Steven C. Stoner and Valerie L. Ruehter
The identification and acceptance of eating disorders as a psychiatric illness is increasingly common. They remain difficult to treat as effectiveness trials are limited, and patients are inherently resistant to accepting treatment.
Eating disorder not otherwise specified is currently the most commonly diagnosed form of eating disorder; however, proposed changes to the diagnostic criteria in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders would separate binge eating disorder as a stand-alone diagnosis.
Despite strong genetic associations for the development of eating disorders as established in monozygotic and dizygotic twin studies, a clear association with a specific genetic link mutation has not been identified.
Shifting between eating disorder diagnostic categories is possible, especially when symptom remission is not achieved with treatment.
Psychiatric comorbidities are common with all forms of eating disorders, and the differential diagnosis should generally include evaluation for depression, schizophrenia, generalized anxiety, and obsessive–compulsive and personality disorders.
During the process of caloric restoration, calories must be gradually introduced to prevent the potentially fatal complication known as refeeding syndrome.
Mortality resulting from suicide in eating disorders is not uncommon, and clinicians must monitor closely for suicidality and educate appropriately as they would during the treatment of patients with major depressive disorder with antidepressant therapy.
The current preferred treatment approach for anorexia nervosa includes a minimum of 6 months of psychotherapy, preferably cognitive behavioral therapy.
Data supporting the use of medication in anorexia nervosa are largely inconclusive. Primary limitations are small sample sizes and a bias in clinical trials because more highly motivated patients participate in studies.
Eating disorders are widely accepted as serious mental illnesses. The spectrum of eating disorders encompasses several complex diseases, sharing the pathologic feature of overevaluation of body shape and weight. Eating disorders arise from the interaction between environmental, societal, developmental, psychosocial, genetic, and biologic factors. It is estimated that 5 to 10 million women and 1 million men in the United States alone have an eating disorder. The urbanization of society, social pressure, and obsession with perfection and being thin have led to an increasing prevalence of eating disorders, with the peak onset being between 16 and 20 years of age.1–4 Anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS) are the primary disorders that have been identified.5
Despite an improved understanding of these cognitively and emotionally disabling and potentially fatal disorders, management remains difficult. Pharmacologic intervention is a small part of a comprehensive plan that emphasizes cognitive behavioral therapy (CBT) and psychotherapy.
AN occurs predominantly in girls and young women (90%) and usually presents in late adolescence (median onset 17 years of age), with new cases rarely diagnosed after age 40. The estimated prevalence of the disorder in the general population is 0.9% of females and 0.3% of males.6 Longitudinal management of AN is difficult, as patients are often resistant to weight restoration plans. Rates of relapse requiring hospitalization within 1 year exceed 30%, and crude mortality rates are estimated at 4%.7,8
The promotion of the virtues of being thin is also a potentially negative environmental factor. Many websites, for example, inappropriately promote healthy lifestyle aspects of anorexia and being thin as a means of being in control, successful, and coping with life’s pressures.9
BN also occurs predominantly in girls and young women (90%) and usually presents in adolescence or early adult life.6 Between 1% and 4.6% of adolescent and young adult females meet the diagnostic criteria for BN, with lifetime prevalence estimates of 1.5% of females and 0.5% of men.3,5,6,10,11
Eating Disorder Not Otherwise Specified
EDNOS is also described in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).3,5 Originally designed to capture eating disorder cases that did not meet diagnostic criteria of AN or BN, it has instead developed into a diagnosis of indifference. The overall prevalence of EDNOS is estimated at 3.5% among women and 2% in men, the highest prevalence of the eating disorders.6 An estimated 50% of patients with an eating disorder admitted to tertiary care settings are believed to have this condition.12 These individuals present with symptoms characteristic of eating disorders but do not meet specific diagnostic criteria. Two examples of EDNOS are night eating syndrome (NES) and binge eating disorder (BED).
NES is common in obesity clinic populations, often accompanied by depressive symptoms. The syndrome is defined by early morning anorexia, hyperphagia in the evening, nighttime insomnia, and subsequent early morning awakening.5,13 NES affects an estimated 1.5% of the general population and 8.9% to 27% of patients in obesity clinics.14–16 Patients with NES are reported to benefit from antidepressant therapy, most notably sertraline 50 to 200 mg daily.13
The diagnostic criteria for BED describe recurrent episodes of binge eating without compensatory behaviors (e.g., purging, excessive exercise, or fasting). BED typically presents later in life (older than 40 years of age), and approximately one fourth of BED patients are male.12,17 CBT and interpersonal psychotherapy are the preferred treatments, although antidepressant therapy has also demonstrated limited benefits.17
ETIOLOGY AND PATHOPHYSIOLOGY
While the exact etiology of eating disorders is not known, it is most likely a combination of genetic, biologic, developmental, and environmental factors. The biologic basis for eating disorders is difficult to delineate because it is unclear if the biologic changes are caused by or are a result of the aberrant eating behavior.
Abnormalities of the hypothalamic–pituitary–gonadal, hypothalamic–pituitary–adrenal, and hypothalamic–pituitary–thyroid axes are described as potential causes of AN. Amenorrhea is found in the majority of females with anorexia, providing support for the association with gonadotropin.11
Serotonin, norepinephrine, and dopamine have been studied extensively with well-described roles in controlling eating behaviors, with more emphasis placed on the role of serotonin. Complicating the study of these abnormalities is that their dysfunction is thought to be secondary to weight loss. There is evidence suggesting serotonin and dopamine function remain abnormal after weight restoration.18,19 Another molecular genetic target of study is brain-derived neurotrophic factor (BDNF), which is also being studied in disease states such as depression.20
There are strong genetic influences in AN and likely associations in both BN and BED. In addition, there is a high degree of premorbid anxiety and obsessive tendencies, which are also symptoms of disorders with suspected genetic associations. Twin studies have shown concordance of ∼55% and 35% in monozygotic twins and 5% and 30% in dizygotic twins for AN and BN, respectively.
One of the most common areas of research has centered on the roles of serotonin, dopamine, and norepinephrine. Serotonin is the most commonly studied neurotransmitter in patients with eating disorders, but its study is complicated by the fact that it is affected by other factors including sex hormones. In addition, reduced dietary intake of food leads to reduced levels of tryptophan, which is required for the development of serotonin.18–20 Serotonin activity is abnormally high in patients recovered from AN. In addition, serotonin 2A receptors are reduced after recovery, while dopamine receptors are increased.18–20
Genetic-based linkage studies have examined multiple single nucleotide peptides to identify predictors for developing AN, which may subsequently help identify appropriate pharmacologic treatments. Studies to date have identified possible associations with chromosomes #1, #2, #3, #4, and #13; however, there are no consistent findings to date, and studies are limited by low sample size.18,21,22 Genetic mutation studies have focused on polymorphisms of the serotonin 2A receptor.17 One acquired hereditary abnormality being studied is the presence of low-function alleles associated with the serotonin transporter (5-HTTLPR) and serotonin 2A receptor gene (–1438G/A), with findings suggesting an association with poor treatment response.23 Recent work has also associated estrogen receptor I gene (ESRI) with the restrictive form of AN.24
Emphasis is also placed on environmental factors such as social stress and psychological and developmental issues related to dysfunctional family relationships triggering abnormal eating behavior.3,11,12,25Athletes are at risk for eating disorders, especially female gymnasts, ballet dancers, figure skaters, distance runners, swimmers, male wrestlers, and body builders.26
DIAGNOSTIC CRITERIA AND CLINICAL PRESENTATION
AN and BN occur together in ∼30% to 64% of patients with eating disorders, and they may not be distinct diagnostic entities, but rather a continuum of symptoms. Thus, careful medical and psychiatric assessment at baseline is essential.27–30 Patients who initially present with either AN or BN may alternate from one to the other, especially in cases where remission is not achieved. Figure 47-1demonstrates similar and unique features of both disorders.
FIGURE 47-1 Signs and symptoms of anorexia nervosa and bulimia nervosa. (DST, dexamethasone suppression test; ECG, electrocardiogram.)
The use of purging methods is not limited to BN. Self-induced vomiting is the most common form of purging behavior.31 Laxative abuse is another form of purging common in both AN and BN, used by an estimated 3% to 70% of patients.31–33 Although ineffective as a weight-loss strategy, laxative abuse is often used in combination with other behaviors, including exercise, diuretics, enemas, and saunas. Within the diagnostic framework of AN, laxative abuse is most common in those identified with the purging subtype.31 Psychiatric symptoms of depression, anxiety, and borderline personality disorder are also reported in those who abuse laxatives.31–33
Depression, schizophrenia, obsessive–compulsive disorder (OCD), and conversion disorders should be included in the differential diagnosis of AN and BN, as eating abnormalities can be a component of these illnesses. The salient differences are the overriding drive for thinness, disturbed body image, increased energy directed at losing weight, and binge eating episodes that are relatively specific for eating disorders. Most patients with eating disorders experience relief of psychiatric symptoms on refeeding.12
The presentation of AN includes a recent period of weight loss as well as associated behaviors to promote this such as vomiting, limiting food intake, and excessive exercise. Current diagnostic criteria for AN include the refusal to maintain a minimal normal body weight, failure to make expected weight gains, intense fear and obsession about weight gain or being “fat,” distorted body image, and amenorrhea for at least three consecutive cycles.5 Patients typically lack an appreciation for the degree of weight loss experienced or are preoccupied with the idea that a part of their body is too large, despite evidence to the contrary. The DSM-IV-TR further classifies AN as restricting type (restricting food intake with no binge eating or purging behavior) or binge eating/purging type, in which patients regularly participate in bingeing or purging.5 The anorexic patient has difficulty sensing when he or she is full (satiety) and commonly complains of feeling bloated after eating. Patients also describe not feeling in control of various aspects of their life, particularly caloric intake. Comorbid psychiatric conditions, such as major depression, are frequent but should initially be considered secondary to starvation and not a true mood disorder.
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) is scheduled for release in 2013. A DSM-V work group is recommending a number of changes to the diagnosis of AN.34 These include the following: elimination of descriptive examples for body weight maintenance, adding behavior as a symptom for failing to gain weight, removal of amenorrhea as a diagnostic component, and limiting the subclassifications of AN to symptoms exhibited in the prior 3 months.22,34,35
Psychiatric comorbidity is common, as up to 75% of patients have a primary mood disorder, and there is also an association with personality disorders and anxiety disorders, such as social phobia and OCD.36 The lifetime prevalence of OCD in patients with AN is reported to be as high as 40%; the lifetime prevalence in the general population is 2.5%.36–38 The impact that psychiatric comorbidity has on treatment outcomes of AN is unknown, but it is important to understand that deprivation of food may contribute to both mood and cognitive fluctuations.
The core feature of BN is recurrent episodes of binge eating (an excessive intake of calorie-laden food over a short period of time). Persons with BN are overly sensitive about their weight and have a distorted body image. Most have normal weight, although they might fluctuate between being underweight and overweight. Patients lack control over their eating and participate in recurrent compensatory behavior to prevent weight gain. These behaviors may include self-induced vomiting; misuse of laxatives, diuretics, enemas, or other medications; strict dieting or fasting; or excessive exercise. To meet DSM-IV-TRcriteria, the binges and compensatory behaviors must occur on average at least twice weekly for 3 months.5 BN can further be differentiated by purging type (regularly engages in self-induced vomiting or the misuse of laxatives, diuretics, or enemas) or nonpurging type (uses other inappropriate compensatory behaviors, such as fasting or excessive exercise, but does not engage in purging activities).5
The DSM-V work group has proposed standardization of the frequency of symptoms for BN and BED, reducing the requirement of binges and compensatory behavior to one time per week for 3 consecutive months.34Subclassifications of BN would be eliminated in the new edition, with BN including what was formerly recognized as the purging form. The nonpurging form would now fall under the category of BED. By broadening the criteria, the size of the population in the EDNOS category should be reduced.
CLINICAL PRESENTATION Anorexia Nervosa
• Patients refuse to maintain body weight and have distorted perceptions about their body.
• Patients have obsessions and fears about eating and gaining weight.
• They complain about feeling full even when they have eaten very little food.
• Denial of symptoms and low self-esteem are the norm. Patients often feel ineffective and have a lack of self-control.
• Weakness, lethargy, cachexia, amenorrhea, vomiting, restricted food intake, inappropriate exercise, delayed sexual development, edema, delayed gastric emptying, constipation, bradycardia, hypotension, osteoporosis, dry cracking skin, lanugo, callus on dorsum of hand, perioral dermatitis, and erosion of dental enamel
• Hypokalemia, hypokalemic alkalosis, hypomagnesemia, leukopenia, QT interval prolongation, ST segment depression, U waves, hypercholesterolemia, and anemia
Other Diagnostic Tests
• Nonspecific electroencephalogram (EEG) changes
CLINICAL PRESENTATION Bulimia Nervosa
• Patients binge eat and stop when they have abdominal pain or self-induced vomiting or are interrupted by another person.
• They have a pattern of severe dieting followed by binge eating episodes.
• They are concerned about their body image but do not have the drive to thinness, which is characteristic of AN.
• Patients do not eat regular meals and do not feel satiety at the end of a meal.
• They may use laxatives for weight control.
• They have guilt, depression, and self-disparagement after binges.
• Social isolation can result from frequent bingeing.
• Chaotic and troubled personal relationships and substance abuse are common.
• Bingeing, vomiting, salivary gland inflammation, erosion of dental enamel, callus on dorsum of hand, perioral dermatitis, dental caries, parotid gland enlargement, abdominal pain, upper end of normal body weight or slightly overweight, frequent weight fluctuations, and diminished masticatory ability
• Hypokalemia, hypochloremic metabolic acidosis, and elevated serum amylase
Other Diagnostic Tests
Patients typically binge and vomit at least once daily. Caloric intake varies, but patients can consume between 5,000 and 20,000 cal (20,929 and 83,716 J) during a single binge. Patients tend to consume foods that are easy to ingest, do not require much chewing or preparation, and are high in carbohydrates or fat. Binge eating is typically secretive and precipitated by a stressful event, followed by postbinge remorse. Binges often last less than 2 hours but can extend to more than 8 hours. To compensate for the excessive caloric intake, many patients fast for prolonged periods, exercise compulsively, purge, or abuse laxatives.
Psychiatric comorbidity includes depression (up to 80%), poor impulse control, and substance abuse. Approximately 30% to 37% of bulimic patients have a personal history of substance abuse.39 Kleptomania and borderline and avoidant personality disorders are also frequently observed.36,40 Patients also commonly steal laxatives and comfort items, such as candies and clothes.11
Binge Eating Disorder
Patients with BED present with recurrent episodes of bingeing without the compensatory behaviors associated with AN or BN. It is estimated that 5% to 10% of patients seeking treatment for obesity have BED. Comorbid psychotic disorders are common and reported in greater than 70% of BED patients.41 Major depressive disorder and low self-esteem are common, although the self-deprecating focus on body image is less severe than in AN or BN.15,38Diagnostic criteria require that episodes of bingeing occur at least twice weekly over a period of 6 months.5
Proposed changes in the DSM-V are to separate out BED from the EDNOS category and change the diagnostic criteria for bingeing frequency to only once weekly.22,34 In addition, what was formerly recognized as nonpurging BN would now be classified as BED.
MEDICAL COMPLICATIONS OF EATING DISORDERS
The potential medical complications of eating disorders involve multiple organ systems. The type of medical complication encountered is dependent on the type and frequency of the eating disorder behavior. Cardiac complications may occur and can include wasted cardiac muscle, orthostatic hypotension, decreased cardiac output, arrhythmia, and QTc interval prolongation.42 During caloric restoration, there is a potential risk for developing refeeding syndrome, which can progress to fatal cardiovascular collapse. This risk is reduced by the gradual versus rapid reintroduction of calories.
Metabolic (metabolic acidosis, metabolic alkalosis) and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, and hypocalcemia) and dehydration are often seen. Elevations in bicarbonate levels during periods of hypokalemia can be an indication that the patient is inducing vomiting or using dietary weight-loss medications. Non–anion-gap acidosis has also been reported with the abuse of laxative agents. Additionally, both acute and chronic renal failures have been reported.
GI, oropharyngeal, and dental complications are frequent, as are general complaints of lethargy and fatigue. Evidence of Russell’s sign may be present signified by skin lesions on the fingers used to induce vomiting.
Hormonal changes related to the hypothalamic–pituitary–gonadal axis resulting from starvation are seen. These abnormalities include effects on estradiol, the gonadotropins (e.g., luteinizing hormone, follicle-stimulating hormone, and gonadotropin-releasing hormone), thyroid function, adrenal function, and growth hormone.11,42 Specific to female athletes is the female athlete triad, defined by the development of irregular menses, osteoporosis, and disordered eating.42,43 An athlete may experience only one or two components of the triad, or all three conditions.44 Osteopenia, osteoporosis, and infertility are potential long-term complications of suppressed estrogen. The restoration of weight, specifically in AN, reverses the bone loss, although estrogen supplementation does not appear to be effective.45 In all cases, the preferred method to address these issues is the normalization of nutrition. The impact on female fertility is not well studied, although the ability to carry a pregnancy to term or to give birth to a child of average birth weight appears reduced.
Chronic starvation can contribute to brain atrophy. Decreases in white matter and cerebrospinal fluid volumes return to normal after a healthy weight is achieved, but gray matter loss can persist.12,46,47 A thorough physical and laboratory evaluation, as described in Table 47-1, is essential to determine the severity of medical complications.5,25,48
TABLE 47-1 Physical and Laboratory Assessment of Eating Disorders
The goals for patients with eating disorders are to reduce distorted body image; restore and maintain healthy body weight; establish normal eating patterns; improve psychological, psychosocial, and physical problems; resolve contributory family problems; enhance compliance; and prevent relapse.12 Specific to BED is the additional goal of weight loss.
The long-term prognosis of patients with AN is not clear, as studies focus only on patients receiving treatment. The course of the disorder most commonly consists of a single episode with subsequent return to normal weight, although patients can still experience issues with disturbed body image, disordered eating, and other psychiatric problems.12 Some patients experience an unremitting course leading to death, whereas others suffer episodically. Remission rates appear to be a function of time in treatment as the lowest rates of remission are reported in shorter-duration followup trials, while remission rates near 80% have been reported in longer-term followup studies at 8 and 16 years.30 Despite this, it is estimated that up to 20% remain chronically ill despite weight normalization, return of menses, and improved eating behaviors.49 The prognosis is more favorable with longer followup care and younger age of onset, whereas a poorer prognosis is associated with chronic illness, lower initial weight, poor family relationships, obsessive–-compulsive personality symptoms, and the presence of bulimia or purging behavior.17,49–51 Crude mortality rates appear to be lower than historically projected at a current estimated rate of 2.8% to 4%, although when associated death occurs, it is most often the result of cardiac arrest or suicide.5,30,49
The prognosis of BN, although not well studied, appears to be better than that of AN. Patients with milder presenting symptoms who are treated as outpatients tend to do better, whereas those with electrolyte imbalances, esophagitis, dental caries, and salivary gland enlargement have a more complicated course.11 The presence of psychiatric comorbidity and greater general psychiatric symptom severity have been determined to be poor prognostic indicators. Longer rates of followup tend to have higher rates of remission, reaching 70% or higher with 5 to 20 years of followup. However, it is important to note that even in cases in which patients respond, they continue to exhibit symptoms that wax and wane, sometimes meeting full criteria for diagnosis of BN or less severe symptoms of EDNOS. Total absence of symptoms is an uncommon outcome, and residual symptoms predispose the patient to relapse.30 The actual definition of recovery varies, as once-a-month binge–purge episodes are considered by some to be recovery if their episodes were previously more frequent, whereas other clinicians consider a patient recovered only when there is complete absence of these behaviors.51
Binge Eating Disorder
Of all of the eating disorders, BED has the least amount of long-term followup data associated with it. Studies to date suggest higher remission rates (25% to 80%) in 1- and 4-year followup studies compared with findings in AN and BN longitudinal studies. These numbers are irrespective of treatment selected and treatment during the followup time frame studied. Estimated crude mortality rates range from 0% to 3% with a cumulative mortality rate reported at 0.5%.30
General Approach to Treatment
Treatment plans are individualized based on the severity of specific core features of the eating disorder and comorbid medical and psychiatric conditions. Psychiatrists, physician assistants, nurses, nutrition specialists, psychologists, and pharmacists play a role in the care of these complex patients. The absence of an adequate support system of family and friends can contribute to failed treatment. A critical first step is to determine the severity of illness, as that drives both the intensity and the setting for delivery of care. Hospitalization is generally reserved for the most severely ill patients. Some criteria for hospitalization are outlined in Table 47-2.17,25,26 Medications are rarely indicated as a sole treatment for eating disorders, and many patients refuse medication, although they remain part of the comprehensive treatment strategy.52–54 Comparative, double-blind, placebo-controlled trials are sparse, and most are limited by small sample sizes, ambivalent patient attitudes toward treatment, medical complications, and high dropout rates.55
TABLE 47-2 Criteria for Hospitalization of Patients with Eating Disorders
Many clinicians believe that extrapolation of study results to AN patients in the clinic is tenuous at best. Most patients in the clinic have a low desire to improve their overall health and well-being, based on an abnormal perception of their body image. Study results have a natural bias, as they include those patients willing to try and get better.
Evidence supports that nonpharmacologic treatments have the greatest likelihood of eliciting a response in AN patients.12,52 This includes CBT, dialectical behavioral therapy, behavioral management, interpersonal psychotherapy, nutritional counseling, and family therapy.12,25,35,56 Current guidelines suggest at least 6 months of psychotherapy is preferred.56 CBT helps the patient overcome distorted thinking, including self-worth as measured by body image, feelings of being fat despite evidence to the contrary, and denial. CBT also teaches patients how to use strategies besides eating to cope.
Interpersonal psychotherapy focuses on interpersonal relationships and functioning, whereas CBT provides positive reinforcement for weight gain.37 A combined approach of interpersonal psychotherapy and CBT is also a reasonable treatment approach.35 The benefit of treatment based on an addiction model (12-step program) is not supported by the literature.12,17 Many psychiatric symptoms in an acutely ill patient, such as depression and anxiety, diminish or disappear with weight restoration. Initial treatment is directed toward restoring a healthy weight (greater than 90% of normal weight for age-matched controls) and treating food phobias.57 After achieving medical stability and appropriate weight, therapy can be redirected toward addressing ongoing interpersonal problems, weight maintenance, cognitive restructuring, and skill development for relapse prevention.58 Oral refeeding, initially with liquid formulas if necessary, is the most common approach to weight restoration.
In severe cases when a patient refuses to eat, nasogastric refeeding is preferred over IV bolus dosing.12 Total parenteral nutrition is reserved only for the management of severely malnourished patients and if other refeeding methods fail. The decision to administer total parenteral nutrition must be made carefully, because of the potentially devastating psychological effect on patients who do not wish to gain weight.
Current clinical evidence suggests a controlled weight gain of 0.9 to 1.4 kg (2 to 3 lb) per week in inpatient settings and 0.2 to 0.5 kg (0.5 to 1 lb) per week in outpatient settings.5,54,57 Recommendations vary; however, it is considered acceptable for patients to begin refeeding at 1,000 to 1,600 cal/day (4186 to 6697 J/day) (30 to 40 cal/kg/day [126 to 167 J/kg]) with slow titration upwards until they begin to demonstrate sustained weight gain.12,56,59This can require the intake of an additional 3,500 to 7,000 cal (14,650 to 29,301 J) per week.56 Slow refeeding is important to minimize the risk of psychological and medical consequences, including refeeding syndrome, which can result in death.
Antidepressants Although many studies examined the role of antidepressants in the treatment of AN, they often have small sample sizes and large confidence intervals.60 Antidepressants currently have no role in the acute treatment of AN, unless there is another clinical indication present.12,17,52
Data suggest that medication is ineffective if a patient weighs less than 85% of his or her expected weight. Thus, antidepressants should be initiated only if depression, anxiety, obsessions, or compulsions persist after the target weight is achieved.17,57,61 The duration of treatment when antidepressants are used in this manner is unclear, but one study showed benefit in treated patients for 1 year, and current guidelines suggest 9 to 12 months of therapy.3,12,56 Antidepressants, along with psychotherapy, have been used to help maintain weight and prevent relapse, but data supporting this are limited.62 Most clinicians prefer the selective serotonin reuptake inhibitor (SSRI) antidepressants because they are better tolerated and have greater cardiovascular safety than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).12,63 Because these patients are sensitive to anticholinergic and cardiovascular effects, if TCAs or MAOIs are used, low starting doses and slow titration toward an effective dose are appropriate. The risk of cardiotoxicity in a malnourished population must not be underestimated, and a baseline electrocardiogram (ECG) should be obtained before initiation of these agents.
Fluoxetine continues to be the most widely studied SSRI in AN. Most clinicians initiate at low doses, for example, 20 mg/day, and increase to a maximum of 60 mg/day based on response and tolerability.59,60,62 Some controversy exists regarding when antidepressant therapy should be initiated. During the starvation phases of anorexia, the majority of clinical trials suggest that antidepressants are ineffective, and there is debate as to their effectiveness once weight restoration has occurred. Evidence from a 52-week, randomized, placebo-controlled clinical trial of 93 patients with the treatment arm receiving doses from 20 to 80 mg/day after weight restoration showed no difference between fluoxetine and placebo for time to relapse.64
Antipsychotics First- and second-generation antipsychotics have been utilized as a treatment for AN, specifically targeting anxiety, and obsessive and paranoid thoughts related to weight gain. First-generation antipsychotics contributed to body mass index (BMI) gains, but provided little benefit overall at reducing other core symptoms, and the associated adverse events were considered to outweigh the benefits. Second-generation antipsychotics have provided an additional alternative for treating AN, with reports of improvement in weight gain and reductions in symptoms such as depression, anxiety, and obsessive–compulsiveness. Most of the data are from case reports or small trials in both adolescents and adults using risperidone 0.5 to 2.5 mg daily, olanzapine 2.5 to 15 mg daily, and quetiapine 50 to 800 mg daily.65–68Notably, olanzapine in combination with day hospital treatment was found to be more effective than day hospital treatment alone in achieving greater weight gain and reducing obsessive symptoms.68 While some benefits have been reported, not all positive findings have been replicated, and caution is urged in patients as there is likely an increased susceptibility to some of the physiologic effects of antipsychotic medications. Optimal treatment duration is unknown, as most of the larger studies are less than or equal to 3 months in duration.
Miscellaneous Agents Metoclopramide can be helpful in reducing bloating, early satiety, and abdominal pain commonly found in AN, but it does not affect weight gain.12 Low-dose, short-acting benzodiazepines (0.25 mg alprazolam or 0.5 mg lorazepam) given before meals are useful when severe anxiety limits eating.12 Estrogen replacement has been used, but restoring menses through refeeding is a preferred approach to minimize bone density loss. Supplementation with zinc is also being studied to assist with weight restoration.35
Many clinicians believe that both diagnosis and research would be advanced by eliminating the subcategories and standardizing the number of bingeing episodes required for the diagnosis of BN. Likely this would decrease the number of individuals who currently fall into the category of EDNOS.
Outpatient-based treatment is most often recommended except in extreme cases (see Table 47-2). The nondrug strategies used in BN are similar to those used with AN, and they are equally critical to success. CBT has the strongest evidence supporting its benefit in managing BN.56 Current treatment guidelines suggest that CBT should consist of 16 to 20 sessions over a 4- to 5-month period.56 Interpersonal psychotherapy also plays a role and has a moderate degree of evidence to support its use, but it is considered less effective than CBT.12,17 Nutritional counseling, planned meals, and self-monitoring can help interrupt the binge–purge cycle. Family therapy in bulimic patients is less critical than with AN, as these patients tend to be older. A recent study suggested that CBT-guided self-care was a more effective treatment approach in adolescents than family therapy. Programs using motivational teaching and self-help guides based on CBT have shown promise.25,69–71 When such programs have been combined with medication, for example, fluoxetine, enhanced response has been reported.72,73 Data support the use of 12-step programs, but they should not be used as monotherapy.12,17 Adjunctive interventions, such as acupuncture and yoga, targeting symptoms of anxiety and depression need further study.74,75
Antidepressants Antidepressants are used in the acute and maintenance phases of BN adjunctively with nonpharmacologic approaches. A wide array of antidepressants, including TCAs, MAOIs, trazodone, serotonin–norepinephrine reuptake inhibitors (SNRIs), bupropion, and SSRIs, have been studied. Additionally, several reviews analyzing this body of literature have been published, although there continues to be limited placebo-controlled, randomized, double-blind clinical studies.17,52,76 Antidepressants are reported to reduce depression, anxiety, obsessions, and impulsive behaviors, such as binge eating and purging, and improve eating habits, although their impact on body dissatisfaction remains unclear. The presence of comorbid mood disorders is not necessary for an antidepressant response.
The benefit appears to be more robust in the acute phase of the illness, as relapse despite continued antidepressant use is common in patients who are in or near remission.17,25,54 Antidepressant response usually occurs in 6 to 8 weeks, and reduction in frequency of binge–purge behavior has been as high as 73% and as low as zero.52 Abstinence rates (elimination of bingeing and purging behaviors) with short-term use range from zero to 68%. More data are needed to determine the long-term benefits of antidepressants for preventing relapse of bulimia symptoms. One trial evaluating the impact of fluoxetine versus placebo in the maintenance phase showed a better outcome in patients receiving fluoxetine 60 mg/day, although high dropout rates in both groups blurred the overall benefit.77
SSRIs are the preferred agents because of their tolerability and because they have been studied in the largest number of patients. Fluoxetine remains the only medication with FDA approval for BN. Efficacy of other SSRI agents is still lacking, but an alternative SSRI may be considered in clinical practice for patients who do not respond to fluoxetine.76 Tolerability is the primary criterion for selecting an antidepressant in the treatment of BN because of patients’ heightened sensitivity to adverse effects and the lack of a clear difference in efficacy between the classes. Even though there is a suggestion that MAOIs produce the most robust effect, the risk of using these medications in impulsive patients limits their use.54 SNRIs have shown promising results; however, the data supporting their use are limited to case reports. Bupropion, a norepinephrine–dopamine reuptake inhibitor, is contraindicated in bulimic patients because of the increased risk of seizures.
Before initiating pharmacologic therapy, a careful baseline physical examination, ECG, and laboratory workup are essential. Underlying ECG changes secondary to hypokalemia or bradycardia and atrioventricular block from starvation can be present. There is potential for fatal outcomes secondary to cardiac arrest or suicide. All antidepressants can cause seizures; thus, a careful risk–benefit assessment is warranted if the patient has predisposing factors such as a personal or family history of seizures, cerebrovascular disease, or alcohol or sedative–hypnotic withdrawal.
Doses in the treatment of BN are similar to those in patients treated for depression, although at the higher end of the range. Readers are referred to Chapter 51 for antidepressant dosing ranges. For fluoxetine, the higher end of the dosing range, 60 mg/day, can be necessary for response.78 With all agents, most clinicians initially target the bottom to the middle of the dosing range and increase the dose if there is an inadequate response. Slow titration is needed to allow time to develop tolerance to adverse effects. If TCAs are used, serum concentration monitoring is recommended to ensure that absorption is not compromised by purging.
The time for antidepressant onset of effect in BN is unclear. In the absence of data, the definition of a therapeutic trial from the depression literature (4 to 8 weeks at a therapeutic dose) should be used. A 2010 report by Sysko et al. identified that response (defined as greater than 60% reduction in binge eating or vomiting frequency) by week 3 is a positive predictor of eventual treatment response.79 Because the majority of subjects will not experience a complete remission, and there are few data on predictors of response or whether switching to another class will improve response, a clear and specific target should be stated initially.18
Optimal duration of treatment after response is poorly defined, although most clinicians treat for 9 months to 1 year and then reevaluate. The evidence is mixed as to whether any early benefit is sustained; hence, the decision to continue treatment should be made based on both initial response and the maintenance of that benefit. If the symptoms return within a few months after antidepressant discontinuation, then the treatment might need to be reinitiated.
Figure 47-2 describes criteria for medication use in BN, but it must be noted that no evidence-based consensus for treatment has been endorsed, even with the recent guidelines, meta-analyses, and reviews of the literature.3,12,17,52,54,56,63
FIGURE 47-2 Bulimia nervosa treatment algorithm. (CBT, cognitive behavioral therapy; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.)
Miscellaneous Agents Because of the lack of evidence demonstrating their benefit, lithium and traditional anticonvulsants are reserved for bulimic patients with a comorbid bipolar affective disorder.12,80Randomized, placebo-controlled trials with topiramate have demonstrated reduced binge/purge frequency and weight loss versus placebo, although side effects including cognitive impairment and paresthesia may hinder medication adherence.81,82 Low-dose benzodiazepines before meals can help reduce anxiety associated with refeeding, although long-term use is not warranted because of the risk of abuse and dependence. One double-blind trial with ondansetron has shown benefit, but there are insufficient data to recommend a specific role for this agent.83 Data are conflicting on the opiate antagonist naltrexone with only modest improvement seen at high doses, but naltrexone is not recommended due to risk of elevated hepatic transaminases.65 Antipsychotics and appetite suppressants do not play a role in managing core symptoms of BN.17
Nonpharmacologic versus Pharmacologic Approaches
The combination of pharmacologic and nonpharmacologic measures appears to produce the best chance for a positive outcome for patients with BN.56 Antidepressants, specifically SSRIs, are the drug class of choice in bulimic patients, whereas other medications are reserved for patients with comorbid psychiatric conditions. Only in unusual circumstances should patients be treated with antidepressants alone. Evidence suggests the greatest benefit is during the acute phase of treatment, whereas data are mixed regarding their role in the prevention of relapse.
Binge Eating Disorder
As in AN and BN, CBT and interpersonal psychotherapy seem to be the most effective interventions.17 Antidepressants and anticonvulsants are the pharmacologic agents with the greatest promise in BED, but data are limited, trials are short in duration (20 weeks or less), and whether there is sustained benefit is unclear.84 Although reports are mixed, antidepressants have demonstrated efficacy as monotherapy at reducing binge eating, decreasing BMI, and improving depressed mood during the acute phases of the illness compared with placebo, but they can also be used in combination with CBT to augment response.17,65,85–87 The results from two different meta-analyses suggest that antidepressants have higher remission rates when compared with placebo.76 The majority of the data are with SSRIs given at antidepressant doses.83 Additionally, atomoxetine has been studied in the dose range of 40 to 120 mg daily and was associated with reduced binge eating and BMI.88 Topiramate 25 to 300 mg daily has produced benefit at reducing binge frequency, body weight, and BMI, with remission rates higher when combined with CBT.89,90Zonisamide (100 to 600 mg/day) alone and in combination with CBT over the course of 16-week and 1-year studies has also demonstrated efficacy at reducing binge eating and weight loss; however, in both instances there have been high dropout rates due to intolerability.76
Orlistat 120 mg given three times daily, along with a calorie-restricted diet, has produced weight reduction in obese patients with BED.91
In summary, the question of where BED fits on the diagnostic spectrum continues to be explored. Current literature suggests that two different types of pharmacologic agents (SSRIs and topiramate) hold promise in the short term, but long-term data are lacking. As with other eating disorders, nonpharmacologic treatments are the key to a successful outcome.
Results from genetic variation studies are largely inconclusive at the present time. While serotonin has been the most widely studied neurotransmitter among the eating disorders, there is not an overwhelmingly consistent response to the serotonin-enhancing medications. Often response is simply a reduction in behaviors such as bingeing and purging, but not a complete amelioration of symptoms. To date, there is no widely accepted pharmacogenomic or pharmacokinetic predictors of medication response to AN, BN, BED, or any EDNOS.
EVALUATION OF THERAPEUTIC OUTCOMES
A combination of subjective and objective measures is used to assess response in patients with AN. A reduction in the frequency and severity of abnormal eating habits, normalized exercise patterns and laboratory tests, and a sustained weight close to age-matched normals are key indicators of response. A diary recording exercise frequency, menses, food intake, patterns of eating, and associated feelings while eating is a useful tool to track progress, especially in the outpatient setting. Weekly weigh-ins on the same scale, preferably at a clinician’s office, help monitor progress early in treatment and reduce the focus on weight and anxiety caused by the variability found among different scales. Followup laboratory tests and ECGs are not part of routine monitoring unless the patient is restricting food intake, is purging, or continues to lose weight despite treatment. Inpatients require daily assessment of weight and caloric intake, vital signs, and urine output because of the severity of their illness. They also can need monitoring of bathroom privileges early in their care. A healthy weight gain of no more than 0.2 to 0.5 kg (0.4 to 1.1 lb) per week toward a goal of 90% to 95% of normal weight or a BMI greater than 18.5 kg/m2 is a critical sign of treatment success. A patient’s use of coping skills and contingencies for dealing with stress, other than manipulating food consumption, also should be assessed. Antidepressants can assist in alleviation of persistent depression, anxiety, and obsessions, after weight restoration. Improvement in mood is expected to occur within 8 weeks. Patients receiving TCAs should be evaluated for dry mouth, constipation, hypotension, and sedation. Patients receiving SSRIs should be monitored for agitation, drug-induced anorexia, nausea, weight loss, and insomnia. The decision to use long-term medication must be based on specific and sustained improvement in the target symptoms, balanced against adverse effects.
An individualized treatment and monitoring plan begins with a thorough assessment describing the baseline frequency and severity of treatment-responsive target symptoms and other associated findings. The assessment must be comprehensive, as a patient can hide his or her illness by shifting from one type of behavior to another (e.g., exercise to purging).
A comprehensive assessment includes a description of psychiatric symptoms, physical findings, frequency and severity of binge–purge episodes, laxative and ipecac use, exercise patterns, and laboratory and ECG abnormalities. Interpersonal and relationship problems should also be evaluated. Some findings indicating a more chronic course of illness, such as salivary gland inflammation and erosion of dental enamel, can take months to reverse or might never normalize. Hence, these are not sensitive indicators of early treatment response. Data describing a patient’s baseline level of functioning and previous response to treatment should be used to set goals in the current treatment plan.
Antidepressant response usually occurs within 4 to 8 weeks after the onset of treatment. If response does not occur, binge–purge behavior should be considered as a factor potentially contributing to the malabsorption of medication. If this behavior is not present, then every attempt should be made to maximize the dose. Serum concentration monitoring, when appropriate as with TCAs, should be done periodically (every 3 to 6 months if a patient is responding and tolerating the medication, or more frequently if clinically indicated). Evaluation of previously described adverse effects also should be part of the monitoring plan. If the patient responds, he or she should be followed for 6 to 12 months, and then reassessed for the need for ongoing medication. If the patient relapses on medication discontinuation, then the medication should be restarted.
Ambulatory eating disorder patients present a particular challenge to clinicians. Impulsivity associated with BN can increase the risk for suicide. Prescriptions should be limited to small supplies. In addition, pharmacists should be alert to persons who make large or frequent purchases of laxatives or ipecac syrup, as this is an indicator of possible bulimic behaviors.
The authors acknowledge the contributions of Patricia A. Marken, PharmD, and Roger W. Sommi, PharmD, authors of Chapter 66 in the seventh edition of Pharmacotherapy: A Pathophysiologic Approach.
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