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BMJ Clin Evid. 2011; 2011: 1011.
Published online 2011 April 11.
PMCID: PMC3275304

Anorexia nervosa

Kathleen Kara Fitzpatrick, Instructor of Psychiatry# and James Lock, Child and Adolescent Psychiatry#

Abstract

Introduction

Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and up to 0.7% of this age group may be affected. While most people with anorexia nervosa recover completely or partially, about 5% die of the condition, and 20% develop a chronic eating disorder. Young women with anorexia nervosa are at increased risk of bone fractures later in life.

Methods and outcomes

We conducted a systematic review, and aimed to answer the following clinical questions: What are the effects of treatments in anorexia nervosa? What are the effects of interventions to prevent or treat complications of anorexia nervosa? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: atypical antipsychotic drugs, benzodiazepines, cyproheptadine, inpatient/outpatient treatment setting, oestrogen treatment (HRT or oral contraceptives), older-generation antipsychotic drugs, psychotherapy, refeeding, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants.

Key Points

Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea.

  • Estimated prevalence is highest in teenage girls, and the condition may affect up to 0.7% of this group.
  • Anorexia nervosa is related to family, sociocultural, genetic, and other biological factors. Psychiatric and personality disorders such as depression, anxiety disorders, obsessive compulsive disorder, and perfectionism are commonly found in people who have anorexia nervosa.
  • Most people with anorexia nervosa recover completely or partially, but about 5% die from the condition and 20% develop a chronic eating disorder.
  • Young women with anorexia nervosa are at increased risk of fractures later in life.
  • Population assessment indicates that risks to fertility may be overstated in those who reach a healthy BMI, but children born to mothers who have recovered from anorexia nervosa seem to have lower birth weights.

There is no strong RCT evidence that any treatments work well for anorexia nervosa. However, there is a gradual accumulation of evidence suggesting that early intervention is effective. Increasing evidence suggests that working with the family may also interrupt the development of a persistent form of the illness, when this work begins early in the disease.

Evidence on the benefits of psychotherapy is unclear.

Refeeding is a necessary and effective component of treatment, but is not sufficient alone.

  • Very limited evidence from a quasi-experimental study suggests that a lenient approach to refeeding is as effective and more acceptable compared with a more strict approach.
  • Refeeding may be as effective in an outpatient setting as during hospital admission.
  • Nasogastric refeeding has been used to speed up weight gain in inpatient observational studies, although it is rarely studied in RCTs. Very limited RCT evidence suggests that adding nasogastric feeding to oral nutrition can increase weight gain and reduce relapse in the short term more than oral nutrition alone, but these gains are not maintained at 1 year post-discharge. Given ethical and medical concerns with tube feeding, this approach is encouraged with caution.
  • Nutritional supplements, including zinc, have only limited evidence for their effectiveness, and additional evaluations of these measures are warranted.

We don't know whether inpatient or outpatient treatment is more effective in people with anorexia nervosa.

Limited evidence from small RCTs has not shown significant weight gain from SSRIs or tricyclic antidepressants, some of which may cause serious adverse effects.

  • Tricyclic antidepressants may cause drowsiness, dry mouth, blurred vision, and a prolonged QT interval in people who have anorexia nervosa.
  • SSRIs have not been shown to be beneficial, but the evidence remains very limited; in the 4 RCTs we found, conclusions were limited because of small trial size and high rates of withdrawal.

Older-generation antipsychotic drugs may prolong the QT interval, increasing the risk of ventricular tachycardia, torsades de pointes, and sudden death.

  • Atypical antipsychotics have been evaluated for their potential role in reducing agitation and anxiety related to refeeding, as well as for potentially increasing appetite. Increasing observational data (case series) have suggested that they may decrease obsessiveness and agitation. However, further evidence from large, well-conducted RCTs is necessary to draw reliable conclusions.
  • Newer atypical antipsychotics, in particular olanzapine, do not seem to be associated with the same cardiac risks as older-generation antipsychotic drugs, but the known association between olanzapine and weight gain may impact compliance in people with anorexia nervosa. However, further research needs to be done.

We found insufficient RCT evidence assessing benzodiazepines or cyproheptadine for treating anorexia nervosa.

Oestrogen treatment has been hypothesised to reduce the negative effects on bone mineral density associated with anorexia nervosa. However, three small RCTs have failed to demonstrate clinically relevant changes in bone mineral density after treatment with oestrogen either HRT or oral contraceptives), and these results are supported by 2-year longitudinal data, which found similar lack of improvement.

About this condition

Definition

Anorexia nervosa is characterised by a refusal to maintain weight at or above a minimally normal weight (<85% of expected weight for age and height, or body mass index [BMI] <17.5 kg/m2), or a failure to show the expected weight gain during growth. There is also often an intense fear of gaining weight, preoccupation with weight, denial of current low weight and its adverse impact on health, and amenorrhoea. Two subtypes of anorexia nervosa, binge–purge and restricting, have been defined.

Incidence/ Prevalence

One population-based study using consultation data from the General Practitioner Database in the UK found a mean incidence for anorexia nervosa of 4/100,000 in people aged 10 to 39 years. One systematic review (5 studies) assessing prevalence in European people aged over 19 years found a 12-month prevalence of 0.2% to 0.7%. Little is known about the incidence or prevalence in Asia, South America, or Africa. Population studies on the incidence of anorexia nervosa among adult ethnic-minority populations in the USA have found a 12-month prevalence of 0.02% in Asian-Americans, 0.03% in Latinos, and 0.05% in African-American and Caribbean adults.

Aetiology/ Risk factors

Anorexia nervosa has been related to family, biological, social, and cultural factors. Studies have found that the condition is associated with a family history of anorexia nervosa (adjusted HR 11.4, 95% CI 1.1 to 89.0), bulimia nervosa (adjusted HR 3.5, 95% CI 1.1 to 14.0), depression, generalised anxiety disorder, obsessive compulsive disorder, or obsessive compulsive personality disorder (adjusted RR 3.6, 95% CI 1.6 to 8.0). A twin study suggested that anorexia nervosa may be related to genetic factors, but it was unable to estimate reliably how non-shared environmental factors contributed. Specific aspects of childhood temperament thought to be related include perfectionism, negative self-evaluation, and extreme compliance. Perinatal factors include prematurity, particularly if the baby was small for gestational age (prematurity: OR 3.2, 95% CI 1.6 to 6.2; prematurity and small for gestational age: OR 5.7, 95% CI 1.1 to 28.7). In a prospective cohort study (51 adolescents with the condition), people with anorexia nervosa were significantly more likely to have an affective disorder than were controls matched for sex, age, and school (lifetime risk of affective disorder 96% in people with anorexia nervosa v 23% in controls; ARI 73%, 95% CI 60% to 85%). It is unclear whether affective disorders precede anorexia nervosa or occur as a consequence of starvation. Similarly, obsessive compulsive disorder was significantly more likely to be present in people with anorexia nervosa compared with controls (30% in people with anorexia nervosa v 10% in controls; ARI 20%, 95% CI 10% to 41%). However, in two-thirds of people with obsessive compulsive disorder and anorexia nervosa, obsessive compulsive disorder preceded the anorexia nervosa.

Prognosis

One prospective study followed up 51 people with teenage-onset anorexia nervosa, about half of whom received no or minimal treatment (fewer than 8 sessions). After 10 years, 14/51 (27%) people had a persistent eating disorder, three (6%) had ongoing anorexia nervosa, and 6 (12%) had experienced a period of bulimia nervosa. About half of all participants in the study continued to have poor psychosocial functioning after 10 years (assessed using the Morgan Russell scale and Global Assessment of Functioning Scale). An extended follow-up RCT of 38 participants, who completed either separate or conjoint family therapy, found that 75% of people had no eating disorder symptoms at 5-year follow-up. It found that those people who had good to intermediate outcomes at the end of treatment were more likely to have good outcomes at the end of the 5-year follow-up. A summary of treatment studies (119 studies published between 1953 and 1999, 5590 people, length of follow-up 1–29 years) found that 47% of people recover completely from anorexia nervosa (range 0–92%), 34% improve (range 0–75%), 21% develop a chronic eating disorder (range 0–79%), and 5% die from the condition (range 0–22%). Favourable prognostic factors include an early age at onset, and a short interval between onset of symptoms and the beginning of treatment. Family criticism, in particular maternal criticism, seems to influence the outcome of treatment. Unfavourable prognostic factors include vomiting, profound weight loss, chronicity, psychiatric comorbidity, psychosocial problems, and a history of premorbid developmental or clinical abnormalities. In particular, psychiatric comorbidities represent significant negative outcomes, with one review of outcomes indicating increased risk for personality disorders (in particular avoidant, dependent, obsessive-compulsive, and passive-aggressive personality disorders), obsessive compulsive disorder, and depression. The all-cause standardised mortality ratio of eating disorders (anorexia nervosa and bulimia nervosa) has been estimated at 538, which is about three times higher than that of other psychiatric illnesses. In studies published between 1970 and 1996, the average annual mortality was 0.59% a year for females in 10 eating-disorder populations (1322 people), with a minimum follow-up of 6 years. Mortality was higher for people with lower weight and older age at presentation. Mortality by suicide represents a significant threat to people who have anorexia nervosa and is reported as the second most common cause of death in this population. A review of studies published on suicide and suicide attempts in people who have eating disorders found that suicide rates were markedly elevated compared with the general population: between 3% and 20% of the inpatient and outpatient groups assessed had attempted suicide at some point. The elevated rates of suicide attempts and death by suicide are present for those receiving both inpatient and outpatient treatment, and seem to exist independently of BMI at the time of death. Assessment of suicide risk remains a critical feature in the evaluation and treatment of people who have anorexia nervosa, particularly among those with comorbid psychiatric illnesses. Young women who have anorexia nervosa are also at an increased risk of fractures later in life. Clinicians often report difficulties with fertility, birth weight, and pregnancy complications for those with active anorexia nervosa as well as for those recovered from anorexia. However, a controlled community-based study comparing outcomes after 18 years in 48 women with adolescent-onset anorexia nervosa with outcomes in 48 matched comparison cases indicated similar rates of pregnancy and delivery (although none of those with active anorexia had become mothers), although birth weights in babies born to women with a history of anorexia were significantly lower (P = 0.03). Feeding difficulties were similar between groups.

Aims of intervention

To restore physical health (weight within the normal range and no sequelae of starvation [e.g., regular menstruation, normal bone mass]), as well as normal patterns of eating and attitudes towards weight and shape; to reduce any additional psychiatric comorbidities (e.g., depression, anxiety, obsessive compulsive disorder); to reduce the impact of extreme personality traits such as high sensitivity to threat, rigidity, and detail rather than global information processing style; and to reduce the impact of the illness on social functioning and quality of life.

Outcomes

Symptom improvement, including weight gain alone and global improvement; assessed most widely by the Morgan Russell scale, which considers nutritional status, menstrual function, mental state, and sexual and social adjustment. Biological outcome criteria alone, such as weight (BMI or in relation to matched population weight) and menstrual function, are also used (more infrequently) as outcome measures. Other validated outcome measures include eating-symptom measures. Bone mineral density is included as a proxy outcome for fracture risk. Adverse effects of treatment.RCTs do not usually have long enough follow-up periods to examine mortality.

Methods

Clinical Evidence search and appraisal April 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2010, Embase 1980 to April 2010, and The Cochrane Database of Systematic Reviews 2010, Issue 2 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, with any level of blinding, and containing >30 individuals, with any loss to follow-up allowed. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we did a search for observational studies of refeeding. We searched for prospective or retrospective cohort studies, case-control studies, and case series. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. We searched for RCTs and observational studies comparing each listed intervention with placebo, no treatment, usual care, or any other listed intervention, and included all RCTs of sufficient quality. We have reported various outcome measures used in included studies (see Outcomes section). However, none of these outcome definitions have systematic support for their utility in predicting long-term remission or recovery. The lack of a clear consensus in the field on defining remission and recovery limits the interpretation of all RCTs concerned with anorexia nervosa. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE Evaluation of interventions for Anorexia nervosa.

Glossary

Beck Depression Inventory
Standardised scale to assess depression. This instrument consists of 21 items to assess the intensity of depression. Each item is a list of 4 statements (rated 0, 1, 2, or 3), arranged in increasing severity, about a particular symptom of depression. The range of scores possible are 0 = least severe depression to 63 = most severe depression. It is recommended for people aged 13 to 80 years. Scores of more than 12 or 13 indicate the presence of depression.
Body mass index
Weight (kg) divided by height (m) squared.
Dietary counselling
An intervention in which dieticians with experience of eating disorders discuss diet, mood, and daily behaviours with patients.
Inpatient treatment
This has been regarded as the standard approach to the management of anorexia nervosa. One of the key components of inpatient treatment is refeeding, which is achieved through structured, supervised meals. Psychotherapy (of a variety of different types) and pharmacotherapy are included in many programmes.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Morgan Russell scale
A widely used measure of outcome for anorexia nervosa consisting of two scores: an average outcome score and a general outcome score (possible total of 12). The average outcome score is based on the outcome in 5 areas: nutritional status, menstrual function, mental state, sexual adjustment, and socioeconomic status.
Psychotherapy
Different types of psychological treatment given individually, in groups, or within the family are included here. These use psychodynamic, cognitive behavioural, or supportive techniques, or combinations of these. Family therapy includes members of the family of origin or the constituted family, and addresses the eating disorder as a problem of family life. Non-Specific Supportive Clinical Management (NSSCM), currently known as Specialist Supportive Clinical Management (SSCM), is a form of supportive treatment that uses some motivational elements to increase engagement. The focus is to return to normal weight and eating in the usual environment. It consists of three phases: orientation, agree target symptoms and goals; monitoring and support to achieve goals; and work on ending therapy and relationship.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Kathleen Kara Fitzpatrick, Stanford University, Stanford, USA.

James Lock, Stanford University, Stanford, USA.

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68. Claudino AM, Hay P, Lima MS, et al. Antidepressants for anorexia nervosa. In: The Cochrane Library, Issue 2, 2010. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005. [PubMed]
69. Attia E, Haiman C, Walsh BT, et al. Does fluoxetine augment the inpatient treatment of anorexia nervosa? Am J Psychiatry 1998;155:548–551. [PubMed]
70. Kaye WH, Nagata T, Weltzin TE, et al. Double-blind placebo-controlled administration of fluoxetine in restricting- and restricting–purging-type anorexia nervosa. Biol Psychiatry 2001;49:644–652. [PubMed]
71. Fassino S, Leombruni P, Daga G, et al. Efficacy of citalopram in anorexia nervosa: a pilot study. Eur Neuropsychopharmacol 2002;12:453–459. [PubMed]
72. Ackerman MJ. The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc 1998;73:250–269. [PubMed]
73. Becker A, Grinspoon SK, Klibanski A, et al. Current concepts: eating disorders. N Engl J Med 1999;340:1092–1098. [PubMed]
74. Yap Y, Camm J. Risk of torsades de pointes with non-cardiac drugs: doctors need to be aware that many drugs can cause QT prolongation. BMJ 2000;320:1158–1159. [PMC free article] [PubMed]
75. Sheridan DJ. Drug-induced proarrhythmic effects: assessment of changes in QT interval. Br J Clin Pharmacol 2000;50:297–302. [PMC free article] [PubMed]
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77. Dunican KC, DelDotto D. The role of olanzapine in the treatment of anorexia nervosa. Ann Pharmacother 2007;41:111–115. [PubMed]
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80. Bissada H, Tasca GA, Barber AM, et al. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2008;165:1281–1288. [PubMed]
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2011; 2011: 1011.
Published online 2011 April 11.

Refeeding

Summary

Refeeding is a necessary and effective component of treatment, but is not sufficient alone.

Very limited evidence from a quasi-experimental study suggests that a lenient approach to refeeding is as effective and is more acceptable compared with a more strict approach.

Refeeding may be as effective in an outpatient setting as during hospital admission.

Nasogastric refeeding has been used to speed up weight gain in inpatient observational studies, although it is rarely studied in RCTs. Very limited RCT evidence suggests that nasogastric feeling can increase weight gain and reduce relapse in the short term more than oral nutrition alone, but these gains are not maintained at 1 year post-discharge. Given ethical and medical concerns with tube feeding, this approach is encouraged with caution. Nasogastric feeding can lead to problems due to hypophosphataemia, although this did not occur in the RCT participants, perhaps because they all had a BMI of over 11 kg/m 2 .

Nutritional supplements, including zinc, have only limited evidence for their effectiveness, and additional evaluations of these measures are warranted.

Benefits and harms

Different approaches to encourage refeeding versus each other:

We found one open-label RCT comparing nasogastric refeeding plus oral refeeding versus oral refeeding alone. We found one quasi-experimental study. See further information on studies for full details of the quasi-experimental study.

Symptom improvement

Nasogastric feeding plus oral nutrition compared with oral nutrition alone Nasogastric feeding may be more effective at increasing weight gain at 2 months and time to relapse, but reductions in relapse may not be sustained at 1 year (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Weight gain

RCT
81 female inpatients with anorexia nervosa, mean BMI 12.1 kg/m2 in refeeding group, 12.8 kg/m2 in oral nutrition group Weight gain 2 months
+1.358 kg/week with nasogastric feeding (continuous enteral nutrition [CEN]) plus oral nutrition
0.882 kg/week with oral nutrition alone

P <0.01
Effect size not calculatedCEN plus oral nutrition

RCT
81 female inpatients with anorexia nervosa, mean BMI 12.1 kg/m2 in refeeding group, 12.8 kg/m2 in oral nutrition group Fat-free mass gain 2 months
+109 g/day (56% of body weight gain) with nasogastric feeding (CEN) plus oral nutrition
+61 g/day (49% of body weight gain) with oral nutrition alone

P <0.01
Effect size not calculatedCEN plus oral nutrition

RCT
81 female inpatients with anorexia nervosa, mean BMI 12.1 kg/m2 in refeeding group, 12.8 kg/m2 in oral nutrition group Time to relapse after discharge from hospital
34.3 weeks with nasogastric feeding (CEN) plus oral nutrition
26.8 weeks with oral nutrition alone

P <0.05
Effect size not calculatedCEN plus oral nutrition

RCT
81 female inpatients with anorexia nervosa, mean BMI 12.1 kg/m2 in refeeding group, 12.8 kg/m2 in oral nutrition group Relapse rates 1 year
44% with nasogastric feeding (CEN) plus oral nutrition
56% with oral nutrition alone
Absolute numbers not reported

Reported as non-significant, P value not reported
Not significant

Bone mineral density

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
81 female inpatients with anorexia nervosa, mean BMI 12.1 kg/m2 in refeeding group, 12.8 kg/m2 in oral nutrition group Adverse effects 2 months
with nasogastric feeding (CEN) plus oral nutrition
with oral nutrition alone
Absolute numbers not reported

The RCT reported adverse effects only in women receiving nasogastric feeding; see further information on studies for full details

Different approaches to nasogastric refeeding:

We found one retrospective chart review; see further information on studies for full details.

Zinc versus placebo:

We found two systematic reviews (search date 2005), which both identified the same RCT.

Symptom improvement

Zinc compared with placebo Zinc may be more effective at increasing the daily rate of weight gain in women with anorexia nervosa who have normal zinc levels before treatment (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Weight gain

RCT
54 women aged >15 years, mean BMI 15.8 kg/m2, mean duration of anorexia nervosa 3.7 years, admitted to 2 eating disorder units Daily rate of gain in BMI
0.079 kg/m2 with zinc (100 mg)
0.039 kg/m2 with placebo

P = 0.03
10 people in the zinc group and 9 in the placebo group did not complete the trial (35%); this analysis is based only on the people who completed the trial
Effect size not calculatedzinc

Bone mineral density

No data from the following reference on this outcome.

Total parenteral nutrition:

We found no observational studies of sufficient quality (see comment).

Calcium and associated supplements:

We found no observational studies of sufficient quality (see comment).

Further information on studies

The RCT excluded participants with a BMI of <11 kg/m2. The RCT reported higher energy intake in people receiving nasogastric feeding (continuous enteral nutrition) plus oral nutrition, with similar oral intake between groups, suggesting that higher rates of energy intake came strictly from nasogastric feeding. The authors also reported significantly higher intake rates in the week following discontinuation of tube feedings with weight loss beginning again thereafter. There were no deaths over the 1-year follow-up. Adverse effects associated with nasogastric feeding included two cases of gastro-oesophageal reflux requiring medication, two cases of sinusitis, and one moderate nasal bleeding episode. Refeeding syndrome, severe hypokalaemia, and hypophosphataemia were not observed, although the authors took care to not institute tube feeding until 3 to 5 days after admission to correct electrolyte imbalances evident upon admission.

This quasi-experimental study (65 consecutive inpatient admissions due to anorexia nervosa) found that a lenient, as opposed to strict, behavioural approach was more acceptable to staff and patients, and equally effective at encouraging refeeding. However, this study was not randomised, and the finding that this approach was more acceptable was by consensus and not tested statistically, so any conclusions should be made with caution.

This retrospective chart review (100 girls with anorexia nervosa, mean age 15.5 years) found that nasogastric feeding increased weight gain and decreased time taken to regain weight compared with oral refeeding. However, as the study was retrospective, participants were analysed according to the treatment that they had already received; thus, any conclusions should be made with caution. Of the nocturnal nasogastric refeeding group, 2/52 (4%) people required an anti-anxiety drug to relieve anxiety about tube placement, 3/52 (6%) removed their own tube, 6/52 (11%) had epistaxis, and 15/52 (29%) had nasal irritation. There were no reported cases of refeeding syndrome or aspiration pneumonia.

All but 3 of the women had normal zinc levels before treatment. Treatment was continued until each woman had gained 10% of her weight on admission on 2 consecutive weeks. The RCT found that none of the people taking zinc reported adverse effects.

Comment

A number of complications can occur during refeeding, particularly with nasogastric or intravenous methods. The so-called "refeeding syndrome" includes a range of electrolyte disturbances or gastrointestinal problems, such as acute gastric dilatation, or both. The most common, rapidly occurring problem is hypophosphataemia, which can cause cardiac and respiratory failure, delirium, and fits.

We have excluded evidence on any form of forced refeeding. We found one RCT comparing calcium plus vitamin D and etidronate versus placebo. However, for the comparison of interest (calcium plus vitamin D versus placebo), it included only 27 people. This is below Clinical Evidence reporting criteria for this review (at least 30 people), so we have not reported it further. People who have anorexia nervosa are at increased risk of bone fractures in later life, owing to decreased bone density. Restoration of weight alone does not seem to reverse bone loss, particularly when not accompanied by a return of menses. This has led to the exploration of supplement use to improve bone density, focusing on calcium and vitamin D, but also on bisphosphates associated with bone growth.

Clinical guide:

Refeeding is a necessary component of treatment but is not sufficient alone. The aim is for the person to increase the amount and variety of food consumed and to reintroduce meals as a source of shared, positive emotions. This can be achieved in the outpatient setting if there is a good alliance, especially in adolescent cases where parents can have support in order to provide the requisite care (the so-called Maudsley Model). However, a proportion of severe cases require more intensive care, such as that provided in inpatient settings. Guidelines on the nutritional management of anorexia nervosa have been produced. In some centres, the calorie deficit is made up with normal, albeit larger, meals or snacks, plus vitamin and mineral supplements. In other centres, liquid foods can be used to supplement or replace some or all of the meals. All of the studies on nutritional approaches are quasi-experimental and underpowered. Rarely is it necessary to resort to nasogastric feeding or percutaneous endoscopic gastrostomy. The legal and ethical considerations of these procedures and assisted feeding by a skilled nurse for severe treatment-resistant anorexia nervosa need to be addressed. To avoid hypophosphataemia, it is advisable to cover an increase in calorie intake with a general vitamin and mineral supplement and to ensure that there is adequate phosphate. The calorie content of the diet should start at approximately 50 kcal/kg and gradually increase. The use of supplements seems to vary widely, and clinical consensus on the use of vitamin and mineral supplementation to assist refeeding and manage the sequelae of malnourishment has not yet been established because of limited evidence. Weight-restoration levels are varied among treatment centres, but weight restoration to normal (rather than subnormal) BMI may be associated with a more positive outcome overall, leading to decreased purging, reductions in excessive exercise, and normalising of body image and cognitions about weight and shape, as well as to the improvements in weight and menses evaluated by the Morgan Russell criteria. Recent evaluations of refeeding that used biological markers such as hormone levels (typically oestradiol, leptin, and cortisol) as well as thyroid function tests indicate that these may be useful in exploring physiological recovery.

Substantive changes

Refeeding New evidence added. Categorisation unchanged (Likely to be beneficial by consensus).

2011; 2011: 1011.
Published online 2011 April 11.

Cyproheptadine

Summary

We found insufficient RCT evidence assessing cyproheptadine for treating anorexia nervosa.

Benefits and harms

Cyproheptadine versus placebo:

We found no systematic review but found two small RCTs.

Symptom improvement

Compared with placebo We don't know whether cyproheptadine is more effective at improving weight gain in women with anorexia nervosa who are in specialised inpatient units (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Weight gain

RCT
4-armed trial
81 women in 3 specialised inpatient units Mean weight gain 10 weeks
5.11 kg with cyproheptadine
4.32 kg with placebo

Reported as not significant
P value not reported
Not significant

RCT
3-armed trial
72 women, mean age 20.6 years, mean 77% of target weight, mean duration of anorexia nervosa 2.9 years, at 2 specialised inpatient units Mean days to target weight 6 weeks
36 days with cyproheptadine (up to a maximum of 32 mg)
45 days with placebo

P <0.05
Effect size not calculatedcyproheptadine

Bone mineral density

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
3-armed trial
72 women, mean age 20.6 years, mean 77% of target weight, mean duration of anorexia nervosa 2.9 years, at 2 specialised inpatient units Adverse effects
with cyproheptadine (up to a maximum of 32 mg)
with placebo
Absolute results not reported

No data from the following reference on this outcome.

Further information on studies

No results on the effect of behavioural therapy were reported. The RCT reported that no one withdrew from the study.

The authors adjusted for withdrawals by assigning a standard time to attainment of target weight of 120 days to all women who withdrew. It is not clear if women also received psychotherapy.

Comment

Both RCTs were of short duration.

Substantive changes

No new evidence

2011; 2011: 1011.
Published online 2011 April 11.

Inpatient versus outpatient treatment setting

Summary

We don't know whether inpatient or outpatient treatment is more effective in people with anorexia nervosa.

Benefits and harms

Inpatient versus outpatient treatment setting:

We found three systematic reviews (search dates 1999 and 2005 ), which assessed RCTs comparing inpatient treatment versus outpatient care. All three reviews identified the same single RCT. We also report results from 5-year follow-up of this trial. See further information on studies for assessment of methodological weaknesses of the trial. We also found one subsequent RCT.

Symptom improvement

Inpatient compared with outpatient treatment setting We don't know whether inpatient treatment, outpatient treatment (individual and group psychotherapy), outpatient psychotherapy, and assessment interview only differ in their effectiveness at improving mean weight gain or symptoms (measured by Morgan Russell scale global scores) at 1, 2, and 5 years, in women with anorexia nervosa who do not require an emergency intervention (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Global symptom improvement

RCT
4-armed trial
90 women referred with anorexia nervosa, mean age 22 years, weight loss 26% of matched population mean weight, mean duration of anorexia nervosa 3.2 years, and not requiring emergency intervention Proportion of participants with good outcome 2 years
5/29 (17%) with inpatient treatment
4/20 (20%) with outpatient treatment (individual and family therapy)
5/19 (26%) with outpatient psychotherapy treatment
2/20 (10%) with assessment interview

Significance not assessed

RCT
4-armed trial
90 women referred with anorexia nervosa, mean age 22 years, weight loss 26% of matched population mean weight, mean duration of anorexia nervosa 3.2 years, and not requiring emergency intervention
Further report of reference
Proportion of participants with good outcome 5 years
9/27 (33%) with inpatient treatment
8/17 (47%) with outpatient treatment (individual and family therapy)
10/19 (53%) with outpatient psychotherapy treatment
6/19 (32%) with assessment interview

Significance not assessed

RCT
3-armed trial
167 adolescents, 92% female, aged 12 to 18 years with anorexia nervosa Proportion of participants with good outcome 1 year
12/57 (21%) with inpatient treatment
8/55 (15%) with specialist outpatient treatment
10/55 (17%) with eating disorder general mental health outpatient treatment selected from general child and adolescent mental health service (CAMHS)

P = 0.22 among groups
Not significant

RCT
3-armed trial
167 adolescents, 92% female, aged 12 to 18 years with anorexia nervosa Proportion of participants with good outcome 2 years
20/57 (36%) with inpatient treatment
13/55 (24%) with specialist outpatient treatment
10/55 (17%) with eating disorder general mental health outpatient treatment selected from general CAMHS

P = 0.89 among groups
Not significant

Bone mineral density

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

The review identified numerous case series, from which it was unable to draw meaningful conclusions because of considerable variation in participant characteristics, treatments, mortality, and outcomes. For example, people admitted for inpatient treatment in the case series had a lower mean weight than those treated as outpatients.

Assessors were not blind to treatment allocation. Difficulties with acceptance of randomised treatment allocation led to more people being assigned to inpatient treatment than to the other interventions, which may have compromised the randomisation of the trial. Adherence to allocated treatment (defined as accepting allocation and at least one attendance at a group or individual treatment session) was significantly higher with outpatient than with inpatient treatment (adherence rates: inpatient treatment 18/30 [60%], outpatient treatment [individual and family therapy] 18/20 [90%], outpatient treatment [group psychotherapy] 17/20 [85%], and assessment interview only 20/20 [100%]; RR for failure to adhere with inpatient v outpatient treatment 1.5, 95% CI 1.1 to 2.0). Average continuation with treatment also varied among groups (mean attendance: 20 weeks' inpatient treatment, 9 outpatient sessions, and 5 group sessions). In the assessment interview only group, 6 people had no treatment of any kind in the first year and the others had treatment elsewhere (6 had inpatient treatment, 5 had outpatient hospital treatment, and 3 had at least weekly contact with their general practitioners). Six people in this group spent almost the entire year in treatment. One person died from anorexia nervosa between the assessment and the start of outpatient group treatment, and one of the people allocated to inpatient treatment died from anorexia nervosa within 5 years.

The RCT found that adherence to randomised treatment type was 65%, but this was different across groups, with inpatient adherence at 49%, specialist outpatient treatment adherence at 74%, and general child and adolescent mental health service treatment adherence at 69%. In assessing outcome based on adherence, the findings indicated that those who fully adhered to treatment in the outpatient arms had better outcomes compared with non-adherents or those who changed, suggesting that length of treatment and adherence to the regimen may be of importance in determining outcomes in outpatients. The authors explored the effects of the low adherence to inpatient treatment by assessing outcomes in those who were admitted (adherents) compared with those who subsequently refused admission and continued with outpatient treatment. It found that, at 1 year, those refusing admission were doing significantly better than adherents as assessed by the Morgan Russell criteria (mean difference 2.0, 95% CI 0.8 to 3.2, P = 0.001), measures of psychopathology, and mood, despite these outcomes being similar in both groups at baseline. Assessing adherence to treatment and admission to hospital over the 2-year follow-up period confirmed the earlier findings that those who were adherent to treatment had improved outcomes compared with those who were non-adherent in the outpatient settings, but those refusing admission to hospital (inpatient treatment) made further gains to those who were admitted. This was true even for adolescents randomised to outpatient treatment who were subsequently admitted to hospital. Given the much higher costs of inpatient treatment, the authors of this trial concluded that outpatient treatment protocols were superior to inpatient treatment protocols. At 2 years, all groups made further progress towards good outcomes (33% of entire group), but 27% still met criteria for anorexia nervosa. There were no deaths.

Comment

Clinical guide:

One prospective longitudinal study (355 people with anorexia nervosa, 169 of whom had bulimic-type anorexia nervosa; mean age 25 years; mean duration of illness 5.7 years; 75% available for 2.5-year follow-up) found that people with a longer duration of illness had a better chance of good outcome with longer duration of inpatient treatment. People with a shorter duration of illness had a higher likelihood of good outcome with briefer inpatient treatment. The median duration of inpatient treatment was 11.6 weeks for anorexia nervosa and 10.6 weeks for bulimic-type anorexia nervosa. Another prospective observational study (57 female adolescents in an inpatient unit, mean age around 16 years) assessed consecutive admissions for an average length of stay of 12.5 weeks and reported general outcomes at 1-year follow-up: 9% of the adolescents had full recovery, 19% had good outcomes, 9% had intermediate outcomes, and 60% had poor outcomes (3% were lost to follow-up). Good outcome was defined as weight within 15% of the average weight range and regular menstrual cycles; intermediate outcome was defined as not being able to consistently maintain weight within 15% of the average weight range and menstrual disturbances; and poor outcome was defined as body weight below 85% of the average, absent or nearly always absent menstruation, and signs of bulimia nervosa. Unlike previous studies, this study suggested that BMI at the outset of treatment, psychiatric comorbidity, and purging behaviours influenced outcome, whereas BMI at discharge, duration of eating disorder, and age at onset of illness did not. Further evaluation of inpatient treatment programmes and elements of inpatient treatment that lead to improved outcomes are necessary for further exploration.

Substantive changes

Inpatient versus outpatient treatment setting New evidence added. Categorisation unchanged (Unknown effectiveness), as it remains unclear how these settings compare.

2011; 2011: 1011.
Published online 2011 April 11.

Psychotherapy

Summary

Evidence on the benefits of psychotherapy is unclear and many of the trials we found had weak methods and the range of psychotherapeutic options assessed has led to conflicting results across trials.

Benefits and harms

Psychotherapy versus treatment as usual or dietary counselling:

We found 4 systematic reviews (search dates 2003, 2005, and 2008), which between them identified 6, mainly small, RCTs (263 people). The reviews did not conduct a meta-analysis, and only 4 of the identified RCTs met our inclusion criteria. The RCTs were of limited quality, and compared different types of psychotherapy versus treatment as usual or versus dietary counselling. One RCT did not report a between-group analysis (see further information on studies). All RCTs were carried out in an outpatient setting in people with either late age-onset anorexia nervosa or long duration of illness, or both.

Symptom improvement

Compared with treatment as usual or dietary counselling We don't know whether psychotherapy is more effective than treatment as usual or dietary counselling at improving outcomes (including "significant improvement" or "good outcome" on Morgan Russell scale score, mean body weight, "full recovery", or resumption of menses) in women with late-age-onset anorexia nervosa, a long duration of illness, or both (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Global symptom improvement

RCT
4-armed trial
84 people with mean age 26.3 years, 2 males, mean BMI 15.4 kg/m2, mean duration of anorexia nervosa 6.3 years Proportion of people recovered or "significantly improved" on Morgan Russell scale 1 year
7/21 (33%) with focal analytical therapy
8/22 (36%) with family therapy
6/22 (27%) with cognitive analytical therapy
1/19 (5%) with treatment as usual

Focal analytical therapy and family therapy were reported to be significantly more effective than usual care. However, the difference between cognitive analytical therapy and usual care was not significant

RCT
30 people with mean age 19.5 years, mean 27% below predicted weight, mean duration of anorexia nervosa 2.25 years Mean Morgan Russell score 1 year
8.8 with psychotherapy (12 sessions)
7.8 with dietary counselling (12 sessions)

Reported as not significant
P value not reported
Not significant

RCT
4-armed trial
33 people with mean age of 25 years, mean BMI 15.5 kg/m2, mean duration of anorexia 7 years Good outcome on Morgan Russell scale 1 year
8/18 (44%) with CBT (50 sessions)
1/15 (7%) with dietary advice (50 sessions)

P <0.02
Effect size not calculatedpsychotherapy

RCT
4-armed trial
33 people with mean age 25 years, mean BMI 15.5 kg/m2, mean duration of anorexia 7 years Full recovery 1 year
3/18 (17%) with CBT (50 sessions)
0/15 (0%) with dietary advice (50 sessions)

P <0.10
Not significant
Weight gain

RCT
4-armed trial
84 people with mean age 26.3 years, 2 males, mean BMI 15.4 kg/m2, mean duration of anorexia nervosa 6.3 years Weight gain 1 year
with focal analytical therapy
with family therapy
with cognitive analytical therapy
with treatment as usual
Absolute results not reported

P = 0.03 for focal analytical therapy v treatment as usual
P = 0.05 for family therapy v treatment as usual
P value not reported for cognitive analytical therapy v treatment as usual
Effect size not calculated

RCT
30 people, mean age 19.5 years, mean 27% below predicted weight, mean duration of anorexia nervosa 2.25 years Mean body weight
45.1 kg with psychotherapy (12 sessions)
46.0 kg with dietary counselling (12 sessions)

Reported as not significant
P value not reported
Not significant
Menstruation

RCT
30 people, mean age 19.5 years, mean 27% below predicted weight, mean duration of anorexia nervosa 2.25 years Return to menses
with psychotherapy (12 sessions)
with dietary counselling (12 sessions)
Absolute results not reported

Reported as not significant
P value not reported
Not significant

No data from the following reference on this outcome.

Bone mineral density

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Psychotherapy versus fluoxetine and versus combined psychotherapy plus fluoxetine:

We found two RCTs. The first RCT was unable to assess clinical outcomes owing to high withdrawal rates, particularly in people receiving drug treatment. Therefore, it assessed the acceptability of treatment; see further information on studies. The second RCT, which is reported below, also conducted a non-randomised follow-up of maintenance treatment; see further information on studies for the follow-up data.

Symptom improvement

Psychotherapy compared with fluoxetine or combined psychotherapy plus fluoxetine We don't know how CBT plus placebo compares with fluoxetine or CBT plus fluoxetine at improving symptoms or increasing time to relapse in women with anorexia nervosa who had previously successfully completed treatment in an inpatient or day programme setting (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Weight gain

RCT
4-armed trial
93 women, mean age 23 years, recruited from inpatient treatment; all had fulfilled DSM criteria for anorexia nervosa within the past year; all had BMI of at least 19.0 kg/m2 Increase in BMI
with CBT plus placebo
with fluoxetine plus CBT
Absolute results not reported

Reported as not significant
P value not reported

No data from the following reference on this outcome.

Bone mineral density

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Different types of psychotherapy versus each other:

We found 4 systematic reviews (search dates 2003, 2005, and 2008), which between them identified 11 RCTs (published in 10 papers) comparing different types of psychotherapy. Only 7 (8 publications) of the identified RCTs met our inclusion criteria. We also found one additional RCT and one subsequent RCT. Six of these RCTs were undertaken in an outpatient setting in people with an early age of onset (mean <18 years) and short duration of illness (mean 1 year or more). Two of the RCTs were carried out in an outpatient setting in people with a later age (mean >18 years) of onset, a longer duration of illness (mean between 2 and 6 years), or both. One RCT, published in two papers, included people with early- and late-onset anorexia nervosa and with long and short duration of illness.

Symptom improvement

Different types of psychotherapy versus each other We don't know whether any one type of psychotherapy is more effective than the others at improving outcomes in women with anorexia nervosa (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Global symptom improvement

RCT
4-armed trial
84 people, mean age 26.3 years, included 2 males, mean BMI 15.4 kg/m2, mean duration of anorexia nervosa 6.3 years Proportion of people recovered or "significantly improved" on Morgan Russell scale 1 year
7/21 (33%) with focal analytical therapy
8/22 (36%) with family therapy
6/22 (27%) with cognitive analytical therapy

Difference among groups reported as not significant
P value not reported
Not significant

RCT
40 people, mean age 15.5 years, 1 male, mean weight 74% of predicted, mean duration of anorexia nervosa 1.1 years Average improvement in Morgan Russell rating scale 1 year
3.1 with conjoint family therapy
2.5 with separated family therapy

P = 0.23
Not significant

RCT
30 people, mean age 25.1 years, included 1 male, mean BMI 15.2 kg/m2, mean duration of anorexia nervosa 4.7 years Average Morgan Russell score 1 year
6.4 with educational behavioural therapy (20 sessions)
7.3 with cognitive analytical therapy (20 sessions)

Reported as not significant
P value not reported
Not significant

RCT
Subgroup 1: 21 people, mean age 16.6 years, mean weight at admission 66% of average body weight (ABW), mean duration of anorexia nervosa 1.2 years
Subgroup analysis
Proportion of people in with good outcome on Morgan Russell scale 1 year
6/10 (60%) with family therapy
1/11 (9%) with individual therapy

RR 7.2
95% CI 1.03 to 50.3
Large effect sizefamily therapy

RCT
Subgroup 1: 21 people, mean age 16.6 years, mean weight at admission 66% of ABW, mean duration of anorexia nervosa 1.2 years
Subgroup analysis
Proportion of people in with good outcome on Morgan Russell scale 5 years
9/10 (90%) with family therapy
4/11 (36%) with individual therapy

RR 2.25
95% CI 1.02 to 4.94
Moderate effect sizefamily therapy

RCT
Subgroup 2: age at onset 18 years or below and duration >3 years, mean age 20.6 years, mean weight 66% of ABW, mean duration of anorexia nervosa 5.9 years
Subgroup analysis
Proportion of people with good outcome on Morgan Russell scale 1 and 5 years
with family therapy
with individual therapy
Absolute results not reported

Reported as not significant at both time frames
P value not reported for any between-group comparisons

RCT
Subgroup 3: age at onset >19 years, mean age 27.7 years, mean weight at admission 63% of ABW, mean duration of anorexia nervosa 3 years
Subgroup analysis
Proportion of people with good outcome on Morgan Russell scale 1 and 5 years
with family therapy
with individual therapy
Absolute results not reported

Reported as not significant at both time frames
P value not reported

RCT
56 people aged 17 to 40 years, mean BMI 17.1 kg/m2, mean duration of anorexia nervosa <5 years, includes people with EDNOS-AN subtype (i.e., people who did not fulfil amenorrhoea criteria or have a BMI of <17.5 kg/m2) Proportion of people rated as having a good outcome (score of 1 or 2 on a non-validated scale from 1–4) 1 year
9/16 (56%) with non-specific supportive clinical management (NSSCM)
2/21 (10%) with interpersonal therapy (IPT)
6/19 (32%) with CBT

NSSCM v IPT: reported as significant
NSSCM v CBT: reported as not significant
P value not reported for IPT v CBT

RCT
33 people, mean age 14 years, mean weight 73% of expected, mean duration of anorexia nervosa 1.1 year Global clinical score 2 years
8.5 with body-awareness therapy plus family therapy (25 sessions)
8.9 with family therapy alone (25 sessions)

Reported as not significant
P value not reported
Not significant

RCT
20 adolescents aged 12 to 16 years (95% with anorexia nervosa for <1 year) and their families Proportion of girls with good outcome on the Morgan Russell scale 6 weeks after initial meeting with family
5/10 (50%) with Maudsley family therapy alone
4/10 (40%) with Maudsley family therapy plus single session of parent-to-parent consultation

Reported as not significant
P value not reported
Not significant
Weight gain

RCT
40 people, mean age 15.5 years, 1 male, mean weight 74% of predicted, mean duration of anorexia nervosa 1.1 years Mean weight gain 1 year
6.4 kg with conjoint family therapy
9.8 kg with separated family therapy

P = 0.09
Not significant

RCT
41 women, mean age 14.1 years, mean BMI 15.9 kg/m2, duration of anorexia nervosa <1 year Proportion at target weight 2.5 years
80% with behavioural family systems therapy
69% with ego-orientated individual therapy

Reported as not significant
P value not reported
Not significant

RCT
30 people, mean age 25.1 years, included 1 male, mean BMI 15.2 kg/m2, mean duration of anorexia nervosa 4.7 years Mean weight gain 1 year
6.7 kg with educational behavioural therapy (20 sessions)
6.9 kg with cognitive analytical therapy (20 sessions)

Reported as not significant
P value not reported
Not significant

RCT
86 children and adolescents aged 12 to 18 years, mean age 15 years, mean duration of anorexia nervosa 12 months, BMI 17 kg/m2 at randomisation and 16 kg/m2 when first identified (30% were hospitalised before randomisation with mean BMI of 16 kg/m2)
Subgroup analysis
Weight 1 year
51 kg with short-term family therapy
53 kg with long-term family therapy

Reported as not significant
P value not reported
Not significant

RCT
86 children and adolescents aged 12 to 18 years, mean age 15 years, mean duration of anorexia nervosa 12 months, BMI 17 kg/m2 at randomisation and 16 kg/m2 when first identified (30% were hospitalised before randomisation with mean BMI of 16 kg/m2)
Subgroup analysis
BMI 1 year
19.0 kg/m2 with short-term family therapy
19.5 kg/m2 with long-term family therapy

Reported as not significant
P value not reported
Not significant

RCT
56 people aged 17 to 40 years, mean BMI 17.1 kg/m2, mean duration of anorexia nervosa <5 years, includes people with EDNOS-AN subtype (i.e., people who did not fulfil amenorrhoea criteria or have a BMI of <17.5 kg/m2) Weight 1 year
50.4 kg with non-specific supportive clinical management
49.0 kg with interpersonal therapy
48.6 kg with CBT

Significance not assessed

RCT
56 people aged 17 to 40 years, mean BMI 17.1 kg/m2, mean duration of anorexia nervosa <5 years, includes people with EDNOS-AN subtype (i.e., people who did not fulfil amenorrhoea criteria or have a BMI of <17.5 kg/m2) BMI 1 year
18.8 kg/m2 with non-specific supportive clinical management
18.1 kg/m2 with interpersonal therapy
18.1 kg/m2 with CBT

Significance not assessed

RCT
20 adolescents aged 12 to 16 years (95% with anorexia nervosa for <1 year) and their families Rate of weight gain
with Maudsley family therapy alone
with Maudsley family therapy plus single session of parent-to-parent consultation

The RCT reported that there was "a small but significant increase in the rate of weight restoration" in adolescents of parents who received parent-to-parent consultation but reported no further data
Effect size not calculatedMaudsley family therapy plus single session of parent-to-parent consultation
Menstruation

RCT
41 women, mean age 14.1 years, mean BMI 15.9 kg/m2, duration of anorexia nervosa <1 year Proportion of women menstruating 2.5 years
93% with behavioural family systems therapy
80% with ego-orientated individual therapy
Absolute numbers not reported

Reported as not significant
P value not reported
Not significant
Mental state

RCT
41 women, mean age 14.1 years, mean BMI 15.9 kg/m2, duration of anorexia nervosa <1 year Eating attitudes 2.5 years
with behavioural family systems therapy
with ego-orientated individual therapy
Absolute results not reported

Reported as not significant
P value not reported
Not significant

RCT
41 women, mean age 14.1 years, mean BMI 15.9 kg/m2, duration of anorexia nervosa <1 year Depression 2.5 years
with behavioural family systems therapy
with ego-orientated individual therapy
Absolute results not reported

Reported as not significant
P value not reported
Not significant

Bone mineral density

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

The RCT excluded people with BMI <12 kg/m2. The RCT reported that 4/84 (5%) failed to take up treatment and that 54/84 (64%) completed the full course of treatment (focal analytical therapy, 12; family therapy, 16; cognitive analytical therapy, 13; treatment as usual, 13). Of the 84 people enrolled, 12 (14%) required admission during the course of treatment (focal analytical therapy, 2; family therapy, 3; cognitive analytical therapy, 2; treatment as usual, 5). One person died in the treatment as usual group.

The RCT reported that no one failed to take up treatment. Follow-up was 14/15 (93%) in the psychotherapy group (1 finished early with good outcome) and 11/15 (73%) in the dietary counselling group. As soon as treatment ended, one person from the psychotherapy group and two people from the dietary counselling group were admitted because of very low weight.

The RCT compared CBT versus dietary counselling (at a ratio of 3:1). It found a significant improvement from baseline for CBT but did not report a between-group analysis. At 6 months, 23/25 (92%) allocated to CBT were still engaged in treatment, whereas all 10 people allocated to dietary counselling had either not taken up or had withdrawn from treatment and refused release of their results, making it impossible to compare the two groups. Dietary counselling involved encouragement towards healthy diet plus regular monitoring of weight plus physical status.

The RCT assessed the effects of 50 sessions of either CBT or dietary advice over 1 year. "Full recovery" was defined as "good outcome" on the Morgan Russell scale plus comparable eating attitudes to those of women with anorexia nervosa and no bingeing or purging.

The RCT (122 people) compared CBT (37 sessions) versus fluoxetine 60 mg versus CBT plus fluoxetine. The RCT was unable to assess clinical outcomes owing to high withdrawal rates (77/122 [63%], with 33/122 [27%] withdrawing in the first 5 weeks). Withdrawal rates were particularly high in the group receiving drug treatment alone (30/41 [73%]). All people included had 18 15-minute sessions of medical management: medical management involved questioning about adverse effects of drugs, difficulties with compliance, and their general health, as well as providing information about their treatment compared with CBT alone, fluoxetine alone, and combined treatment.

The RCT found no significant difference in time to relapse following weight restoration between fluoxetine plus CBT and placebo plus CBT (HR 1.12, 95% CI 0.65 to 2.01; P = 0.64). As with other studies in adults who have anorexia nervosa, attrition rates were high (53/93 [57%] of those randomised terminated treatment prematurely), which makes drawing definitive conclusions problematic. The authors concluded that the evidence suggests the need to explore other types of treatment both to achieve and maintain weight restoration. In a non-randomised follow-up of maintenance treatment following this RCT, a subset of 46 participants who completed the RCT (50 sessions of CBT plus fluoxetine) were compared with 42 people engaging in treatment as usual in order to assess the role of CBT following weight restoration on time to relapse. Like the RCT, this study also had relatively high withdrawal rates from both groups, although withdrawal rates were not significantly different between groups (20/46 [43%] with CBT v 12/42 [29%] with treatment as usual; P = 0.57). When relapse was defined (either a BMI <17.5 kg/m2 for 3 months, binge eating and purging behaviours regularly for 3 months, or both), the study found that CBT was significantly more effective than treatment as usual in lengthening time to relapse (P = 0.007, absolute results presented graphically). This translated into 65% of people receiving CBT and 34% receiving treatment as usual remaining relapse-free at 1 year (significance not assessed).

Three of the initial eligible families refused to participate; 4 withdrew within the first 3 months; 29 completed 12 months of treatment. Four (10%) people were admitted to hospital (1 in the separated family therapy group and 3 in the conjoint family therapy group) for 2.0 to 5.5 months. A mean of 12 sessions of treatment was given.

16/41 (39%) women were admitted for inpatient treatment.

The RCT excluded people with severe weight loss. Of the people enrolled, 1/31 (3%) refused randomisation, and 10/30 (33%) withdrew from treatment. The RCT reported that 10 people in each group completed treatment. No one was admitted to hospital.

The RCT stratified 57 people into three subgroups based on clinical parameters: subgroup 1, onset of anorexia nervosa at <18 years of age and duration of <3 years; subgroup 2, onset of anorexia nervosa at 18 years of age or younger and duration of illness of >3 years; and subgroup 3, onset of anorexia at >19 years of age. Subgroups were defined before randomisation. The RCT reported that 16/57 (28%) of people withdrew from the study.

Everyone enrolled in the trial was offered inpatient treatment as needed: all received approximately 35 short (10- to 15-minute) check-ups with a paediatrician during the year. Short-term family therapy consisted of 10 sessions over 6 months, compared with 20 sessions of family therapy over 12 months for long-term treatment. Family therapy in both groups was based on the Maudsley model. The RCT reported that 22% of people were admitted to hospital during the intervention, and 10% of people did not complete 80% of the sessions.

The RCT excluded people with severe illness. The interventions were carried out over 20 weekly sessions, and sessions were conducted as described in a treatment manual. Non-specific supportive clinical management (NSSCM) is now known as Specialist Supportive Clinical Care (SSCM). The RCT found no significant difference among groups in the proportion of people who completed treatment (69% with NSSCMv 57% with interpersonal therapy v 63% with CBT; reported as not significant; P value not reported).

Seven families refused to participate. Number of treatment sessions taken varied between 8 and 157. Number of cases admitted for inpatient treatment was 8/33 (24%).

Parent-to-parent consultation involved RCT participants in the intervention group attending a single structured interview with families who had successfully navigated Maudsley model family therapy.

Comment

The acceptability of the treatment varied among RCTs. Failure to take up treatment ranged from 0% to 30%, and withdrawal from treatment ranged from 0% to 70% among RCTs, but this may have been caused by different methods of case ascertainment. The proportion of people admitted for inpatient treatment also varied among RCTs, ranging from 0% to 36%. One death was attributed to anorexia nervosa in the control group in one outpatient RCT with a 1-year follow-up. Three deaths attributed to anorexia nervosa occurred in the 5-year follow-up period of one inpatient-based RCT.

All of the RCTs were small and had limited power to detect clinically important differences between groups. The amount of therapeutic input varied considerably among and within the RCTs. There was variation in methods of recruitment, reporting of key results (e.g., withdrawal rates), and the description of participants' characteristics and selection.

We found one systematic review (search date 2002, 2 small RCTs, 32 people) comparing psychotherapies versus each other, although it used a narrower definition of psychotherapy than we have used in this review. Neither RCT identified by the review met our inclusion criteria. One RCT comparing short- versus long-term family therapy found that the severity of obsessive-compulsive features and family structure affected treatment outcome. These findings suggest that people with more severe eating-related obsessive-compulsive thinking and those from non-intact families may respond better to long-term treatment. Studies of adult participant reactions to treatment indicate that outpatient psychotherapy is a preferred means of treatment, although those focusing specifically on weight gain were viewed negatively by participants.

Substantive changes

Psychotherapy New evidence added. Categorisation unchanged (Unknown effectiveness) as the range of psychotherapeutic options assessed is diverse, leading to conflicting results across trials.

2011; 2011: 1011.
Published online 2011 April 11.

SSRIs

Summary

Limited evidence from small RCTs has not shown significant weight gain from SSRIs, some of which may cause serious adverse effects.

SSRIs have not been shown to be beneficial, but the evidence remains very limited; in the 4 RCTs we found, conclusions were limited because of small trial size and high withdrawal rates.

Benefits and harms

Fluoxetine or citalopram versus placebo:

We found three systematic reviews (search date 2005). Between them, the reviews found three small RCTs of sufficient quality. The reviews did not pool data, and so we report data separately from the individual RCTs.

Symptom improvement

Fluoxetine or citalopram compared with placebo Fluoxetine may be no more effective than placebo at improving weight gain, eating symptoms, or depressive symptoms in women inpatients with anorexia nervosa who also have individual and group psychotherapy. We don't know whether citalopram is more effective than waiting list control at improving weight gain or self-reported depressive symptoms in adults with moderately severe restricting-type anorexia nervosa (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Weight gain

RCT
33 women, mean age 26.2 years, mean BMI 15.0 kg/m2, mean duration of anorexia nervosa 8.0 years Weight gain mean follow-up of 36 days
with fluoxetine (60 mg)
with placebo
Absolute results not reported

Reported as not significant
P value not reported
Not significant

RCT
52 adults with moderately severe restricting-type anorexia nervosa, BMI 15.8 kg/m2 Mean weight gain (change from baseline) 12 weeks
2.99 kg (from 43.5 kg to 46.5 kg) with citalopram (10 mg/day increasing to 20 mg/day)
1.44 kg (from 42.5 kg to 43.9 kg) with waiting list control
Absolute results not reported

Significance not assessed
Psychological outcomes

RCT
33 women, mean age 26.2 years, mean BMI 15.0 kg/m2, mean duration of anorexia nervosa 8.0 years Eating symptoms and depressive symptoms mean follow-up of 36 days
with fluoxetine (60 mg)
with placebo
Absolute results not reported

Reported as not significant
P value not reported
Not significant

RCT
52 adults with moderately severe restricting-type anorexia nervosa, BMI 15.8 kg/m2 Change from baseline in Beck Depression Inventory (self-reported) 12 weeks
From 14.5 to 7.3 with citalopram (10 mg/day increasing to 20 mg/day)
From 12.7 to 12.3 with waiting list control
Absolute results not reported

Significance not assessed

No data from the following reference on this outcome.

Bone mineral density

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Fluoxetine versus psychotherapy alone or versus fluoxetine plus psychotherapy:

See option on psychotherapy.

Further information on studies

The RCT compared fluoxetine 60 mg versus placebo for the duration (mean 36 days) of inpatient treatment, which included individual and group psychotherapy. Two people withdrew early from the fluoxetine group.

The RCT (39 women, binge–purge subtype of anorexia nervosa excluded, mean age about 22 years, mean duration of anorexia nervosa 4–7 years) compared fluoxetine (starting dose 20 mg/day) versus placebo for 1 year. All women had been discharged from hospital after weight gain (minimum weight restoration was to 75% of average body weight). Women were allowed additional psychotherapy. Women who had substantial and incapacitating symptoms were encouraged to withdraw from the study. Withdrawal rates were too high to draw reliable conclusions about effects, although the withdrawal rate was significantly lower with fluoxetine compared with placebo (6/16 [38%] with fluoxetine v 16/19 [84%] with placebo; RR 0.45, 95% CI 0.23 to 0.86).

The RCT compared citalopram (10 mg/day increasing to 20 mg/day) versus waiting list control for 12 weeks before the start of standard integrated dietary and psychiatric treatment. Reliability was limited because withdrawal rates were high (7/26 [27%] with citalopram v 6/26 [23%] with control). The RCT gave no information on reasons for withdrawal.

Comment

There have been a number of drug safety alerts regarding the use of SSRIs in adults and adolescents (see reviews on depression in adults: drug and other physical treatments and generalised anxiety disorder).

Substantive changes

No new evidence

2011; 2011: 1011.
Published online 2011 April 11.

Benzodiazepines

Summary

We found no direct information from RCTs on the effects of benzodiazepines in people with anorexia nervosa.

Benefits and harms

Benzodiazepines:

We found no systematic review or RCTs of sufficient quality on the effects of benzodiazepines in the treatment of people who have anorexia nervosa.

Further information on studies

None.

Comment

Clinical guide:

Benzodiazepines are generally not used in current clinical practice because of the potential for adverse effects. However, we have found no RCTs assessing this risk and we are not aware of ongoing trials.

Substantive changes

No new evidence

2011; 2011: 1011.
Published online 2011 April 11.

Older-generation antipsychotic drugs

Summary

We found no RCT evidence assessing older-generation antipsychotics in people with anorexia nervosa.

The QT interval may be prolonged in people with anorexia nervosa, and many neuroleptic drugs (haloperidol, pimozide, sertindole, thioridazine, chlorpromazine, and others) also increase the QT interval. Prolongation of the QT interval may be associated with increased risk of ventricular tachycardia, torsades de pointes, and sudden death.

Benefits and harms

Older-generation antipsychotic drugs:

We found no systematic review or RCTs of sufficient quality on the effects of older-generation antipsychotics drugs in the treatment of people who have anorexia nervosa.

Further information on studies

None.

Comment

Clinical guide:

The QT interval may be prolonged in people who have anorexia nervosa, and many neuroleptic drugs (haloperidol, pimozide, sertindole, thioridazine, chlorpromazine, and others) may also increase the QT interval. One observational study (495 people with mental illness and 101 healthy controls) found an increased risk of prolonged QT interval with high- and very high-dose neuroleptic use, after adjusting for age and other drug use (high dose: adjusted OR 3.4, 95% CI 1.2 to 10.1; very high dose: adjusted OR 5.6, 95% CI 1.6 to 19.3). The FDA has issued a drug safety alert on haloperidol relating to cardiovascular adverse effects and sudden death relating to the risk of QT prolongation and torsades de pointes (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm216907.htm). General harms of neuroleptic drugs are described in our review on schizophrenia).

Substantive changes

No new evidence

2011; 2011: 1011.
Published online 2011 April 11.

Atypical antipsychotic drugs

Summary

Atypical antipsychotic drugs have been evaluated for their potential role in reducing agitation and anxiety related to refeeding, as well as for potentially increasing appetite. Increasing observational data from case series have suggested that atypical antipsychotics may decrease obsessiveness and agitation. However, further evidence from large, well-conducted RCTs is necessary to draw reliable conclusions.

Newer atypical antipsychotics, in particular olanzapine, do not seem to be associated with the same cardiac risks as older-generation antipsychotic drugs, but the known association between olanzapine and weight gain may impact compliance in people with anorexia nervosa. However, further research needs to be done.

Benefits and harms

Atypical antipsychotic drugs versus placebo:

We found two systematic reviews (search date 2006 and 2007) of RCTs and case reports. The first review identified no RCTs that met Clinical Evidence inclusion criteria (see comment below). The second review identified one RCT. We found one subsequent RCT.

Symptom improvement

Atypical antipsychotics compared with placebo Olanzapine may be more effective at increasing rates of weight gain and reducing obsessive symptoms (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Weight gain

RCT
30 female outpatients aged 18 to 35 years, 18 with restricting-type anorexia nervosa and 12 with a binge–purge subtype BMI 3 months
17.2 kg/m2 with olanzapine
16.9 kg/m2 with placebo

Reported as not significant
P value not reported
Not significant

RCT
34 inpatients, average age 30 years undergoing intensive day hospital treatment Proportion of participants achieving weight restoration 13 weeks
88% with olanzapine
56% with placebo
Absolute numbers not reported

P = 0.02
Effect size not calculatedolanzapine

RCT
34 inpatients, average age 30 years undergoing intensive day hospital treatment Rate of increase in BMI over 13 weeks
with olanzapine
with placebo
Absolute results not reported

P = 0.03
Effect size not calculatedolanzapine
Mental state

RCT
34 inpatients, average age 30 years undergoing intensive day hospital treatment Change in obsessions from baseline 13 weeks
Mean change from 11.06 to 6.54 with olanzapine
Mean change from 9.11 to 5.86 with placebo

P = 0.02
Effect size not calculatedolanzapine

RCT
34 inpatients, average age 30 years undergoing intensive day hospital treatment Change in compulsions from baseline 13 weeks
Mean change from 11.06 to 7.62 with olanzapine
Mean change from 9.50 to 5.21 with placebo

Reported as not significant
P value not reported
Not significant

RCT
34 inpatients, average age 30 years undergoing intensive day hospital treatment Change in depression from baseline 13 weeks
Mean change from 78.25 to 60.86 with olanzapine
Mean change from 77.17 to 66.38 with placebo

P >0.13
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
34 inpatients, average age 30 years undergoing intensive day hospital treatment Adverse effects over 13 weeks
with olanzapine
with placebo

No data from the following reference on this outcome.

Bone mineral density

No data from the following reference on this outcome.

Further information on studies

The RCT suggested that olanzapine was useful in reducing obsessions and other psychological variables associated with relapse from baseline, although differences between olanzapine and placebo were not significant (reported as not significant; P value not reported). Although the authors conducted stratified analyses by type of anorexia nervosa, the sample sizes were too small to draw valid conclusions by subtype.

After a 2-week baseline period in treatment, olanzapine or placebo were prescribed for 10 weeks. Olanzapine was prescribed on a flexible dose scheduling, starting at a minimum dose of 2.5 mg/day and increasing up to a maximum dose of 10 mg/day. Adherence was measured with urine samples and participants were reported to be compliant. Discontinuation rates were similar between the groups (2 people receiving olanzapine, 4 placebo). Reasons for discontinuation were stopping day hospital treatment, stopping medication, and discharge for non-compliance with day hospital rules.

Comment

Clinical guide:

Given the challenges in identifying appropriate pharmacotherapy for anorexia nervosa, several case reports, open trials, and one placebo-controlled trial have been conducted using atypical antipsychotic drugs, most notably olanzapine. These drugs are typically prescribed during acute refeeding to assist with management of agitation, obsessions, and anxiety related to refeeding, but have also been explored for their potential to increase appetite and weight. Reviews of case studies and open trials indicated preliminary support for the use of olanzapine for reducing agitation and psychological distress during weight restoration. One small RCT that did not meet Clinical Evidence inclusion criteria compared olanzapine versus chlorpromazine in 15 adult inpatients with anorexia nervosa. Individualised doses were not reported and the length of treatment varied between groups (mean length of treatment: 46 days with olanzapine v 53 days with chlorpromazine). The RCT found no significant difference between groups in average weight gain, although the authors reported a reduction in ruminative thinking with olanzapine. Case reports and open-label trials have also been reported assessing risperidone and quetiapine. However, evidence from large, well-conducted RCTs is necessary in order to draw reliable conclusions about effectiveness, dosing, and clinical indications. As with other trials for medication to treat anorexia nervosa, studies of atypical antipsychotics are currently compromised by small sample sizes and participant loss to follow-up because of failure to take up treatment or treatment withdrawal. Some atypical antipsychotics do not seem associated with the same cardiac risks as older-generation antipsychotics. However, atypical antipsychotics are associated with increased risk for dysregulated blood sugar levels, possible extrapyramidal adverse effects, excessive sleepiness, and dizziness. Although not considered a harm for the treatment of anorexia nervosa, the atypical antipsychotics are associated with increased weight gain, which may make compliance with the medication regimen challenging for some patients.

Substantive changes

Atypical antipsychotic drugs New option for which we found only two small RCTs. Categorised as Unknown effectiveness.

2011; 2011: 1011.
Published online 2011 April 11.

Tricyclic antidepressants

Summary

Limited evidence from small RCTs has not shown significant weight gain from tricyclic antidepressants, some of which may cause serious adverse effects.

Tricyclic antidepressants may cause drowsiness, dry mouth, blurred vision, and a prolonged QT interval in people who have anorexia nervosa.

The QT interval may be prolonged in people who have anorexia nervosa, and tricyclic antidepressants (amitriptyline, protriptyline, nortriptyline, doxepin, and maprotiline) also increase the QT interval. Prolongation of the QT interval may be associated with increased risk of ventricular tachycardia, torsades de pointes, and sudden death.

Benefits and harms

Tricyclic antidepressants versus placebo:

We found three systematic reviews (search date 2005). Two reviews were narrative and did not pool data. The other review pooled data for tricyclic antidepressants; however, there was significant heterogeneity in the analysis, so it presented data separately for the included RCTs. Between them the reviews identified two small RCTs of amitriptyline of sufficient quality, both of which were of short duration.

Symptom improvement

Tricyclic antidepressants compared with placebo Amitriptyline may be more effective at increasing the rate of weight gain, but may be no more effective at improving global response (defined as >50% improvement) in people with anorexia nervosa (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Global symptom improvement

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Proportion of people with >50% improvement in global response 5 weeks
1/11 (9%) with amitriptyline
1/14 (7%) with placebo
0/18 (0%) with control (people who refused to participate)

Significance not assessed
Weight gain

RCT
72 women, mean age 20.6 years, mean duration 2.9 years Mean days to target weight 5 weeks
32 days with amitriptyline (up to 160 mg)
45 days with placebo

P <0.05
Effect size not calculatedamitriptyline

Bone mineral density

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
72 women, mean age 20.6 years, mean duration 2.9 years Adverse effects
with amitriptyline (up to 160 mg)
with placebo
Absolute results not reported

Fewer people taking amitriptyline had adverse physical symptoms (including drowsiness, excitement, tachycardia, and increased motor activity) rated moderate or severe compared with people taking placebo, but the RCT did not report absolute numbers

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Increased perspiration 5 weeks
2/11 (18%) with amitriptyline
0/14 (0%) with placebo

Significance not assessed

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Drowsiness 5 weeks
6/11 (55%) with amitriptyline
0/14 (0%) with placebo

Significance not assessed

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Dry mouth 5 weeks
4/11 (36%) with amitriptyline
2/14 (14%) with placebo

Significance not assessed

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Blurred vision 5 weeks
1/11 (9%) with amitriptyline
0/14 (0%) with placebo

Significance not assessed

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Urinary retention 5 weeks
1/11 (9%) with amitriptyline
0/14 (0%) with placebo

Significance not assessed

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Hypertension 5 weeks
2/11 (18%) with amitriptyline
0/14 (0%) with placebo

Significance not assessed

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Leukopenia 5 weeks
1/11 (9%) with amitriptyline
0/14 (0%) with placebo

Significance not assessed

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Palpitations 5 weeks
0/11 (0%) with amitriptyline
1/14 (7%) with placebo

Significance not assessed

RCT
3-armed trial
43 people, 5 of them outpatients, with early-onset and short-duration anorexia nervosa, mean age 16.6 years, mean 27% below average weight, mean duration of anorexia nervosa 1.5 years Dizziness 5 weeks
0/11 (0%) with amitriptyline
2/14 (14%) with placebo

Significance not assessed

Further information on studies

Women were withdrawn from the trial if they failed to gain at least 2 kg after 6 weeks; 10 women were withdrawn for this reason, but the total withdrawal rate is unclear. The authors adjusted for withdrawals by assigning a standard time to attainment of target weight of 120 days to all women who withdrew. It is not clear if people also received psychotherapy.

A total of 18 people refused to participate and were used as a third comparison group.

Comment

The QT interval may be prolonged in people who have anorexia nervosa, and tricyclic antidepressants (amitriptyline, protriptyline, nortriptyline, doxepin, and maprotiline) also increase the QT interval.

In an observational study (495 people with mental illness and 101 healthy controls), an increased risk of prolonged QT interval was seen with tricyclic antidepressant use, adjusting for age and other drug use (adjusted OR 2.6, 95% CI 1.2 to 5.6). General harms of tricyclic antidepressants are described in the review on depression in adults: drug and other physical treatments. Prolongation of the QT interval may be associated with an increased risk of ventricular tachycardia, torsades de pointes, and sudden death.

Substantive changes

No new evidence

2011; 2011: 1011.
Published online 2011 April 11.

Oestrogen treatment (HRT or oral contraceptives )

Summary

Oestrogen treatment (HRT or oral contraceptives) has been hypothesised to reduce the negative effects on bone mineral density associated with anorexia nervosa. However, three small RCTs have failed to demonstrate clinically relevant changes in bone mineral density after treatment with oestrogen and these results are supported by longitudinal data, which found similar lack of improvement.

Benefits and harms

Oestrogen treatment versus control:

We found no RCTs that measured the effects of oestrogen treatment directly on fracture rates; all of the RCTs we identified measured surrogate outcomes such as changes in bone mineral density. We found two systematic reviews (search date 2005), which both identified the same RCT. We also found one additional RCT and one subsequent RCT examining the effect of oestrogen treatment on bone mineral density.

Bone mineral density

Compared with placebo or no treatment Oestrogen treatment (as HRT or oral contraceptives) may be no more effective at improving bone mineral density in women who have anorexia nervosa (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Bone mineral density

RCT
48 women, mean age 23.7 years, mean duration of anorexia nervosa 4 years Mean bone mineral density 6 months
128 mg K2HPO4/cm3 with oestrogen
132 mg K2HPO4/cm3 with no treatment

Significance not assessed

RCT
4-armed trial
60 women aged 18 to 38 years, mean weight 44.7 kg, BMI 16.6 kg/m2, duration of anorexia nervosa 2.3 years, and with osteopenia at entry Bone mineral density 9 months
with oral contraceptives
with placebo
Absolute results not reported

Hip density: P = 0.071
Spine density: P = 0.21
Not significant

RCT
146 adolescent girls aged 11 to 17 years with anorexia nervosa or eating disorder not otherwise specified (EDNOS), with an age-adjusted BMI of <10% Change in bone mineral density thirteen 28-day cycles
with norgestimate/ethinylestradiol
with placebo
Absolute results not reported

Hip density: P = 0.78
Spine density: P = 0.24
Not significant

Symptom improvement

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
4-armed trial
60 women aged 18 to 38 years, mean weight 44.7 kg, BMI 16.6 kg/m2, duration of anorexia nervosa 2.3 years, and with osteopenia at entry Breast tenderness 9 months
1/15 (6.7%) with oral contraceptives
1/15 (6.7%) with placebo

Significance not assessed

RCT
146 adolescent girls aged 11 to 17 years with anorexia nervosa or eating disorder not otherwise specified (EDNOS), and who have an age-adjusted BMI of <10% Withdrawal because of adverse effects thirteen 28-day cycles
3/61 (5%) with norgestimate/ethinylestradiol
1/62 (2%) with placebo
Absolute results not reported

Significance not assessed

No data from the following reference on this outcome.

Further information on studies

The RCT compared an oestrogen group, which included women taking either HRT (conjugated oestrogens 0.625 mg on days 1–25 of each month plus medroxyprogesterone 5 mg on days 16–25; 16 women) or an oral contraceptive containing ethinylestradiol 35 micrograms (6 women), depending on whether oral contraception was required, versus a no treatment group (26 women), for 6 months. All women maintained a calcium intake of 1500 mg using oral calcium carbonate, and spinal bone mineral density was measured. A total of 44/48 (92%) women completed the study. The RCT did not separately report results for HRT alone versus no treatment or oral contraceptive alone versus no treatment.

The RCT compared 4 treatments: oral contraceptive alone (ethinylestradiol 35 micrograms plus norethisterone 0.4 mg); placebo; recombinant human insulin-like growth factor I alone; and oral contraceptive plus recombinant human insulin-like growth factor I. In addition, all women received calcium 1500 mg daily and vitamin D 400 IU daily. A total of 7/60 (12%) people did not complete the study, with similar rates of withdrawal in each group.

The subsequent double-blind RCT compared norgestimate/ethinylestradiol (NGM/EE: norgestimate 180–250 micrograms and ethinylestradiol 35 micrograms on days 1–21 and inactive tables on days 22–28) versus placebo for 13 consecutive 28-day cycles. Interpretation is complicated by treatment withdrawal. Of 73 women initially randomised to each group (146 women in total), 23 were omitted as they were screening failures. Of the remaining 123 women, only 40/61 (66%) women who took at least one dose of NGM/EE and 49/62 (79%) women who took at least one dose of placebo completed 13 cycles of treatment. The rate of exposure was lower for those in the NGM/EE group compared with placebo (mean duration: 280 days with NGM/EE v 329 days with placebo; P value not reported). Bone mineral density was measured by dual energy absorptiometry scan at lumbar spine (L1–L4) or hip. Eleven people in the NGM/EE group and 6 people in the placebo group discontinued because of "subject choice" (not further defined; P value not reported). One person with NGM/EE was withdrawn because of bone loss (11% loss of lumbar spine bone mineral density at cycle 6).

Comment

See also adverse effects of oestrogen in review on stress incontinence.

Improvements in bone mineral density may not reduce fracture risk. The results of the RCTs are supported by a longitudinal study (45 women with anorexia) comparing outcomes in 12 women who received HRT (oestradiol) because of low bone mineral density (T score less than –2.5) with outcomes in 33 women who did not receive HRT. The study found no found no attenuation of bone loss in women receiving HRT (changes from baseline in measurement of bone mineral density of lumbar spine, femoral neck, and total hip all P >0.05), although weight recovery was the best predictor of gain in spinal and hip bone mass.

Substantive changes

Oestrogen treatment (HRT or oral contraceptives) New evidence added. Categorisation unchanged (Unknown effectiveness) as there remains insufficient evidence assessing whether oestrogen reduces the negative effect on bone mineral density caused by anorexia, owing to the weak methods of RCTs identified.


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