www.elsevier.com/locate/jad

Journal of Affective Disord

Special review

Comorbidity of bipolar and eating disorders: distinct or related

disorders with shared dysregulations?

Susan L. McElroya,*, Renu Kotwala, Paul E. Keck Jr.a, Hagop S. Akiskalb

aPsychopharmacology Research Program, University of Cincinnati College of Medicine, P.O. Box 670559, 231 Bethesda Avenue, Cincinnati,

OH 45267-0559, USAbInternational Mood Center, Department of Psychiatry, University of California at San Diego and Veterans Administration Hospital,

San Diego, CA, USA

Received 26 April 2004; accepted 30 November 2004

Abstract

Background: The co-occurrence of bipolar and eating disorders, though of major clinical and public health importance, remains

relatively unexamined.

Methods: In reviewing the literature on this comorbidity, we compared bulimia, anorexia nervosa, bulimia nervosa, binge eating

disorders and bipolar disorders on phenomenology, course, family history, biology, and treatment response.

Results: Epidemiological studies show an association between subthreshold bipolar disorder and eating disorders in adolescents,

and between hypomania and eating disorders, especially binge eating behavior, in adults. Of the clinical studies, most show that

patients with bipolar disorder have elevated rates of eating disorders, and vice versa. Finally, the phenomenology, course,

comorbidity, family history, and pharmacologic treatment response of these disorders show considerable overlap on all of these

parameters. In particular, on phenomenologic grounds – eating dysregulation, mood dysregulation, impulsivity and compulsivity,

craving for activity and/or exercise – we findmany parallels between bipolar and eating disorders. Overall, the similarities between

these disorders were more apparent when examined in their spectrum rather than full-blown expressions.

Limitations: Despite an extensive literature on each of these disorders, studies examining their overlap across all these

parameters are relatively sparse and insufficiently systematic.

Conclusions: Nonetheless, the reviewed literature leaves little doubt that bipolar and eating disorders – particularly bulimia

nervosa and bipolar II disorder – are related. Although several antidepressants and mood stabilizers have shown promise for

eating disorders, their clinical use when these disorders co-exist with bipolarity is still very much of an art. We trust that this

review will stimulate more rigorous research in their shared putative underlying psychobiologic mechanisms which, in turn,

could lead to more rational targeted treatments.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorder; Anorexia; Bulimia; Binge eating; Comorbidity

0165-0327/$ - s

doi:10.1016/j.jad

* Correspondi

E-mail addr

ers 86 (2005) 107–127

ee front matter D 2004 Elsevier B.V. All rights reserved.

.2004.11.008

ng author. Tel.: +1 513 558 1132; fax: +1 513 558 2882.

ess: susan.mcelroy@uc.edu (S.L. McElroy).

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127108

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

2. Comorbidity of bipolar disorder and eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

2.1. Epidemiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

2.2. Clinical studies of eating disorders in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

2.3. Clinical studies of bipolar in eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

3. Phenomenologic similarities between bipolar disorder and eating disorders . . . . . . . . . . . . . . . . . . . 113

3.1. Eating and weight dysregulation as symptoms of bipolar disorder . . . . . . . . . . . . . . . . . . . . . 113

3.2. Mood dysregulation, including atypicality, behavioral activation, lability, cyclicity, and mixity, are

symptoms of eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

3.3. Impulsivity and compulsivity as features of bipolarity and eating disorders . . . . . . . . . . . . . . . . 114

4. Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

5. Family history of mood and eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

6. Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

7. Treatment response data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

7.1. Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

7.2. Other mood stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

7.3. Other antiepileptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

7.4. Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

7.5. Psychological treatments in bipolar disorder and eating disorders . . . . . . . . . . . . . . . . . . . . . 118

7.6. Summary on treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

8. Theoretical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

8.1. Theoretical models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

8.2. Co-occurrence by chance? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

8.3. Common pathophysiologic basis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

8.4. Separate disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

8.5. Toward an integration of the theoretical models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

9. Clinical implications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

10. Conflict of Interest Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

1. Introduction

It is well documented that bipolar disorder co-

occurs with substance use and anxiety disorders

(Boyd et al., 1984; Kessler et al., 1997; McElroy

et al., 2001), and that eating disorders co-occur

with depressive, substance use, and anxiety disor-

ders (Halmi et al., 1991; Braun et al., 1994;

Garfinkel et al., 1995; Bulik et al., 2004b). The

co-occurrence of bipolar disorder and eating dis-

orders, however, has received extremely little

empirical attention (Shisslak et al., 1991; Mury et

al., 1995).

To enhance understanding of the relationship

between bipolar disorder and eating disorders, we

evaluated studies of eating disorders (anorexia

nervosa [AN], bulimia nervosa [BN], and binge

eating disorder [BED]) in persons with bipolar

disorder, and studies of bipolar disorder (types I

and II and other bsoft spectrumQ forms) in persons

with eating disorders. We also compared bipolar

and eating disorders regarding phenomenology,

course, family history, biology, and treatment

response.

In undertaking this review, we used the strategy

of examining both narrow (syndromal) and broad

(spectrum) diagnostic criteria to define both groups

of disorders. We did so for several reasons. First, for

both bipolar disorder and eating disorders, when

compared to those without these disorders, persons

with subsyndromal symptoms have been shown to

be more similar to those with syndromal disorders

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127 109

with respect to distress, comorbidity, and treatment

utilization (Shisslak et al., 1995; Angst, 1998; Crow

et al., 2002; Judd and Akiskal, 2003). Second,

although important qualitative differences exist

among the individual disorders within each diag-

nostic category, considerable phenomenologic,

course, and family history data support their

inclusion in their respective broad diagnostic cate-

gories (Akiskal and Mallya, 1987; Akiskal, 2002,

2003; Fairburn and Harrison, 2003; Keel et al.,

2004). Third, the most severe forms of both

conditions – e.g., mania in bipolar disorder and

AN in the eating disorders – are each relatively

uncommon disorders; by contrast, when viewed as a

spectrum of related disorders, both bipolar and

eating disorders emerge as prevalent conditions

(see Table 1). In brief, we believe the strategy we

adopted is more likely to reveal relatively little

known relationships between the two spectrum

groups of disorders.

Table 1

Estimated lifetime prevalence rates of bipolar disorder (BP) and

eating disorders (EDs) in adults in the general population (all

ascertained through interview)

Rate (%)

Bipolar disorder (BP)a

BP I 0.0–1.6

BP II 0.5–11.0

Subthreshold BP 2.8–12.7

BP spectrum 3.0–24.2

Eating disorders (EDs)b

AN 0.1

BN 1.0

AN or BN 0.7–1.8

BED 1.5–4.6

Subthreshold EDsc 1.4–3.6

ED spectrumd 3.6–10.0

AN=anorexia nervosa; BED=binge eating disorder; BN=bulimia

nervosa.a Adapted from Kessler et al. (1994), Angst (1998), Bijl et al.

(1998), Szadoczky et al. (1998), Wells et al. (1989), Angst et al.

(2003), and Judd and Akiskal (2003).b Adapted from Wells et al. (1989), Spitzer et al. (1993), Spaner et

al. (1994), Bijl et al. (1998), Smith et al. (1998), Kringlen et al.

(2001), and Fairburn and Harrison (2003).c Estimated by doubling the sum of the prevalence rates of AN or

BN (Fairburn and Harrison, 2003).d Estimated by adding the prevalence rates of AN, BN, BED, and

subthreshold EDs.

2. Comorbidity of bipolar disorder and eating

disorders

2.1. Epidemiology

Of the four studies on the co-occurrence of bipolar

disorder and eating disorders in community samples,

some have focused on syndromal, and others on

subthreshold disorders. These studies are reviewed in

their order of sophistication with respect to the

definition of subthreshold cases.

The Fogarty et al. (1994) study, which evaluated

3258 community residents aged 18 years from

Edmonton, Canada with the Diagnostic Interview

Schedule (DIS), did not study subthreshold cases.

There was no overlap between the 22 (0.6%) persons

who had a lifetime manic episode and the 4 (0.1%)

who met lifetime criteria for AN. There also was no

overlap between AN and the 344 persons (8.6%)

with major depressive disorder either (Spaner et al.,

1994).

Wittchen et al. (2003) evaluated DSM-IV mental

disorders in 2548 adolescents and young community

adults aged 14 to 24. Persons with hypomania (1.8) or

major depressive disorder (2.7), but not mania (2.1),

had significantly increased odds of having eating

disorders. Specifically, 8.6% of individuals with

hypomania, 8.6% of those with major depressive

disorder, and 7.9% of those with mania had an eating

disorder. Unfortunately, bipolar and eating disorder

diagnostic subtypes assessed were not provided in this

otherwise interesting study.

Lewinsohn et al. (1993, 2000, 2003) used the

Schedule for Affective Disorders and Schizophrenia

for School-Age Children (K-SADS) to evaluate DSM-

III-R and subthreshold bipolar and eating disorders in

1710 randomly selected senior high school students.

There was no overlap between bipolar disorder

(lifetime prevalence 0.6%) and eating disorders (life-

time prevalence 0.8%) when assessed as threshold

conditions. However, both full threshold and sub-

threshold eating disorders significantly co-occurred

with subthreshold bipolar disorder (Lewinsohn et al.,

2004). A separate analysis examining comorbidity

was done in the sample of 810 females 1 year later

and in a stratified subset (N=538) during their 24th

year. Three eating disorder groups were identified: full

syndrome (N=19; 7 AN), partial syndrome (N=23; 9

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127110

AN), and no disorder (N=768). As in the initial

sample, the groups with a full- or a partial-syndrome

eating disorder had rates of full-syndrome bipolar

disorder (0% and 4.3%, respectively) that were similar

to the group with no eating disorder (1.2%), but both

eating disorder groups had significantly higher rates

of subthreshold bipolar disorder (26.3% and 21.7%,

respectively) than the no eating disorder group

(3.8%). At the age 24 assessment, 2 other groups (a

depressed group [n=207] and a nonaffective disorder

group [n=83]) were added to the 3 initial groups to

make 5 mutually exclusive comparison groups based

on psychopathology through age 18. At this time,

both the full- and partial-syndrome eating disorder

groups had significantly elevated period prevalence

(ages 19–23) rates of bipolar disorder (10.5% and

8.3%, respectively) compared with the no disorder

(0%) and depressed groups (0.5%).

Angst (1998) evaluated 4547 subjects from the

general population of Zurich for the comorbidity of

hypomania, defined several different ways, and

binge eating, defined as four binge eating attacks

in 1 year. Rates of binge eating were higher in all

subgroups of hypomania than in the group with

depression and the controls. Specifically, rates of

binge eating were 12.8% for DSM-IV hypomania,

22.2% for recurrent brief hypomania, 15.4% for

sporadic brief hypomania, and 14.3% for manic

symptoms, as compared to 10.8% for depression

and 4.7% for normal controls.

To recapitulate, 3 of these 4 studies found an

association between bipolar disorder, particularly in

its soft spectrum and subthreshold forms, and syn-

dromal or subsyndromal eating disorders in adoles-

cents or adults in the community. The association of

eating disorders with subthreshold, but not threshold,

forms of bipolar disorder in female adolescents

(Lewinsohn et al., 2000) is consistent with clinical

and epidemiologic research showing that subthreshold

presentations are substantially more common than

threshold forms in children and adolescents (Akiskal

et al., 1985; Lewinsohn et al., 1995; Faedda et al.,

2004).

The lack of co-occurrence between AN and mania

in the Fogarty et al. (1994) study could be due to

several reasons. The study had several limitations:

principally, that eating disorders other than AN and

bipolar subtypes other than type I were not assessed;

and that too small a number of persons with either

eating (4 cases of AN) or bipolar (22 cases of

lifetime mania) disorders were found for a realistic

examination of their comorbidity. As noted earlier,

since mania and AN represent the rarest forms of

their respective diagnostic spectra, bipolar I disorder

comorbid with AN may represent the least frequent

co-occurrence of bipolar disorder with an eating

disorder. It is also possible that bipolar disorder

might be more strongly related to BN than AN, or

conversely, soft spectrum or subthreshold bipolarity

may be more likely to occur with eating disorders

than with bipolar I disorder.

2.2. Clinical studies of eating disorders in bipolar

disorder

Table 2 summarizes studies that used structured

clinical interviews and diagnostic criteria to evaluate

eating disorders in patients with bipolar disorder. Of

the studies assessing AN and BN, most, though not

all (Vieta et al., 2001), found rates that were higher

than combined rates of AN and BN reported for

general population samples in adults of both genders

(Wells et al., 1989; Bijl et al., 1998; Wittchen et al.,

1998; Kringlen et al., 2001). In the two studies

assessing BED (Kruger et al., 1996; MacQueen et

al., 2003), the rates of 13.1% and 8.6% were higher

than the highest general population rate for BED of

4.6% (Spitzer et al., 1993) as well as more recent

general population rates of 1% to 2% (Smith et al.,

1998; Dingemans et al., 2002). In the only study

(MacQueen et al., 2003) which assessed the full

spectrum of eating disorders, 15% of patients had at

least one eating disorder, with BED occurring in

8.6%, BN in 6.5%, and AN in 2.9%. In this study,

eating disorders were significantly more common in

patients with subsyndromal affective symptoms

(27.8%) as compared to euthymic patients (4.5%)

or syndromal patients (15.5%).

In the only controlled clinical study (Schuckit et

al., 1996) on AN and BN in alcohol-dependent

women, structured interviews evaluating DSM-III-R

substance use and psychiatric disorders were con-

ducted in 2283 women and 1982 men, including

alcohol-dependent female and male probands, their

relatives, and comparison subjects. Women with a

primary diagnosis of bipolar disorder had a higher rate

Table 2

Studies of eating disorders in patients with bipolar disorder

Study Study patients Evaluation; diagnostic criteria Eating disorder findings

Strakowski et al., 1992 41 inpatients with BP disorder and

first episode mania (25 women)

SCID; DSM-III-R 3 (7.3%) had BN; 12.0% of

women and 0 of men had BN

Strakowski et al., 1993 60 inpatients with BP I disorder

and first episode mania

SCID; DSM-III-R 4 (6.6%) had BN

McElroy et al., 1995 71 inpatients with BP I disorder

and acute mania (39 women)

SCID; DSM-III-R 6 (8.5%) had AN or BN

Kruger et al., 1996 61 euthymic outpatients with

BP I disorder (N=43) or BP II

(N=18) disorder (38 women)

Semistructured Clinical

Interview; DSM-IV

8 (13.1%) had BED; 23 (37.7%)

had recurrent binge eating

episodes

Schuckit et al., 1996 14 women with BD and 1,176

women with no major

psychiatric disordera

SAGA; DSM-III-R Of women with BD, none had AN

and 1 (7.1%) had BN compared

with 4 (0.3%) and 7 (0.6%) of

controls ( pb0.01 for BN)

Cassano et al., 1998 47 inpatients with BP I disorder

with psychotic features

SCID; DSM-III-R 3 (6.4%) had AN (N=1) or BN

(N=2)

Edmonds et al., 1998 64 persons with BP I disorder

(N=44) or BP II disorder (N=11)

from a BD registry

DIGS; DSM-IV 4 (7.3%) had a DSM-IV ED

Pini et al., 1999 125 patients with BP I disorder

with psychotic features (69 women)

SCID; DSM-III-R 5 (4.0%) had BN and 3 (2.4%)

had AN

McElroy et al., 2001 288 outpatients with BPI or BP

II disorder (162 women)

SCID; DSM-IV 17 (5.9%) had AN (N=6) or

BN (N=11)

Vieta et al., 2001 129 outpatients with BP I

disorder (76 women)

SCID; DSM-IV 3 (2.3%) had BN

MacQueen et al., 2003 139 outpatients with BP I or

BP II disorder (94 women)

SCID; DSM-IV 21 (15%) had an ED; AN (N=4),

BN (N=9), and/or BED (N=12)

AN=anorexia nervosa; BD=bipolar disorder; BED=binge eating disorder; BN=bulimia nervosa; BP=Bipolar; DIGS=Diagnostic Interview for

Genetic Studies; ED=eating disorder; SAGA=Semi-Structured Assessment for the Genetics of Alcoholism; SCID=Structured Clinical Interview

for DSM.a Subjects were participants of the Collaborative Study of the Genetics of Alcoholism.

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127 111

of DSM-III-R BN (7.1%) than those with no major

psychiatric disorder (0.6%; pb0.01).

Taken together, these studies suggest that eating

disorders do occur in patients with bipolar disorder

at rates higher than those in general population

samples. Furthermore, the data suggest an intriguing

relationship between bipolar disorders and two

appetitive disorders (alcoholism and binge eating)

in females.

2.3. Clinical studies of bipolar in eating disorders

Table 3 summarizes studies that used structured

clinical interviews and diagnostic criteria to assess

bipolar disorder in patients with eating disorders. All

studies found high lifetime rates of any mood

disorder, but rates of lifetime bipolar disorder ranged

from none (Bushnell et al., 1994; Specker et al., 1994;

Bellodi et al., 2001; Fontenelle et al., 2003) to 63.6%

(Simpson et al., 1992). This wide range in rates is

likely due to several factors, including use of different

conceptualizations and definitions of bipolarity (nar-

row versus broad) and the boundaries between mood

and eating disorders (some investigators did not

diagnose mood disorders in AN patients while they

were underweight), different assessment techniques,

and different eating disorder patient populations

(outpatient versus inpatient). Nonetheless, the

weighted mean of bipolar disorder was 7.25% (see

Table 2), suggesting that the rate of this illness may be

elevated in patients with eating disorders.

At least four of the studies listed in Table 3

reported rates of bipolar disorder in different eating

disorder diagnoses. Two of these studies found that

patients with AN (including restricting AN) had rates

of bipolar disorder similar to those in patients with BN

Table 3

Studies of bipolar disorder in patients with eating disordersa

Study Study patients Evaluation;

diagnostic criteria

Any mood disorder,

N (%)

Bipolar disorder findings

Hudson et al., 1983 90 patients with AN (N=15),

BN (N=49), or both (N=25)

DIS; DSM-III 79 (87.8%) 13 (14.4%) had BD: 12 had BP

I disorder and 1 had cyclothymia

Gershon et al., 1984 24 female inpatients with

AN

SADS; DSM-III

and RDC

22 (91.7%) 2 (8.3%) had BD: 1 had BP

II and 1 had cyclothymia

Stern et al., 1984 47 females with BN and

27 controls

Semi-Structured

Interview; RDC

15 (55.6%) 5 (18.5%) BN patients had a

history of manic or hypomanic

disorder or cyclothymic

personality compared with none

of the controls

Piran et al., 1985 47 female inpatients with

BN (N=33) or AN (N=14)

SADS; DSM-III 40 (85.1%) 3 (6.4%) had BD; all 3 had

cyclothymia and BN

Walsh et al., 1985 41 female patients with

BN and 9 with AN

SADS; DSM-III 44 (88.0%) 5 (10.0%) had BD: 4 had BP II

disorder and 1 had cyclothymia

Hudson et al.,

1987a,b

70 female outpatients

with BN and 28

nonpsychiatric control

subjects

DIS; DSM-III 49 (70.0%) 8 (11.4%) BN patients had BD

compared with none of the

controls

Powers et al., 1988 30 female clinical trial

subjects with BN

SCID; DSM-III-R 19 (63.3%) 2 (6.7%) had BD: 1 had BD,

manic and 1 had BD NOS

Hudson et al., 1988 23 obese BN subjects,

47 normal weight BN

subjects, and 47 obese

subjects without BN

DIS or SADS;

DSM-III

21 (91%), 33

(70%), and

21 (45%)

1 (4%) obese BN subject had BD

and 5 (11%) normal weight BN

subjects had BD, compared with

2 (4%) obese non-BN subjects

Toner et al., 1988 47 patients who had AN

5 to 14 years earlier and

26 normal weight,

age-matched controls

DIS; DSM-III 27 (57.4%)and 3

(11.5%)

3 (6.4%) AN patients and no

controls had BDb

Keck et al., 1990 67 female outpatients with

BN and 28 nonpsychiatric

control subjects

SCID; DSM-III-R 48 (71.6%) 4 (6.0%) BN patients had BD

compared with none of the

controls

Halmi et al., 1991 62 females with AN and

62 controls

DIS; DSM-III-R 45(72.6%) 10 (16.1%) AN patients had BD

(2 mania, 2 BD, and 6 atypical

BD) compared with none of the

controls

Herzog et al., 1992;

Eddy et al., 2002

229 female patients with

AN (N=41), BN (N=98),

or both (N=90)

SADS; DSM-III-R 144 (62.9%) 11 (4.8%) had BD; 3 had BP I

disorder, 2 BP II disorder, 4 had

cyclothymia , and 2 had numerous

probable hypomanias. Also, 10

were blabileQ and 4 had SAD

Simpson et al., 1992 22 inpatients with AN

(N=7) or BN (N=15)

SADS; DSM-III-R 19 (86.4%) 14 (63.6%) had BD; 1 (4.5%) had

BP I and 13 (59.0%) had BP II

disorder

Yanovski et al., 1993 Obese subjects with BED

(N=43) or without BED

(N=85)

SCID; DSM-III-R 22 (51.2%) and

12 (14.1%)

1 (2.3%) BED subject had BD

compared with none of the non-

BED subjects

Braun et al., 1994 105 female inpatients

with AN (56) or BN (49)

SCID; DSM-III-R 66 (62.9%) 8 (7.6%) had BD

Bushnell et al., 1994 25 female patients with

BN, 20 females from the

general population with

BN, and 777 female

general population

controls

DIS; DSM-III 84%, 34% and 19% None from either the clinical or

general population groups with

BN had mania compared with 1

(0.1%) person from the general

population group

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127112

Table 3 (continued)

Study Study patients Evaluation;

diagnostic criteria

Any mood disorder,

N (%)

Bipolar disorder findings

Specker et al., 1994 Obese female clinical trial

subjects with BED (N=43)

or without BED (N=57)

SCID; DSM-IV 21 (48.8%) and

17 (29.5%)

None of the BED subjects had BD

compared with 1 (1.7%) non-BED

subject

Brewerton et al., 1995 59 female clinical trial

subjects with BN

SCID; DSM-IV 44 (74.6%) 2 (3.4%) had BD (all cyclothymia);

lifetime psychosis was an

exclusion criteria

Grilo et al., 1996 31 female inpatients with

AN (N=11), BN (N=9),

or EDNOS (N=11)

SADS and SCID;

DSM-III-R

24 (77.4%) 2 (6.5%) had BD and 4 (12.9%)

had SAD

Lilenfeld et al., 1997 47 female patients with

BN and 47 community

control females without EDs

SADS; DSM-III-R 26 (55.3%) 1 (2.1%) BN patient had BD

compared with none of the

controls

Lilenfeld et al., 1998 73 female patients with AN

(N=26) or BN (N=47)

SADS; DSM-III-R 38 (52.1%) None had BD

Telch and Stice, 1998 61 community women with

BED and 60 overweight

controls

SCID; DSM-III-R 31 (50.8%) and

17 (28.3%)

1 (1.6%) BED women had BD

compared with none of the

controls

Iwasaki et al., 2000 171 Japanese outpatients

with AN (98) or BN (73)

SCID; DSM-IV 98 (57%) 7 (4.1%) had BD; 5 had BP II

and 2 had BP NOS disorder

Ivarsson et al., 2000 51 adolescents with AN

followed for 10 years and

51 sex and age matched

controls

SCID; DSM-III-R 43 (84.3%) and

9 (17.6)

3 (5.9%) AN girls and 1

(2.0%) controls had BDc

McElroy et al., 2003 61 clinical trial subjects

with BED

SCID; DSM-IV 39 (63.9%) 6 (9.8%) had BD

Fontenelle et al., 2003 32 Brazilian outpatients

with BED

SCID; DSM-IV 11 (34.3%) None had BD

Weighted mean 1668 121 (7.25%) had BD

AN=anorexia nervosa; BED=binge eating disorder; BN=bulimia or bulimia nervosa; BP=bipolar disorder; DIS=Diagnostic and Interview

Schedule; DSM=Diagnostic and Statistical Manual; RDC=Research Diagnostic Criteria; SAD=schizoaffective disorder; SADS=Schedule for

Affective Disorders and Schizophrenia; SCID=Structured Clinical Interview for DSM.a Only studies that used operationalized diagnostic criteria and structured interviews to diagnose mood disorders and =20 subjects were

included. Also, quantitative results for bipolar vs. depressive disorders had to be presented.b AN was improved in 1 patient and asymptomatic in the other 2.c All 3 girls with AN had manic episodes upon follow-up; AN had resolved in 1.

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127 113

(Hudson et al., 1983; Simpson et al., 1992). One study

found bipolar disorder only in patients with BN or AN

with BN (5.85%), and none in patients with AN only

(Herzog et al., 1992). The other found all bipolar

cases in patients with BN (12.2%) but none in those

with AN, though all AN patients also met criteria for

BN (Walsh et al., 1985). Regarding bipolar subtype,

one controlled study (Halmi et al., 1991) found female

AN patients had a significantly higher rate of DSM-

III-R atypical bipolar disorder compared with controls

(13.3% vs. 0).

In summary, significantly high rates of bipolar

disorder in eating disorders tended to be associated

with the BN subtype.

3. Phenomenologic similarities between bipolar

disorder and eating disorders

3.1. Eating and weight dysregulation as symptoms of

bipolar disorder

Core features of eating disorders include severe

disturbances in eating behavior and weight (Dinge-

mans et al., 2002; Fairburn and Harrison, 2003). For

AN, such disturbances include severe food restriction

with or without binge eating, and inappropriate

compensatory behaviors, while weight, by definition,

is decreased. For BN, these disturbances are binge

eating and inappropriate compensatory behaviors;

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127114

weight is usually normal or increased. For BED,

binging and a general tendency to overeat without

inappropriate compensatory behaviors is usually

associated with increased weight.

Bipolar disorder is also characterized by disturban-

ces in eating behavior and weight regulation. Hypo-

mania, mania, and melancholic depression are

associated with anorexia, hypophagia, and weight

loss; whereas atypical depression is associated with

increased appetite, overeating, and weight gain

(Cassidy et al., 1957; McElroy et al., 2004b,c).

Regarding disturbances in actual body weight, mel-

ancholic depression is associated with weight loss,

whereas atypical depression is associated with over-

weight. Patients with bipolar disorder have elevated

rates of overweight and obesity compared with control

populations (McElroy et al., 2002, 2004c). Moreover,

the hyperphagia of seasonal affective disorder, which

often meets criteria for bipolar II disorder (Rosenthal

et al., 1984), has been likened to the binge eating of

BN and BED (Mury et al., 1995).

3.2. Mood dysregulation, including atypicality, behav-

ioral activation, lability, cyclicity, and mixity, are

symptoms of eating disorders

Numerous studies have found high rates of

depressive symptoms in patients with AN, BN, and

BED (Rothenberg, 1988; Pope et al., 1989; Mitchell

and Mussell, 1995), but closer inspection suggests

these conditions also share other core features of

bipolarity. Atypical depressive features are associated

with both bipolarity and binge eating (Perugi et al.,

1998; Angst et al., 2002). BN patients with major

depression have been shown to have significantly

higher ratings of hypomania than patients with major

depression without BN (Cooper and Fairburn, 1986).

In addition, binge eating may be associated with mood

changes that may have a bipolar quality. Thus, many

persons with BED describe depressive, anxious, and

other negative affects before binge eating; relief that

may be pleasurable with the act of binge eating; and

depressive affects, particularly self-reproach, guilt, or

disgust, after binge eating (McElroy and Kotwal, in

press). For example, in the only study to use the

General Behavior Inventory, a measure of bipolarity,

to assess the relationship between binge eating and

mood, the interaction between dietary restraint and

affective lability, defined as biphasic mood shifts, was

a better predictor of the severity of binge eating than

an interaction between dietary restraint and depressed

mood (Greenberg and Harvey, 1987).

Manic symptoms have also been described in

patients with AN. These have included elation,

irritability, mood lability, hyperactivity, hypertalka-

tiveness, insomnia, poor insight, delusionality, and

behavioral activation (Kron et al., 1978; Winokur et

al., 1980; Casper, 1998; Brambilla et al., 2001).

Kron et al. (1978) retrospectively evaluated the

bparadoxical featureQ of bincreased physical activityQduring the bacute dieting–weight loss phaseQ of 33

patients with AN. Twenty-five (76%) patients were

bhyperactiveQ prior to or during hospitalization; 84%

of the latter were also described as being extremely

active before they had even dieted or lost weight.

Many patients stated they were unable to sit still,

experienced a diffuse restlessness associated with

insomnia, and felt compelled to pace or exercise.

Winokur et al. (1980) reported that 21 (84 %) of 25

patients with AN described bepisodes of racing

thoughtsQ compared with 6 (24%) of 25 control

subjects. Casper (1998) reviewed historical descrip-

tions of AN and concluded that bdenial and lack of

concern,Q bcontentment and a peculiar euphoric

mental state,Q and bparadoxical liveliness and over-

activityQ appeared to be core symptoms of the

disorder. She collectively referred to the features as

bbehavioral activation.QOf importance, recent clinical research has sup-

ported the multidimensional phenomenology of bipo-

larity, but suggested that behavioral activation, rather

than euphoria, is the core feature of mania (Akiskal et

al., 2003) and hypomania (Benazzi and Akiskal,

2003). In short, these observations suggest that eating

disorders are characterized by core features of

bipolarity, including mood dysregulation, behavioral

activation, and, additionally, poor insight and psycho-

sis in AN.

3.3. Impulsivity and compulsivity as features of

bipolarity and eating disorders

Mania, hypomania, and mixed states are funda-

mentally impulsive conditions (McElroy et al., 1996),

with behavioral activation being increasingly viewed

as the core feature of mania (Akiskal et al., 2003).

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127 115

Moreover, patients with bipolar disorder have ele-

vated ratings of impulsivity even when in remission

(Swann et al., 2001; 2003), and bipolar disorder is

highly comorbid with other psychiatric disorders

characterized by impulsive features, including alcohol

and substance use, conduct, and attention deficit

hyperactivity disorders (Kessler et al., 1997; McElroy,

2004). These observations have led to the view that

impulsivity may be a trait, as well as a symptom, of

bipolarity (Swann et al., 2003).

However, bipolar disorder is also related to

obsessive compulsive disorder (OCD), which in turn

is related to the eating disorders AN and BN. In the

Epidemiologic Catchment Area study, for example,

persons with bipolar disorder had a significantly

higher risk of OCD than those with no mood disorder

and those with major depression (Chen and Dilsaver,

1995). Also, the comorbidity between bipolar disorder

and OCD is a significant clinical problem in tertiary

care centers (Perugi et al., 1999; 2002). It should not

come as a surprise then that AN and BN have each

been hypothesized to be forms of OCD spectrum

disorder from phenomenologic, comorbidity, family

history, and treatment response data (McElroy et al.,

1994; Bellodi et al., 2001).

Patients with binge eating tend to differ from those

with restrictive eating, though, by having higher

measures of impulsivity, higher rates of impulsive

behaviors (such as self-injury, substance misuse,

promiscuity, and theft), and higher rates of comorbid

mental disorders with impulsive features, such as

substance use, impulse control, and Cluster B person-

ality disorders (Bulik et al., 2004a,b; Dawe and

Loxton, 2004; Steiger, 2004). Women with AN with

restrictive eating, by contrast, tend to score higher on

measures of obsessionality, perfectionism, rigidity,

and harm avoidance. However, substantial heteroge-

neity in diagnosis along these variables has also been

reported (Steiger, 2004). Westen and Harnden-Fischer

(2001) used cluster analytic techniques to identify

three personality profiles among 103 eating disorder

patients: high functioning/perfectionistic, constricted/

overcontrolled, and emotionally dysregulated/under-

controlled. Although the last two clusters showed

substantial differentiation by lifetime eating disorder

diagnosis, the first did not. Thus, there were two

subgroups of AN patients (high-functioning/perfec-

tionistic and constricted) and two subgroups of BN

patients (high-functioning/perfectionistic and emo-

tionally dysregulated).

These findings have led to the proposal that eating

disorders may be subtyped according to their degree

of impulsive/emotionally dysregulated versus com-

pulsive/constricted features—as opposed to their

eating behavior (Dawe and Loxton, 2004; Steiger,

2004). Despite the foregoing relationships among

bipolarity, impulsivity, and OCD, we found no studies

that assessed the relationship among these 3 variables

in eating disorder patients. However, some of the

studies of impulsivity in eating disorders also found

elevated ratings of depression and obsessionality or

impulsive behavior in the groups with high impulsiv-

ity (Newton et al., 1993; Favaro and Santonastaso,

1998; Paul et al., 2002). We have hypothesized that

such observations could be accounted for by mixed

states—the co-occurrence of manic activation and

depressive inhibition, or more broadly, manic, depres-

sive, and compulsive symptoms (McElroy et al.,

1996). One possibility, therefore, is that some of the

impulsivity in patients with eating disorders (includ-

ing impulsivity that co-exists or rapidly alternates with

compulsivity) could reflect comorbid bipolarity,

including subthreshold forms of mixed states (Akiskal

and Benazzi, 2003).

It is also important to point out in this context that

temperamentally, bipolar II patients are notorious for

their craving for activity—they can indeed be

considered bactivity junkiesQ (Akiskal, in press).

bExercise addictionQ (Klein et al., 2004) among AN,

and many bulimic patients, though a somewhat

different pathology, nonetheless highlights the impor-

tance of behavioral activation in eating disorders.

In sum, bipolar disorder and eating disorders share

important phenomenological similarities regarding

impaired regulation in eating behavior, weight main-

tenance, mood, and control of activity and impulses.

How much these phenomenologic similarities repre-

sents overlap of disorders (true comorbidity) versus

shared underlying behavioral dimensions needs fur-

ther study.

4. Course

Bipolar and eating disorders show similarities in

onset and course. Both disorders often begin in

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127116

adolescence or early adulthood, and both may be

episodic or chronic (Goodwin and Jamison, 1990;

Keel and Mitchell, 1997; Steinhausen, 2002; Fairburn

and Harrison, 2003). The course of eating disorders

may be phasic or cyclic, like that of bipolar disorder.

Fairburn and Harrison (2003) have discussed how

eating disorder patients tend to bmigrateQ among the

diagnostic categories. For example, about half of

patients of AN develop BN. In addition, the long-term

course of bipolar I and II disorders (Judd et al., 2002,

2003), AN (Rothenberg, 1988; R3stam et al., 1995),

and BN (Keel et al., 2000) are all often characterized

by a predominance of depressive symptoms. Lastly,

like bipolar disorder, AN is associated with increased

mortality from suicide (Nielsen et al., 2001; Osby et

al., 2001).

5. Family history of mood and eating disorders

Controlled family interview studies (in which

first-degree relatives are directly assessed for psy-

chopathology) have consistently found elevated rates

of both bipolar and unipolar depressive disorders in

the first-degree relatives of probands with bipolar

disorder (Goodwin and Jamison, 1990; Kelsoe,

2003). Such studies have also consistently found

elevated rates of both eating and unipolar depressive

disorders in the first-degree relatives of probands

with AN and/or BN (Lilenfeld et al., 1998; Hudson

et al., 2001; Mangweth et al., 2003). Moreover,

adoption and twin studies have shown that heritable

factors contribute substantially to the familiality of

both bipolar (McGuffin et al., 2003) and eating

disorders (Bulik et al., 1998, 2000).

Although we found no controlled family inter-

view studies that evaluated eating disorders in the

relatives of bipolar probands, six studies evaluated

bipolar disorder in the relatives of eating disorder

probands. Three of these studies found significantly

higher rates of bipolar disorder in the relatives of

probands with AN (Winokur et al., 1980; Gershon

et al., 1984) or BN (Kassett et al., 1989) than in

those of controls. The other three studies found

elevated rates of depressive disorders, but not

bipolar disorder, in the relatives of eating disorder

probands (Logue et al,. 1989; Lilenfeld et al., 1997,

1998).

In sum, the consistent findings of high familial

rates of depressive disorders in the families of both

bipolar and eating disorder probands, the mixed

findings of high familial rates of bipolar disorder in

eating disorder probands, the likely relationship of

recurrent major depression to bipolar disorder (Good-

win and Jamison, 1990; Akiskal, 2003), and the high

rates of misattribution of bipolarity, especially soft

spectrum bipolarity, to unipolar depressive disorder

(Akiskal, 1983; Cassano et al., 2004) suggest that the

comorbidity between bipolar disorder and eating

disorders may have familial contributions in some

cases. Future family interview studies of bipolar and

eating disorders should assess the full diagnostic

spectrums of both conditions to further clarify their

familial relationship.

6. Biology

A series of studies comparing levels of various

hormones, neurotransmitters, neurotransmitter metab-

olites, and neuropeptides in the cerebrospinal fluid

(CSF) of patients with bipolar disorder, women with

AN, patients with major depression, and normal

controls was conducted in 1981. No differences were

found between manic patients, AN patients, and

normal controls in CSF levels of GABA (Gerner

and Hare, 1981), beta-endorphin immunoreactivity

(Gerner and Sharp, 1982), bombesin-like immunor-

eactivity (Gerner and Yamada, 1982), or cholecysto-

kinen-like immunoreactivity (Gerner and Yamada,

1982). However, somatostatin-like immunoreactivity

was decreased in the CSF of AN patients and

depressed patients, but not in patients with mania

(Gerner and Yamada, 1982). By contrast, CSF cortisol

was comparably elevated in patients with bipolar

mania (N=10), AN (N=21), and major depression

(N=30), as compared to normal control subjects

(Gerner and Wilkins, 1983).

Certain neurobiological systems have received

fairly extensive study in both conditions, particularly

the hypothalamic–pituitary–adrenal (HPA) axis and

central serotonergic system. Abnormalities in each of

these systems have been reported in both bipolar

(Goodwin and Jamison, 1990; Mahmood and Silver-

stone, 2001; Sobczak et al., 2002) and eating

disorders (Kaye et al., 2004; Steiger, 2004).

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127 117

It would appear from the foregoing review that

cumulatively, biologic investigations have failed to

discriminate bipolar from eating disorders. This

failure may simply mean that the parameters thus

far studied are nonspecific regarding mental

disorders at large. It may prove fruitful to

examine among bipolar patients such parameters

as leptin and neuropeptides (Monteleone et al.,

2004; Jimerson and Wolfe, 2004), as well as

molecular genetic markers (reviewed in Bulik and

Tozzi, 2004) that appear relevant to eating

disorders.

7. Treatment response data

7.1. Lithium

The antimanic, antidepressant, and long-term

prophylactic mood-stabilizing effects of lithium in

bipolar disorder, including suicide prevention, have

been well documented (Baldessarini et al., 2003; Keck

and McElroy, 2004).

In the only placebo-controlled trial of lithium in

AN, the 8 patients receiving lithium showed greater

weight gain after 3 and 4 weeks of treatment than the

8 patients receiving placebo (Gross et al., 1981).

Lithium-treated patients also showed significantly

more improvement on an item measuring bdenialand minimization of illness.Q In the placebo-controlled

trial in BN, lithium (mean level 0.62 mEq/l) was not

superior to placebo in decreasing binge eating

episodes, except possibly in depressed patients (Hsu

et al., 1991).

In the first open trial in BN, lithium decreased

binge–purge episodes in 12 of 14 women after 4 to 8

weeks of treatment (Hsu, 1984), including their

bmood swings and emotional instability.Q In the

second open trial of lithium in BN, 11 (65%) of 17

patients showed a 75% or greater reduction in binge–

purge episodes in combination with cognitive behav-

ior therapy (Hsu, 1987).

Lithium was reported effective in 5 of 5 patients

with AN (Barcai, 1977; Reilly, 1977; Stein et al.,

1982; Hudson et al., 1985) and 4 of 6 patients with

BN (Pope et al., 1986; Leyba and Gold, 1988;

Shisslak et al., 1991), sometimes in combination with

other psychoptropics, including amitryptyline (Pope et

al., 1986; Leyba and Gold, 1988) and carbamazepine

(Hudson et al., 1985).

7.2. Other mood stabilizers

Double-blind, placebo-controlled trials have estab-

lished the efficacy of valproate, carbamazepine, and

several atypical antipsychotics (olanzapine, risperi-

done, quetiapine, ziprasidone, and aripiprazole) in

acute bipolar mania (Keck and McElroy, 2004).

Olanzapine, alone and in combination with fluoxetine,

has been shown to be effective in acute bipolar

depression (Tohen et al., 2003). Olanzapine has also

been shown superior to placebo in preventing

recurrent mood episodes in bipolar I disorder (Keck

and McElroy, 2004).

Although there have been no adequately sized

controlled studies of any of these agents in eating

disorders, both valproate and carbamazepine have been

reported to be effective in BN comorbid with bipolar

disorder in case reports (Kaplan et al., 1983; Herridge

and Pope, 1985). However, a small (N=6) double-

blind, placebo-controlled, crossover study of carbama-

zepine in BN was negative (Kaplan et al., 1983). Also,

valproate, which is associated with appetite stimulation

and weight gain, has been reported to worsen binge

eating associated with BED in patients with comorbid

bipolar disorder (Shapira et al., 2000). Similarly,

atypical antipsychotics have been reported to induce

or exacerbate binge eating in patients with BN (Brew-

erton and Shannon, 1992), bipolar disorder (Paquet et

al., 2002), and psychotic disorders (Crockford et al.,

1997; Bromel et al., 1998; Theisen et al., 2003).

By contrast, there have been many case reports and

one open study of atypical antipsychotics, particularly

olanzapine and to a lesser extent risperidone, in the

successful treatment of AN, including in treatment

refractory cases (Hansen, 1999; Jensen and Majlhede,

2000; Newman-Toker, 2000; Mehler et al., 2001;

Boachie et al., 2002; Powers et al., 2002; Malina et

al., 2003). In these reports, olanzapine and risperidone

were helpful for weight restoration; for many of the

core psychological symptoms of AN, such as fear of

fatness, difficulty eating, distorted body image, and

poor insight; and for many of the associated symp-

toms of AN, including binge eating, purging, hyper-

activity, delusionality, depression, anxiety, and mood

instability.

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127118

7.3. Other antiepileptic drugs

Several anticonvulsants with unclear efficacy in

bipolar disorder have been reported to be effective in

some eating disorders. Early positive open reports of

phenytoin in patients with binge eating (Green and

Rau, 1974) were followed by one negative (Greenway

et al., 1977) and another modestly positive (Wermuth

et al., 1977) study. An open-label, prospective 12-

week trial of zonisamide in 15 patients suggested this

agent may be effective for binge eating and weight

loss in patients with BED without comorbid bipolar

disorder (McElroy et al., 2004a); interestingly tested

against placebo, it has been found to be effective in

obesity (Gadde et al., 2003).

Two randomized, double-blind trials have shown

that topiramate is superior to placebo in BED and BN,

respectively. In the first study, a 14-week trial in 61

patients with BED associated with obesity (9.8% of

whom had bipolar disorder), topiramate was signifi-

cantly superior to placebo in reducing binge frequency,

as well as global severity of illness, obsessive–

compulsive features of binge eating symptoms, body

weight, and BMI (McElroy et al., 2003). In the second

study, a 10-week trial in 69 patients with BN, top-

iramate was superior to placebo in reducing the

frequency of binge and purge days (days during which

at least one binge eating or purging episode, respec-

tively, occurred) as well as improving measures of

anxiety and eating pathology (Hoopes et al., 2003).

Available 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 controlled comparison

trial with bupropion in bipolar depression, and numer-

ous positive open-label reports in soft spectrum forms

of bipolarity (McElroy andKeck, 2004;McIntyre et al.,

2002). Interestingly, in double-blind, placebo-con-

trolled trials in conditions that co-occur with bipolar

and eating disorders – such as alcohol dependence

(Johnson et al., 2003) and obesity (Bray et al., 2003) –

topiramate has shown efficacy.

7.4. Antidepressants

The treatment of bipolarity with antidepressants is

controversial because of inadequate double-blind,

placebo-controlled data regarding their short- and

long-term efficacy in bipolar depression (and mania),

and clinical studies showing that some bipolar

disorder patients destabilize upon antidepressant

exposure by developing manic, hypomanic, mixed,

and rapid cycling symptoms and episodes (Ghaemi et

al., 2003; Keck and McElroy, 2004). However,

clinical studies also show that some bipolar patients

require acute and even maintenance treatment with

antidepressants (typically in combination with mood

stabilizers) for optimal response (Altshuler et al.,

2003; Tohen et al., 2003).

Taken together, data regarding the efficacy of

antidepressants in eating disorders are also mixed.

Antidepressants of several different classes have been

shown to be effective in double-blind, placebo-

controlled trials in BN and BED (Bacaltchuk et al.,

2000a; Zhu and Walsh, 2002; Carter et al., 2003).

However, induction of manic symptoms with anti-

depressant treatment has been described in patients

with BN (Ghadirian et al., 1989; Siegel, 1989;

Shisslak et al., 1991). In addition, double-blind,

placebo-controlled studies of antidepressants in AN

for weight restoration have been negative (Attia et al.,

1998; Zhu and Walsh, 2002). Nutritional supplemen-

tation of fluoxetine aimed to enhance serotonergic

neurotransmission was also ineffective in promoting

weight gain in AN (Barbarich et al., 2004). In one

study, however, weight-restored patients with AN

without binge eating maintained their weight to a

significantly greater degree with fluoxetine than with

placebo (Kaye et al., 2001).

7.5. Psychological treatments in bipolar disorder and

eating disorders

Several psychological treatments have been studied

in both bipolar and eating disorders. In particular,

cognitive behavioral therapy (CBT) has been shown to

be effective for binge eating in BN and BED (Whittal et

al., 1999; Fairburn and Harrison, 2003). CBT may also

be effective for weight maintenance in AN, especially

in combination with antidepressants (Pike et al., 2003).

CBT in combination with antidepressants may be more

effective than either treatment alone for BN (Whittal et

al., 1999; Bacaltchuk et al., 2000b). CBT and group

psychoeducation have been shown to be effective in

combination with pharmacotherapy in the treatment of

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127 119

bipolar disorder (Colom et al., 2003; Lam et al., 2003).

We found no reports on the use of a psychological

treatment, including CBT, in the management of

bipolar disorder co-occurring with an eating disorder.

7.6. Summary on treatment

No controlled pharmacologic or psychologic treat-

ment studies of bipolar disorder co-occurring with an

eating disorder have been conducted. Moreover,

medications with well-documented efficacy in bipolar

disorder (mood stabilizers) have received very little

systematic study in the treatment of eating disorders.

Nonetheless, the two conditions share some important

similarities in treatment response, including induction

of hypomania with antidepressants.

8. Theoretical implications

8.1. Theoretical models

The epidemiologic and clinical comorbidity data

reviewed in this paper indicate that bipolar disorder

and eating disorders do in fact co-occur. Although the

degree and nature of this co-occurrence is not fully

understood, it could be explained by at least three

hypothetical conceptual models. In the first model,

bipolar and eating disorders are pathophysiologically

distinct entities which overlap by chance, but with

significant frequency, because both are common

disorders when their full diagnostic spectra are

considered. In the second model, bipolar disorder

and eating disorders overlap because they share the

same fundamental pathophysiology of dysregulation

in mood, eating behavior, body weight, and impulse

control, and therefore are manifestations of the same

basic underlying abnormality. The third model is that

bipolar disorder and eating disorders co-occur because

they are separate but pathophysiologically related

disorders.

8.2. Co-occurrence by chance?

This model is supported to some degree by the

different gender distributions of the two conditions

(Kessler et al., 1997; Fairburn and Harrison, 2003) and

by clinical observations that some agents with efficacy

in mania (atypical antipsychotics, valproate) may

induce or worsen binge eating, including in patients

with bipolar disorder (Shapira et al., 2000; Theisen et

al., 2003). However, this model is not supported by

other epidemiological data showing that hypomania

co-occurs with eating disorders and binge eating

behavior more often than expected by chance alone

in adults (Angst, 1998; Wittchen et al., 2003) and that

threshold and subthreshold bipolar disorder is associ-

ated with AN and BN in adolescents (Lewinsohn et al.,

2000). It is also not supported by those family history

studies showing elevated rates of mood disorder in

general (Hudson et al., 2001; Mangweth et al., 2003)

and bipolar disorder in particular (Winokur et al., 1980;

Gershon et al., 1984; Kassett et al., 1989) in the family

members of probands with AN or BN. Finally, it is not

supported by epidemiologic studies showing that

eating disorders are associated with depressive, anxi-

ety, and substance use disorders (Garfinkel et al., 1995;

Bulik et al., 2002, 2004b)—the same disorders that are

related to bipolar disorder (Kessler et al., 1997; Spaner

et al., 1994).

8.3. Common pathophysiologic basis?

This model is supported by data showing that

pathological eating behaviors are common in manic,

depressed, and mixed affective states, and con-

versely, that affective instability and mood signs

and symptoms are common in eating disorders

(Perugi and Akiskal, 2002). This model also

explains some of the potential treatment response

similarities between bipolar and eating disorders

(e.g., response of mania and possibly AN to lithium

and atypical antipsychotics, lack of response of

mania and AN to antidepressants, and response of

depression and binge eating to antidepressants), as

well as reports of the emergence of hypomania or

mania with antidepressant use in both eating

disorder and bipolar patients. However, this model

fails to account for the differences between bipolar

disorder and eating disorders discussed for the first

model.

8.4. Separate but related disorders?

The third model, in which bipolar disorder and

eating disorders are separate but pathophysiologically

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127120

related conditions, is supported by the epidemiolog-

ical overlap and the phenomenological, longitudinal,

familial history, biological, and treatment response

similarities between bipolar disorder and eating

disorders reviewed in this paper. Such a model could

also account for the differences between the two

conditions.

Indeed, bivariate genetic analyses applied to

definitions of AN or BN and lifetime major depres-

sion in community-based samples of female twins

have suggested that the comorbidity between these

eating disorders and major depression is due to

modestly overlapping genetic factors that influence

the risk for both disorders (Walters et al., 1992; Wade

et al., 2000). As discussed earlier, substantial research

indicates that recurrent major depression is related to

bipolar disorder (Akiskal et al., 1983; Goodwin and

Jamison, 1990; Cassano et al., 2004). Familial co-

aggregation and potential genetic linkage data have

been shown for bipolar disorder with co-occurring

panic disorder, suggesting that this form of bipolar

disorder is a genetic subtype (MacKinnon et al., 1998;

Rotondo et al., 2002). If separate but related disorders,

bipolar disorder co-occurring with an eating disorder

might similarly be regarded as a genetic subtype of

bipolar disorder. Specific pathological eating symp-

toms occurring during manic, mixed, hypomanic, or

depressive episodes, and/or comorbid eating syn-

dromes accompanying bipolar syndromes, might

therefore prove to be clinically and theoretically

relevant ways to classify bipolar disorder. Conversely,

degree of associated mood dysregulation (none versus

unipolar versus bipolar II versus bipolar I) might

prove to be a useful means of classifying eating

disorders.

Another aspect of this model is that certain

individual eating disorders (e.g., those with binge

eating, such as BN, BED, and possibly AN with BN)

may be more likely to be related to bipolar disorder

than others (e.g., restricting AN). Another possibility

is that eating disorders with greater degrees of

behavioral and affective dysregulation might be more

strongly associated with bipolar disorder as compared

to those with greater behavioral and affective con-

striction—regardless of eating behavior. Conversely,

certain bipolar subtypes (e.g., soft spectrum) may be

more closely related to eating disorders than others

(bipolar I). Alternatively, eating disorders with binge

eating and soft spectrum and subthreshold forms of

bipolarity may be more likely to co-occur (than AN

and bipolar I disorder) simply because each are the

most common forms of their respective diagnostic

spectra.

8.5. Toward an integration of the theoretical models

It is currently unknown which of these three

models is correct, although available community,

clinical, and family history data argue against the

first as the only explanation of the overlap between

bipolar disorder and eating disorders. As bipolar

disorder and eating disorders are both likely to be

heterogeneous, oligogenic conditions (Walters et al.,

1992; Wade et al., 2000; Kelsoe, 2003), all three

models might be correct in different subsets of

comorbid patients. Molecular genetic studies should

help elucidate the nature of the molecular relation-

ships among these disorders. The final common

(shared) pathophysiologic mechanisms may involve

eating dysregulation, mood dysregulation, craving for

activation, impulsivity, and compulsivity.

9. Clinical implications

Comorbid eating disorders may contribute to some

of the obesity seen in bipolar patients (McElroy et al.,

2002), and conversely, comorbid bipolarity may

contribute to some of the treatment-resistance seen

among eating disorder patients (Simpson et al., 1992).

Therefore, clinicians should assess for all syndromal

and subsyndromal eating disorders in patients pre-

senting with bipolar disorder, and conversely, for

bipolar spectrum disorders in patients presenting with

eating disorders.

Potential indicators for an eating disorder in a

bipolar patient may include refusal of mood stabilizers

for fear of weight gain, rapid weight gain with (or

without) mood stabilizer treatment, and severe weight

disturbance (underweight, overweight, or obesity).

Potential indicators for bipolarity in an eating disorder

patient may include early age at onset of comorbid

depressive or other Axis I disorders, high degree of

depressive recurrence, behavioral activation or impul-

sivity, family history of bipolarity, and poor response

to standard eating disorder treatment.

S.L. McElroy et al. / Journal of Affective Disorders 86 (2005) 107–127 121

The interface of bipolar and eating disorders is

diagnostically complex, fraught with uncertainties,

difficult therapeutic decisions, and suboptimal out-

come. Regrettably, despite evidence to the contrary

(Pope et al., 1987), some authors further obfuscate this

realm by invoking the all-engulfing concept of border-

line personality disorder (Steiger et al., 1993; Paris,

2004). The continued use of the bborderlineQ label toexplain away complex dysregulations involving poor

impulse control represents a serious barrier for genuine

understanding of psychopathology (Akiskal, 2004).

There are no generally accepted treatment guide-

lines for the management of patients with comorbid

bipolar and eating disorders. Regarding pharmaco-

therapy, it may be important to begin with agents with

mood stabilizing rather than antidepressant properties.

To provide optimal treatment for these patients, the

clinician will have to be knowledgeable about the

pharmacotherapy literature for both bipolar and eating

disorders.

To conclude, the co-occurrence of bipolar disorder

with eating disorders is an important psychiatric

comorbidity that has largely been neglected by both

the bipolar and eating disorder literatures. Further

research is greatly needed into the overlap of these

conditions, so that patients with both disorders can be

properly diagnosed and adequately treated. Research

focusing on these disorders in their full-blown and

spectrum expressions is likely to be more rewarding.

Finally, such research could further inform the

relationships among mood, eating behavior, weight,

and impulse control at the trait level.

10. Conflict of Interest Statements

Dr. McElroy is a consultant to, or member of the scientific

advisory boards of: Abbott Laboratories, Bristol-Myers Squibb,

GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Com-

pany, Novartis, Ortho-McNeil, and Wyeth-Ayerst. Dr. McElroy is

a principal or co-investigator on research studies sponsored by

Forrest Labs, Esai, Eli Lilly, Ortho-McNeil, Pfizer, Sanofi-

Synthelabo, Astra Zeneca, and Bristol-Myers Squibb.

Dr. Keck is a consultant to, or member of the scientific

advisory boards of: Abbott Laboratories, AstraZeneca Pharma-

ceuticals, Bristol-Myers Squibb, Corcept, GlaxoSmithKline,

Janssen Pharmaceutica, Eli Lilly and Company, Novartis,

Ortho-McNeil, Pharmacia, Pfizer, UCB Pharma, Shire, Solvay

and Wyeth. Dr. Keck is a principal or co-investigator on research

studies sponsored by: Abbott Laboratories, AstraZeneca, Bristol-

Myers Squibb, GlaxoSmithKline, Elan, Eli Lilly, National

Institute of Mental Health (NIMH), National Institute of Drug

Abuse, National Institute of Mental Health, National Institute of

Drug Abuse (NIDA), Organon, Pfizer, the Stanley Medical

Research Institute (SMRI), and UCB Pharma.

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