Focus Points

• The co-occurrance of bipolarity and eating disorders is an underrecognized comorbidity.

• Eating disorders with comorbid bipolarity may present with pathological affective instability and impulsivity and poor response to antidepressants.

• Empirical treatment studies of comorbid bipolarity and eating disorders have not yet been conducted, but achieving stabilization of mood is likely to be important in achieving stabilization of eating behavior.

Abstract

Epidemiological and clinical studies show that bipolar disorder and eating disorders co-occur more often than expected by chance alone, yet little is known about treatment of these disorders when they co-occur. Furthermore, eating disorders with comorbid bipolarity may present with pathological affective instability and impulsivity and poor response to antidepressants. Thus, stabilization of mood is likely to be important in achieving stabilization of eating behavior. This article briefly reviews studies examining the co-occurrence of these disorders, compares studies of their treatment, and presents preliminary suggestions for the management of the patient with bipolarity and an eating disorder.

Introduction

The co-occurrence of bipolar disorder and eating disorders has received extremely little empirical attention.1-4 To enhance awareness of this important comorbidity, this article briefly reviews studies of eating disorders (ie, anorexia nervosa, bulimia nervosa, and binge-eating disorder5,6) in persons with bipolar disorder, and studies of bipolar disorder (bipolar I disorder, bipolar II disorder, and milder or “subthreshold” forms of bipolarity5,7,8) in patients with eating disorders. It also compares available treatment response data for both conditions. The article concludes by presenting suggestions for the clinical management of the patient with bipolarity and an eating disorder.

Literature on the Comorbidity of Bipolar Disorder and Eating Disorders

Community Studies

Only four studies have assessed the co-occurrence of bipolar disorder and eating disorder syndromes in community samples.7,9-11 One study found no overlap between a group of 22 (0.6%) patients who had a lifetime manic episode and a group of 4 patients (0.1%) who met lifetime criteria for anorexia nervosa (both by Diagnostic and Statistical Manual of Mental Disorders, Third Edition,12 criteria) among 3,258 residents >18 years of age from Edmonton, Canada.9 Hypomania, subthreshold bipolar disorders, and eating disorders other than anorexia nervosa were not assessed. The other three studies, which assessed hypomania or subthreshold bipolarity and binge eating, found associations between bipolarity and eating disorders.

One of these studies,10 which used the Schedule for Affective Disorders and Schizophrenia for School-Age Children to evaluate Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),5 bipolar disorder, anorexia nervosa, and bulimia nervosa in 891 randomly selected senior high school girls from western Oregon, found that the groups with a partial-syndrome (or subthreshold) eating disorder and a full-syndrome eating disorder both had significantly higher rates of subthreshold bipolar disorder (21.7% and 26.3%, respectively) than the group with no eating disorder (3.8%).10 The groups with a partial-syndrome eating disorder or a full-syndrome eating disorder, however, had rates of full-syndrome bipolar disorder (4.3% and 0%, respectively) that were similar to the group with no eating disorder (1.2%).

In another study,11 adolescents and young adults from Munich (assessed with the Composite International Diagnostic Interview) with hypomania (1.8%) or major depressive disorder (2.7%), but not mania (2.1%), had significantly increased odds of having eating disorders (by DSM-IV criteria).11

In the fourth study,7 the comorbidity of hypomania, defined several different ways, and binge eating, defined as four binge-eating attacks in 1 year, was evaluated in 4,547 subjects from the general population of Zurich.7 Rates of binge eating were higher in all subgroups with hypomania, no matter how hypomania was defined, than in the group with depression and in the normal control group.

Taken together, these studies suggest an association between bipolar disorder, particularly soft-spectrum or subthreshold bipolarity, and both syndromal and subsyndromal eating disorders, especially those characterized by binge eating. This association occurred in adolescent females10,11 and women and men in the community.7 Of note, the lack of co-occurrence between mania and anorexia nervosa in one study9 may be due in part to the fact that both conditions are the rarest forms of their respective diagnostic spectrums.6,8

Clinical Studies of Eating Disorders in Bipolar Disorder

At least nine studies have used structured clinical interviews and diagnostic criteria to evaluate eating disorders in patients with bipolar disorder.3,13-21 Most studies have assessed the presence of anorexia nervosa and bulimia nervosa; one study3 evaluated only binge-eating disorder. Of the studies assessing anorexia nervosa and bulimia nervosa, most,13-20 though not all,21 found rates (ranging from 5.9% to 8.5%)15,20 that were higher than combined rates of anorexia nervosa and bulimia nervosa reported for general population samples (0.7% to 1.8%).22,23 In the only study assessing binge-eating disorder,3 the rate of 13.1% was substantially higher than the highest general population binge-eating disorder rate of 4.6%,24 as well as more recent general population rates of 1% to 2%.24,25

Clinical Studies of Bipolar Disorder in Eating Disorders

There are at least 18 studies of bipolar disorder in patients with eating disorders that used structured clinical interviews and diagnostic criteria to assess both conditions.2,26-40 All studies found high lifetime rates of any mood disorder (ranging from 52.1% to 91.7%),27,39 but rates of lifetime bipolar disorder ranged from 0%35,39 to 63.6%.2 This wide range in rates is likely due to several factors, including use of different definitions of bipolarity (ie, narrow versus broad), different assessment techniques, and different patient populations (inpatient versus outpatient). For example, one of the studies finding no bipolar disorder reported only rates of mania, used lay interviewers, and used eating disorder outpatients.35 Mania is less common than soft-spectrum forms of bipolar disorder,8 and lay interviewers may be less likely to diagnose subtle bipolarity than clinicians with expertise in the management of bipolar disorder.41 Indeed, the rate of mania in the general population sample in this study was only 0.1%, which is 10 times lower than the average prevalence of mania (1%).

By contrast, in the study with the highest rate of bipolarity, a group with nationally recognized expertise in the diagnosis of bipolar disorder used a broader definition of bipolarity (hypomania was diagnosed with symptoms of only 2 days duration) and patients who had been hospitalized for their eating disorders.2 The most common form of mood disorder in this study was bipolar II disorder, present in 59% of eating disorder inpatients.2

Treatment Response Data

No controlled pharmacologic or psychologic treatment studies of bipolar disorder co-occurring with an eating disorder have been conducted. Moreover, medications with well-documented efficacy in bipolar disorder (ie, mood stabilizers)42 have received very little systematic study in the treatment of eating disorders, whereas those that have been relatively well studied in eating disorders (ie, antidepressants)43-45 have received little systematic study in bipolar disorder. Nonetheless, preliminary suggestions can be made about the treatment of the patient with both disorders.

Mood Stabilizers in Eating Disorders

Although lithium is the best studied mood stabilizer in eating disorders, studies have been limited to case reports in anorexia nervosa and bulimia nervosa1,46-48; two open trials in bulimia nervosa49,50; a 4-week, double-blind, placebo-controlled trial in 16 underweight inpatients with anorexia nervosa51; and an 8-week, double-blind, placebo-controlled trial in 91 outpatient females with bulimia nervosa.52

Taken together, these reports suggest that lithium may have beneficial effects on eating behavior and mood in anorexia nervosa and bulimia nervosa. In the case reports, lithium was reported effective for weight restoration in patients with anorexia nervosa46,47 and for binge eating and purging in patients with bulimia nervosa.1,48 Some,1,48 but not all patients,46-48 had comorbid bipolar disorder. In the placebo-controlled trial of lithium in anorexia nervosa, the eight patients receiving lithium showed greater weight gain after 3 and 4 weeks of treatment than the eight patients receiving placebo, as well as significantly more improvement on an item measuring “denial and minimization of illness.”51

In the first open trial in bulimia nervosa,49 lithium reduced “bulimic episodes” in 12 of 14 women after 4–8 weeks of treatment. The author hypothesized that lithium may have been effective by treating the patients’ “mood swings and emotional instability.” In the second open trial,50 11 of 17 (65%) patients with bulimia nervosa responded to lithium in combination with cognitive-behavioral therapy (CBT). In the placebo-controlled trial in bulimia nervosa,52 lithium (mean level: 0.62 mEq/L) was not superior to placebo in decreasing binge-eating episodes, except possibly in depressed patients. However, nondepressed patients receiving placebo showed just as significant a reduction in binge eating as did nondepressed patients receiving lithium, making this study difficult to interpret. Importantly, in all these studies, lithium was well tolerated and there were no reports of serious adverse events.

Double-blind, placebo-controlled trials have established the efficacy of valproate, carbamazepine, and several atypical antipsychotics (ie, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole) in acute bipolar mania.42 Olanzapine, alone and in combination with fluoxetine, has been shown to be effective in acute bipolar depression.53 Olanzapine and lamotrigine have been shown to be superior to placebo in preventing recurrent mood episodes in bipolar I disorder, although olanzapine may be better at preventing mania and lamotrigine may be better at preventing depression.42

Although there have been no adequately sized controlled studies of any of these agents in eating disorders, both valproate54 and carbamazepine55 have been reported to be effective in isolated patients with bulimia nervosa and bipolar disorder. Also, valproate in combination with clonazepam was reported to successfully treat a patient with anorexia nervosa and epilepsy.56 However, a small (N=6), double-blind, placebo-controlled study of carbamazepine in bulimia nervosa had negative results.55 Also, valproate, which is associated with appetite stimulation and weight gain, has been reported to worsen binge eating in binge-eating disorder patients with comorbid bipolar disorder.57 Similarly, atypical antipsychotics have been reported to exacerbate or induce binge eating in patients with bulimia nervosa,58 bipolar disorder,59 and psychotic disorders.60,61

Conversely, there have been many case reports and several open studies of atypical antipsychotics, particularly olanzapine, in the successful treatment of anorexia nervosa, including in treatment-refractory cases.62-65 In these reports, olanzapine was helpful for weight restoration; for many of the core psychological symptoms of anorexia nervosa, such as fear of fatness, difficulty eating, and distorted body image; and for many of the associated symptoms of anorexia nervosa, including binge eating, purging, hyperactivity, poor insight, delusionality, depression, anxiety, insomnia, and mood instability.

Other Antiepileptic Drugs

Several anticonvulsants with unclear efficacy in bipolar disorder have been reported to be effective in eating disorders. Early positive open reports of phenytoin in patients with binge eating were followed by two small double-blind, placebo-controlled crossover trials.66,67 Although one study (N=4) was negative,66 the other (N=19) was modestly positive.67

A recent open-label, prospective, 12-week trial of zonisamide suggested this agent may be effective for reducing binge eating and body weight in 15 patients with binge-eating disorder without comorbid bipolar disorder.68

Two recently completed randomized, double-blind trials showed that topiramate was superior to placebo in binge-eating disorder40 and bulimia nervosa.69 In the first study,40 a 14-week trial of 61 patients with binge-eating disorder associated with obesity (9.8% of whom had bipolar disorder), topiramate was significantly superior to placebo in reducing binge frequency and body weight. In the second study,69 a 10-week trial of 69 patients with bulimia nervosa, topiramate was superior to placebo in reducing the frequency of days during which at least one binge-eating or purging episode occurred. There also have been several clinical reports57,70 of topiramate successfully reducing bulimia nervosa or binge-eating disorder symptoms in patients with comorbid bipolar I and II disorders, including in patients receiving mood stabilizers associated with appetite stimulation and weight gain.

The spectrum of efficacy of these particular antiepileptics in bipolar disorder is presently unclear. There is a positive, double-blind, placebo-controlled study of phenytoin in acute mania,71 and a positive, open-label study of zonisamide in acute mania.72 The efficacy data for topiramate in bipolar disorder are mixed, with five negative, double-blind, placebo-controlled trials in adult mania; one positive, double-blind, placebo-controlled trial in adolescent mania; one positive, single-blind comparison trial with bupropion in bipolar depression; and numerous positive clinical reports in soft spectrum forms of bipolarity.73,74 Moreover, some of these agents have been shown to be effective in conditions that co-occur with both bipolar and eating disorders, including topiramate75,76 for alcohol dependence and obesity, and zonisamide for obesity.77

Antidepressants

The treatment of bipolar disorder with antidepressants is controversial because of inadequate double-blind, placebo-controlled data regarding their short- and long-term efficacy in bipolar depression,42 and because clinical studies have shown that some bipolar patients destabilize upon antidepressant exposure by developing manic, hypomanic, mixed, and rapid-cycling symptoms and episodes.78,79 Nonetheless, clinical studies also show that other bipolar patients require treatment with antidepressants (typically in combination with mood stabilizers) for optimal response.80

Data regarding the efficacy of antidepressants in eating disorders are similarly mixed. Antidepressants of several different classes have been shown to be effective in bulimia nervosa and binge-eating disorder.43-45 However, induction of manic symptoms with antidepressant treatment has been described in patients with bulimia nervosa.81 In the comorbid patient, worsening of bipolar symptoms induced by antidepressant treatment is often accompanied by exacerbation of eating disorder symptoms. Such patients may do well with antidepressant reduction or discontinuation and institution of a mood stabilizer, such as lithium for patients with manic symptoms or lamotrigine for those with depressive symptoms.

In addition, double-blind, placebo-controlled studies of antidepressants in anorexia nervosa for weight restoration have had negative results.44,82 In one study,83 however, weight-restored patients with anorexia nervosa without binge eating maintained their weight to a significantly greater degree on fluoxetine than on placebo. Some anorexia nervosa patients, including those with bipolarity, often do well on combinations of antidepressants and atypical antipsychotics for weight maintenance pharmacotherapy.

Psychological Treatments in Bipolar Disorder and Eating Disorders

Several psychological treatments, including CBT, have been shown to be effective in controlled studies for binge eating and associated eating behavior pathology in bulimia nervosa and binge-eating disorder.6 CBT may also be effective for weight maintenance in anorexia nervosa, especially in combination with antidepressants.84 Meta-analyses suggest that CBT in combination with antidepressants may be more effective than either treatment alone for bulimia nervosa, although individual studies often find the combination is comparable to CBT alone.85,86 Similar psychological treatments, including CBT and psychoeducation, have also been shown to be effective in combination with pharmacotherapy in the treatment of bipolar disorder.87,88 The authors have found no reports on the use of a psychological treatment in the management of bipolar disorder co-occurring with an eating disorder. However, pharmacotherapy in combination with psychoeducational and/or cognitive-behavioral approaches may be particularly helpful in such patients.

Clinical Implications

The comorbidity between bipolar disorder and eating disorders is an important clinical issue affecting a substantial number of patients seeking treatment for mood-, eating-, and weight-related complaints. Accurate diagnosis is essential. In patients presenting with bipolar disorder, clinicians must screen for all syndromal and subsyndromal eating disorders. Similarly, clinicians must assess for the full bipolar spectrum in patients presenting with eating disorders. The suspicion of this comorbidity should be high in eating disorder patients who have been poorly responsive or refractory to treatment, especially those who have destabilized with antidepressants.

When treating patients with comorbid bipolar disorder and eating disorders, it is important to begin with agents that have mood stabilizing as opposed to mood-destabilizing properties. Indeed, initiating an antidepressant before achieving adequate mood stabilization may worsen the eating symptoms by exacerbating the bipolar disorder. However, since there have been no definitive studies of established mood stabilizers in eating disorders, and no studies that compare the effectiveness of different mood stabilizers in bipolar patients with and without different eating disorder comorbidities, no firm recommendations can be made as to which mood stabilizer would be best for which individual bipolar patient based on his or her particular comorbid eating symptoms or disorder. Preliminary treatment suggestions can be based only on extremely limited data. Thus, lithium has been reported effective in anorexia nervosa and bulimia nervosa both with and without bipolar disorder. Olanzapine has been reported to successfully treat many cases of anorexia nervosa, but atypical antipsychotics have also been associated with induction of binge eating. Topiramate, which may have mood-stabilizing properties in adolescent mania and soft-spectrum bipolar disorder and has been found to be effective in bulimia nervosa and binge-eating disorder, has been reported to stabilize mood and reduce binge eating in patients with bulimia nervosa or binge-eating disorder and comorbid bipolarity. Combination therapy of topiramate or zonisamide with weight-inducing mood stabilizers (eg, lithium, valproate, and atypical antipsychotics) is increasingly used to treat bipolar disorder associated with weight gain or obesity.42 The authors have found that addition of either of these agents to a mood stabilizer may be a useful strategy for the bipolar patient with bulimia nervosa, binge-eating disorder, binge-eating behavior and pathological weight gain, overweight, or obesity.

Lamotrigine is a good alternative to antidepressants in treating depressive symptoms. CBT may be a good alternative to antidepressants in treating symptoms of anorexia nervosa, bulimia nervosa, or binge-eating disorder in bipolar patients, especially in those who are at risk for switching or cycle acceleration with antidepressant exposure. If antidepressants are to be used in patients with concurrent bipolar and eating disorders, adequate mood stabilization should first be achieved. Antidepressants may then be added cautiously while patients are monitored carefully for emerging symptoms of hypomania, mania, mixed states, or affective cycling. Importantly, if these symptoms emerge, they may mimic or induce worsening eating disorder symptoms. Daily charting of mood, along with comorbid eating symptoms, for the patient with both disorders not only aids in assessing diagnosis and treatment response, but also helps educate the patient about the relationship between his or her bipolar and eating disorders and enhances compliance with often complex medical and psychological treatment regimens.

Conclusion

It is important for clinicians to be aware of the comorbidity that exists between bipolar disorder and eating disorders. Treatment recommendations for patients with bipolarity and eating disorders include choice of a mood stabilizer that might have some efficacy in the patient’s eating disorder (eg, an atypical antipsychotic in the bipolar I patient with anorexia nervosa, or topiramate in the bipolar II patient with binge-eating disorder). Response of both disorders to the mood stabilizer, and any subsequent medical or psychological intervention, must be closely monitored (ideally with daily charting of mood and eating symptoms). Antidepressants should always be used with caution, as they also may induce or worsen hypomanic, manic, mixed, or rapid-cycling states, which, in turn, may destabilize the co-occurring eating disorder. When antidepressants are used, adequate mood stabilization should first be achieved. CBT may be helpful in treating both bipolar disorder and eating disorders, but the bipolar disorder should be adequately pharmacologically treated in order to achieve good results. Many patients are likely to require complex combinations of medications and psychotherapy for optimal response. PP

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Dr. McElroy is professor of psychiatry, director of the Obesity and Eating Disorder Research and Treatment Program, and co-director of the Psychopharmacology Research Program at the University of Cincinnati College of Medicine in Ohio.

Dr. Kotwal is assistant professor of psychiatry at the University of Cincinnati College of Medicine.

Dr. Malhotra is director of psychiatric clinical research at United Health Network Clinical Research Associates in Canton, Ohio.

Disclosure: Dr. McElroy is a consultant to Abbott, Bristol-Myers Squibb, Elan, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Ortho-McNeil, UCB Pharma, and Wyeth; serves on the advisory boards of Abbott, Bristol-Myers Squibb, Elan, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Ortho-McNeil, UCB Pharma, and Wyeth; and is a principal or co-investigator on research studies sponsored by Elan, Eli Lilly, Forrest, GlaxoSmithKline, Merck, Ortho-McNeil, Pfizer, Sanofi-Synthelabo, and UCB Pharma. Dr. Kotwal is on the speaker’s bureaus of AstraZeneca, Ortho-McNeil, and Pfizer; has received grant support from Elan; and has received honoraria for speaking engagements from AstraZeneca, Elan, Ortho-McNeil, and Pfizer. Dr. Malhotra is a consultant to Eli Lilly, Ortho-McNeil, and Pfizer; serves on the speaker’s bureaus of Eli Lilly, Ortho-McNeil, and Pfizer; receives grant and/or research support from Bristol-Myers Squibb, Eli Lilly, Ortho-McNeil, and Pfizer; and receives honorarium and/or expenses from Bristol-Myers Squibb and GlaxoSmithKline.

Please direct all correspondence to: Susan L. McElroy, University of Cincinnati College of Medicine, PO Box 670559, 231 Albert Sabin Way, Cincinnati, OH 45267-0559; Tel: 513-558-1132; Fax: 513-558-2882; Email: susan.mcelroy@uc.edu.