Eating Disorders

Number: 0511

Policy

Aetna considers the following services and procedures medically necessary for the management of members with anorexia or bulimia.

1. Assessment:

   • Blood count and serum chemistry (e.g., CBC, electrolytes, BUN/creatinine)
   • Bone density measurement (for evaluation of anorexic members) (see CPB 0134 - Bone Mass Measurements)
   • Electrocardiography
   • Liver function tests
   • Medical evaluation (complete medical history and physical examination)
   • Psychiatric/psychological consultation and testing
   • Urinalysis.

2. Treatment:

   • Nutritional counseling (see CPB 0049 - Nutritional Counseling)
   • Pharmacotherapy for the treatment of anorexia (e.g., selective serotonin reuptake inhibitors and anti-psychotics)Footnotes for coverage of particular drugs^**
   • Pharmacotherapy for the treatment of bulimia (e.g., selective serotonin reuptake inhibitors such as fluoxetine, tricyclic anti-depressants, trazodone, topiramate)Footnotes for coverage of particular drugs^**
   • Pharmacotherapy for the treatment of binge-eating disorder (e.g., lisdexamfetamine dimesylate (Vyvanse)) (Note: Coverage may be excluded under plans that exclude coverage of medications to decrease or increase weight. Please check benefit plan descriptions.)Footnotes for coverage of particular drugs^**
   • Psychotherapy (e.g., cognitive behavioral therapy, family psychotherapy, interpersonal psychotherapy, and psychodynamic psychotherapy).

Footnotes^** Note: Coverage of particular drugs within each class may be subjected to formulary restrictions, where applicable.

Aetna considers the following services/procedures experimental and investigational for the diagnosis and treatment of anorexia and bulimia because of insufficient evidence in the peer-reviewed literature.

1. Assessment:

   • Brain imaging
   • Catechol-O-methyltransferase (COMT) Val158Met polymorphism genotyping
   • Estrogen receptor 1 gene (ESR1) polymorphism testing (for anorexia)
   • Evaluation of olfaction
   • Individual Optimal Nutrition (ION) analysis/profile
   • Measurement of blood levels of peripheral brain derived neurotrophic factor (BDNF) (for bulimia)
   • Measurement of plasma levels of hypothalamic neuropeptides (e.g., kisspeptin, nesfatin-1, phoenixin, and spexin) (for anorexia)
   • Measurement of plasma levels of adiponectin as a prognostic biomarker for bulimia
   • Measurement of serum concentration of brain derived neurotrophic factor (for anorexia)
   • Measurements of serum zinc levels
   • Serotonin transporter gene (5-HTTLPR) polymorphism testing (for anorexia and bulimia)

2. Treatment:

   • Acamprosate calcium (Campral) for the treatment of binge eating disorder
   • Acupuncture
   • Bisphosphonates and other anti-resorptive agents in the management of osteopenia in anorexic members
   • Bright light therapy for the treatment of eating disorders (including light therapy for the treatment of night eating syndrome)
   • Bupropion (Zyban), lithium, and naltrexone for the treatment of bulimia and binge eating disorder (bupropion only)
   • Cholinesterase inhibitors (e.g., donepezil) for the treatment of anorexia
   • Chromium for the treatment of binge eating disorder
   • Deep brain stimulation (treatment-refractory anorexia)
   • Dehydroepiandrosterone for the treatment of anorexia.
   • Estrogen for the treatment of anorexia (including transdermal estradiol patch)
   • E-therapy (via Internet and mobile-device applications) for the treatment of eating disorders
   • Food-specific inhibition training for the treatment of binge eating disorder
   • Ghrelin agonists (for anorexia)
   • Glucagon-like peptide-1 receptor agonists (for bulimia)
     
   • Intranasal naloxone for the treatment of binge eating disorder
   • Melatonergic medications for the treatment of night eating syndrome
   • Neural therapy (superficial injection of local anesthetic; for bulimia)
   • Oral contraceptives in preventing bone loss in amenorrheic persons with an eating disorder
   • Oxytocin
   • Qsymia (phentermine and topiramate ER; for bulimia)
     
   • Relaxation therapy
   • Repetitive transcranial magnetic stimulation
   • The Mandometer treatment
   • Transcranial direct current stimulation.

Background

The majority of patients with eating disorders can be treated in the outpatient settings.  Hospitalization is usually reserved for severely symptomatic patients such as individuals with extremely low body weight (75 % or less of expected body weight) whose condition must be hemodynamically stabilized, or those with medical problems requiring intensive monitoring such as patients with electrolyte imbalances, cardiac arrhythmias, profound hypoglycemia, self-mutilation, impaired capacity for self-care, or active suicidal ideation.  Furthermore, failure of outpatient treatment may also constitute grounds for inpatient treatment.  It should be noted that patients with bulimia rarely need hospitalization unless binge-purge cycle has led to anorexia resulting in severe metabolic deficiencies such as severe electrolyte imbalances, or suicidal depression is present.

A complete blood count may reflect anemia due to nutritional deficiency.  Serum electrolyte imbalances may occur in patients with bulimia.  Other laboratory tests include blood urea nitrogen/creatinine levels, serum measurements of calcium, magnesium, phosphorus, urinalysis, and liver function tests.  An electrocardiogram may aid to identify cardiac abnormalities such as sinus bradycardia, as well as signs of hypokalemia or ipecac-induced myopathy.  In general, brain imaging and bone mineral density studies are not necessary.  A psychiatric assessment of patients with an eating disorder is appropriate for identification of any concurrent psychiatric illness, evaluation of the risk of suicide, and exploration of the psychosocial context of the symptoms.

Treatments for patients with eating disorders include nutritional counseling; psychotherapy such as cognitive behavioral therapy, family psychotherapy, inter-personal psychotherapy, and psychodynamic psychotherapy; as well as pharmacotherapy.  Nutritional counseling, with a reasonable, graduated eating plan tied to specific weight goals, as well as psychotherapy are essential.  Medication plays an important, but limited role in the management of eating disorders.  In general, drug therapy is not effective in treating anorexia -- zinc, cyproheptadine, anti-depressants, and neuroleptic agents -- have not been shown to improve symptoms.

On the contrary, pharmacotherapy is moderately effective in treating bulimia.  High-dose (60-mg) fluoxetine (Prozac) and other selective serotonin reuptake inhibitors (SSRIs) such as trazodone (Desyrel) have been shown to be helpful in treating bulimia.  Tricyclic anti-depressants such as imipramine (Tofranil) and desipramine (Norpramin) have been demonstrated to reduce binge eating and vomiting in bulimic patients.  Monoamine oxidase inhibitors such as phenelzine (Nardil) should not be used as initial pharmacotherapy for bulimia because of their considerable side effects.  Bupropion (Zyban) is contraindicated in the treatment of bulimia because of increased risk of seizures.  Neither naltrexone nor lithium has been shown to be effective in treating bulimia. The role of bisphosphonates (e.g., alendronate and risedronate) and other anti-resorptive agents in the management of osteopenia in anorexic patients has not been established.  In a randomized controlled trial (RCT), Golden et al (2005) concluded that in adolescents with anorexia nervosa, weight restoration is the most important determinant of bone mineral density, but treatment with alendronate did increase the bone mineral densities of the lumbar spine and femoral neck within the group receiving alendronate, but not compared with placebo in the primary analysis.  Until additional studies have demonstrated efficacy and long-term safety, the use of alendronate in this population should be confined to controlled clinical trials.  Dietary supplements are usually not recommended for anorexia.  In a RCT, Barbarich et al (2004) concluded that supplement strategies are not a substitute for adequate nutrition and are ineffective in increasing the efficacy of fluoxetine in underweight anorexia nervosa subjects.  Tube or intravenous feeding is rarely needed or recommended unless the patient's condition is life threatening.

An evidence review on the management of eating disorders prepared for the Agency for Healthcare Research and Quality (AHRQ) (Berkman et al, 2006) stated that no medications are available that effectively treat patients suffering from anorexia nervosa, but a few behavioral therapies may help prevent a relapse and offer other limited benefits.  A Cochrane review on anti-depressants for anorexia nervosa (Claudino et al, 2006) also concluded that a lack of quality information precludes definite conclusions or recommendations being rendered on the use of anti-depressants in acute anorexia nervosa.  Future studies testing safer and more tolerable anti-depressants in larger, well-designed studies are needed to provide guidance for clinical practice.

The review by AHRQ also noted that both medications (e.g., fluoxetine, tricyclic anti-depressants) and behavioral therapies were found helpful in treating bulimia nervosa; however, there was no clear information about how to combine medications with behavioral treatments (Berkman et al, 2006).

In a clinical trial, Miljic et al (2006) evaluated the effects of ghrelin, a gastric hormone, on appetite, sleepiness, and neuroendocrine responses in patients with anorexia nervosa.  A total of 25 young women, including 9 patients diagnosed with anorexia nervosa with very low body weight, 6 patients who partially recovered their body weight but were still amenorrheic, and 10 constitutionally thin female subjects, without history of eating disorder, weight loss, with regular menstrual cycles, were included in the study.  Each patient received 300-min intravenous infusion of ghrelin 5 pmol/kg/min and was asked to complete visual analog scale (VAS) questionnaires hourly.  Main outcome measures were VAS scores for appetite and sleepiness, growth hormone (GH), prolactin, and cortisol responses were measured.  At baseline, patients with anorexia nervosa had significantly higher ghrelin, GH, and cortisol levels and significantly lower leptin than constitutionally thin subjects.  Responses of GH to ghrelin infusion were blunted in patients with anorexia nervosa. Ghrelin administration did not significantly affect appetite but tended to increase sleepiness in patients with anorexia nervosa.  These investigators concluded that ghrelin is unlikely to be effective as a single appetite stimulatory treatment for patients with anorexia nervosa.  These results suggested that patients with anorexia nervosa are less sensitive to ghrelin in terms of GH response and appetite than healthy controls.  Ghrelin effects on sleep need further studies.

The Mandometer treatment is a controversial program for patients with eating disorders.  It is a residential program that averages approximately 12 months in duration.  While management of patients with eating disorder has often included psychiatric treatment, advocates of the Mandometer treatment assert that standard psychiatric treatment is largely ineffective for these patients.  They believe anorexia and bulimia to be essentially the same disorder.  The Mandometer treatment for both anorexics and bulimics consists of re-teaching eating habits with a computerized, hand-held Mandometer (it gives continuous biofeedback about food intake over the course of meals), re-learning sensations of satiety, external heating by resting in warm rooms and using warm jackets, restriction of physical activity, and social re-construction to restore normal social interactions without the use of psychoactive drugs.

The clinical value of the Mandometer treatment for the management of patients with eating disorders has not been established.  Its effectiveness need to be validated by well-designed studies. Evidence for the effectiveness of the Mandometer treatment came primarily from a Swedish group (Bergh et al, 1996; Bergh et al, 2002; Court et al, 2005).  In a RCT, Bergh and colleagues (2002) assessed the effectiveness of the Mandometer treatment. A total of 16 patients, randomly selected out of a group composed of 19 patients with anorexia nervosa and 13 with bulimia nervosa, were trained to eat and recognize satiety by using computer support.  They rested in a warm room after eating, and their physical activity was restricted. The patients in the control group (n = 16) received no treatment.  Remission was defined by normal body weight (anorexia), cessation of binge eating and purging (bulimia), a normal psychiatric profile, normal laboratory test values, normal eating behavior, and resumption of social activities.  Fourteen patients went into remission after a median of 14.4 months (range of 4.9 to 26.5 months) of treatment, but only 1 patient went into remission while waiting for treatment (p = 0.0057).  Relapse is considered a major problem in patients who have been treated to remission.  Thus, these researchers reported results on a total of 168 patients who have entered their treatment program.  The estimated rate of remission was 75 %, and estimated time to remission was 14.7 months (quartile range of 9.6 greater than or equal to 32).  Six patients (7 %) of 83 who were treated to remission relapsed, but the others (93 %) have remained in remission for 12 months (quartile range of 6 to 36 months).  Because the risk of relapse is maximal in the first year after remission, the authors suggested that most patients treated with this method recover.  Furthermore, these investigators noted that although these results are promising, they realized the necessity to further develop their method.  For example, it is necessary to examine if one of their interventions is more important than another, and if their procedures should be modified.  More importantly, however, is that a RCT comparing this method with the standard of care for eating disorders is needed.  Court et al (2005) presented the case of a girl with severe anorexia nervosa who had previously been resistant to treatment, and who was subsequently treated successfully by the Mandometer program.

In a single-center, randomized, double-blind, sham-controlled study, Walpoth et al (2008) examined the effectiveness of repetitive transcranial magnetic stimulation in the treatment of bulimia nervosa.  A total of 14 women meeting DSM-IV criteria for bulimia nervosa (BN) were included in this trial.  In order to exclude patients highly responsive to placebo, all patients were first submitted to a 1-week sham treatment.  Randomization was followed by 3 weeks of active treatment or sham stimulation.  The main outcome criterion was the change in binges and purges.  Secondary outcome variables were the decrease of the Hamilton Depression Rating Scale (HDRS), the Beck Depression Inventory (BDI) and the Yale-Brown Obsessive Compulsive Scale (YBOCS) over time.  The average number of binges per day declined significantly between baseline and the end of treatment in the 2 groups.  There was no significant difference between sham and active stimulation in terms of purge behavior, BDI, HDRS and YBOCS over time.  The authors concluded that these findings indicated that repetitive transcranial magnetic stimulation in the treatment of BN does not exert additional benefit over placebo.

McElroy and colleagues (2009) discussed the role of anti-epileptic drugs (AEDs) in the management of patients with eating disorders.  Of the available AEDs, topiramate appears to have the broadest spectrum of action as an anti-binge eating, anti-purging and weight loss agent, as demonstrated in 2 placebo-controlled studies in BN and 3 placebo-controlled studies in binge-eating disorder (BED) with obesity.  Topiramate may also have beneficial effects in night-eating syndrome and sleep-related eating disorder, but controlled trials in these conditions are needed.  The results of 1 small controlled study suggest that zonisamide may have efficacy in BED with obesity.  However, both topiramate and zonisamide are associated with adverse effect profiles that may limit their use in patients with eating disorders.  Phenytoin may be effective in some patients with compulsive binge eating, especially if co-morbid EEG abnormalities are present, but available data are too varied to allow definitive conclusions to be made.  Carbamazepine and valproate may be effective in treating patients with BN or anorexia nervosa when they are used to treat an associated psychiatric (e.g., mood) or neurological (e.g., seizure) disorder; otherwise, both agents, particularly valproate, are associated with weight gain.  The authors concluded that AEDs have an emerging role in the management of some eating disorders.

Mehler and MacKenzie (2009) reviewed the evidence on the treatment of osteopenia and osteoporosis in patients with anorexia nervosa.  These researchers identified controlled clinical studies of interventions for low bone mass in patients with anorexia nervosa via searches of MEDLINE; the Cochrane Library; EMBASE; PsycINFO; and cumulative index to nursing and allied health literature.  Outcomes of interest were changes in bone mineral density and fracture incidence.  A total of 6 RCTs and 2 cohort trials examined 5 classes of medical therapy on bone mineral density outcomes.  One RCT of bisphosphonates showed no benefit and a second flawed RCT showed some benefit; 1 RCT showed a benefit of insulin-like growth factor-I; none of the 5 trials evaluating estrogen therapy showed benefit.  The authors concluded that although patients with anorexia nervosa are often losing bone mass when they should be optimizing bone growth, there is no good evidence to guide medicinal interventions.  Thus, early detection and weight restoration are of utmost importance whereas ongoing trials define effective therapies.

American Psychiatric Association guidelines on eating disorders (2006) state that, although hormone replacement therapy (HRT) is frequently prescribed to improve bone mineral density in female patients, no good supporting evidence exists either in adults or in adolescents to demonstrate its efficacy. Hormone therapy usually induces monthly menstrual bleeding, which may contribute to the patient's denial of the need to gain further weight. Before estrogen is offered, it is recommended that efforts be made to increase weight and achieve resumption of normal menses.

Guidelines on eating disorders from the American Psychiatric Association (2006) state that there is no indication for the use of bisphosphonates such as alendronate in patients with anorexia nervosa. Although there is no evidence that calcium or vitamin D supplementation reverses decreased bone mineral density, when calcium dietary intake is inadequate for growth and maintenance, calcium supplementation should be considered, and when the individual is not exposed to daily sunlight, vitamin D supplementation may be used. However, large supplemental doses of vitamin D may be hazardous.

NICE guidelines (2004) state that oral estrogen and oral DHEA do not appear to have a positive impact on bone density and hormone replacement therapy is not recommended in children and adolescents as it may cause premature fusion of the bones.

Halabe Bucay (2009) stated that anorexia nervosa is a serious, multi-factorial disease, characterized by psychiatric and neurological disturbances, which would appear to be similar to the manifestations of dementia.  Patients with anorexia nervosa present compromised affectivity, characterized by hypomanic, manic and depressive symptoms, and their cholinergic system is altered with a decrease in the release of acetylcholine.  Donepezil is a drug that been proven to be effective in the treatment of dementia, including Alzheimer's; it has been used for affective disorders and its mechanism of action is to inhibit the acetylcholinesterase enzyme to increase acetylcholine.  Thus, donepezil could be effective in treating anorexia nervosa.  However, there is a lack of evidence regarding the clinical value of cholinesterase inhibitors in treating anorexia.

In a review on the identification and treatment of eating disorders in the primary care setting, Sim and colleagues (2010) focused on the practical issues faced by primary care physicians in the management of these conditions and other issues central to the care of these complex patients with medical and psychiatric co-morbid conditions.  These investigators noted that there is little evidence to support the use of oral contraceptives in preventing bone loss in amenorrheic patients with an eating disorder.  They also stated that SSRIs have little benefits in treating eating disorder symptoms or preventing relapse in patients with anorexia nervosa.

In a placebo-controlled trial, McElroy and colleagues (2011) evaluated preliminarily the effectiveness of acamprosate in binge eating disorder (BED).  In this 10-week, flexible dose RCT, a total of 40 outpatients with BED received acamprosate (n = 20) or placebo (n = 20).  The primary outcome measure was binge eating episode frequency.  While acamprosate was not associated with a significantly greater rate of reduction in binge eating episode frequency or any other measure in the primary longitudinal analysis, in the endpoint analysis it was associated with statistically significant improvements in binge day frequency and measures of obsessive-compulsiveness of binge eating, food craving, and quality of life.  Among completers, weight and bone mass index decreased slightly in the acamprosate group but increased in the placebo group.  The authors concluded that although acamprosate did not separate from placebo on any outcome variable in the longitudinal analysis, results of the endpoint and completer analyses suggested the drug may have some utility in BED.

Brandys et al (2011) noted that brain derived neurotrophic factor (BDNF) is involved in neuroplasticity, and in the homeostatic regulation of food intake and energy expenditure.  It also has a role in stress responsivity and reward processing.  On the basis of its involvement in these various processes, BDNF can be hypothesized to be an important factor in the development and maintenance of anorexia nervosa (AN).  These reserchers meta-analytically summarized investigations of serum BDNF concentrations in people currently ill with AN, in comparison to healthy controls.  A total of 7 studies measuring BDNF in serum of individuals with AN (n = 155) and healthy controls (n = 174) were identified and included in the meta-analysis of the mean differences between case and control groups.  This study confirmed that AN is associated with decreased serum BDNF concentrations, in comparison to healthy controls.  The combined effect size (standardized mean difference, SMD) was large (SMD = -0.96; 95 % confidence interval [CI]: -1.33 to -0.59; p < 0.001).  Significant heterogeneity of effect sizes was identified (I(2) = 58.3 %; p < 0.001), which emerged as being primarily attributable to the first published study on the investigated association.  The authors concluded that meta-analytical summary of studies measuring circulating BDNF concentrations in women with AN and healthy controls confirms that it is significantly reduced in this patient group.  Moreover, difficulties associated with the measurement of BDNF have been identified and potential confounding factors have been discussed.  They stated that current data do not allow inferences to be made about causal links between levels of circulating BDNF and AN.  However, possible explanations for the relationship between BDNF and AN have been presented.

Dodds et al (2012) noted that the dopamine D(3) receptor is thought to be a potential target for treating compulsive disorders such as drug addiction and obesity.  These researchers used functional magnetic resonance imaging (fMRI) to investigate the effects the selective dopamine D(3) receptor antagonist GSK598809 on brain activation to food images in a sample of over-weight and obese binge-eating subjects.  Consistent with previous studies, processing of food images was associated with activation of a network of reward areas including the amygdala, striatum and insula.  However, brain activation to food images was not modulated by GSK598809.  The results demonstrated that D(3) receptor manipulation does not modulate brain responses to food images in over-weight and obese subjects.

Anorexia nervosa is characterized by a chronic course that is refractory to treatment in many patients and has one of the highest mortality rates of any psychiatric disorder.  Deep brain stimulation (DBS) has been applied to circuit-based neuropsychiatric diseases, such as Parkinson's disease and major depression, with promising results.  In a pilot study, Lipsman et al (2013) evaluated the safety of DBS to modulate the activity of limbic circuits and examined how this might affect the clinical features of AN.  In this prospective trial, subcallosal cingulate DBS was administered in 6 patients with chronic, severe, and treatment-refractory AN.  Eligible patients were aged 20 to 60 years, had been diagnosed with restricting or binge-purging AN, and showed evidence of chronicity or treatment resistance.  Patients underwent medical optimization pre-operatively and had baseline body-mass index (BMI), psychometric, and neuroimaging investigations, followed by implantation of electrodes and pulse generators for continuous delivery of electrical stimulation.  Patients were followed-up for 9 months after DBS activation, and the primary outcome of adverse events associated with surgery or stimulation was monitored at every follow-up visit.  Repeat psychometric assessments, BMI measurements, and neuroimaging investigations were also done at various intervals.  Deep brain stimulation was associated with several adverse events, only one of which (seizure during programming, roughly 2 weeks after surgery) was serious.  Other related adverse events were panic attack during surgery, nausea, air embolus, and pain.  After 9 months, 3 of the 6 patients had achieved and maintained a BMI greater than their historical baselines.  Deep brain stimulation was associated with improvements in mood, anxiety, affective regulation, and AN-related obsessions and compulsions in 4 patients and with improvements in quality of life in 3 patients after 6 months of stimulation.  These clinical benefits were accompanied by changes in cerebral glucose metabolism (seen in a comparison of composite PET scans at baseline and 6 months) that were consistent with a reversal of the abnormalities seen in the anterior cingulate, insula, and parietal lobe in the disorder.  The authors concluded that subcallosal cingulate DBS seems to be generally safe in this sample of patients with chronic and treatment-refractory AN.  The effectiveness of this approach awaits results from well-designed studies.

The ION™ (Individual Optimal Nutrition) analysis/profile (Metametrix, Norcross, GA) is a comprehensive combination of nutritional analyses that measures blood and urine levels of amino acids including arginine, glycine, and tryptophan  (plasma), anti-oxidants, fatty acids including monounsaturated fatty acids, polyunsaturated omega-3 and omega-t fatty acids (plasma), minerals/elements including calcium, copper, manganese, magnesium, potassium, selenium, and zinc  (red blood cells), organic acids (urine), oxidation products, toxins, and vitamins including vitamin A, B, C, D and E (serum for fat-soluble vitamins).  It supposedly offers a complete evaluation of functions that impact patients' mental and physical well-being. However, there is a lack of evidence regarding the clinical value of the ION analysis/profile in the diagnosis/evaluation of patients with eating disorders. 

Zhang et al (2013) stated that estrogen plays essential roles in the regulation of food intake, adiposity, and body weight control.  The estrogen alpha receptor, encoded by estrogen receptor 1 gene (ESR1), has been implicated with AN.  A previous study indicated that the rs2295193 polymorphism in ESR1 may confer a genetic susceptibility to AN.  In a case-control study, these researchers evaluated 195 AN probands and 93 healthy controls; 99 trios were studied in a family-based association analysis through genotyping the rs2295193 polymorphism in ESR1.  Additionally, these investigators carried out a meta-analysis of the combined sample groups.  There were no significant differences in the genotype or allele frequencies of the rs2295193 polymorphism between the AN and control groups (Ps > 0.05).  In the transmission disequilibrium test (TDT) analyses, there was no evidence for biased transmission of the G allele of rs2295193 polymorphism (p = 0.32).  In female-only samples, no significant association was observed between the rs2295193 polymorphism and AN in either case-control or TDT analyses (Ps > 0.05).  The meta-analysis revealed that no excess of transmission of the G allele in AN families (pooled odds ratio = 1.10, p = 0.79).  The authors concluded that meta-analytically combined evidence from the present genotyping and the literature showed that rs2295193 polymorphism in ESR1 is not a major genetic susceptibility factor in AN.

Slof-Op 't Landt et al (2014) noted that the female preponderance and onset around puberty in the majority of eating disorders suggest that sex hormones, like estrogens, may be involved in the onset of these disorders.  An 8- single-nucleotide polymorphisms (SNP) haplotype at the ESR1 gene was found to be associated with AN and 3 SNPs from this haplotype (rs726281, rs2295193, and rs3798577) were associated with AN and/or eating disorders.  These researchers attempted to replicate these findings in an independent cohort of 520 patients with an eating disorder, of whom 244 had AN (142 restricting type) from the GenED study and 2,810 random women from the Netherlands Twin Registry.  The frequencies of the 8-SNP haplotype and 3 ESR1 SNPs were compared between patients with an eating disorder, with AN (restricting type), with BN, and the control women.  Neither the haplotype nor the 3 ESR1 SNPs were associated with eating disorders, BN, AN, or restricting type AN.  The author concluded that despite sufficient statistical power, the associations reported by Versini et al (2010) were not replicated.

Phillips et al (2014) stated that there is currently limited understanding of the etiology of BN.  While multi-faceted etiology is likely, several neurobiological factors may play a role.  Brain derived neurotrophic factor (BDNF), a potential biomarker linked to eating and weight disorders, is one factor of recent investigation.  These investigators examined studies comparing BDNF blood levels in BN to healthy control (HC) subjects.  A systematic review of the literature was conducted utilizing 5 databases (PubMed, CINAHL, EMBASE, PsycINFO, and Medline).  Key terms included eating disorders, BDNF, and bulimia nervosa.  The authors concluded that BDNF blood levels appear lower in BN than in HC subjects; however, studies are needed to examine the influence of possible correlates including symptom severity, mood, medications, exercise, and substance use.

Gluck et al (2014) stated that ghrelin, a peptide hormone secreted mainly by the stomach, increases appetite and food intake.  Surprisingly, ghrelin levels are lower in obese individuals with BED than in obese non-BED individuals.  Acute psychological stress has been shown to raise ghrelin levels in animals and humans.  These researchers evaluated ghrelin levels after a cold pressor test (CPT) in women with BED.  They also examined the relationship between the cortisol stress response and changes in ghrelin levels.  A total of 21 obese (mean [standard deviation] BMI = 34.9 [5.8] kg/m(2)) women (10 non-BED, 11 BED) underwent the CPT, hand submerged in ice water for 2 minutes.  Blood samples were drawn for 70 minutes and assayed for ghrelin and cortisol.  There were no differences between the groups in ghrelin levels at baseline (-10 minutes).  Ghrelin rose significantly after the CPT (F = 2.4, p = 0.024) peaking at 19 minutes before declining (F = 17.9, p < 0.001), but there were no differences between the BED and non-BED groups.  Area under the curve for ghrelin was not related to ratings of pain, stress, hunger, or desire to eat after CPT.  In addition, there were no observed relationships between the area under the curves for ghrelin or cortisol after stress.  The authors concluded that although there were no differences between BED groups, there was a significant rise in ghrelin in obese humans after a stressor, consistent with other recent reports suggesting a stress-related role for ghrelin.

In a randomized, double-blind, placebo-controlled trial, White and Grilo (2013) evaluated the short-term effectiveness of bupropion for the treatment of BED in over-weight and obese women.  A total of 61 over-weight and obese (mean BMI = 35.8) women who met DSM-IV-TR research criteria for BED were randomly assigned to receive bupropion (300 mg/day) or placebo for 8 weeks.  Participants were enrolled from November 2006 to December 2010.  No dietary or lifestyle intervention was given.  Primary outcome measures were binge-eating frequency and percent BMI loss.  Secondary outcome measures were dimensional measures of eating disorder psychopathology, food craving, and depression levels.  A total of 54 (89 %) of randomized participants completed the trial, without differential drop-out between the bupropion and placebo groups.  Mixed-effects analyses revealed significant time effects for all outcomes but no significant differences between bupropion and placebo on any outcome measure except for weight loss.  Participants taking bupropion lost significantly more weight (1.8 % versus 0.6 % BMI loss; F = 10.57, p = 0.002).  The authors concluded that bupropion was well-tolerated and produced significantly greater-albeit quite modest-short-term weight loss in over-weight and obese women with BED.  Bupropion did not improve binge eating, food craving, or associated eating disorder features or depression relative to placebo.  These findings did not support bupropion as a stand-alone treatment for BED.  The authors stated that these preliminary findings regarding short-term weight losses suggested the need for larger and longer-term trials to evaluate the potential utility of bupropion for enhancing outcomes of psychological interventions that have demonstrated effectiveness for BED but fail to produce weight loss.

In a double-blind, randomized, pilot trial, Brownley et al (2013) examined if chromium may be useful in the treatment of BED.  A total of 24 over-weight adults with BED were enrolled in a 6-month double-blind placebo-controlled trial and randomly assigned to receive either 1,000 mcg chromium/day ("high dose"; n = 8) or 600 mcg chromium/day ("moderate dose"; n = 9) as chromium picolinate or placebo (n = 7).  Mixed linear regression models were used to estimate mean change in binge frequency and related psychopathology, weight, symptoms of depression, and fasting glucose.  Fasting glucose was significantly reduced in both chromium groups compared to the placebo group; similarly, numerically, but not significantly, greater reductions in binge frequency, weight, and symptoms of depression were observed in those treated with chromium versus placebo, although statistical power was limited in this pilot trial.  For fasting glucose, the findings suggested a dose-response with larger effects in the high dose compared to moderate dose group.  The authors concluded that these initial findings supported further larger trials to determine chromium's effectiveness in maintaining normal glucose regulation, reducing binge eating and related psychopathology, promoting modest weight loss, and reducing symptoms of depression in individuals with BED.  Studies designed to link the clinical effects of chromium with changes in underlying insulin, serotonin, and dopamine pathways may be especially informative.  The stated that chromium supplementation, if effective, may provide a useful, low-cost alternative to or augmentation strategy for SSRIs, which have partial efficacy in BED.

Loucas et al (2014) stated that the widespread availability of the Internet and mobile-device applications (apps) is changing the treatment of mental health problems.  These investigators reviewed the research on the effectiveness of e-therapy for eating disorders, using the methodology employed by the UK's National Institute for Health and Care Excellence (NICE).  Electronic databases were searched for published RCTs of e-therapies, designed to prevent or treat any eating disorder in all age groups.  Studies were meta-analyzed where possible, and effect sizes with confidence intervals were calculated.  The GRADE approach was used to determine the confidence in the effect estimates.  A total of 20 trials met the inclusion criteria.  For prevention, a CBT-based e-intervention was associated with small reductions in eating disorder psychopathology, weight concern and drive for thinness, with moderate confidence in the effect estimates.  For treatment and relapse prevention, various e-therapies showed some beneficial effects, but for most outcomes, evidence came from single studies and confidence in the effect estimates was low.  The authors concluded that although some positive findings were identified, the value of e-therapy for eating disorders must be viewed as uncertain.  They stated that further research, with improved methods, is needed to establish the effectiveness of e-therapy for people with eating disorders.

McElroy et al (2015) noted that psycho-pharmacologic treatment is playing a greater role in the management of patients with eating disorders.  These investigators reviewed RCTs conducted in AN, BN, BED, and other eating disorders over the past 3 years.  Fluoxetine remains the only medication approved for an eating disorder, that being BN.  Randomized controlled trials of anti-psychotics in AN have had mixed results; the only agent with some evidence of efficacy was olanzapine.  One study suggested dronabinol may induce weight gain in AN.  Preliminary studies suggested lack of efficacy of alprazolam, dehydroepiandrosterone, or physiologic estrogen replacement in AN; erythromycin in BN; and the opioid antagonist ALKS-33 in BED.  In BED with obesity or over-weight, bupropion may cause mild weight loss without seizures, and chromium may improve glucose regulation.  Also in BED, 3 RCTs suggested the stimulant prodrug lisdexamfetamine may reduce binge eating episodes, and another RCT suggested intranasal naloxone may decrease time spent binge eating.  The authors concluded that there remains a disconnection between the size of eating disorders as a public health problem and the lack of pharmacotherapy research of these conditions.

American Psychiatric Association (2006) guidelines state that antianxiety agents used selectively before meals may be useful to reduce patients' anticipatory anxiety before eating, but because eating disorder patients may have a high propensity to become dependent on benzodiazepines, these medications should be used routinely only with considerable caution.

Kucukgoncu et al (2015) stated that night eating syndrome (NES) is a unique disorder characterized by a delayed pattern of food intake in which recurrent episodes of nocturnal eating and/or excessive food consumption occur after the evening meal.  Night eating syndrome is a clinically important disorder due to its relationship to obesity, its association with other psychiatric disorders, and problems concerning sleep.  However, NES often goes unrecognized by both health professionals and patients.  The lack of knowledge regarding NES in clinical settings may lead to inadequate diagnoses and inappropriate treatment approaches.  Therefore, the proper diagnosis of NES is the most important issue when identifying NES and providing treatment for this disorder.  Clinical assessment tools such as the Night Eating Questionnaire may help health professionals working with populations vulnerable to NES.  Although NES treatment studies are still in their infancy, anti-depressant treatments and psychological therapies can be used for optimal management of patients with NES.  Other treatment options such as melatonergic medications, light therapy, and the anti-convulsant topiramate also hold promise as future treatment options.

Lisdexamfetamine Dimesylate (Vyvanse) for Binge-Eating Disorder:

On January 30, 2015, the Food and Drug Administration (FDA) expanded the approved uses of Vyvanse (lisdexamfetamine dimesylate) to treat binge-eating disorder in adults.  The drug is the first FDA-approved medication to treat this condition.  The efficacy of Vyvanse in treating binge-eating disorder was shown in 2 clinical studies that included 724 adults with moderate-to-severe binge-eating disorder.  In the studies, subjects taking Vyvanse experienced a decrease in the number of binge eating days per week and had fewer obsessive-compulsive binge eating behaviors compared to those on placebo.

McElroy et al (2015) examined the safety and effectiveness of lisdexamfetamine dimesylate to treat moderate to severe binge-eating disorder (BED).  These researchers performed a randomized, double-blind, parallel-group, forced dose titration, placebo-controlled clinical trial at 30 sites from May 10, 2011, through January 30, 2012.  Safety and intention-to-treat analyses included 259 and 255 adults with BED, respectively.  Lisdexamfetamine dimesylate at dosages of 30, 50, or 70 mg/day or placebo were provided to study participants (1:1:1:1).  Dosages were titrated across 3 weeks and maintained for 8 weeks.  These investigators followed-up participants for a mean (SD) of 7 (2) days after the last dose.  They assessed the change in binge-eating (BE) behaviors measured as days per week (baseline to week 11) with a mixed-effects model using transformed log (BE days per week) + 1.  Secondary measures included BE cessation for 4 weeks.  Safety assessments included treatment-emergent adverse events, vital signs, and change in weight.  At week 11, log-transformed BE days per week decreased with the 50-mg/day (least squares [LS] mean [SE] change, -1.49 [0.066]; p = 0.008) and 70-mg/day (LS mean [SE] change, -1.57 [0.067]; p < 0.001) treatment groups but not the 30-mg/day treatment group (LS mean [SE] change, -1.24 [0.067]; p = 0.88) compared with the placebo group.  Non-transformed mean (SD) days per week decreased for placebo and the 30-, 50-, and 70-mg/day treatment groups by -3.3 (2.04), -3.5 (1.95), -4.1 (1.52), and -4.1 (1.57), respectively.  The percentage of participants achieving 4-week BE cessation was lower with the placebo group (21.3 %) compared with the 50-mg/day (42.2 % [p = 0.01]) and 70-mg/day (50.0 % [p < 0.001]) treatment groups.  The incidence of any treatment-emergent adverse events was 58.7 % for the placebo group and 84.7 % for the combined treatment group.  In the treatment groups, 1.5 % of participants had serious treatment-emergent adverse effects.  Events with a frequency of at least 5 % and changes in heart rate were generally consistent with the known safety profile.  The mean (SD) change in body weight was -0.1 (3.09), -3.1 (3.64), -4.9 (4.43), -4.9 (3.93), and -4.3 (4.09) kg for the placebo group, the 30-, 50-, and 70-mg/day treatment groups, and the combined treatment groups, respectively (p < 0.001 for each dose versus placebo group comparison in post-hoc analysis).  The authors concluded that the 50- and 70-mg/day treatment groups demonstrated efficacy compared with the placebo group in decreased BE days, BE cessation, and global improvement.  The safety profile was generally consistent with previous findings in adults with attention-deficit/hyperactivity disorder. 

Complementary and Alternative Medicine:

In a systematic review, Fogarty and associates (2016) examined the role of complementary and alternative medicine in the treatment of those with an eating disorder. A total 0f 16 studies were included in the review.  The results of this review showed that the role of complementary and alternative medicine in the treatment of those with an eating disorder is unclear and further studies should be conducted.  A potential role was found for massage and bright light therapy for depression in those with BN and a potential role for acupuncture and relaxation therapy, in the treatment of state anxiety, for those with an eating disorder.

Evaluation of Olfaction:

Islam et al (2015) provided a systematic review on the current literature on olfactory capacity in abnormal eating behavior. The objective was to present a basis for discussion on whether research in olfaction in eating disorders may offer additional insight with regard to the complex etiopathology of eating disorders and abnormal eating behaviors.  Electronic databases (Medline, PsycINFO, PubMed, Science Direct, and Web of Science) were searched using the components in relation to olfaction and combining them with the components related to abnormal eating behavior.  Out of 1,352 articles, titles were first excluded by title (n = 64) and then by abstract and full-text resulting in a final selection of 14 articles (820 patients and 385 control participants) for this review.  The highest number of existing literature on olfaction in ED were carried out with AN patients (78.6 %) followed by BN patients (35.7 %) and obese individuals (14.3 %).  Most studies were only conducted on females.  The general findings supported that olfaction is altered in AN and in obesity and indicated toward there being little to no difference in olfactory capacity between BN patients and the general population.  The authors concluded that due to the limited number of studies and heterogeneity, this review emphasized on the importance of more research on olfaction and abnormal eating behavior.

Residential and Partial Hospital-Based Treatment:

Friedman and colleagues (2016) reviewed the current eating disorders outcome literature after residential or partial hospitalization program (PHP) treatment. Articles were identified through a systematic search of PubMed and PsycINFO.  A total of 22 PHP and 6 residential treatment studies reported response at discharge and tended to find improvement.  Fewer studies (9 PHP and 3 residential) reported outcome at some interval after discharge from treatment.  These tended to find sustained improvement.  A substantial proportion of patients were lost to follow-up, particularly for residential treatment.  Only 2 follow-up studies used controlled trials; both showed effectiveness for PHP compared with inpatient treatment with regard to maintaining symptom remission.  The authors concluded that improvement at discharge may not predict long-term outcome; and long-term follow-up studies were confounded by high drop-out rates.  These investigators stated that while higher levels of care may be essential for reversing malnutrition, there remains a lack of controlled trials showing long-term effectiveness, particularly for residential treatment settings.

Serotonin Transporter Gene Polymorphism:

Polsinelli et al (2012) stated that several lines of research have found that genes in the serotonergic system may cause susceptibility to eating disorders.  In particular, functional polymorphisms of the serotonin transporter gene (5-HTT) have been suspected to play a role in the pathogenesis of eating disorders.  Several studies have examined the association between the 5-HTTLPR polymorphism and BN.  The results of these investigations have been unclear.   In a meta-analysis, these researchers attempted to clarify the association between BN and 5-HTTLPR using statistical models not used by previous meta-analyses, and extend upon previous meta-analyses by including new samples.  PsychINFO, ISI, and PubMed databases were searched for studies published up to May 2011.  Ultimately, 6 case-control samples were included.  Data were pooled using dominant and additive models.  Both models showed a non-significant association between the 5-HTTLPR polymorphism and BN.  However, this does not detract from recent research suggesting that the 5-HTTLPR polymorphism may be responsible for the phenotypic variability in the psychopathological symptoms observed in patients with BN.  The authors concluded that future research should examine the association of BN with 5-HTTLPR using the recently proposed tri-allelic model.

Solmi and co-workers (2016) stated that growing interest focuses on the association between 5-HTTLPR polymorphism and eating disorders (ED), but published findings have been conflicting. The Italian BIO.VE.D.A. biobank provided 976 samples (735 ED patients and 241 controls) for genotyping.  These researchers conducted a literature search of studies published up to April 1, 2015, including studies reporting on 5HTTLPR genotype and allele frequencies in obesity and/or ED.  They also performed a meta-analysis, including data from BIO.VE.D.A. and compared low and high-functioning genotype and allele frequencies in ED versus controls.  Data from 21 studies, plus BIO.VE.D.A., were extracted providing information from 3,736 patients and 2,707 controls.  Neither low- nor high-functioning genotype frequencies in ED patients, with both bi- and tri-allelic models, differed from controls.  Furthermore, neither low- nor high-functioning allele frequencies in ED or in BN, in both bi- and tri-allelic models, differed from control groups.  After sensitivity analysis, results were the same in AN versus controls.  Results remained unaltered when investigating recessive and dominant models.  The authors concluded that 5HTTLPR does not seem to be associated with ED in general, or with AN or BN in particular.  Moreover, they stated that future studies in ED should explore the role of ethnicity and psychiatric co-morbidity as a possible source of bias.

Bisphosphonates and Estradiol for Anorexia Nervosa:

In a systematic review, Misra and colleagues (2016) synthesized information from key physiologic and prospective studies and trials, and provided a thorough understanding of impaired bone health in AN and its management.  Search terms included "anorexia nervosa" and "bone density" for the period 1995 to 2015, limited to articles in English.  Papers were screened manually based on journal impact factor, sample size, age of participants, and inclusion of a control group.  When necessary, these investigators included seminal papers published before 1995.  Anorexia nervosa leads to low bone mineral density (BMD), impaired bone quality and increased fracture risk.  Important determinants are low lean mass, hypogonadism, insulin-like growth factor-1 (IGF-1) deficiency, and alterations in other hormones that impact bone health.  Weight gain and menses restoration are critical for improving bone outcomes in AN.  Physiologic estrogen replacement as the transdermal patch was shown to increase bone accrual in 1 study in adolescent females with AN; however, residual deficits persist; bisphosphonates are potentially useful in adults with AN.  The authors concluded that available evidence suggested that the safest and most effective strategy to improve bone health in AN is normalization of weight with restoration of menses.  Pharmacotherapies that show promise include physiologic estradiol replacement (as the transdermal estradiol patch), and in adults, bisphosphonates.  They stated that further studies are needed to determine the best strategies to normalize BMD in AN.

Non-Invasive Brain Stimulation for Eating Disorders:

Hall and colleagues (2017) described the state of the human research literature pertaining to the use of non-invasive brain stimulation (NIBS) procedures for modulating food cravings, food consumption, and treating disorders of eating (i.e., obesity, AN, and BN).  These researchers carried out a narrative review of methods, empirical findings, and current areas of controversy.  Both single-session experimental and multi-session therapeutic modalities were considered, separately for repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) technologies.  Single-session studies involving NIBS reported more consistent effects of rTMS than tDCS, but this advantage is clearer in relation to food cravings than actual food consumption.  Multi-session therapeutic approaches have been applied to both obesity and eating disorders.  With respect to obesity, the 3 published (tDCS) and 1 ongoing trial (rTMS) have yielded promising though very preliminary findings.  Application of multi-session NIBS (predominantly rTMS) to eating disorders has also yielded promising but ultimately inconclusive results, both in relation to BN and BED.  Findings regarding excitatory NIBS in the context of AN are more controversial, with evidence of improvement in affective functioning, but a trend of iatrogenic weight loss.  The authors concluded that excitatory NIBS-particularly rTMS-can reliably reduce food cravings in single and multi-session format.  For multi-session treatment of clinical conditions, more studies are needed for both rTMS and tDCS, particularly in relation to obesity, bulimia, and BED.  Moreover, they stated that application of NIBS for anorexia is less clear at this point, and excitatory NIBS may be contraindicated on theoretical and empirical grounds.

Dalton and colleagues (2018) provided an update of the literature examining the effects of DBS, rTMS and tDCS on eating behaviors, body weight and associated symptoms in people with eating disorders (EDs) and relevant analogue populations.  Using PRISMA guidelines, these investigators reviewed articles in PubMed, Web of Science, and PsycINFO from January 1, 2013 until August 14, 2017, to update their earlier search.  Studies assessing the effects of neuro-stimulation techniques on eating and weight-related outcomes in people with EDs and relevant analogue populations were included.  Data from both searches were combined.  These researchers included a total of 32 studies (526 participants); of these, 18 were newly identified by the update search. While findings were somewhat mixed for BN, neuro-stimulation techniques have shown potential in the treatment of other EDs, in terms of reduction of ED and associated symptoms.  Studies exploring cognitive, neural, and hormonal correlates of these techniques are also beginning to appear.  The authors concluded that neuro-stimulation approaches showed promise as treatments for EDs; however, large, well-conducted RCTs are lacking.  They stated that more information is needed regarding treatment targets, stimulation parameters and mechanisms of action.

Bright Light Therapy for Eating Disorders:

Food-Specific Inhibition Training for Binge Eating Disorder:

Giel and colleagues (2017) noted that impulsivity might contribute to the development and maintenance of obesity and eating disorders.  Patients suffering from BED show an impulsive eating pattern characterized by regular binge eating episodes.  Novel behavioral interventions increasing inhibitory control could improve eating behavior in BED.  In a randomized controlled, proof-of-concept study, these researchers piloted a novel food-specific inhibition training in individuals with BED (n =22).  Patients according to SCID-I were randomly assigned to 3 sessions of a training or control condition.  In both conditions, pictures of high-caloric food items were presented in peripheral vision on a computer screen while assessing gaze behavior.  The training group had to suppress the urge to turn their gaze towards these pictures (i.e., to perform anti-saccades).  The control group was allowed to freely explore the pictures.  These investigators assessed self-reported food craving, food addiction, and wanting/liking of food pictures pre- and post-intervention.  A total of 20 subjects completed the study.  The training proved to be feasible and acceptable.  Patients of the training group significantly improved inhibitory control towards high-caloric food stimuli.  Both groups reported a significantly lower number of binge eating episodes in the last 4 weeks after termination of the study.  No changes were found in food craving, food addiction, liking, and wanting ratings.  The authors concluded that a food-specific inhibition training could be a useful element in the treatment of BED and other eating disorders; however, larger efficacy studies are needed to examine the effectiveness of this and similar training approaches.

Naso-Gastric Tube Feeding for Anorexia Nervosa:

Kells and Kelly-Weeder (2016) evaluated outcomes of naso-gastric (NG) tube feedings for individuals with AN and developed recommendations for future research, policy, and practice.  An integrative review of the research literature was conducted.  Of the 19 studies reviewed, all indicated short-term weight gain following NG feeding; 4 studies examined adherence; nearly 30 % of subjects were non-adherent as evidenced by tube manipulation; 7 studies reported psychiatric outcomes, suggesting NG feeding reduced eating disorder behaviors but not overall symptomology.  The authors concluded that NG feeding promoted short-term weight gain; however, long-term outcomes are poorly understood.  They stated that future research, using rigorous methods, is still needed to inform practice.

Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism Genotyping:

Collantoni and associates (2017) examined if catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with EDs.  These researchers conducted a systematic literature search of studies published until January 15, 2017 and added data from the Italian “Biobanca Veneta per i Disturbi Alimentari” biobank, and performed a meta-analysis comparing COMT Val158Met genotype and allele frequencies in patients with EDs and AN or BN versus controls.  A total of 10 studies plus Biobanca Veneta per i Disturbi Alimentari (ED: n = 920, controls: n = 261 controls) with 3,541 ED patients (AN = 2,388; BN = 233) and 3,684 controls were included.  There were no significant group differences in COMT Val158Met alleles and genotype frequencies between patients and controls, for all EDs pooled together [range of odds ratios (ORs): 0.96 to 1.04, p : 0.46 to 0.97, I2  = 0 %] and when analyzing separately patients with AN (ORs: 0.94 to 1.04, p : 0.31 to 0.61, I2  = 0 %) or BN (ORs: 0.80 to 1.09, p : 0.28 to 0.64, I2  = 0 to 44 %).  The authors concluded that results from 11 studies and 7,225 subjects showed that COMT Val158Met polymorphism was not associated with EDs.

Measurement of Plasma Levels of Hypothalamic Neuropeptides for the Diagnosis of Anorexia:

Pałasz and co-workers (2018) stated that due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years.  Contemporary techniques of selective molecular detection e.g., in-situ Real-Time PCR, micro-diffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced.  A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system.  The newly discovered but uncharacterized regulatory factors kisspeptin, nesfatin-1, phoenixin, and spexin have the potential to be unique modulators of stress responses and eating behavior.  Accumulating basic studies reveled an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behavior.  Nesfatin-1, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centers.  Moreover, in patients suffered from anxiety and AN, a significant, sex-related changes in the plasma neuropeptide levels occurred.  Thus, it should be noted the targeted pharmaco-modulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders.

Measurement of Plasma Levels of Adiponectin as a Prognostic Biomarker for Bulimia:

Syk and co-workers (2017) noted that BN is characterized by dysregulated eating behavior and available data suggest that adipokines may regulate food intake.  These researchers investigated a possible association between BN and adipokine levels and hypothesized that plasma (P)-adiponectin would be elevated and P-leptin and P-leptin-adiponectin-ratio would be reduced in women with BN.  The study was designed as a cross-sectional study with a longitudinal arm for patients with BN.  Plasma-adiponectin and leptin was measured in 148 female patients seeking psychiatric ambulatory care and 45 female controls.; 15 patients were diagnosed with BN and the remaining with other affective and anxiety disorders.  P-adiponectin and P-leptin levels were compared between patients with BN, patients without BN and controls.  At follow-up of 1 to 2 years, adipokines were re-assessed in patients with BN and the Eating Disorder Examination (EDE) Questionnaire was used to assess symptom severity.  Plasma adiponectin was elevated in patients with BN at baseline and at follow-up when compared to patients without BN and controls (p < 0.004 and p < 0.008, respectively).  The difference remained significant after controlling for BMI.  Plasma adiponectin was correlated to symptom severity at follow-up in patients with BN without morbid obesity (ρ = 0.72, p < 0.04).  Plasma leptin-adiponectin-ratio was significantly lower in patients with BN compared to controls (p < 0.04) and P-leptin non-significantly lower.  The authors concluded that the findings of this study indicated a stable elevation of P-adiponectin in women with BN; P-adiponectin at follow-up correlated to eating disorder symptom severity in patients without morbid obesity, indicating that P-adiponectin should be further investigated as a possible potential prognostic biomarker for BN.

Measurement of Serum Zinc Levels for the Diagnosis of Anorexia and Bulimia:

Zepf and colleagues (2017) stated that research has implicated that changes in zinc (Zn) metabolism may be associated with the biological underpinnings of EDs, especially AN.  However, current research on the role of Zn in patients with BN is scarce.  In a cross-sectional, pilot study, these investigators examined serum Zn concentrations in young patients with BN, with a focus on the stage of the disorder, comparing acutely ill and recovered patients with BN with healthy controls.  Serum Zn concentrations were obtained from healthy controls and from acutely ill and remitted young patients with BN.  Mean duration of remission was 4.0 ± 3.5 years.  Remitted patients showed elevated serum Zn concentrations when compared to controls (Cohen's d = 2.022), but concentrations were still in the normal range.  Acutely ill patients also had higher serum Zn levels when compared to controls (all values still being within the reference range, Cohen's d = 0.882).  There was no difference between acutely ill and remitted patients with BN in serum Zn concentrations.  Of note, remitted patients had a significantly higher body weight when compared to the other 2 groups.  Overall, there were no significant differences in dietary preferences with regard to Zn-containing foods between the groups.  The authors concluded that the findings of this study provided preliminary evidence that the underlying factors for changes in Zn serum concentrations in young patients with BN did not vary with regard to the stage of illness (acute versus remitted BN).  Moreover, they stated that further prospective research is needed in order to disentangle the possible interplay between serum Zn status and bulimic eating behaviors.

Neuroimaging for the Diagnosis of Anorexia and Bulimia:

Donnelly and associates (2018) noted that in recent decades there has been growing interest in the use of neuroimaging techniques to explore the structural and functional brain changes that take place in those with eating disorders.  However, to-date, the majority of research has focused on patients with AN.  This systematic review addressed a gap in the literature by providing an examination of the published literature on the neurobiology of individuals who binge eat; specifically, individuals with BN and BED.  A systematic review was conducted in accordance with PRISMA guidelines using PubMed, PsycInfo, Medline and Web of Science, and additional hand searches through reference lists.  A total of 1,003 papers were identified in the database search.  Published studies were included if they were an original research paper written in English; studied humans only; used samples of participants with a diagnosed eating disorder characterized by recurrent binge eating; included a healthy control sample; and reported group comparisons between clinical groups and healthy control groups.  A total of 32 papers were included in the systematic review.  Significant heterogeneity in the methods used in the included papers coupled with small sample sizes impeded the interpretation of results; 21 papers utilized functional magnetic resonance imaging (fMRI); 7 papers utilized MRI with 1 of these using both MRI and positron emission technology (PET); 3 studies used single-photon emission computed tomography (SPECT) and 1 study used PET only.  A small number of consistent findings emerged in individuals in the acute phase of illness with BN or BED including: volume reduction and increases across a range of areas; hypo-activity in the fronto-striatal circuits; and aberrant responses in the insula, amygdala, middle frontal gyrus and occipital cortex to a range of different stimuli or tasks; a link between illness severity in BN and neural changes; diminished attentional capacity and early learning; and in SPECT studies, increased regional cerebral blood flow in relation to disorder-related stimuli.  The authors concluded that studies included in this review were heterogeneous, preventing many robust conclusions from being drawn.  The precise neurobiology of BN and BED remains unclear and ongoing, large-scale investigations are needed.  One clear finding was that illness severity, exclusively defined as the frequency of binge eating or bulimic episodes, was related to greater neural changes.  They stated that the results of this review indicated additional research is needed, especially extending findings of reduced cortical volumes and diminished activity in regions associated with self-regulation (fronto-striatal circuits) and further exploring responses to disorder-related stimuli in people with BN and BED.

Ghrelin Agonists for the Treatment of Anorexia Nervosa:

In a randomized, double-blind, placebo-controlled study, Fazeli and colleagues (2018) examined the effects of relamorelin, an agonist of the appetite-stimulating hormone ghrelin, which has effects on gastric emptying-on weight gain and gastric emptying in women with AN.  A total of 22 out-patient women with AN (diagnosed using DSM-5 criteria) were included in this trial; 10 participants were randomly assigned to relamorelin 100 μg subcutaneously daily (mean ± SEM age of 28.9 ± 2.4 years), and 12 were randomly assigned to placebo (28.9 ± 1.9 years).  These researchers measured changes in weight and gastric emptying time using a gastric emptying breath test (GEBT) for relamorelin versus placebo after 4 weeks of treatment.  At baseline, subjects did not differ in weight, plasma ghrelin levels, or gastric emptying time; 3 subjects randomized to relamorelin stopped use of the study medication due to reported feelings of increased hunger.  After 4 weeks, there was a trend toward an increase in weight in participants randomized to relamorelin (mean ± SEM change of 0.86 ± 0.40 kg) compared to placebo (0.04 ± 0.28 kg; p = 0.07), and gastric emptying time was significantly shorter in patients taking relamorelin (median [interquartile range (IQR)]: 58.0 [51.0 to 78.0] minutes) compared to placebo (85.0 [75.8 to 100.5] minutes; p = 0.03).  The authors concluded that treatment with a ghrelin agonist in women with AN significantly decreased gastric emptying time, led to a trend in weight gain after only 4 weeks, and was well-tolerated.  Moreover, they stated that further study is needed to determine the long-term safety and efficacy of a ghrelin agonist in the treatment of AN.

Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Bulimia:

McElroy and colleagues (2018) stated that binge eating is a defining feature of the eating disorders BED and BN.  Both BED and BN are important public health problems for which there are few medical treatments.  However, almost all drugs with central nervous system (CNS)-mediated weight loss properties studied thus far in randomized, placebo-controlled trials in persons with BED or BN have been efficacious for reducing binge eating behavior.  Glucagon-like peptide-1 (GLP-1) receptor agonists, marketed for type 2 diabetes and chronic weight management, produce weight loss in a dose-dependent manner and have favorable psychiatric adverse event (AEs) profiles.  These researchers hypothesized that GLP-1 receptor agonists will safely reduce binge eating behavior in individuals with BED or BN, including those with co-occurring psychiatric disorders, and proposed that randomized, placebo-controlled clinical trials of GLP-1 receptor agonists be conducted in persons with BED and those with BN.  To support this hypothesis, the authors reviewed studies of GLP-1 and GLP-1 receptor agonists in pre-clinical models of binge eating, studies of GLP-1 levels in individuals with BED or BN, and preliminary data of GLP-1 receptor agonists in humans with abnormal eating behavior.

Neural Therapy (Superficial Injection of Local Anesthetic) for the Treatment of Bulimia:

Gurevich and colleagues (2017) noted that conventional treatment of BN is long-term, expensive, and often ineffective.  Neural therapy (NT) holds promise for treating BN in a shorter term, lower cost, and more effective manner.  Much of NT entails superficial injections of local anesthetic.  These investigators presented 2 cases of adult BN patients who responded very quickly to out-patient therapy that included NT.  A 48‐year‐old woman responded after 1 NT treatment session and had been free of BN for the last 23 months.  A 29‐year‐old man’s self‐induced vomiting was eliminated after the 1st visit.  He had 2 vomiting episodes at the 6‐month mark and had no vomiting episodes the past 12 months.  The authors stated that the main drawbacks of this report were the small sample size (n = 2), its retrospective nature with the possibility of selection bias, and the lack of controlled replication.   They stated that more vigorously designed future studies are needed to determine the contributions of the individual components and the entire regime OF NT in the treatment of BN.

Oxytocin for the Treatment of Anorexia and Bulimia:

Giel and co-workers (2017) stated that the hypothalamic neuropeptide oxytocin regulates reproductive behavior and mother-infant interaction, and conclusive studies in humans indicated that oxytocin is also a potent modulator of psychosocial function.  Pilot experiments had yielded first evidence that this neuropeptide influences eating behavior.  Brain administration of oxytocin in animals with normal weight, but also with diet-induced or genetically induced obesity, attenuated food intake and reduced body weight.  In normal-weight and obese individuals, acute intranasal oxytocin delivery curbed calorie intake from main dishes and snacks.  Such effects might converge with the poignant social and cognitive impact of oxytocin to also improve dysfunctional eating behavior in the therapeutic context.  This assumption has received support in first studies showing that oxytocin might play a role in the disease process of AN.  In contrast, respective experiments in patients with BN and BED are still scarce.  These investigators summarized currently available studies on the involvement of the oxytocin system in the pathophysiology of eating disorders, as well as on the effects of oxytocin administration in patients with these disorders.  They proposed a framework of oxytocin's role and its therapeutic potential in eating disorders that aims at integrating social and metabolic aspects of its pharmacological profile, and ponder perspectives and limitations of oxytocin use in the clinical setting.

Qsymia (Phentermine and Topiramate ER) for the Treatment of Bulimia:

Dalai and associates (2018) stated that BN and BED are associated with severe psychological and medical consequences.  Current therapies are limited, leaving up to 50 % of patients symptomatic despite treatment, underscoring the need for additional therapeutic options.  Qsymia, an FDA-approved medication for obesity, combines phentermine and topiramate ER.  Topiramate has demonstrated efficacy for both BED and BN, but limited tolerability.  Phentermine is FDA-approved for weight loss.  A rationale for combined phentermine/topiramate for BED and BN is improved tolerability and efficacy.  While a prior case series exploring Qsymia for BED showed promise, randomized studies are needed to evaluate Qsymia's safety and efficacy when re-purposed in EDs.  These researchers presented a study protocol for a phase I/IIa single-center, prospective, double-blinded, randomized, cross-over trial examining safety and preliminary efficacy of Qsymia for BED and BN.  Adults with BED (n = 15) or BN (n = 15) will be randomized 1:1 to receive 12 weeks of Qsymia (phentermine/topiramate ER, 3.75 mg/23 mg to 1 5mg/92 mg) or placebo, followed by 2-weeks wash-out and 12-weeks cross-over, where those on Qsymia receive placebo and vice versa.  Subsequently, participants will receive 8 weeks follow-up off-study medications.  The primary outcome is the number of binge days/week measured by EDE Questionnaire.  Secondary outcomes include average number of binge episodes, percentage abstinence from binge eating, and changes in weight/vitals, eating psychopathology, and mood.  The authors concluded that to their knowledge this is the first randomized, double-blind protocol investigating the safety and efficacy of phentermine/topiramate in BED and BN.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
76977	Ultrasound bone density measurement and interpretation,peripheral site(s), any method
77078	Computerized tomography, bone mineral density study, 1 or more sites
77080 - 77081	Dual energy x-ray absorptiometry (DXA), bone density study, 1 or more sites
80047	Basic metabolic panel (Calcium, ionized)
80048	Basic metabolic panel (Calcium, total)
80050	General health panel
80053	Comprehensive metabolic panel
80076	Hepatic function panel
81000 - 81005	Urinalysis
85025 - 85027	Blood count; complete (CBC)
90791 - 90792	Psychiatric diagnostic evaluation, without and with medical services
90832 - 90838	Psychotherapy
90845 - 90853	Other psychotherapy
90863	Pharmacologic management, including prescription and review of medication, when performed with psychotherapy services (List separately in addition to the code for primary procedure)
93000	Electrocardiogram, routine ECG with at least 12 leads; with interpretation and report
96101 - 96103	Psychological testing
96150 - 96151	Health and behavior assessment or re-assessment
96152 - 96155	Health and behavior intervention
CPT codes not covered for indications listed in the CPB:
No specific code:
Measurement of serum concentration of brain derived nurotrophic factor, evaluation of olfaction and serotonin transporter gene (5-HTTLPR) polymorphism testing or relaxation therapy, , catechol-O-methyltransferase (COMT) Val158Met polymorphism genotyping, measurement of plasma levels of hypothalamic neuropeptides (e.g., kisspeptin, nesfatin-1, phoenixin, and spexin), measurement of plasma levels of adiponectin as a prognostic biomarker, ghrelin agonists, neural therapy
70450 - 70470	Computed tomography, head or brain
70496	Computed tomographic angiography, head, with contrast material(s), including non-contrast images, if peformed, and image post-processing
70551 - 70553	Magnetic resonance (e.g., proton) imaging, brain (including brain stem)
70554 - 70555	Magnetic resonance imaging, brain, functional MRI
78600 - 78610	Brain imaging
84630	Zinc
90867	Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; initial, including cortical mapping, motor threshold determination, delivery and management
90868	subsequent delivery and management, per session
90869	subsequent motor threshold re-determination with delivery and management
96900	Actinotherapy (ultraviolet light)
97810 - 97814	Acupuncture
Other CPT codes related to the CPB:
90785	Interactive complexity (List separately in addition to the code for primary procedure)
96127	Brief emotional/behavioral assessment (eg, depression inventory, attention-deficit/hyperactivity disorder [ADHD] scale), with scoring and documentation, per standardized instrument
HCPCS codes not covered for indications listed in the CPB:
Food-specific inhibition training, Qsymia (phentermine and topiramate ER, Glucagon-like peptide-1 receptor agonists - no specific code:
A4633	Replacement bulb/lamp for ultraviolet light therapy system, each
E0691 - E0694	Ultraviolet light therapy system, includes bulbs/lamps, timer and eye protection
J1740	Injection, ibandronate sodium, 1 mg
J2310	Injection ,naloxone HCI, per 1 mg
J2315	Injection, naltrexone, depot form, 1 mg
J2430	Injection, pamidronate disodium, per 30 mg
J2590	Injection, oxytocin, up to 10 units
J3110	Injection, teriparatide, 10 mcg
J3489	Injection, zoledronic acid, 1 mg
S0106	Bupropion HCl sustained release tablet, 150 mg, per bottle of 60 tablets
ICD-10 codes covered if selection criteria are met:
F50.00 - F50.02	Anorexia nervosa
F50.2	Bulimia nervosa
F50.81	Binge eating disorder
F50.82	Avoidant/restrictive food intake disorder
Deep Brain Stimulation:
CPT codes not covered for indications listed in the CPB:
61863	Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array
+61864	each additional array (List separately in addition to primary procedure)
61867	Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array
+61868	each additional array (List separately in addition to primary procedure)
61880	Revision or removal of intracranial neurostimulator electrodes
61885	Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array
+61886	with connection to 2 or more electrode arrays
90867	Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; initial, including cortical mapping, motor threshold determination, delivery and management
90868	subsequent delivery and management, per session
90869	subsequent motor threshold re-determination with delivery and management
95970	Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude, pulse duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); simple or complex brain, spinal cord, or peripheral (ie, cranial nerve, peripheral nerve, sacral nerve, neuromuscular) neurostimulator pulse generator/transmitter, without programming
95971	simple spinal cord, or peripheral (ie, peripheral nerve, sacral nerve, neuromuscular) neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming
95974	complex cranial nerve neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming, with or without nerve interface testing, first hour
+95975	complex cranial nerve neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming, each additional 30 minutes after first hour (List separately in addition to code for primary procedur
95978	Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude and duration, battery status, electrode selectability and polarity, impedance and patient compliance measurements), complex deep brain neurostimulator pulse generator/transmitter, with initial or subsequent programming; first hour
95979	each additional 30 minutes after first hour (List separately in addition to code for primary procedure)
96020	Neurofunctional testing selection and administration during noninvasive imaging functional brain mapping, with test administered entirely by a physician or other qualified health care professional (ie, psychologist), with review of test results and report
HCPCS codes not covered for indications listed in the CPB :
C1767	Generator, neurostimulator (implantable), nonrechargeable
C1778	Lead, neurostimulator (implantable)
C1816	Receiver and/or transmitter, neurostimulator (implantable)
C1883	Adaptor/ extension, pacing lead or neurostimulator lead (implantable)
C1897	Lead, neurostimulator test kit (implantable)
E0745	Neuromuscular stimulator, electronic shock unit
L8680 - L8683, L8685 - L8689	Neurostimulators and accessories
L8695	External recharging system for battery (external) for use with implantable neurostimulator, replacement only
ICD-10 codes not covered for indications listed in the CPB:
F50.00 - F50.02	Anorexia nervosa
Individual Optimal Nutrition (ION) analysis/profile:
No specific code
ICD-10 codes not covered for indications listed in the CPB::
F50.00 - F50.02	Anorexia nervosa
F50.2	Bulimia nervosa

The above policy is based on the following references: