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1.  Relationship between Affective Symptoms and Malnutrition Severity in Severe Anorexia Nervosa 
PLoS ONE  2012;7(11):e49380.
Background
Very few studies have investigated the relationship between malnutrition and psychological symptoms in Anorexia Nervosa (AN). They have used only body weight or body mass index (BMI) for the nutritional assessment and did not always report on medication, or if they did, it was not included in the analysis of results, and they did not include confounding factors such as duration of illness, AN subtype or age. The present study investigates this relationship using indicators other than BMI/weight, among which body composition and biological markers, also considering potential confounders related to depression and anxiety.
Methods
155 AN patients, (DSM-IV) were included consecutively upon admission to inpatient treatment. Depression, anxiety, obsessive behaviours and social functioning were measured using various scales. Nutritional status was measured using BMI, severity of weight loss, body composition, and albumin and prealbumin levels.
Results
No correlation was found between BMI at inclusion, fat-free mass index, fat mass index, and severity of weight loss and any of the psychometric scores. Age and medication are the only factors that affect the psychological scores. None of the psychological scores were explained by the nutritional indicators with the exception of albumin levels which was negatively linked to the LSAS fear score (p = 0.024; beta = −0.225). Only the use of antidepressants explained the variability in BDI scores (p = 0.029; beta = 0.228) and anxiolytic use explained the variability in HADs depression scores (p = 0.037; beta = 0.216).
Conclusion
The present study is a pioneer investigation of various nutritional markers in relation to psychological symptoms in severely malnourished AN patients. The clinical hypothesis that malnutrition partly causes depression and anxiety symptoms in AN in acute phase is not confirmed, and future studies are needed to back up our results.
doi:10.1371/journal.pone.0049380
PMCID: PMC3504017  PMID: 23185320
2.  The ANTOP study: focal psychodynamic psychotherapy, cognitive-behavioural therapy, and treatment-as-usual in outpatients with anorexia nervosa - a randomized controlled trial 
Trials  2009;10:23.
Background
Anorexia nervosa is a serious eating disorder leading to high morbidity and mortality as a result of both malnutrition and suicide. The seriousness of the disorder requires extensive knowledge of effective treatment options. However, evidence for treatment efficacy in this area is remarkably weak. A recent Cochrane review states that there is an urgent need for large, well-designed treatment studies for patients with anorexia nervosa. The aim of this particular multi-centre study is to evaluate the efficacy of two standardized outpatient treatments for patients with anorexia nervosa: focal psychodynamic (FPT) and cognitive behavioural therapy (CBT). Each therapeutic approach is compared to a "treatment-as-usual" control group.
Methods/Design
237 patients meeting eligibility criteria are randomly and evenly assigned to the three groups – two intervention groups (CBT and FPT) and one control group. The treatment period for each intervention group is 10 months, consisting of 40 sessions respectively. Body weight, eating disorder related symptoms, and variables of therapeutic alliance are measured during the course of treatment. Psychotherapy sessions are audiotaped for adherence monitoring. The treatment in the control group, both the dosage and type of therapy, is not regulated in the study protocol, but rather reflects the current practice of established outpatient care. The primary outcome measure is the body mass index (BMI) at the end of the treatment (10 months after randomization).
Discussion
The study design surmounts the disadvantages of previous studies in that it provides a randomized controlled design, a large sample size, adequate inclusion criteria, an adequate treatment protocol, and a clear separation of the treatment conditions in order to avoid contamination. Nevertheless, the study has to deal with difficulties specific to the psychopathology of anorexia nervosa. The treatment protocol allows for dealing with the typically occurring medical complications without dropping patients from the protocol. However, because patients are difficult to recruit and often ambivalent about treatment, a drop-out rate of 30% is assumed for sample size calculation. Due to the ethical problem of denying active treatment to patients with anorexia nervosa, the control group is defined as "treatment-as-usual".
Trial registration
Current Controlled Trials ISRCTN72809357
doi:10.1186/1745-6215-10-23
PMCID: PMC2683809  PMID: 19389245
3.  Complement C3 serum levels in anorexia nervosa: a potential biomarker for the severity of disease? 
Background
Anorexia nervosa carries the highest mortality rate of any psychiatric disorder. Even the most critically ill anorexic patients may present with normal 'standard' laboratory values, underscoring the need for a new sensitive biomarker. The complement cascade, a major component of innate immunity, represents a driving force in the pathophysiology of multiple inflammatory disorders. The role of complement in anorexia nervosa remains poorly understood. The present study was designed to evaluate the role of complement C3 levels, the extent of complement activation and of complement hemolytic activity in serum, as potential new biomarkers for the severity of anorexia nervosa.
Patients and methods
This was a prospective cohort study on 14 patients with severe anorexia nervosa, as defined by a body mass index (BMI) <14 kg/m2. Serum samples were obtained in a biweekly manner until hospital discharge. A total of 17 healthy subjects with normal BMI values served as controls. The serum levels of complement C3, C3a, C5a, sC5b-9, and of the 50% hemolytic complement activity (CH50) were quantified and correlated with the BMIs of patients and control subjects.
Results
Serum C3 levels were significantly lower in patients with anorexia nervosa than in controls (median 3.7 (interquartile range (IQR) 2.5-4.9) vs 11.4 (IQR 8.9-13.7, P <0.001). In contrast, complement activation fragments and CH50 levels were not significantly different between the two groups. There was a strong correlation between index C3 levels and BMI (Spearman correlation coefficient = 0.71, P <0.001).
Conclusions
Complement C3 serum levels may represent a sensitive new biomarker for monitoring the severity of disease in anorexia nervosa. The finding from this preliminary pilot study will require further investigation in future prospective large-scale multicenter trials.
doi:10.1186/1744-859X-10-16
PMCID: PMC3110119  PMID: 21542928
4.  The impact of hyperactivity and leptin on recovery from anorexia nervosa 
Journal of Neural Transmission  2007;114(9):1233-1237.
Summary
In anorexia nervosa (AN), hyperactivity is observed in about 80% of patients and has been associated with low leptin levels in the acute stage of AN and in anorexia animal models. To further understand the importance of this correlation in AN, we investigated the relationship between hypoleptinaemia and hyperactivity in AN patients longitudinally and assessed their predictive value for recovery.
Body weight, activity levels, and serum leptin levels were assessed in adolescents and adult AN patient groups at the start and during treatment, up to a year. In the adolescent group, initial leptin and activity levels were correlated. This negative correlation changes over time into a positive correlation with physiological recovery. Treatment outcome in both groups could be predicted by initial BMI and leptin levels but not by activity levels. No major relationship of activity with the course of recovery was detected, suggesting that in contrast to the acute stage of the disease, leptin and activity levels during the recovery process are dissociated.
doi:10.1007/s00702-007-0740-6
PMCID: PMC2798977  PMID: 17530161
Keywords: Anorexia nervosa; hyperactivity; leptin; recovery; eating disorders; physical activity
5.  Emotion brain alterations in anorexia nervosa: a candidate biological marker and implications for treatment 
Background
Identification of the biological markers of anorexia nervosa (AN) is crucial for the development of new treatments. We aimed to determine whether AN is associated with disturbances in the nonconscious neural processing of innate signals of emotion and whether these disturbances persist after weight gain.
Methods
In a retest design, 28 adolescent females with AN were tested at first admission to hospital and again after they had gained weight. Matched healthy control participants were tested at the same times. We assessed emotion-elicited event-related potentials (ERPs) during overt and covert presentation of emotion expressions, scores on an emotion-identification behavioural task, and symptom measures. We performed between and within group analyses.
Results
Individuals with AN had a marked alteration in ERPs relative to healthy controls. Irrespective of the form of stimulus, early and late ERP components were significantly reduced in AN patients at baseline (when underweight) and on retest (after weight gain), especially in the temporo-occipital regions, suggesting a persistent disruption of the early automatic appraisal of salient emotional signals.
Limitations
This study could have been improved with a longer standardized retest interval.
Conclusion
There is likely a core, generic disturbance in AN in the early “automatic” neural processing of emotion irrespective of weight or nutritional status. New innovative emotion-based psychologic or pharmacologic treatments targeting these nonconscious processes may prove beneficial.
doi:10.1503/jpn.090073
PMCID: PMC2895157  PMID: 20598239
6.  Malnutrition and Hemodynamic Status in Adolescents Hospitalized for Anorexia Nervosa 
Objective
To determine the effects of malnutrition on hemodynamic status of adolescents hospitalized for anorexia nervosa.
Design
Longitudinal observational study.
Setting
Tertiary care pediatric hospital.
Patients
Thirty-eight adolescents with anorexia nervosa, aged 13 to 21 years, with a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 15.9 (1.8).
Intervention
Subjects received standard care, including bed rest and graded nutritional therapy. A subsample of subjects (n = 19) returned 11 to 57 weeks following hospitalization for a second cardiac evaluation.
Main Outcome Measures
Results from a 15-lead electrocardiogram, echocardiogram, treadmill stress test, and spinal bone mineral density measurement.
Results
On admission, 26 subjects (68%) had sinus bradycardia. Bradycardia was less common in participants with a longer duration of illness (P = .04). Left ventricle mass was lower than predicted for age (Z score <−1.0) in 11 subjects (31%). Exercise tolerance was normal by all measures. Both heart rate and QT interval were predictors of spinal bone mineral density. In those who returned for follow-up, absolute measures of left ventricle mass did not change (P = .27). However, the corresponding Z scores declined over time (mean [SD] change, −0.9 [1.3]; P = .02).
Conclusions
In acutely malnourished adolescents with anorexia nervosa, few truly pathologic cardiac findings were identified. Sinus bradycardia was observed in most cases. Mild reductions in left ventricle mass and left ventricle function were seen both at baseline and at follow-up, suggesting early sparing of cardiac muscle in the face of moderate malnutrition as well as a relative delay of cardiac muscle restoration. The association of hemodynamic status with altered spinal bone mineral density emphasizes the range of systems affected by malnutrition in anorexia nervosa.
doi:10.1001/archpediatrics.2010.138
PMCID: PMC3205985  PMID: 20679161
7.  Anorexia nervosa--diagnosis, aetiology, and treatment. 
Postgraduate Medical Journal  1995;71(842):712-716.
The aetiology, assessment and treatment of anorexia nervosa are reviewed in the light of the classical accounts of Morton, Lasègue and Gull. The core symptoms are deliberate weight loss, disturbed body image and amenorrhoea, and complications may include cardiac failure, electrolyte disturbances, hypothermia and osteoporosis. Common clinical findings are described. Disturbed brain serotonin activity is implicated in the aetiology of anorexia nervosa, but there is little support for the use of pharmacological treatments. Psychological theories of aetiology are discussed with reference to Bruch, Crisp, Palazzoli and Minuchin: the common theme is the reaction of the patient and her family to the physical and social changes of puberty. Individual and/or family psychotherapy is seen as central to the treatment of anorexia nervosa, and the relevant clinical research is reviewed. The roles of general practitioners, general psychiatrists and eating disorder specialists are discussed in the light of recent consensus treatment guidelines.
Images
PMCID: PMC2398291  PMID: 8552532
8.  Extreme Achalasia Presenting as Anorexia Nervosa 
Case Reports in Surgery  2012;2012:985454.
Background. Achalasia may lead to cachexia if not diagnosed in an early stage. Surgery in cachectic patients is hazardous and complications may result in a protracted recovery or even death. Different treatment options have been described. In this paper, we report a stepwise surgical laparoscopic approach which appears to be safe and effective. Methods. Over a one-year period, a patient with a body mass index (BMI) below 17 being treated for anorexia nervosa was referred with dysphagia. Because of the extreme cachexia, a laparoscopic feeding jejunostomy (LFJ) was fashioned to enable long-term home enteral feeding. The patient underwent a laparoscopic Heller myotomy (LHM) when the BMI was normal. Results. The patient recovered well following this stepwise approach. Conclusion. Patients with advanced achalasia usually present with extreme weight loss. In this small group of patients, a period of home enteral nutrition (HEN) via a laparoscopically placed feeding jejunostomy allows weight gain prior to safe definitive surgery.
doi:10.1155/2012/985454
PMCID: PMC3471404  PMID: 23091768
9.  Study of EEG sleep characteristics in patients with anorexia nervosa before and after restoration of matched population mean weight consequent on ingestion of a ‘normal’ diet 
Postgraduate Medical Journal  1976;52(603):45-49.
This experimental study confirms that insomnia and especially early morning waking is associated with low body weight in anorexia nervosa. It extends the view that there is a relationship between reduced nutritional intake and consequent change in weight and sleep disturbance. This relationship was studied by comparison of certain sleep EEG parameters in a group of hospitalized anorexia nervosa patients before and after a regime of re-feeding to matched population mean weight on a ‘normal’ diet. At low body weights, the patients had less sleep and more restlessness, especially in the last 4 hr of the night. After weight gain, there was a significant increase in length of sleep and REM sleep. The implications of these results are discussed with particular reference to an association between various anabolic profiles and differing need for REM sleep.
PMCID: PMC2496229  PMID: 1257174
10.  Resting Energy Expenditure in Anorexia Nervosa: Measured versus Estimated 
Introduction. Aim of this study was to compare the resting energy expenditure (REE) measured by the Douglas bag method with the REE estimated with the FitMate method, the Harris-Benedict equation, and the Müller et al. equation for individuals with BMI < 18.5 kg/m2 in a severe group of underweight patients with anorexia nervosa (AN). Methods. 15 subjects with AN participated in the study. The Douglas bag method and the FitMate method were used to measure REE and the dual energy X-ray absorptiometry to assess body composition after one day of refeeding. Results. FitMate method and the Müller et al. equation gave an accurate REE estimation, while the Harris-Benedict equation overestimated the REE when compared with the Douglas bag method. Conclusion. The data support the use of the FitMate method and the Müller et al. equation, but not the Harris-Benedict equation, to estimate REE in AN patients after short-term refeeding.
doi:10.1155/2012/652932
PMCID: PMC3175729  PMID: 21941638
11.  Weight gain and the sleeping electroencephalogram: study of 10 patients with anorexia nervosa. 
British Medical Journal  1975;4(5996):556-558.
The relation between reduced nutritional intake, with consequent weight loss, and sleep disturbance was studied by comparing certain sleep encephalogram patterns in a group of inpatients with anorexia nervosa before, during, and after a regimen of refeeding with a normal diet to a matched population mean weight. At low body weights patients had less sleep and more restlessness, especially in the last four hours of the night. During refeeding and weight gain slow-wave sleep initially increased and then tended to decrease during the final stage of restoration of weight back to matched population mean levels. With the overall weight gain, however, there was a significant increase in length of sleep and rapid eye movement sleep, the latter increasing especially during the later stages of weight gain. These results reaffirm that insomnia, and especially early morning waking, is associated with low body weight in anorexia nervosa, and their implications are discussed with particular reference to a hypothetical association between various anabolic profiles and the need for differing components of sleep.
PMCID: PMC1675923  PMID: 173448
12.  Cognitive flexibility in verbal and nonverbal domains and decision making in anorexia nervosa patients: a pilot study 
BMC Psychiatry  2011;11:162.
Background
This paper aimed to investigate cognitive rigidity and decision making impairments in patients diagnosed with Anorexia Nervosa Restrictive type (AN-R), assessing also verbal components.
Methods
Thirty patients with AN-R were compared with thirty age-matched healthy controls (HC). All participants completed a comprehensive neuropsychological battery comprised of the Trail Making Test, Wisconsin Card Sorting Test, Hayling Sentence Completion Task, and the Iowa Gambling Task. The Beck Depression Inventory was administered to evaluate depressive symptomatology. The influence of both illness duration and neuropsychological variables was considered. Body Mass Index (BMI), years of education, and depression severity were considered as covariates in statistical analyses.
Results
The AN-R group showed poorer performance on all neuropsychological tests. There was a positive correlation between illness duration and the Hayling Sentence Completion Task Net score, and number of completion answers in part B. There was a partial effect of years of education and BMI on neuropsychological test performance. Response inhibition processes and verbal fluency impairment were not associated with BMI and years of education, but were associated with depression severity.
Conclusions
These data provide evidence that patients with AN-R have cognitive rigidity in both verbal and non-verbal domains. The role of the impairment on verbal domains should be considered in treatment. Further research is warranted to better understand the relationship between illness state and cognitive rigidity and impaired decision-making.
doi:10.1186/1471-244X-11-162
PMCID: PMC3199238  PMID: 21982555
13.  Neural correlates of viewing photographs of one’s own body and another woman’s body in anorexia and bulimia nervosa: an fMRI study 
Background
In spite of many similarities in the psychopathology of anorexia nervosa (AN) and bulimia nervosa (BN), the 2 groups seem to differ in terms of body image disturbances. Therefore, the aim of the present study was to compare neuronal correlates of viewing photographs of one’s own body and another woman’s body in patients with these forms of eating disorders as well as controls.
Methods
We performed functional magnetic resonance imaging while women with AN (n = 13), BN (n = 15) and healthy controls (n = 27) viewed 16 standardized pictures of their own body and another woman’s body, taken while the participants were wearing a bikini.
Results
When viewing their own body, participants with AN and BN showed reduced activity in the inferior parietal lobule compared with healthy women. In response to looking at another woman’s body, participants with AN had higher amygdala activity than did those in the BN and control groups.
Limitations
The generalizability of the results is limited by the small sample size.
Conclusion
Our data suggest decreased attentional processes in AN and BN toward one’s own body, possibly reflecting body-related avoidance behaviour. Enhanced limbic activity elicited by looking at another woman’s body in participants with AN might be a neural correlate of stronger emotional activation and enhanced vigilance, possibly resulting from social comparison processes. Our study reveals hints about body image–associated alterations in brain activity, which seem to be more pronounced among women with AN than among those with BN.
doi:10.1503/jpn.090048
PMCID: PMC2861133  PMID: 20420767
14.  Resting tachycardia, a warning sign in anorexia nervosa: case report 
Background
Among psychiatric disorders, anorexia nervosa has the highest mortality rate. During an exacerbation of this illness, patients frequently present with nonspecific symptoms. Upon hospitalization, anorexia nervosa patients are often markedly bradycardic, which may be an adaptive response to progressive weight loss and negative energy balance. When anorexia nervosa patients manifest tachycardia, even heart rates in the 80–90 bpm range, a supervening acute illness should be suspected.
Case presentation
A 52-year old woman with longstanding anorexia nervosa was hospitalized due to progressive leg pain, weakness, and fatigue accompanied by marked weight loss. On physical examination she was cachectic but in no apparent distress. She had fine lanugo-type hair over her face and arms with an erythematous rash noted on her palms and left lower extremity. Her blood pressure was 96/50 mm Hg and resting heart rate was 106 bpm though she appeared euvolemic. Laboratory tests revealed anemia, mild leukocytosis, and hypoalbuminemia. She was initially treated with enteral feedings for an exacerbation of anorexia nervosa, but increasing leukocytosis without fever and worsening left leg pain prompted the diagnosis of an indolent left lower extremity cellulitis. With antibiotic therapy her heart rate decreased to 45 bpm despite minimal restoration of body weight.
Conclusions
Bradycardia is a characteristic feature of anorexia nervosa particularly with significant weight loss. When anorexia nervosa patients present with nonspecific symptoms, resting tachycardia should prompt a search for potentially life-threatening conditions.
doi:10.1186/1471-2261-4-10
PMCID: PMC503388  PMID: 15257758
anorexia nervosa; bradycardia; tachycardia; malnutrition
15.  Impact of speed and magnitude of weight loss on the development of brain trophic changes in adolescents with anorexia nervosa: a case control study 
Background
Anorexia nervosa commonly arises during adolescence and is associated with more than one medical morbidity. Abnormalities in brain structure (defined as “pseudoatrophy”) are common in adolescents with anorexia nervosa; however, their correlations with endocrinological profiles and clinical parameters are still unclear. In particular, no study has described the impact of BMI (body mass index) variations (speed and magnitude of weight loss) on cerebral trophism changes.
Methods
Eleven adolescents with anorexia nervosa and 8 healthy controls underwent cerebral MRI (magnetic resonance imaging) examination to obtain global and partial volumes (gray matter, white matter and cerebrospinal fluid) and clinical evaluation. The Mann-Whitney U test was used to compare partial volumes and clinical variables between cases and controls. The Spearman non-parametric test was performed in order to explore correlations between the variables studied.
Results
The patients diagnosed with AN showed significantly increased cerebrospinal fluid (CSF) volumes and decreased total gray (GM) and white matter (WM) volumes. The degree of weight loss (deltaBMI) correlated inversely with the GM volume; the increase of CSF compartment correlated directly with the rapidity of weight loss (DeltaBMI/disease duration).
Conclusions
This study suggests a correlation between cerebral alterations in AN and the speed and magnitude of weight loss, and outlines its importance for the therapeutic treatment.
doi:10.1186/1824-7288-39-14
PMCID: PMC3599113  PMID: 23418915
Adolescent; Anorexia nervosa; Brain; BMI
16.  Cardiac abnormalities in young women with anorexia nervosa. 
British Heart Journal  1994;71(3):287-292.
OBJECTIVE--To identify the characteristics of cardiac involvement in the self-induced starvation phase of anorexia nervosa. METHODS--Doppler echocardiographic indices of left ventricular geometry, function, and filling were examined in 21 white women (mean (SD) 22 (5) years) with anorexia nervosa according to the DSMIII (Diagnostic and Statistical Manual of Mental Disorders) criteria, 19 women (23 (2) years) of normal weight, and 22 constitutionally thin women (21 (4) years) with body mass index < 20. RESULTS--13 patients (62%) had abnormalities of mitral valve motion compared with one normal weight woman and two thin women (p < 0.001) v both control groups). Left ventricular chamber dimension and mass were significantly less in women with anorexia nervosa than in either the women of normal weight or the thin women, even after standardisation for body size or after controlling for blood pressure. There were no substantial changes in left ventricular shape. Midwall shortening as a percentage of the values predicted from end systolic stress was significantly lower in the starving patients than in women of normal weight: when endocardial shortening was used as the index this difference was overestimated. The cardiac index was also significantly reduced in anorexia nervosa because of a low stroke index and heart rate. The total peripheral resistance was significantly higher in starving patients than in both control groups. The left atrial dimension was significantly smaller in anorexia than in the women of normal weight and the thin women, independently of body size. The transmitral flow velocity E/A ratio was significantly higher in anorexia than in both the control groups because of the reduction of peak velocity A. When data from all three groups were pooled the flow velocity E/A ratio was inversely related to left atrial dimension (r = -0.43, p < 0.0001) and cardiac output (r = -0.64, p < 0.0001) independently of body size. CONCLUSIONS--Anorexia nervosa caused demonstrable abnormalities of mitral valve motion and reduced left ventricular mass and filling associated with systolic dysfunction.
PMCID: PMC483668  PMID: 8142200
17.  Measurement of Daily Activity in Restrictive Type Anorexia Nervosa 
Objective
The assessment of daily activity in patients with restrictive type anorexia nervosa is limited by an absence of accurate and precise technology. We wanted to test a daily activity detecting device named, the Physical Activity Monitoring System (PAMS).
Method
Women participants with restrictive type anorexia nervosa (n = 8, 36 ± 11 years, 17 ± 2 kg/m2) and healthy women participants (n = 8, 30 ± 11 years, 27 ± 7 kg/m2) were asked to lie, sit and stand motionless, and walk at 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 mph whilst wearing PAMS.
Results
For all restrictive type anorexia nervosa and healthy participants, body posture was correctly detected for all measurements (300/300). There was excellent correlation of an individual’s body acceleration with walking velocity and walking energy expenditure (r2> 0.99).
Conclusions
The PAMS technology could serve as a tool for lending insight into the pathophysiology of restrictive type anorexia nervosa; and potentially measuring compliance with activity recommendations for medical professionals treating individuals with restrictive type anorexia nervosa.
doi:10.1002/eat.20486
PMCID: PMC2705949  PMID: 18004719
18.  Anorexia nervosa 
Clinical Evidence  2009;2009:1011.
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 which aimed to answer the following clinical questions: What are the effects of treatments for 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 August 2007 (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: anxiolytic drugs, cyproheptadine, inpatient/outpatient treatment setting, oestrogen treatment, psychotherapy, refeeding, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants.
Key Points
Anorexia nervosa is characterised by a low 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 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.
There is no strong research evidence that any treatments work well for anorexia nervosa. However, there is a gradual accumulation of evidence which suggests that early intervention is effective. Working with the family may also interrupt the development of a persistent form of the illness.
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 feeding is rarely required and can lead to problems due to hypophosphataemia.Nutritional supplements, including zinc, have only limited evidence for their effectiveness, and additional evaluation of these measures are warranted.
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 four RCTs we found, conclusions were limited due to small trial size and high withdrawal rates.
Anxiolytic drugs (mainly 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. Weak observational evidence has suggested that they may decrease obsessiveness and agitation. However, we found no RCTs of sufficient quality on the effects of atypical antipsychotics, and further evidence from large, well-conducted RCTs is necessary to draw reliable conclusions. Some atypical antipsychotics do not appear to be associated with the same cardiac risks as older-generation antipsychotic drugs. However, further research needs to be done.
We found insufficient evidence assessing cyproheptadine for treating anorexia nervosa.
Oestrogen treatment has been hypothesized to reduce the negative effects on bone mineral density associated with anorexia nervosa. However, three small RCTs have failed to demonstrate significant changes in bone mineral density after treatment with oestrogen.
PMCID: PMC2907776  PMID: 19445758
19.  Psychological and weight-related characteristics of patients with anorexia nervosa-restricting type who later develop bulimia nervosa 
Background
Patients with anorexia nervosa-restricting type (AN-R) sometimes develop accompanying bulimic symptoms or the full syndrome of bulimia nervosa (BN). If clinicians could predict who might change into the bulimic sub-type or BN, preventative steps could be taken. Therefore, we investigated anthropometric and psychological factors possibly associated with such changes.
Method
All participants were from a study by the Japanese Genetic Research Group for Eating Disorders. Of 80 patients initially diagnosed with AN-R, 22 changed to the AN-Binge Eating/Purging Type (AN-BP) and 14 to BN for some period of time. The remaining 44 patients remained AN-R only from the onset to the investigation period. Variables compared by ANOVA included anthropometric measures, personality traits such as Multiple Perfectionism Scale scores and Temperament and Character Inventory scores, and Beck Depression Inventory-II scores.
Results
In comparison with AN-R only patients, those who developed BN had significantly higher current BMI (p < 0.05) and maximum BMI in the past (p < 0.05). They also scored significantly higher for the psychological characteristic of parental criticism (p < 0.05) and lower in self-directedness (p < 0.05), which confirms previous reports, but these differences disappeared when the depression score was used as a co-variant. No significant differences were obtained for personality traits or depression among the AN-R only patients irrespective of their duration of illness.
Conclusion
The present findings suggest a tendency toward obesity among patients who cross over from AN-R to BN. Low self-directedness and high parental criticism may be associated with the development of BN by patients with AN-R, although the differences may also be associated with depression.
doi:10.1186/1751-0759-2-5
PMCID: PMC2275291  PMID: 18267038
20.  Comparison of a high-carbohydrate and high-protein breakfast effect on plasma ghrelin, obestatin, NPY and PYY levels in women with anorexia and bulimia nervosa 
Background
The present study investigated plasma levels of gut-brain axis peptides ghrelin, obestatin, NPY and PYY after consumption of a high-carbohydrate (HC) and high-protein (HP) breakfast in patients with anorexia nervosa, bulimia nervosa and in healthy controls. These peptides play an important role in regulation of energy homeostasis and their secretion is disturbed under condition of eating disorders. As various types of consumed macronutrients may induce different plasma hormone responses, so we examined these responses in women patients with eating disorders and compared them with those of healthy controls.
Methods
We examined plasma hormone responses to HC and HP breakfast in patients with AN (n = 14; age: 24.6 ± 1.8 years, BMI: 15.3 ± 0.7), BN (n = 15; age: 23.2 ± 1.7 years, BMI: 20.5 ± 0.9) and healthy controls (n = 14; age: 24.9 ± 1.4 years, BMI: 21.1 ± 0.8). Blood samples were drawn from the cubital vein, the first blood drawn was collected before meal, and then 30, 60, 90, 120 and 150 min after breakfast consumption. Plasma hormone levels were determined by commercially available RIA kits.
Results
Fasting and postprandial plasma obestatin levels were significantly increased in both AN and BN patients, while plasma ghrelin levels were significantly increased in AN patients only. After breakfast consumption, plasma levels of ghrelin and obestatin decreased, although they were still above the range of values of healthy controls. Fasting NPY plasma levels were significantly increased in AN and BN patients and did not change postprandially. Fasting PYY levels were comparable in AN, BN and healthy controls, but postprandially significantly increased after HP breakfast in AN and BN patients. Different reactions to breakfast consumption was found for ghrelin and PYY among investigated groups, while for obestatin and NPY these reactions were similar in all groups.
Conclusions
Significant increase of obestatin and NPY in AN and BN patients may indicate their important role as the markers of eating disorders. Different reactions of ghrelin and PYY to breakfast consumption among groups suggest that role of these hormones in regulation of energy homeostasis can be adjusted in dependence to acute status of eating disorder.
doi:10.1186/1743-7075-9-52
PMCID: PMC3533897  PMID: 22681985
Ghrelin; Obestatin; NPY; PYY; Anorexia nervosa; Bulimia nervosa; High-carbohydrate breakfast; High-protein breakfast
21.  Olfactory identification ability in anorexia nervosa. 
OBJECTIVE: The hypothesis tested was that patients with severe eating disorders would demonstrate olfactory identification deficits as a result of zinc deficiency or malnutrition. METHOD: The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 27 hospitalized female patients with anorexia nervosa and 50 normal control female subjects. For a subgroup of patients, serum zinc levels and body mass indices were obtained at pre- and post-nutritional repletion phases. RESULTS: UPSIT scores for patients with eating disorders were equivalent to normal control subjects in spite of the fact that the patients were nutritionally compromised as determined by body mass index. Serum zinc levels were not significantly different at pre- and post-nutritional repletion. CONCLUSIONS: In contrast to patients with schizophrenia, patients with severe eating disorders have intact olfactory function. This finding suggests that transient metabolic or nutritional disturbances alone cannot account for previously reported olfactory deficits.
PMCID: PMC1188703  PMID: 7647081
22.  Social Cognition in Anorexia Nervosa: Evidence of Preserved Theory of Mind and Impaired Emotional Functioning 
PLoS ONE  2012;7(8):e44414.
Background
The findings of the few studies that have to date investigated the way in which individuals with Anorexia Nervosa (AN) navigate their social environment are somewhat contradictory. We undertook this study to shed new light on the social-cognitive profile of patients with AN, analysing Theory of Mind and emotional functioning. Starting from previous evidence on the role of the amygdala in the neurobiology of AN and in the social cognition, we hypothesise preserved Theory of Mind and impaired emotional functioning in patients with AN.
Methodology
Thirty women diagnosed with AN and thirty-two women matched for education and age were involved in the study. Theory of Mind and emotional functioning were assessed with a set of validated experimental tasks. A measure of perceived social support was also used to test the correlations between this dimension and the social-cognitive profile of AN patients.
Principal Findings
The performance of patients with AN is significantly worse than that of healthy controls on tasks assessing emotional functioning, whereas patients’ performance is comparable to that of healthy controls on the Theory of Mind task. Correlation analyses showed no relationship between scores on any of the social-cognition tasks and either age of onset or duration of illness. A correlation between social support and emotional functioning was found. This latter result seems to suggest a potential role of social support in the treatment and recovery of AN.
Conclusions
The pattern of results followed the experimental hypothesis. They may be useful to help us better understand the social-cognitive profile of patients with AN and to contribute to the development of effective interventions based on the ways in which patients with AN actually perceive their social environment.
doi:10.1371/journal.pone.0044414
PMCID: PMC3432108  PMID: 22952975
23.  Decreases in blood perfusion of the anterior cingulate gyri in Anorexia Nervosa Restricters assessed by SPECT image analysis 
BMC Psychiatry  2001;1:2.
Background
It is possible that psychopathological differences exist between the restricting and bulimic forms of anorexia nervosa. We investigated localized differences of brain blood flow of anorexia nervosa patients using SPECT image analysis with statistic parametric mapping (SPM) in an attempt to link brain blood flow patterns to neurophysiologic characteristics.
Methods
The subjects enrolled in this study included the following three groups: pure restrictor anorexics (AN-R), anorexic bulimics (AN-BP), and healthy volunteers (HV). All images were transformed into the standard anatomical space of the stereotactic brain atlas, then smoothed. After statistical analysis of each brain image, the relationships among images were evaluated.
Results
SPM analysis of the SPECT images revealed that the blood flow of frontal area mainly containing bilateral anterior cingulate gyri (ACC) was significantly decreased in the AN-R group compared to the AN-BP and HV groups.
Conclusions
These findings suggest that some localized functions ofthe ACCare possibly relevant to the psychopathological aspects of AN-R.
doi:10.1186/1471-244X-1-2
PMCID: PMC32312  PMID: 11407997
24.  Olanzapine Use for the Adjunctive Treatment of Adolescents with Anorexia Nervosa 
Abstract
Objective
To examine assessment and treatment profiles of adolescent patients with anorexia nervosa and eating disorder not otherwise specified who received olanzapine as compared with an untreated matched sample.
Method
A retrospective, matched-groups comparison study was completed. Medical files of 86 female patients treated in the eating disorder program at the Children's Hospital of Eastern Ontario were examined. Patients treated with olanzapine were initially identified through chart review and then matched to a diagnosis, age, and, when possible, treatment group that served as the active comparator. Weight gain was examined in a sample of 22 inpatients.
Results
Patients treated with olanzapine displayed greater evidence of psychopathology and medical compromise at the time of first assessment compared with those not treated. Rate of weight gain was not statistically different between groups when olanzapine was started during inpatient admissions. Medication effect on eating disorder cognitions could not be assessed given the presence of multiple confounders relating to treatment. Notable side effects included sedation and dyslipidemia in 56% of patients.
Conclusions
Despite our best attempts at matching olanzapine-treated subjects with a control sample, analysis revealed significant differences between groups, suggesting greater illness severity in those augmented with olanzapine. Given these inherent differences, we were unable to draw any firm conclusions regarding the potential efficacy of olanzapine. Factors associated with the prescription of adjunctive pharmacotherapy in this cohort appear to be linked to illness severity, acuity, and associated comorbidity. The observed side-effect profile indicates the need for more consistent predrug screening and for closer monitoring during treatment.
doi:10.1089/cap.2010.0131
PMCID: PMC3111870  PMID: 21510781
25.  A Randomized Controlled Trial of Adjunctive Family Therapy and Treatment as Usual Following Inpatient Treatment for Anorexia Nervosa Adolescents 
PLoS ONE  2012;7(1):e28249.
Research on treatments in anorexia nervosa (AN) is scarce. Although most of the therapeutic programs used in ‘real world practice’ in AN treatment resort to multidisciplinary approaches, they have rarely been evaluated.
Objective
To compare two multidimensional post-hospitalization outpatients treatment programs for adolescents with severe AN: Treatment as Usual (TAU) versus this treatment plus family therapy (TAU+FT).
Method
Sixty female AN adolescents, aged 13 to 19 years, were included in a randomized parallel controlled trial conducted from 1999 to 2002 for the recruitment, and until 2004 for the 18 months follow-up. Allocation to one of the two treatment groups (30 in each arm) was randomised. The TAU program included sessions for the patient alone as well as sessions with a psychiatrist for the patient and her parents. The TAU+FT program was identical to the usual one but also included family therapy sessions targeting intra-familial dynamics, but not eating disorder symptoms. The main Outcome Measure was the Morgan and Russell outcome category (Good or Intermediate versus Poor outcome). Secondary outcome indicators included AN symptoms or their consequences (eating symptoms, body mass index, amenorrhea, number of hospitalizations in the course of follow-up, social adjustment). The evaluators, but not participants, were blind to randomization.
Results
At 18 months follow-up, we found a significant group effect for the Morgan and Russell outcome category in favor of the program with family therapy (Intention-to-treat: TAU+FT :12/30 (40%); TAU : 5/29 (17.2%) p = 0.05; Per Protocol analysis: respectively 12/26 (46.2%); 4/27 (14.8%), p = 0.01). Similar group effects were observed in terms of achievement of a healthy weight (i.e., BMI≥10th percentile) and menstrual status.
Conclusions
Adding family therapy sessions, focusing on intra-familial dynamics rather than eating symptomatology, to a multidimensional program improves treatment effectiveness in girls with severe AN.
Trial Registration
Controlled-trials.com ISRCTN71142875
doi:10.1371/journal.pone.0028249
PMCID: PMC3251571  PMID: 22238574

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