Clinicians treating patients with eating disorders find the challenge great with many treatment-resistant cases.

To some extent, this is true of any clinical disorder. Outpatient treatment rolls and inpatient samples are over-represented by those failing to respond to initial interventions.

A medical example is helpful here. Endocrinologists specializing in diabetes see more complicated cases where glucose control is difficult and diabetic complications are common.

Diabetics with easy glucose control and no complications do not need to see an endocrinologists. To an endocrinologist, clinical practice seems to point to the disease as a treatment-resistant and clinically challenging disorder.

Nevertheless, treatment resistance in eating disorders is a significant issue that has been recently summarized in a nice review by Dr. Katherine Halmi.

Here are my notes from review of the Halmi manuscript using her key headings:

Core eating disorder psychopathology

• Adolescent eating disorder subjects lack insight into the seriousness of illness
• Many do not acknowledge need for treatment
• Body weight, exercise and dieting provide a distraction from other life problems
• Malnutrition in eating disorders contributes to cognitive impairment, treatment engagement problems
• Bulimia treatment resistance has been linked to greater depression, lower BMI and social adjustment problems

Psychiatric and psychological comorbidity

• U.S. National Survey found high rates of psychiatric comorbidity in eating disorders (56% in anorexia nervosa, 95% in bulimia nervosa and 79% in binge eating disorder)
• Anxiety disorders rates are elevated in eating disorders with obsessive compulsive disorder and social anxiety disorder two common conditions
• Anxiety disorders can contribute to resistance of treatment of eating disorder symptoms
• Cluster B personality disorders are elevated in bulimia nervosa and appear related to higher rates of substance dependence in this disorder
• Perfectionism is common in anorexia nervosa. Early onset and high perfectionism traits contribute to higher treatment resistance

Biological features

• Serotonin receptor and transporter function appear to influence course of illness in eating disoders
• GABA receptor genotype appears to be related to level of trait anxiety in both bulimia nervosa and anorexia nervosa
• GABA receptor abnormalities are also possibly related to treatment resistance

Treating refractory patients

• Quetiapine, olanzapine, haloperidol and duloxetine are drugs with some promise in treatment resistant anorexia nervosa
• Novel psychotherapies including CBT and the Maudsley Model  target key features of resistance in anorexia nervosa
• Treatment resistant bulimia nervosa may respond to sequential treatment strategies that include partial hospitalization, selective serotonin reuptake inhibitor (SSRI) drugs and cue exposure
• Binge eating disorder may respond to high dose SSRI therapy or topiramate in a graduated dosing schedule

This review points to the key elements for treatment of the difficult eating disorder patient.

This population needs access to specialized hospitalization units, psychopharmacology expertise and specialized psychotherapy services.

Dr. Halmi notes advances in the treatment of this population may require advances in understanding the neurobiology and neurocircuitry for the disorder.

Readers with more interest in this summary can find the free full-text manuscript by clicking on the DOI link in the citation below.

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Halmi, K. (2013). Perplexities of treatment resistence in eating disorders BMC Psychiatry, 13 (1) DOI: 10.1186/1471-244X-13-292

The recent revision of the American Psychiatric Associations Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5) altered several eating disorder diagnostic criteria.

Some have expressed concern that these revisions are overly broad and may result in over diagnosis in some clinical populations. One clinical population where this is a concern is obesity.

A research study has been recently published addressing this issue.

Jennifer Thomas and colleagues at Harvard University and Massachusetts General Hospital recruited a series of subjects from an obesity program for eating disorder diagnostic assessment.

All subjects completed an assessment for presence of an eating disorder 
diagnosis using both DSM-IV and DSM-5 criteria.

For DSM-IV eating disorder diagnoses, the research team used a validated module from a validated measure known as SCID-IV. For DSM-5 eating disorder diagnosis an early structured interview developed by the DSM-5 Eating Disorders Task Group was used.

The key findings from the study included:

• Prevalence rates for eating disorders using DSM-5 criteria did not increase compared to DSM-IV criteria
• Bulimia nervosa prevalence rates were 2% in both interviews
• Binge eating disorder prevalence rates were 9% in both interviews
• An additional 20% of the obese sample met residual eating disorder criteria in both interviews

Obese individuals with a formal eating disorder diagnosis endorsed higher rates of psychological impairment, depression and anxiety validating the impact of eating disorder comorbidity.

Assessment for the presence of eating disorders is an important part of treatment planning. Eating disorders are more prevalent in obese populations are relatively easy to diagnose.

Some studies have found poor outcomes in obese populations with severe binge eating behaviors.

Treatment of a comorbid eating disorder in obese populations may improve weight and psychological outcomes.

Readers with more interest in this research can access the free full-text manuscript by clicking on the PMID link below.

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Thomas JJ, Koh KA, Eddy KT, Hartmann AS, Murray HB, Gorman MJ, Sogg S, & Becker AE (2014). Do DSM-5 eating disorder criteria overpathologize normative eating patterns among individuals with obesity? Journal of obesity, 2014 PMID: 25057413

There is increasing evidence for inflammation contributing to risk for a variety of psychiatric disorders.

I previously summarized research supporting use of anti-inflammatory drugs in the treatment of depression.

A recent study from Finland supports an inflammation link to the eating disorder categories.

The key elements of the design of this study included:

• Subjects: 2342 subjects admitted for treatment in the Eating Disorders Unit at the central hospital in Finland. Four controls were identified for each case matched by age, gender and place of residence
• Identification of presence for autoimmune diseases: Cases and controls were examined for the presence of one of 30 autoimmune diagnoses in their Hospital Discharge Register
• Statistical analysis: Period and lifetime rates for autoimmune disorders were compared between eating disorder cases and control using logistic regression modeling with calculation of odds ratios and 95% confidence intervals.

Here are the important findings from the study:

• Eating disorders subjects had a 5.6% rate for presence of any autoimmune disease compared to only 2.8% of controls (Odds ratio 2.13, 95% confidence interval 1.71-2.65)
• Rates for autoimmune disorders were increased across all eating disorder diagnostic categories including anorexia nervosa, bulimia nervosa and binge eating disorder
• Within autoimmune disease subtypes, endocrinological and gastroenterological diseases were statistically increased in eating disorders
• Type I diabetes and Crohn's disease were individual autoimmune disorders found at higher rates in eating disorders

The authors note there are several methods that could explain the association between autoimmunity and eating disorder risk. Higher rates of autoantibodies against peptides that control appetite and stress response could contribute to eating disorder risk.

Additionally, the authors note disturbed eating may contribute to disturbance of the microbiome of the gut. Gut microbiome is a known regulator of autoimmunity and a contributor to allergies and type I diabetes risk.

The authors noted additional specific autoimmune disorders may be increased in eating disorders but due to small sample size their study may have not found a statistical association.

Systemic lupus erythematosis rates were increased in the eating disorder group but this was one of the individual disorders that failed to reach statistical significance.

The take home message for clinicians treating eating disorder patients is to be vigilant for the presence of autoimmune medical disorders in this population. Accurate and early detection of autoimmune disorders in those with eating disorders may contribute to improved medical outcomes.

Readers with more interest can access the free full text manuscript by clicking on the PMID link below.

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Raevuori A, Haukka J, Vaarala O, Suvisaari JM, Gissler M, Grainger M, Linna MS, & Suokas JT (2014). The increased risk for autoimmune diseases in patients with eating disorders. PloS one, 9 (8) PMID: 25147950

I am focusing on recent research in eating disorders this month on Brain Posts.

Here are some of the research abstracts I will be reviewing for upcoming posts.

Clicking on the title will take you to the PubMed abstract and also to a link for the free full-text manuscript.

Higher parental education as a risk factor for eating disorders
This study of the Swedish population examined the effect education and social class on risk for eating disorders. Individuals diagnosed with an eating disorder were more likely to have higher educational levels in their parents. This is an interesting finding as educational typically reduces rates for many psychiatric disorders. 

Increased rates of autoimmune diseases in patients with eating disorders
A study of a large cohort from Finland found higher rates of a variety of autoimmune disorders in a sample of patients treated for eating disorders. Type I diabetes and Crohn's disease were two of the disorders that were more likely to be seen in eating disorder patients compared to controls.

Epidemiology of eating disorders
This literature examined 149 studies on the epidemiology of eating disorders. The review found evidence for genetic and environmental factors as risk factors for eating disorders. Additionally, the review found support for esthetic or weight-oriented sport participation also as risk factors for eating disorders.

Evidence for effective treatment options of eating disorders in young people
This review examined evidence for effective prevention and treatment of eating disorders in adolescents and young adults. The authors note the paucity of large well-designed clinical trials for the treatment of most eating disorders and make recommendations about directions for future research. 

Inferior frontal cortex network abnormalities in anorexia nervosa
This study examined resting functional connectivity in 12 subjects with anorexia nervosa compared to controls. The study found impairment in connectivity in the inferior frontal cortex in those with anorexia nervosa.

Binge eating and risk for gastrointestinal disorders
The Swedish Twin Study of Adults: Genes and Environment (STAGE) cohort was used to look for associations between binge eating and gastrointestinal disorders. Binge eating was found to be increased in irritable bowel syndrome and may be important in effectively managing this disorder. 

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Brain research in anorexia nervosa presents several challenges.

Current knowledge of cognitive function in anorexia supports impairment in set shifting and global brain processing or central coherence.

However, there are two issues that complicate understanding the underlying brain effects in anorexia nervosa.

First, individuals with anorexia nervosa often have additional anxiety and mood disorders. It can be difficult to tease out the specific effects of anorexia nervosa from the effects of these comorbid conditions.

Second, fasting and starvation are common metabolic issues in anorexia. These metabolic stresses can also influence brain function.

Sarah Pender and colleagues from University College London and Spain recently published a research study on the neuropsychology of starvation.

The key elements of their study included the following elements:

• Subjects: Healthy females recruited by poster in a university sample. Subjects were required to not have a lifetime history of any psychiatric disorder including anorexia nervosa.
• Measures: A test of set-shifting ability using a test called the rule-change task. A test of local versus global cognitive processing style. A second test of global processing known as the group embedded figures task.
• Metabolic status: Each subject was studied on the above measures after eating and following a period of 18 hours of fasting. 

The authors then compared performance on these neuropsychology tests in the fasting versus satiated state. The main findings from the study included findings in set-shifting and central coherence.

Set-shifting: Performance on set-shifting was not slowed or impaired in the fasting state compared to the satiated state. However, fasting appeared to increase the difficulty (or effort) to set shift.

Central coherence: During the fasting state, subjects shifted processing to a stronger local processing style and a weaker global processing style. This is consistent with reduced central coherence with fasting.

A relevant potential confounding variable in this type of task is the contribution of anxiety and depression in neuropsychological task performance.

I previously collaborated with Dr. Rebecca Marshall and other colleagues at the Laureate Institute of Brain Research in a study of neuropsychological function in a group of women with a variety of eating disorders. In this study, we found subjective anxiety ratings contributed to a significant about of variance in neuropsychological performance in eating disorders. Additionally, we found executive function impairment, a component of central coherence in 30 % of the clinical sample.

Pender and colleagues looked for effects of anxiety and depression in their study and did not find any confounding effects. Obviously, their sample was likely to only have minimal sub-clinical levels of anxiety/depression given the requirement for no current or lifetime psychiatric problem for enrollment.

The authors conclude even short-term fasting "might trigger weak central coherence, and thus play a role in maintaining behaviors characteristic of AN". 

The authors also note the brain effects of fasting, starvation and anorexia nervosa may have difficulty participating in psychotherapy. Psychotherapy requires a more global processing style to be effective.

Readers with more interest in this research can access the free full-text manuscripts by clicking on the PMID link in the citations below.

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Pender, S., Gilbert, S., & Serpell, L. (2014). The Neuropsychology of Starvation: Set-Shifting and Central Coherence in a Fasted Nonclinical Sample PLoS ONE, 9 (10) DOI: 10.1371/journal.pone.0110743

Billingsley-Marshall RL, Basso MR, Lund BC, Hernandez ER, Johnson CL, Drevets WC, McKee PA, & Yates WR (2013). Executive function in eating disorders: the role of state anxiety. The International journal of eating disorders, 46 (4), 316-21 PMID: 23354876

In November I will be looking at some research research in eating disorders.

On my first look at some of important research these five studies stood out for more review.

I will be posting more on several of these studies in the next few weeks.

You can click on the manuscript title to go to the abstract.  All studies have free full-text manuscripts that can be access through the abstract link.

The Neuropsychology of Starvation
One of the key problems in studying anorexia nervosa is the isolation of psychological effects from the effects of starvation on the brain. In this study, 60 healthy female subjects were studied after 18 hours of starvation and again when satiated. Short-term starvation was linked to changes in set-shifting and central coherence.

Resting State Connectivity in Anorexia Nervosa
In this study, 35 subjects with anorexia nervosa were studied using resting state functional magnetic resonance imaging. The study found increased connectivity between the angular gyrus and the fronto-parietal brain ciruit. Additionally, anterior insula connectivity was linked to deficits in interoceptive awareness.

Neuropsychology of Body Perception in Anorexia Nervosa
Patients with anorexia nervosa commonly display impaired perception of body shape and size. They often feel "fat" with body part size misperception. This manuscript reviews studies of nonvisual multisensory neuropsychological performance in anorexia nervosa. The review found support for deficits in tactile and proprioreceptive function in patients with anorexia nervosa.

Body Fat Distribution in Anorexia Nervosa
This literature review examined studies of body fat distribution before and during weight loss and with weight restoration. The authors found key differences between body fat distribution patterns in adolescents with anorexia nervosa compared to adult women with anorexia. The authors note body fat loss and re-accumulation may be an important metabolic and nutritional component of anorexia nervosa treatment.

Anorexia Nervosa Treatment Outcome After Urgent Hospitalization
This study examined the effect of several variables on outcome following urgent inpatient hospitalizations. Several psychological variables failed to contribute to poor outcome. However, lower BMI at admission was linked to several poor outcome measures.

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