reported emerging evidence for the use of risk of refeeding syndrome (eg, those with BMI <13).
olanzapine, an atypical antipsychotic in reducing illness Nutritional therapy includes supervised meals and, if
preoccupations and anxiety during refeeding. The necessary, additional high-protein oral liquid
inconsistent results and inability to achieve significance supplements. In severely emaciated patients at high
in pooled meta-analyses of placebo controlled trials for medical risk, nasogastric feeding, including professional
weight gain100–102 have led to a consensus in the medical and supportive supervision, could be indicated. On very

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Review

rare occasions and after failure of the above nutritional placebo-controlled randomised trial (n=14) of food
strategies, parenteral nutrition might be indicated. In exposure and D-cycloserine (DCS) in anorexia nervosa,
adolescent patients with a short duration of illness, a based on evidence that DCS enhances fear extinction
more rapid refeeding protocol can be applied. In during exposure therapy in anxiety disorders (for
principle, the least intrusive and most physiological references on single trials see appendix). DCS compared
normal method of nutrition should be applied.73 with placebo had no effect in any of the training or test
meals. One further randomised trial (n=32) compared
Osteoporosis prevention and treatment food exposure with CRT in weight-restored anorexia
The most efficient strategy to improve bone density is to nervosa and found greater test-meal consumption at end
restore weight and, in women, menstrual function. of treatment in the exposure treatment group.
Oestrogen-replacement therapy, primarily via transdermal Other promising psychobiological treatments include
application, only partially increases bone density in cognitive bias modification treatments,112 based on
adolescents.35 Oral oestrogen-progesterone combinations converging evidence suggesting a range of cognitive
are ineffective in increasing bone mineral density in biases (attention, memory) in relation to illness-relevant
adolescent and adult anorexia nervosa patients.106 Moreover, and emotional stimuli in anorexia nervosa. However,
neuroendocrine changes can have a direct effect on randomised trials are so far not available.
neurocognition and mood as well as on core eating
disorder psychopathology.35 Neurobiological treatments
Improved understanding of the neurocircuitry involved
Experimental treatments in anorexia nervosa113 has given rise to the use of
There is widespread agreement that new interventions neuromodulation treatments, such as deep brain
are needed to improve outcomes, especially in adults stimulation (DBS), repetitive transcranial current stimu-
with anorexia nervosa. Such interventions should target lation (rTMS), and transcranial direct current stimulation
specific disease mechanisms.107,108 We describe some of (tDCS), especially in severe and enduring anorexia
the more promising experimental treatments. nervosa. We identified two systematic reviews114,115
summarising cases studies and three further case studies
Psychobiological treatments describing use of these techniques (for references on
Cognitive remediation therapy (CRT) for anorexia single trials see appendix). As yet, no randomised trials
nervosa targets neuropsychological inefficiencies in of therapeutic use of neuromodulation treatments have
executive functioning, chiefly poor set-shifting and weak been published. Several cases studies or series of DBS
central coherence (extreme attention to detail at the (nucleus accumbens, ventral capsule or ventral striatum,
expense of the bigger picture). Two systematic reviews109,110 or subcallosal cingulate cortex) targeting anorexia
identified four small to medium sized nervosa symptomatology directly (n=12) or targeting
(n=32–82 participants) randomised trials of CRT (for obsessive-compulsive disorder or depression with
references on single trials see appendix). These studies parallel improvements in anorexia nervosa symptoms
varied in populations, intensity of CRT (8–30 sessions), (n=2) have been identified. These studies suggest that
comparison treatments (CBT, treatment as usual, DBS might have promise in highly selected severe and
exposure treatment, non-specific neurocognitive enduring cases. Likewise, rTMS (DLPFC) or tDCS
training), and primary outcomes (eating disorder (anodal, DLPFC) case studies (n=13) have shown promise
symptoms, test meal consumption, set-shifting, in enduring anorexia nervosa.
treatment dropout). Therefore no meta-analysis was
possible. Two studies found differential short-term Evidence-based prevention programmes
improvements in neurocognition for CRT versus Prevention efforts can be divided into universal, selective,
comparison treatment. One trial of CRT plus treatment and indicated, depending on whether they address the
as usual versus treatment as usual alone in inpatients general population or populations with increased risk
with either anorexia nervosa or bulimia nervosa found (eg, children of eating disordered mothers; elite athletes)
greater improvement in quality of life at end of treatment or those exhibiting early signs of a disorder. Eating
and greater improvement on eating disorders symptoms disorder prevention has focused on either risk factors
at 6 months follow-up in the group containing CRT than (eg, body dissatisfaction) or eating disorder pathology or
in the TAU alone group. These findings are promising caseness. A systematic review116 of eating disorders
but well designed large-scale studies of CRT are as yet prevention programmes for young people between the
not available. ages of 12 and 25 years identified six reviews and
Abnormalities in fear conditioning have been thought 46 universal prevention trials, with psychoeducation the
to be causally implicated in anorexia nervosa. In line most commonly tested intervention (26 trials).116 The
with this thought, exposure therapy (to food or body review also identified six reviews and 40 trials in at-risk
stimuli) might be another promising treatment for populations, where psychoeducation and cognitive
anorexia nervosa. One systematic review111 identified one dissonance programmes were equally common (12 each).

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Review

Meta-analyses of controlled trials from other reviews


Panel 3: Key unmet challenges in the management of anorexia nervosa were summarised as indicating that “prevention
Adolescents with anorexia nervosa programmes generally produce large effects on outcomes
• Which factors are essential to identify patients at risk and how could we address this related to eating disorder knowledge, and only small net
target group with adequate and effective prevention programmes? effects for other important prevention targets such as
• What are the predictors, moderators, and mediators of outcome in the treatment of reducing exhibited risk factors, changing attitudes, and
adolescent patients with anorexia nervosa? reducing eating pathology”.116 The review also found that
• What to do when family-based treatment is unsuccessful or inappropriate larger effect sizes are usually seen for studies of at-risk
(eg, if there is substantial intrafamilial abuse)? populations and interactive programmes using multi-
session formats.
Adults with anorexia nervosa Other systematic reviews117 have specifically examined
• How can we improve treatment outcomes–ie, what works and for whom and in what school-based interventions,118 e-health interventions, and
setting? the role of parental involvement119 in eating disorders and
• What is the best first-line outpatient treatment? body dissatisfaction prevention programmes for children
• What treatments should be used as second-line treatments? and adolescents, suggesting that these settings and ways of
• How important is it to involve family members and partners in treatment? delivery are fruitful avenues to explore in future studies.
• How can we prevent relapse after inpatient or day-patient treatment?
Across the age range Conclusions
• What brain circuits are involved in the onset and maintenance of anorexia nervosa? The past 5 years have seen substantial advances in the
• Which structures are implicated for which subtypes of anorexia nervosa? knowledge of anorexia nervosa. Recent treatment studies
• Are there imaging markers to identify treatment responders and non-responders? suggest that patients with anorexia nervosa have a
• In view of the typical age of onset of anorexia nervosa, does it make sense to have realistic chance of recovery, especially if treated early, or
separate adolescent and adult eating disorder services or should there be seamless at least, to achieve substantial improvement. However,
services across the ages? there is widespread agreement that several challenges
• How should treatment and treatment goals be adjusted for different stages of illness? remain in the management of anorexia nervosa (panel 3)
• What is an adequate course of treatment for anorexia nervosa? and new interventions are needed to improve outcomes,
• How should treatment resistance and palliative care be defined? especially in adults with the disorder. Such interventions
• How can we help the subgroup of patients with severe hyperactivity? should target specific disease mechanisms. The neuro-
psychological constructs introduced within the research
Treatment of comorbidities (psychiatric or physical) domain criteria (RDoC) matrix offer a new systematic
• How can we reduce mortality and suicide in individuals with anorexia nervosa? basis for determining the neural substrates underlying
• How can we help the subgroup of patients with severe psychiatric comorbidities? the biological predisposition to anorexia nervosa.120 A
• What is the treatment for patients suffering from comorbid post-traumatic stress clearer understanding of how anorexia nervosa behaviour
disorder, personality disorder, developmental disorders (eg, autism spectrum is encoded in neural circuits would provide a key for
disorder), and alcohol or substance misuse? developing more effective treatments. To conclude, we
• How can we help the subgroup of patients with a severe somatic comorbid disorder? still need to discover how to provide better, faster, and
• What is the treatment for patients with comorbidities such as diabetes mellitus or lasting improvements in the management of this
inflammatory bowel disease? enigmatic disorder.
• What is the optimum management of osteopenia and osteoporosis in anorexia
Contributors
nervosa? All authors contributed to the search and selection of the medical
• What is the treatment for patients with a comorbidity such as food-related allergy? literature and to the writing of the Review.
Declaration of interests
CB is a grant recipient from Shire Pharmaceuticals and an author for
Pearson and Walker. PH receives royalties or honoraria for works on
Search strategy and selection criteria eating disorders from BMJ Publishing House, Hogrefe & Huber, and
McGraw Hill.
We searched PubMed for articles published between Jan 1, 2010, and Dec 31, 2014,
Acknowledgments
covering the time period since the review by Treasure and colleagues,4 published in We thank the anonymous reviewers for their comments on early drafts
The Lancet. We combined the search term “anorexia nervosa” each with “chronicity”, of this Review.
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