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1.  Do Mortality Rates in Eating Disorders Change over Time? A Longitudinal Look at Anorexia Nervosa and Bulimia Nervosa 
The American journal of psychiatry  2013;170(8):917-925.
Objective
Although anorexia nervosa has a high mortality rate, our understanding of the timing and predictors of mortality in eating disorders is limited. The authors investigated mortality in a long-term study of patients with eating disorders.
Method
Beginning in 1987, 246 treatment-seeking women with anorexia nervosa or bulimia nervosa were interviewed every 6 months for a median of 9.5 years to obtain weekly ratings of eating disorder symptoms, comorbidity, treatment participation, and psychosocial functioning. From January 2007 to December 2010 (median follow-up of 20 years), vital status was ascertained with a National Death Index search.
Results
Sixteen deaths (6.5%) were recorded (lifetime anorexia nervosa, N=14; bulimia nervosa with no history of anorexia nervosa, N=2). The standardized mortality ratio was 4.37 [95% CI=2.4-7.3] for lifetime anorexia nervosa and 2.33 [95% CI=0.3-8.4] for bulimia nervosa with no history of anorexia nervosa. Risk of premature death among women with lifetime anorexia nervosa peaked within the first 10 years of follow-up resulting in a standardized mortality ratio of 7.7 [95% CI=3.7-14.2]. The standardized mortality ratio varied by duration of illness and was 3.2 [95% CI=0.9-8.3] for women with lifetime anorexia nervosa for 0-15 years (4/119 died), and 6.6 [95% CI=3.2-12.1] for women with lifetime anorexia nervosa for >15-30 years (10/67 died). Multivariate predictors of mortality included alcohol abuse (p<0.0001), low body mass index (p=0.0005), and poor social adjustment (p=0.0090).
Conclusions
These findings highlight the need for early identification and intervention and suggest that a long duration of illness, substance abuse, low weight, and/or poor psychosocial functioning raise the risk for mortality in anorexia nervosa.
doi:10.1176/appi.ajp.2013.12070868
PMCID: PMC4120076  PMID: 23771148
2.  The MOSAIC study - comparison of the Maudsley Model of Treatment for Adults with Anorexia Nervosa (MANTRA) with Specialist Supportive Clinical Management (SSCM) in outpatients with anorexia nervosa or eating disorder not otherwise specified, anorexia nervosa type: study protocol for a randomized controlled trial 
Trials  2013;14:160.
Background
Anorexia nervosa (AN) is a biologically based serious mental disorder with high levels of mortality and disability, physical and psychological morbidity and impaired quality of life. AN is one of the leading causes of disease burden in terms of years of life lost through death or disability in young women. Psychotherapeutic interventions are the treatment of choice for AN, but the results of psychotherapy depend critically on the stage of the illness. The treatment response in adults with a chronic form of the illness is poor and drop-out from treatment is high. Despite the seriousness of the disorder the evidence-base for psychological treatment of adults with AN is extremely limited and there is no leading treatment. There is therefore an urgent need to develop more effective treatments for adults with AN. The aim of the Maudsley Outpatient Study of Treatments for Anorexia Nervosa and Related Conditions (MOSAIC) is to evaluate the efficacy and cost effectiveness of two outpatient treatments for adults with AN, Specialist Supportive Clinical Management (SSCM) and the Maudsley Model of Treatment for Adults with Anorexia Nervosa (MANTRA).
Methods/Design
138 patients meeting the inclusion criteria are randomly assigned to one of the two treatment groups (MANTRA or SSCM). All participants receive 20 once-weekly individual therapy sessions (with 10 extra weekly sessions for those who are severely ill) and four follow-up sessions with monthly spacing thereafter. There is also optional access to a dietician and extra sessions involving a family member or a close other. Body weight, eating disorder- related symptoms, neurocognitive and psychosocial measures, and service use data are measured during the course of treatment and across a one year follow up period. The primary outcome measure is body mass index (BMI) taken at twelve months after randomization.
Discussion
This multi-center study provides a large sample size, broad inclusion criteria and a follow-up period. However, the study has to contend with difficulties directly related to running a large multi-center randomized controlled trial and the psychopathology of AN. These issues are discussed.
Trial Registration
Current Controlled Trials ISRCTN67720902 - A Maudsley outpatient study of treatments for anorexia nervosa and related conditions.
doi:10.1186/1745-6215-14-160
PMCID: PMC3679869  PMID: 23721562
Anorexia nervosa; Eating disorder not otherwise specified; Outpatient treatment; Randomized controlled trial; Cost effectiveness
3.  Remission of anorexia nervosa after thyroidectomy: A report of two cases with Graves' disease and anorexia nervosa 
Thyroid Research  2011;4:17.
We report two patients with anorexia nervosa and Graves' disease who received subtotal thyroidectomy for Graves' disease and concomitantly experienced remission from anorexia nervosa. Both were young women (aged 20 and 26) at the time of surgery. Both had well controlled thyroid function and eating behavior at the time of surgery. Both were followed for over five years without relapse of anorexia nervosa or hyperthyroidism. These cases suggest the existence of an endocrine factor originating from the thyroid gland that is involved in the pathogenesis of anorexia nervosa. Since patients of thyroidectomy can remain in good health with supplement of thyroxine alone, it can be hypothesized that this anorexigenic endocrine factor is an evolutionary relic not necessary for the normal function of humans and does not have physiological effects unless secreted beyond normal levels. Given that, it implies the existence of a creature in the animal kingdom for which such an anorexigenic hormone is essential for survival. Migrating birds eat beyond their caloric expenditure before migration and become anorexic for the duration of their flight. It is also known that their thyroid function is elevated during migration. The normal physiology of migration is a complex mechanism involving the hypothalamic, pituitary, thyroid, adrenal and reproductive hormones. The mechanism of disease, however, can be simpler. A review of the literature is presented that suggest a heretofore unreported thyroid hormone, which is involved in the regulation of migration behavior, may be the responsible factor behind anorexia nervosa.
doi:10.1186/1756-6614-4-17
PMCID: PMC3253671  PMID: 22128818
thyroid; anorexia nervosa; thyroidectomy; avian migration
4.  Long-Term Physiological Alterations and Recovery in a Mouse Model of Separation Associated with Time-Restricted Feeding: A Tool to Study Anorexia Nervosa Related Consequences 
PLoS ONE  2014;9(8):e103775.
Background
Anorexia nervosa is a primary psychiatric disorder, with non-negligible rates of mortality and morbidity. Some of the related alterations could participate in a vicious cycle limiting the recovery. Animal models mimicking various physiological alterations related to anorexia nervosa are necessary to provide better strategies of treatment.
Aim
To explore physiological alterations and recovery in a long-term mouse model mimicking numerous consequences of severe anorexia nervosa.
Methods
C57Bl/6 female mice were submitted to a separation-based anorexia protocol combining separation and time-restricted feeding for 10 weeks. Thereafter, mice were housed in standard conditions for 10 weeks. Body weight, food intake, body composition, plasma levels of leptin, adiponectin, IGF-1, blood levels of GH, reproductive function and glucose tolerance were followed. Gene expression of several markers of lipid and energy metabolism was assayed in adipose tissues.
Results
Mimicking what is observed in anorexia nervosa patients, and despite a food intake close to that of control mice, separation-based anorexia mice displayed marked alterations in body weight, fat mass, lean mass, bone mass acquisition, reproductive function, GH/IGF-1 axis, and leptinemia. mRNA levels of markers of lipogenesis, lipolysis, and the brown-like adipocyte lineage in subcutaneous adipose tissue were also changed. All these alterations were corrected during the recovery phase, except for the hypoleptinemia that persisted despite the full recovery of fat mass.
Conclusion
This study strongly supports the separation-based anorexia protocol as a valuable model of long-term negative energy balance state that closely mimics various symptoms observed in anorexia nervosa, including metabolic adaptations. Interestingly, during a recovery phase, mice showed a high capacity to normalize these parameters with the exception of plasma leptin levels. It will be interesting therefore to explore further the central and peripheral effects of the uncorrected hypoleptinemia during recovery from separation-based anorexia.
doi:10.1371/journal.pone.0103775
PMCID: PMC4121212  PMID: 25090643
5.  Treatment of anorexia nervosa with long-term risperidone in an outpatient setting: case study 
SpringerPlus  2014;3:706.
Introduction
There are currently few studies focusing on the efficacy of long-term atypical antipsychotics to treat anorexia nervosa in the pediatric population.
Case description
This case report follows the treatment of a 17 year-old female with anorexia nervosa over her four-year undergraduate career. After two years of multidisciplinary treatment, low-dose risperidone was initiated due to persistence of her disease. She expressed decreased rigidity around meal times, her weight improved and she had resumption of menses. She was compliant with treatment through graduation and maintained her weight gain.
Discussion & evaluation
Atypical antipsychotics are a treatment option in the management of anorexia nervosa. Risperidone has not been studied as frequently as olanzapine for eating disorders. Risperidone was chosen for its more favorable side effect profile and decreased cost to the patient. Previous studies on anorexia nervosa treatment have occurred during inpatient treatment and have limited follow-up due to patients’ refusal to initiate or maintain medication compliance. This case presents 17 months of outpatient data. The efficacy of risperidone therapy was evaluated with frequent weight checks, subjective decrease in rigidity, serial complete metabolic panels, and restoration of menses.
Conclusions
In this case report, an adolescent female treated with low-dose risperidone had decreased rigid thinking, weight gain and resolution of secondary amenorrhea without medication side effects. Therefore, the atypical antipsychotic risperidone may be an effective long-term outpatient treatment option for patients with anorexia nervosa.
doi:10.1186/2193-1801-3-706
PMCID: PMC4265638  PMID: 25525567
Anorexia nervosa; Risperidone; Secondary amenorrhea; Eating disorders; Outpatient treatment; Case report
6.  Chronic Anorexia Nervosa: Medical Mimic 
Western Journal of Medicine  1981;135(4):257-265.
While anorexia nervosa is typically construed as an acute, dramatic disorder of younger women, long-term follow-up studies indicate that morbidity is chronic or relapsing in 30 percent to 50 percent of cases and sometimes leads to death. In older patients or those with atypical clinical features or obscure complications, chronic starvation may mimic other diseases, and rigid adherence to current diagnostic criteria may impede recognition and appropriate treatment. Anorexia nervosa should be viewed as a spectrum of disorders, with varying courses and presentations, in order that clinicians in nonpsychiatric settings may be equipped to provide adequate care of patients with this complex psychosomatic disease.
PMCID: PMC1273165  PMID: 7342455
7.  Anorexia nervosa 
Clinical Evidence  2011;2011:1011.
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, 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.
PMCID: PMC3275304  PMID: 21481284
8.  Psychosomatic syndromes and anorexia nervosa 
BMC Psychiatry  2013;13:14.
Background
In spite of the role of some psychosomatic factors as alexithymia, mood intolerance, and somatization in both pathogenesis and maintenance of anorexia nervosa (AN), few studies have investigated the prevalence of psychosomatic syndromes in AN. The aim of this study was to use the Diagnostic Criteria for Psychosomatic Research (DCPR) to assess psychosomatic syndromes in AN and to evaluate if psychosomatic syndromes could identify subgroups of AN patients.
Methods
108 AN inpatients (76 AN restricting subtype, AN-R, and 32 AN binge-purging subtype, AN-BP) were consecutively recruited and psychosomatic syndromes were diagnosed with the Structured Interview for DCPR. Participants were asked to complete psychometric tests: Body Shape Questionnaire, Beck Depression Inventory, Eating Disorder Inventory–2, and Temperament and Character Inventory. Data were submitted to cluster analysis.
Results
Illness denial (63%) and alexithymia (54.6%) resulted to be the most common syndromes in our sample. Cluster analysis identified three groups: moderate psychosomatic group (49%), somatization group (26%), and severe psychosomatic group (25%). The first group was mainly represented by AN-R patients reporting often only illness denial and alexithymia as DCPR syndromes. The second group showed more severe eating and depressive symptomatology and frequently DCPR syndromes of the somatization cluster. Thanatophobia DCPR syndrome was also represented in this group. The third group reported longer duration of illness and DCPR syndromes were highly represented; in particular, all patients were found to show the alexithymia DCPR syndrome.
Conclusions
These results highlight the need of a deep assessment of psychosomatic syndromes in AN. Psychosomatic syndromes correlated differently with both severity of eating symptomatology and duration of illness: therefore, DCPR could be effective to achieve tailored treatments.
doi:10.1186/1471-244X-13-14
PMCID: PMC3556145  PMID: 23302180
Anorexia nervosa; Eating disorders; Psychosomatic syndromes; Illness denial; Alexithymia
9.  Stability of Neuropsychological Performance in Anorexia Nervosa 
Background
We investigated the stability of neuropsychological performance and eating disorder (EDO) symptoms before, immediately after, and 2 years after inpatient treatment. We also examined relationships between neuropsychological and EDO measures.
Methods
Sixteen women who were admitted for inpatient treatment of anorexia nervosa participated in three evaluations: (1) at admission to the hospital, (2) at discharge, and (3) at a follow-up exam approximately two years after discharge.
Results
Body mass index increased significantly from each testing session to the next. Endorsement of eating disorder symptoms was significantly decreased at discharge and at follow-up compared to admission. In terms of cognitive performance, total scores on a brief neuropsychological battery (RBANS) were significantly greater at follow-up than at admission. We found no relationships between EDO symptoms and cognitive function at follow-up.
Conclusions
The current findings suggest that EDO symptoms and cognitive performance in anorexia nervosa patients can show improvement as long as two years after hospitalization, but there is no evidence that EDO symptoms are related to neuropsychological performance at that time.
doi:10.1080/10401230701844836
PMCID: PMC3808087  PMID: 18297581
anorexia nervosa; neuropsychological functioning; body mass index
10.  “Fixing a heart”: the game of electrolytes in anorexia nervosa 
Nutrition Journal  2014;13(1):90.
Case
A 25-year-old woman with chronic anorexia nervosa and depression presented with sudden weakness and fatigue. Psychosocial history was notable for binge-starve cycles over the past year and a decline in overall well-being. Vitals on presentation were notable for hypothermia, hypotension, and bradycardia. Initial exam was significant for emaciation, lethargy, and lower extremity edema. Laboratory work-up revealed markedly elevated LFTs, hypoglycemia, thrombocytopenia and elevated INR and lipase. ECG showed sinus bradycardia with prolonged QTc. Ultrasound revealed normal liver and biliary tree. Serum acetaminophen, alcohol level, and urinary toxicology were unremarkable. Work up for infectious, autoimmune, and genetic causes of hepatitis was negative. Echocardiogram revealed left ventricular hypokinesis and EF 10-15%. Nutritional support was begun slowly, however electrolyte derangements began to manifest on hospital day 2, with hypophosphatemia, hypokalemia, hypocalcemia, and hypomagnesemia. Multiple medical and psychiatric disciplines were consulted, and aggressive electrolyte monitoring and repletion were done. The patient’s overall clinical status improved slowly during her hospital course. Her liver enzymes trended down, and her QTc interval eventually returned toward the normal range. Repeat echocardiogram following treatment revealed improvement of her EF to 40%.
Discussion
Anorexia nervosa is an eating disorder characterized by extremely low body weight, fear of gaining weight or distorted perception of body image, and amenorrhea. Anorexia can lead to life threatening medical complications, and thus constitutes a major challenge to manage. Central to the pathogenesis of the refeeding syndrome is a weakened cardiopulmonary system, electrolytes abnormalities, hepatic dysfunction, liver hypoperfusion and failure.
Conclusion
Given the clinical presentation, this patient likely presented on the brink of developing frank refeeding syndrome, with cardiac dysfunction and hypovolemia, leading to hepatic hypoperfusion and ischemic hepatitis. Subsequently, she developed electrolyte disturbances characteristic of refeeding syndrome, which were managed without major complication. Her hospital course is encouraging not only for her recovery, but for the collaboration of the different teams involved in her care, and it highlights the importance of a multidisciplinary approach to caring for patients with the potential dire complications of a complex psychiatric illness.
doi:10.1186/1475-2891-13-90
PMCID: PMC4168120  PMID: 25192814
11.  Long-term misuse of zopiclone in an alcohol dependent woman with a history of anorexia nervosa: a case report 
Introduction
The Z-drugs, zaleplon, zopiclone and zolpidem, are short-acting hypnotics which act at the same receptor as the benzodiazepines, but seemingly without the potential for misuse and the development of dependence of the older benzodiazepines. However, with increased prescribing of Z-drugs, reports of misuse and possible dependence began to appear in the literature, particularly in people with a history of substance misuse and comorbid psychiatric illness. Here we report the case of a woman with a history of chronic zopiclone use and anorexia nervosa, admitted for alcohol detoxification.
Case presentation
A 31-year old Caucasian British woman with a history of long-term zopiclone use and anorexia nervosa was admitted as an inpatient for a ten-day alcohol detoxification. Her weekly (four days out of seven) intake of alcohol was 180 units and her daily intake of zopiclone, 30 mg. Apart from a short period five years ago, she had been taking zopiclone for 13 years at daily doses of up to 90 mg. She admitted to using 'on top' of her prescribed medication, purchasing extra tablets from friends or receiving them gratis from her partner. After detoxification from alcohol and zopiclone, she was prescribed diazepam which she found ineffectual and voiced her intention of returning to zopiclone on leaving the hospital.
Conclusion
Zopiclone is generally regarded as safer than benzodiazepines, however, this particular individual, who was using high doses of zopiclone over many years, may provide further evidence of a risk of dependency when this drug is prescribed for substance users with a comorbid psychiatric illness.
doi:10.1186/1752-1947-4-403
PMCID: PMC3014964  PMID: 21143957
12.  Internet-based relapse prevention for anorexia nervosa: nine- month follow-up 
Background
To study the longer term effects of an internet-based CBT intervention for relapse prevention (RP) in anorexia nervosa.
Methods
210 women randomized to the RP intervention group (full and partial completers) or the control group were assessed for eating and general psychopathology. Multiple regression analysis identified predictors of favorable course concerning Body Mass Index (BMI). Logistic regression analysis identified predictors of adherence to the RP program.
Results
Most variables assessed showed more improvement for the RP than for the control group. However, only some scales reached statistical significance (bulimic behavior and menstrual function, assessed by expert interviewers blind to treatment condition). Very good results (BMI) were seen for the subgroup of “full completers” who participated in all nine monthly RP internet-based intervention sessions. “Partial completers” and controls (the latter non-significantly) underwent more weeks of inpatient treatment during the study period than “full completers”, indicating better health and less need for additional treatment among the “full completers”. Main long-term predictors for favorable course were adherence to RP, more spontaneity, and more ineffectiveness. Main predictors of good adherence to RP were remission from lifetime mood and lifetime anxiety disorder, a shorter duration of eating disorder, and additional inpatient treatment during RP.
Conclusions
Considering the high chronicity of AN, internet-based relapse prevention following intensive treatment appears to be promising.
doi:10.1186/2050-2974-1-23
PMCID: PMC4081799  PMID: 24999404
Anorexia nervosa; Relapse prevention; Internet-based prevention; Online psychotherapy; Risk of relapse; Adherence; Eating disorder; Internet; Follow-up; Maintenance
13.  Inpatient Cognitive Behaviour Therapy for Anorexia Nervosa: A Randomized Controlled Trial 
Psychotherapy and Psychosomatics  2013;82(6):390-398.
Background
The aim of this study was to compare the immediate and longer-term effects of two cognitive behaviour therapy programmes for hospitalized patients with anorexia nervosa, one focused exclusively on the patients' eating disorder features and the other focused also on mood intolerance, clinical perfectionism, core low self-esteem or interpersonal difficulties. Both programmes were derived from enhanced cognitive behaviour therapy (CBT-E) for eating disorders.
Methods
Eighty consecutive patients with severe anorexia nervosa were randomized to the two inpatient CBT-E programmes, both of which involved 20 weeks of treatment (13 weeks as an inpatient and 7 as a day patient). The patients were then followed up over 12 months. The assessments were made blind to treatment condition.
Results
Eighty-one percent of the eligible patients accepted inpatient CBT-E, of whom 90% completed the 20 weeks of treatment. The patients in both programmes showed significant improvements in weight, eating disorder and general psychopathology. Deterioration after discharge did occur but it was not marked and it was restricted to the first 6 months. There were no statistically significant differences between the effects of the two programmes.
Conclusions
These findings suggest that both versions of inpatient CBT-E are well accepted by these severely ill patients and might be a viable and promising treatment for severe anorexia nervosa. There appears to be no benefit from using the more complex form of the treatment.
doi:10.1159/000350058
PMCID: PMC3884188  PMID: 24060628
Anorexia nervosa; Body mass index; Cognitive behaviour therapy; Eating disorders, diagnosis, therapy; Female; Follow-up studies; Humans; Inpatient treatment; Relapse

14.  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
15.  Is deep brain stimulation a treatment option for anorexia nervosa? 
BMC Psychiatry  2013;13:277.
Anorexia nervosa (AN) is a severe psychiatric disorder with high rates of morbidity, comorbidity and mortality, which in a subset of patients (21%) takes on a chronic course. Since an evidence based treatment for AN is scarce, it is crucial to investigate new treatment options, preferably focused on influencing the underlying neurobiological mechanisms of AN. The objective of the present paper was to review the evidence for possible neurobiological correlates of AN, and to hypothesize about potential targets for Deep brain stimulation (DBS) as a treatment for chronic, therapy-refractory AN. One avenue for exploring new treatment options based on the neurobiological correlates of AN, is the search for symptomatologic and neurobiologic parallels between AN and other compulsivity- or reward-related disorders. As in other compulsive disorders, the fronto-striatal circuitry, in particular the insula, the ventral striatum (VS) and the prefrontal, orbitofrontal, temporal, parietal and anterior cingulate cortices, are likely to be implicated in the neuropathogenesis of AN. In this paper we will review the few available cases in which DBS has been performed in patients with AN (either as primary diagnosis or as comorbid condition). Given the overlap in symptomatology and neurocircuitry between reward-related disorders such as obsessive compulsive disorder (OCD) and AN, and the established efficacy of accumbal DBS in OCD, we hypothesize that DBS of the nucleus accumbens (NAc) and other areas associated with reward, e.g. the anterior cingulated cortex (ACC), might be an effective treatment for patients with chronic, treatment refractory AN, providing not only weight restoration, but also significant and sustained improvement in AN core symptoms and associated comorbidities and complications. Possible targets for DBS in AN are the ACC, the ventral anterior limb of the capsula interna (vALIC) and the VS. We suggest conducting larger efficacy studies that also explore the functional effects of DBS in AN.
doi:10.1186/1471-244X-13-277
PMCID: PMC4229382  PMID: 24175936
Anorexia nervosa; Deep brain stimulation; Compulsivity; Reward; Neurobiology
16.  Reduced salience and default mode network activity in women with anorexia nervosa 
Background
The neurobiology of anorexia nervosa is poorly understood. Neuronal networks contributing to action selection, self-regulation and interoception could contribute to pathologic eating and body perception in people with anorexia nervosa. We tested the hypothesis that the salience network (SN) and default mode network (DMN) would show decreased intrinsic activity in women with anorexia nervosa and those who had recovered from the disease compared to controls. The basal ganglia (BGN) and sensorimotor networks (SMN) were also investigated.
Methods
Between January 2008 and January 2012, women with restricting-type anorexia nervosa, women who recovered from the disease and healthy control women completed functional magnetic resonance imaging during a conditioned stimulus task. Network activity was studied using independent component analysis.
Results
We studied 20 women with anorexia nervosa, 24 recovered women and 24 controls. Salience network activity in the anterior cingulate cortex was reduced in women with anorexia nervosa (p = 0.030; all results false-discovery rate–corrected) and recovered women (p = 0.039) compared to controls. Default mode network activity in the precuneus was reduced in women with anorexia compared to controls (p = 0.023). Sensorimotor network activity in the supplementary motor area (SMA; p = 0.008), and the left (p = 0.028) and right (p = 0.002) postcentral gyrus was reduced in women with anorexia compared to controls; SMN activity in the SMA (p = 0.019) and the right postcentral gyrus (p = 0.008) was reduced in women with anorexia compared to recovered women. There were no group differences in the BGN.
Limitations
Differences between patient and control populations (e.g., depression, anxiety, medication) are potential confounds, but were included as covariates.
Conclusion
Reduced SN activity in women with anorexia nervosa and recovered women could be a trait-related biomarker or illness remnant, altering the drive to approach food. The alterations in the DMN and SMN observed only in women with anorexia nervosa suggest state-dependent abnormalities that could be related to altered interoception and body image in these women when they are underweight but that remit following recovery.
doi:10.1503/jpn.130046
PMCID: PMC3997603  PMID: 24280181
17.  Bulimia nervosa, binge eating, and psychogenic vomiting: a controlled treatment study and long term outcome. 
An "epidemic" prevalence of binge eating and vomiting (bulimia nervosa) has been reported, and treatment has been claimed to be difficult. This paper describes a short term outpatient treatment programme of eclectic orientation capable of being conducted by non-specialist staff, under medical supervision, in local centres. The treatment programme was evaluated in a controlled trial and in long term follow up. In 30 women with severe bulimia the treatment programme significantly reduced their incidence of dietary manipulation without producing weight gain, weight disorder, or neurotic illness. After treatment all the women had fewer symptoms; 24 stopped binge eating and vomiting at the end of treatment, and a further four stopped shortly afterwards. During formal follow up 20 showed no dietary abuse and a further eight reduced their attacks to an average of three episodes a year: all judged treatment to be a success. Pretreatment indicators of poorer prognosis include alcohol abuse and a history of anorexia nervosa. Married patients experienced marital difficulties or illness in the spouse.
PMCID: PMC1547940  PMID: 6405908
18.  Factors Associated With Recovery from Anorexia Nervosa 
Journal of psychiatric research  2013;47(7):972-979.
Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors—eating disorder features, personality traits, and psychiatric comorbidity—and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.
doi:10.1016/j.jpsychires.2013.02.011
PMCID: PMC3682792  PMID: 23535032
Eating disorders; anorexia nervosa; recovery; prognostic factors; personality; comorbidity
19.  Determinants of delayed gastric emptying in anorexia nervosa and bulimia nervosa. 
Gut  1988;29(4):458-464.
Gastric emptying was measured using a gamma camera in 22 patients with anorexia nervosa, in 10 patients of normal or high weight with bulimia nervosa and in 10 controls. Patients with anorexia nervosa were tested (1) while underweight and selecting their own diet (10 patients); (2) underweight, but receiving an adequate diet on an inpatient unit (refeeding diet) (12 patients); and (3) under refeeding diet conditions after weight gain (eight patients). Three meals, each labelled with technetium 99m-sulphur colloid, 3.7 MBq were used: (1) a mixed solid meal containing labelled poached egg; (2) 200 ml d-glucose solution, 0.5 kcal/ml, and (3) 200 ml physiological saline. Only gastric emptying rates of the solid meal and glucose solution were significantly delayed. Gastric emptying of saline was normal. The gastric disturbance was confined to patients with anorexia nervosa selecting their own diet. Patients receiving adequate nutrition on the ward had normal gastric emptying and weight gain in this group had no significant effect on emptying. Slow emptying was observed in patients who maintained a low weight solely by food restriction as well as in patients whose anorexia nervosa was complicated by episodes of bulimia. Thus, slow gastric emptying occurred when the quantity of food reaching the duodenum was sufficiently reduced to result in severe weight loss. Moreover, abnormal gastric emptying was seen only after the two meals that contained calories and were hypertonic to plasma, either of which properties could mediate the disturbance. Gastric emptying in bulimia nervosa was normal. Slow gastric emptying could exacerbate undereating in starving patients with anorexia nervosa by enhancing satiety.
PMCID: PMC1433555  PMID: 3371714
20.  THE ENDOCRINOPATHIES OF ANOREXIA NERVOSA 
Endocrine Practice  2008;14(8):1055-1063.
Objective
To describe the hormonal adaptations and alterations in anorexia nervosa.
Methods
We performed a PubMed search of the English-language literature related to the pathophysiology of the endocrine disorders observed in anorexia nervosa, and we describe a case to illustrate these findings.
Results
Anorexia nervosa is a devastating disease with a variety of endocrine manifestations. The effects of starvation are extensive and negatively affect the pituitary gland, thyroid gland, adrenal glands, gonads, and bones. Appetite is modulated by the neuroendocrine system, and characteristic patterns of leptin and ghrelin concentrations have been observed in anorexia nervosa. A thorough understanding of refeeding syndrome is imperative to nutrition rehabilitation in these patients to avoid devastating consequences. Although most endocrinopathies associated with anorexia nervosa reverse with recovery, short stature, osteoporosis, and infertility may be long-lasting complications. We describe a 20-year-old woman who presented with end-stage anorexia nervosa whose clinical course reflects the numerous complications caused by this disease.
Conclusions
The effects of severe malnutrition and subsequent refeeding are extensive in anorexia nervosa. Nutrition rehabilitation is the most appropriate treatment for these patients; however, it must be done cautiously.
PMCID: PMC3278909  PMID: 19095609
21.  Prognosis in anorexia nervosa as influenced by clinical features, treatment and self-perception. 
Canadian Medical Association Journal  1977;117(9):1041-1045.
The use of behaviour modification in the treatment of anorexia nervosa has been controversial and has not undergone controlled studies. An investigation of 42 patients with anorexia nervosa treated a mean of 31.7 months earlier was conducted to determine factors related to prognosis. The three areas studied were (a) clinical features, (b) treatment (behaviour modification versus medical and psychologic therapy) and (c) self-perception (with a distorting photographic technique). Clinical outcome was assessed as "excellent" in 7, "much improved" in 14, "symptomatic" in 13 and "poor" In 8. Analysis of variance showed that vomiting (P less than 0.01), bulimia (P less than 0.01), poor educational/vocational adjustment (P less than 0.01) and higher global clinical score (P less than 0.001) were associated with a poor prognosis. There were no differences at follow-up between patients treated by behaviour modification and those treated by other methods; the data suggest that behaviour modification, while not harmful, does not provide long-term benefits. Self-estimates of body size were highly predictive of outcome (P less than 0.002); all patients with a poor outcome overestimated their size. Patients with only marginal improvement might be helped by treatment directed to self-perceptual disturbances.
PMCID: PMC1880207  PMID: 912628
22.  Focus on anorexia nervosa: modern psychological treatment and guidelines for the adolescent patient 
Anorexia nervosa is a serious condition associated with high mortality. Incidence is highest for female adolescents, and prevalence data highlight a pressing unmet need for treatment. While there is evidence that adolescent-onset anorexia has relatively high rates of eventual recovery, the illness is often protracted, and even after recovery from the eating disorder there is an ongoing vulnerability to psychosocial problems in later life. Family therapy for anorexia in adolescence has evolved from a generic systemic treatment into an eating disorder-specific format (family therapy for anorexia nervosa), and this approach has been evidenced as an effective treatment. Individual treatments, including cognitive behavioral therapy, also have some evidence of effectiveness. Most adolescents can be effectively and safely managed as outpatients. Day-patient treatment holds promise as an alternative to inpatient treatment or as an intensive program following a brief medical admission. Evidence is emerging of advantages in detecting and treating adolescent anorexia nervosa in specialist community-based child and adolescent eating-disorder services accessible directly from primary care. Limitations and future directions for modern treatment are considered.
doi:10.2147/AHMT.S70300
PMCID: PMC4316908
AN; evidence; family; therapy; FT-AN; inpatient; outpatient; day patient; specialist
23.  Cholecystokinin Revisited: CCK and the Hunger Trap in Anorexia Nervosa 
PLoS ONE  2013;8(1):e54457.
Objective
Despite a number of studies in the past decades, the role of Cholecystokinin (CCK) in anorexia nervosa (AN) has remained uncertain. In this study a highly specific assay for the biologically active part of CCK was used in patients with bulimic as well as with the restricting type of AN who were followed over the course of weight gain.
Methods
Ten patients with restricting and 13 with bulimic AN were investigated upon admission (T0), after a weight gain of at least 2 kg on two consecutive weighting dates (T1), and during the last week before discharge (T2) from inpatient treatment in a specialized clinic. Blood samples were drawn under fasting conditions and 20 and 60 minutes following a standard meal (250 kcal). Data were compared to those of eight controls matched for sex and age. Gastrointestinal complaints of patients were measured by a questionnaire at each of the follow-up time points.
Results
At admission, AN patients exhibited CCK-levels similar to controls both prior to and after a test meal. Pre and post-meal CCK levels increased significantly after an initial weight gain but decreased again with further weight improvement. CCK release was somewhat lower in bulimic than in restricting type AN but both subgroups showed a similar profile. There was no significant association of CCK release to either initial weight or BMI, or their changes, but CCK levels at admission predicted gastrointestinal symptom improvement during therapy.
Conclusions
Normal CCK profiles in AN at admission indicates hormonal responses adapted to low food intake while change of eating habits and weight gain results in initially increased CCK release (counteracting the attempts to alter eating behavior) that returns towards normal levels with continuous therapy.
doi:10.1371/journal.pone.0054457
PMCID: PMC3547916  PMID: 23349895
24.  Irisin Levels are Not Affected by Physical Activity in Patients with Anorexia Nervosa 
Irisin was recently identified as muscle-derived hormone that increases energy expenditure. Studies in normal weight and obese subjects reported an increased irisin expression following physical activity, although inconsistent results were observed. Increased physical activity in a subgroup of patients with anorexia nervosa (AN) complicates the course of the disease. Since irisin could account for differences in clinical outcomes, we investigated irisin levels in anorexic patients with high and moderate physical activity to evaluate whether irisin differs with increasing physical activity. Hospitalized female anorexic patients (n = 39) were included. Plasma irisin measured by enzyme-linked immunosorbent assay and locomotor activity were assessed at the same time. Patients were separated into two groups (n = 19/group; median excluded): moderate and high activity (6331 ± 423 vs. 13743 ± 1047 steps/day, p < 0.001). The groups did not differ in body mass index (14.2 ± 0.4 vs. 15.0 ± 0.4 kg/m2), irisin levels (558.2 ± 26.1 vs. 524.9 ± 25.2 ng/ml), and body weight-adjusted resting energy expenditure (17.6 ± 0.3 vs. 18.0 ± 0.3 kcal/kg/day, p > 0.05), whereas body weight-adjusted total energy expenditure (46.0 ± 1.4 vs. 41.1 ± 1.1 kcal/kg/day), metabolic equivalents (METs, 1.9 ± 0.1 vs. 1.7 ± 0.1 METs/day), body weight-adjusted exercise activity thermogenesis (1.8 ± 0.5 vs. 0.6 ± 0.3 kcal/kg/day), duration of exercise (18.6 ± 4.7 vs. 6.2 ± 3.1 min/day), and body weight-adjusted non-exercise activity thermogenesis (21.6 ± 1.0 vs. 18.8 ± 0.8 kcal/kg/day) were higher in the high activity compared to the moderate activity group (p < 0.05). No correlations were observed between irisin and activity parameters in the whole sample (p > 0.05). In conclusion, the current data do not support the concept of irisin being induced by exercise, at least not under conditions of severely reduced body weight like AN.
doi:10.3389/fendo.2013.00202
PMCID: PMC3880939  PMID: 24432013
brown adipose tissue; energy expenditure; exercise; FNDC5; myokine; SenseWear™ armband
25.  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

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