Clinical Therapeutics/Volume 43, Number 1, 2021

Reviews
Psychotherapy and Medications for Eating Disorders:
Better Together?
Deborah L. Reas, PhD1,2; and Carlos M. Grilo, PhD3,4
1
Regional Department for Eating Disorders, Division of Mental Health and Addiction, Oslo
University Hospital, Oslo, Norway; 2Institute of Psychology, Faculty of Social Sciences, Uni-
versity of Oslo, Oslo, Norway; 3Department of Psychiatry, Yale University School of Medicine,
New Haven, CT, USA; and 4Department of Psychology, Yale University, New Haven, CT,
USA

ABSTRACT Implications: Despite the public health significance

of eating disorders, the scope of research performed
Purpose: Eating disorders are prevalent public
on the utility of combining treatments is limited. To
health problems associated with broad psychosocial
date, the few RCTs testing combined pharmacologic
impairments and with elevated rates of psychiatric and
plus psychological treatments for eating disorders
medical comorbidities. Critical reviews of the
have yielded mostly nonsignificant findings. Future
treatment literature for eating disorders indicate that
RCTs should focus on testing additive benefits of
although certain specialized psychological treatments
medications with relevant mechanisms of action to
and specific medications show efficacy to varying
available effective psychological interventions. In
degrees across the different eating disorders, many
addition, future RCTs that test additive effects should
patients fail to derive sufficient benefit from existing
use adaptive designs, which could inform treatment
treatments. This article addresses whether combining
algorithms to enhance outcomes among both
psychological and pharmacologic interventions confers
responders and nonresponders to initial interventions.
any additional benefits for treating eating disorders.
(Clin Ther. 2021;43:17e39) © 2020 The Authors.
Methods: This study was a critical review of
Published by Elsevier Inc. This is an open access article
randomized controlled trials (RCTs) testing combined
under the CC BY license (http://creativecommons.org/
psychological and pharmacologic treatment
licenses/by/4.0/).
approaches for eating disorders with a focus on
Key words: anorexia nervosa, binge-eating disorder,
anorexia nervosa (AN), bulimia nervosa (BN), and
bulimia nervosa, eating disorders, pharmacotherapy,
binge-eating disorder (BED).
psychotherapy.
Findings: For AN, 3 of the 4 RCTs reported no
significant advantage for combining treatments; the
fourth reported a statistically significant, albeit
clinically modest, advantage. For BN, 10 of the 12 INTRODUCTION
RCTs reported no significant advantage for Eating disorders, which comprise the formal diagnoses
combining treatments; 2 RCTs found that combining of anorexia nervosa (AN), bulimia nervosa (BN), and
fluoxetine with specific psychological treatments binge-eating disorder (BED) in addition to atypical or
enhanced outcomes relative to medication only but not-otherwise-specified categories, were recently
not relative to the psychological treatments only. For
BED, of the 12 RCTs, only 2 (both with antiseizure
Accepted for publication October 16, 2020
medications) significantly enhanced both binge-eating https://doi.org/10.1016/j.clinthera.2020.10.006
and weight outcomes, and only 2 (with orlistat, a 0149-2918/$ - see front matter
weight-loss medication) enhanced weight loss but not © 2020 The Authors. Published by Elsevier Inc. This is an open access
binge-eating outcomes. article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).

January 2021 17
 Clinical Therapeutics
updated by the American Psychiatric Association in the
fifth edition of the Diagnostic and Statistical Manual of
Mental Disorders1 and by the World Health
Organization in the 11th edition of the International
Classification of Diseases and Related Health
Problems.2 Eating disorders are prevalent3 and
significantly associated with psychiatric and medical
comorbidities,4 as well as with broad psychosocial
impairments, including suicidality.5 Despite the
availability of psychological and pharmacological
interventions supported to varying degrees by
controlled research, naturalistic treatment seeking by
persons with eating disorders is low, and the types of
help received may not be evidence based.6
Critical reviews of the treatment literature for eating
disorders have generally converged in supporting
certain specialized psychological treatments and
specific medications to varying degrees across the
different eating disorders.7e9 This Special Issue of the
Journal includes updated critical reviews of
psychological and pharmacological treatment
literatures specifically targeting AN, BN, and BED.
The present review focuses on a different question,
which concerns whether combining psychological and
pharmacological interventions confers any additional
benefits for treating eating disorders. Clinical lore and
“expert opinion,” for example, in the American
Psychiatric Association's Practice Guidelines,10 suggest
that more intensive and combined treatment
approaches might enhance outcomes for complex
patients such as those with comorbidities. This clinical
question concerning combining treatments has
received remarkably little attention,11 and a critical
synthesis of the relevant controlled treatment research
is needed to inform clinical practice for eating
disorders. Thus, the goal of the present article was to
provide a brief state-of-the-art review of randomized
controlled trials (RCTs) for combined psychological
and pharmacological treatment of AN, BN, and BED.
MATERIALS AND METHODS
An electronic search was performed for all English-
language articles using MEDLINE via PubMed and
the Cochrane Library published through August 1,
2020. Registered and ongoing clinical trials for eating
disorders were identified via the US National
Institutes of Health web-based registry of private and
publicly supported clinical studies (ClinicalTrials.
gov). All RCTs investigating the effects of
18
pharmacotherapy in combination with psychological
interventions were considered. Exclusion criteria
were: (1) Phase I trials (open-label, case series, and
retrospective cohort designs); (2) non-English
language; (3) trials involving individuals aged <18
years; (4) studies pertaining to nonpurging BN,
mixed eating disorder samples, or atypical eating
disorders, or the International Classification of
Diseases, Tenth Revision, category overeating
associated with psychological disturbances; and (5)
RCTs investigating either monotherapy
psychopharmacological treatment or psychological
treatment delivered alone (which are reviewed
elsewhere in this Special Issue of the Journal).
RESULTS
Characteristics of Studies with AN
Although several medications have been tested as
part of a multidisciplinary approach within the
context of day-hospital or in-patient treatment
programs, few studies were randomized, placebo-
controlled, double-blind trials either sufficiently
powered or designed to allow for conclusions
regarding the effects of pharmacotherapy in
combination with a specific psychological-behavioral
intervention. Four studies using placebo-controlled
designs were identified and included in this review,
including 2 RCTs studying the additive effects of
fluoxetine12,13 and 2 RCTs investigating the atypical
antipsychotic olanzapine.14,15 Fluoxetine has been
investigated within the context of a structured
behavioral inpatient treatment for AN12 and within an
outpatient setting, in which 12 months of cognitive-
behavioral therapy (CBT) were provided with either
fluoxetine or placebo after weight restoration.13 One
of the olanzapine RCTs tested intensive day-hospital
treatment plus 10 weeks of either olanzapine or
placebo,14 and the other RCT tested 12 weeks of CBT
plus either olanzapine or placebo on an outpatient
basis.15 With the exception of the multisite study by
Walsh et al,13 which included 93 participants, the
trials were small, with sample sizes of 30
participants,15 31 participants,12 and 34
14
participants ; 3 of the 4 trials were short in duration,
ranging from 7 weeks to 12 weeks, and none reported
follow-up data. Outcome measures for 3 RCTs
included weight gain and changes in eating-disorder
psychopathology and psychological functioning12,14,15;
in the RCT by Walsh et al,13 the primary outcomes
Volume 43 Number 1

were time to relapse and the rate of study completion
after having achieved weight restoration.
Characteristics of Studies with BN
Table I lists 12 published RCTs that tested
combination treatments for BN. Most studies
examined the addition of pharmacotherapy to CBT
delivered in various formats, including
individual,16e21 pure self-help,22 guided self-help,23
or group24 methods. A few studies tested the addition
of pharmacotherapy to other forms of “talk”
treatments, including nutritional counseling,25 a
supportive psychodynamically oriented
psychotherapy,21 and an intensive, eclectic inpatient
psychotherapy program.26 Early studies tested
tricyclic antidepressants, including desipramine16,19,21
and imipramine,27 and later studies focused on
fluoxetine.18,20,22,24,26 One trial compared the relative
efficacy of adding D-fenfluramine (an appetite
suppressant) versus placebo to CBT.17 Two studies
used more complex adaptive-type designs: one study
used a stepped-care approach that stratified patients
based on initial response to treatment,20 and a
second study used a sequential approach involving a
2-stage medication intervention (switching to
fluoxetine if desipramine was ineffective or poorly
tolerated).21 The RCTs ranged from 7 to 20 weeks; 2
trials reported 6-month follow-up data,19,24 and 1
trial reported 12-month follow-up data.20 Sample
sizes ranged from 21 participants19 to 293
participants,20 with 8 of the 11 trials including <20
participants per treatment arm. The RCTs included
only female subjects except for one study, which
enrolled one male subject,26 and all were conducted
on an outpatient basis except for one.26
Characteristics of Studies with BED
Table II lists 12 published RCTs that tested
combination treatments for BED; there are also two
ongoing registered clinical trials testing the
effectiveness of combination approaches for patients
with BED comorbid with obesity (NCT03924193
and NCT03045341). The 12 RCTs testing
combination treatments for BED ranged in treatment
duration from 8 to 36 weeks; all but two studies28,29
reported follow-up data that ranged from 3 to 24
months after completing treatments. Sample sizes
ranged from 52 to 191 participants. Participants were
primarily white women, with an average age of ~40
January 2021
D.L. Reas and C.M. Grilo
years and a body mass index (BMI) of 38 kg/m2.
Designs and medications tested included unblinded
additions of several medications, including
desipramine,30 imipramine,31 fluoxetine and
fluvoxamine,32 and zonisamide,33 and double-blind
placebo-controlled addition of various selective
serotonin reuptake inhibitors (SSRIs), antiepileptic
agents, and weight loss medications (specifically,
fluoxetine,34,35 orlistat,29,36e38 topiramate,28 and
sibutramine38,39) to either CBT or behavioral weight
loss (BWL) methods.
Findings of Combined Treatments for AN
Attia et al12 conducted a 7-week, double-blind,
placebo-controlled RCT testing fluoxetine (60 mg/d)
combined with a structured inpatient program for
AN. Thirty-one patients were randomized to
treatment after achieving medical stabilization and
reaching 65% of ideal body weight. Attrition rates
did not differ significantly (27% for fluoxetine and
25% for placebo), and dropouts were attributable to
premature discharge, worsening depression or severe
anxiety, or side effects. Overall, analyses revealed
significant improvements in the percentage of ideal
body weight over time but no significant differences
between treatments (increase from 72.5% to 87.0%
with fluoxetine vs 71.8%e87.4% with placebo).
Similarly, significant improvements in measures of
psychological functioning were observed over time,
but fluoxetine did not confer significant additional
benefit relative to placebo to the structured inpatient
treatment.
Walsh et al13 conducted a 2-site (Columbia
University, New York, NY, and Toronto, Ontario,
Canada) randomized, double-blind, placebo-
controlled trial to examine whether the addition of
fluoxetine reduced relapse and enhanced outcomes
during the year after successful weight restoration
achieved during prior inpatient or intensive
outpatient treatment. Ninety-three participants (with
a minimum BMI of 19.0 kg/m2) received up to 12
months of outpatient individual CBT and were
randomized to receive either fluoxetine (60 mg/d) or
placebo. Exhaustive analyses revealed no significant
differences between fluoxetine and placebo conditions
in the time to relapse, rate of study completion, or
the average number of treatment (CBT) sessions
attended. At 52 weeks, 57% of the total 93
participants had terminated the study prematurely
19
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Clinical Therapeutics
Table I. Study characteristics of randomized controlled trials investigating combined psychotherapy and pharmacotherapy for bulimia nervosa.
Study N % Female % White Age (y) BMI (kg/m2) Trial FUP Treatment conditions Study Design
(wk) (mo)
Agras et al (1992)16 71 100 100 29.6 NA 16 1 a) SSRI 16 wk a) Flexible dosage desipramine,
16 wk
b) SSRI 24 wk b) Flexible dosage desipramine,
24 wk
c) CBT + SSRI 16 wk c) Individual CBT delivered in 50-
min sessions + SSRI, 16 wk
d) CBT + SSRI 24 wk d) Individual CBT delivered in 50-
min sessions + SSRI, 24 wk
e) CBT 24 wk e) Individual CBT, 24 wk

Beumont et al (1997)25 67 100 NA a) 24.2 a) 22.2 8 3 a) Nutritional counseling + placebo a) Intensive nutritional counseling,
weekly individual
sessions + placebo
b) 25.1 b) 22.2 b) Nutritional counseling + SSRI b) Intensive nutritional
counseling + fluoxetine (60 mg/d)

Fahy et al (1993)17 43 100 NA a) 23.0 a) 22.0 8 2 a) CBT + D-fenfluramine a) CBT + fixed-dose 45 mg/d D-
fenfluramine
b) 25.0 b) 22.9 b) CBT + placebo b) CBT, individual for
8 wk + placebo

Fichter et al (1991)26 40 97.5 NA a) 26.5 a) 54.7 kg 7 e a) Inpatient treatment + SSRI a) Inpatient behavioral
psychotherapy + fluoxetine
60 mg/d
b) 24.6 b) 56.7 kg b) Inpatient treatment + placebo b) Inpatient behavioral
psychotherapy + placebo

Goldbloom et al (1997)18 76 100 NA 25.8 23.0 16 e a) CBT a) CBT, individual

b) SSRI b) Fluoxetine fixed dose 60 mg/d
c) CBT + SSRI c) Fluoxetine-CBT
Volume 43 Number 1

Jacobi et al (2002)24 53 100 NA 26.0 20.6 16 6 a) CBT a) CBT, group, 20 sessions, 16 wk

b) SSRI b) Fluoxetine 60 mg/d, 16 wk
c) CBT + SSRI c) CBT + fluoxetine

Leitenberg et al (1994)19 21 100 NA 26.7 NA 20 6 a) CBT a) CBT 22 individual sessions over

20 wk
b) TCA b) Desipramine 150 mg/d
c) CBT + TCA c) CBT + desipramine
January 2021
Table I. (Continued )

Study N % Female % White Age (y) BMI (kg/m2) Trial FUP Treatment conditions Study Design
(wk) (mo)
Mitchell et al (1990)27 171 100 NA a) 24.4 NA 12 e a) Placebo a) Placebo
b) 24.1 b) Imipramine b) Imipramine, up to 300 mg/d
c) 22.8 c) Intensive group c) Intensive group psychotherapy.
psychotherapy + placebo
d) 24.3 d) Intensive group d) Intensive group
psychotherapy + medication psychotherapy + imipramine

Mitchell et al (2001)22 91 100 96.7 a) 26.6 NA 16 e a) SSRI a) Fluoxetine, fixed-dose 60 mg/d

b) 26.8 b) shCBT + placebo b) shCBT + placebo
c) 29.3 c) shCBT + SSRI c) shCBT + fluoxetine, 60 mg/d
d) 23.8 d) Placebo d) Placebo

Mitchell et al (2011)20 293 100 a) 84 a) 29.5 a) 23.4 18 12 a) CBT a) CBT, 20 sessions of 50 min, +
fluoxetine 60 mg/d offered to
those failing to reduce purging by
70% after session 6 (week 4).
Medications continued until 1-
year FUP
b) 88 b) 29.8 b) 23.5 b) Stepped-care b) Therapist assisted self-help,
manual + eight 20-min in-person
sessions. Nonresponders at
session 6 (week 10) were offered
fluoxetine 60 mg/d. At the end of
treatment (week 18), CBT for was
offered to those who did not
achieve abstinence. Medications
continued until 1-year FUP

Walsh et al (1997)21 120 100 83 a) 26.1 21.9 16 e a) CBT-SSRI a) Individual CBT, 20

sessions + desipramine 200

D.L. Reas and C.M. Grilo

e300 mg/d for 8 wk, followed by
fluoxetine (60 mg/d) if no
improvement
b) 25.8 b) CBT-placebo b) CBT + placebo
c) 28.0 c) SPT-SSRI c) Supportive therapy, 20
sessions + desipramine 200
e300 mg/d for 8 wk, followed by

(continued on next page)

21
Clinical Therapeutics

due to treatment failure, voluntary withdrawal, or

c) gSH manual + six to eight 30-min

BMI ¼ body mass index; CBT ¼ cognitive-behavioral therapy; F ¼ female; FUP ¼ follow-up; gSH ¼ guided self-help; NA ¼ data not available; sh ¼ self-help;
staff-initiated withdrawal due to nonadherence or
adverse effects. Regardless of the stringency of

d) Fluoxetine 60 mg/d + gSH

fluoxetine (60 mg/d) if no
outcome criteria applied, similar proportions of the
Study Design

d) Supportive therapy, 20 fluoxetine versus placebo groups had relapsed by 52

b) Fluoxetine 60 mg/d

sessions with nurse

sessions + placebo weeks (ie, 29% vs 27% for the least conservative
e) Medication only

SPT ¼ supportive, psychodynamically oriented therapy; SSRI ¼ selective serotonin reuptake inhibitor; TCA ¼ tricyclic antidepressant; W ¼ white.
manual + visits
estimate and 57% vs 55% for the most conservative
improvement

estimates, respectively). Similarly, none of the clinical

a) Placebo
outcome measures (including AN severity ratings,
depression, and BMI) differed significantly according
to treatment condition. For instance, a similar
proportion of patients in the fluoxetine (65%) versus
placebo (57%) conditions met the modified
Treatment conditions

MorganeRussell criteria for fair or better outcome at

termination. These findings represent strong evidence
that fluoxetine fails to confer significant benefit over
d) Medication + gSH

placebo when delivered in combination with CBT for

b) Fluoxetine alone
c) Placebo + gSH
d) SPT-placebo

AN following successful initial weight restoration

achieved with intensive treatment.
a) Placebo

Bissada et al14 conducted a double-blind, placebo-

e) SSRI

controlled, 10-week flexible dose RCT to test

olanzapine versus placebo in combination with an
(wk) (mo)
N % Female % White Age (y) BMI (kg/m2) Trial FUP

intensive day-hospital intervention (supervised meals

e

plus group therapies 4 days/week) for AN. Thirty-

four patients with AN were randomized to treatment,
16

and 28 (82.3%) completed treatments; olanzapine

and placebo conditions did not differ in attrition. A
significantly greater proportion of patients receiving
d) 22.78
c) 21.79
b) NA

olanzapine than placebo (87.5% vs 55.6%,

a) NA

respectively) achieved successful weight restoration

criteria, and olanzapine was associated with a
d) 26.9

e) 24.3

significantly more rapid achievement of target BMI

30.6

(~2 weeks) than placebo. Olanzapine was associated

with significantly greater reduction in obsessional
symptoms but not with improvements in compulsive
92.3

symptoms, depressive symptoms, or anxiety relative

to placebo.
Brambilla et al15 performed a 12-week, multisite,
outpatient-based, placebo-controlled double-blind
100

RCT to test weekly CBT plus either olanzapine or

91

placebo. Twenty-five of the 30 patients completed the

RCT. Overall, significant improvements in BMI were
observed, but no significant differences were observed
Table I. (Continued )

Walsh et al (2004)23

between the olanzapine and placebo conditions.

Similarly, overall improvements in eating-disorder
psychopathology scores were observed at
Study

posttreatment that did not differ significantly between

the olanzapine and placebo groups. Overall,
depression scores improved significantly in both

22 Volume 43 Number 1
January 2021

Table II. Study characteristics of randomized controlled trials investigating combined psychotherapy and pharmacotherapy for binge-eating
disorder.
Study N % F % W Age (y) BMI, Trial FUP Treatment Conditions Study Design
(kg/m2) (wk) (mo)
Agras et al (1994)30 108 100 NA 45.0 38.6 36 3 a) BWL-only a) 9 mo (30 sessions)
b) CBT/BWL b) 3 mo (12 sessions) + 6 mo (18 sessions)
c) CBT/BWL + desipramine c) 3 mo + 6 mo + drug (mean dose, 285 mg/d)

Laederach-Hoffman et al (1999)31 31 87 NA a) 35.7 39.5 8 6 a) Diet counseling + supportive a) Bi-weekly (30 min) diet counseling + bi-
therapy weekly (15e25 min) supportive
therapy + monthly sessions of group
(90 min) behavior therapy
b) 40.7 b) Imipramine b) Fixed dosage of 25 mg TID

Ricca et al (2001)32 108 59 NA 25.9 32.3 24 12 a) CBT a) 22 individual sessions

b) CBT + fluoxetine b) CBT + 60 mg/d
c) CBT + fluvoxamine c) CBT + 300 mg/d
d) Fluoxetine only d) Drug-only, as b above
e) Fluvoxamine only e) Drug-only, as c above

Devlin et al (2005, 2007)34,42 116 78 77 43.0 40.9 20 24 a) Fluoxetine a) Flexible dosage of 60 mg/d
b) Placebo b) Placebo
c) CBT + placebo c) 20 individual CBT sessions
d) CBT + fluoxetine d) As above, a + c
Note: All of the above given in Note: Maintenance treatment included double-
combination with group BWL (16 blind medication for 18/24 mo and monthly
sessions for 5 mo) BWL groups

Golay et al (2005)29 89 91 97 a) 41 a) 35.7 24 None a) Orlistat + hypocaloric diet a) Fixed dosage of 120 mg TID + hypocaloric
diet (600 kcal/d subtracted from daily energy
expenditure)
b) 41 b) 37.3 b) Placebo + hypocaloric diet b) Placebo + hypocaloric diet

D.L. Reas and C.M. Grilo

Grilo et al (2005)36 50 88 88 47 36.0 12 3 a) Orlistat + CBT gSH a) Fixed dosage of 120 mg TID + CBT gSH (CBT
sh manual, plus six 15- to 20-min individual
meetings over 12 wk)
b) Placebo + CBT gSH b) Placebo + CBT gSH

Grilo et al (2005, 2012)35,43 108 78 89 44 36.3 16 6, 12 a) Fluoxetine only a) Fixed dosage of 60 mg/d
b) Placebo b) Placebo
23

(continued on next page)

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Clinical Therapeutics
Table II. (Continued )

Study N % F % W Age (y) BMI, Trial FUP Treatment Conditions Study Design
(kg/m2) (wk) (mo)
b) CBT + placebo c) 16 individual weekly (60 min) sessions
c) CBT + fluoxetine d) As above, a + c

Claudino et al (2007)28 73 96 58 a) 35 a) 37.4 21 None a) CBT + placebo a) 19 group sessions of CBT

b) 41 b) 37.4 b) CBT + topiramate b) CBT + flexible dosage of 200 mg/d

Ricca et al (2009)33 52 83 NA a) 35 a) 39.2 24 12 a) CBT a) 22 individual sessions of CBT for 24 wk

b) 36 b) 38.4 b) CBT + zonisamide b) CBT + zonisamide 25 mg/d for 7 d, increased
as tolerated by 50 mg/d every week to a
maximum of 100 mg/d for BMI <35 kg/m2
or 150 mg/d for BMI >35 kg/m2

Grilo and White (2013)37 40* 78 0 a) 46 a) 37.2 16 6 a) BWL + placebo a) 16 weekly sessions of a culturally enhanced
adaptation of the Diabetes Prevention
Program
b) 46 b) 39.0 b) BWL + orlistat b) Fixed dosage of 120 mg TID + BWL

Grilo et al (2014)39 104 73 45 44 38.3 16 6,12 a) Sibutramine a) Fixed dosage of 15 mg/d

b) Placebo b) Placebo
c) shCBT + sibutramine c) shCBT + sibutramine (15 mg/d)
d) shCBT + placebo d) shCBT + placebo

Grilo et al (2020)38,44 191 71.2 78.5 48.4 39.0 24 6,12 a) Standard treatment a) BWL (1 mo) followed by stratification by
response:
b) Stepped-care Rapid respondersy:
1a) BWL + medicationz (5 mo)
1b) BWL + placebo (5 mo)
Nonrapid responders:
2a) CBT gSH + medication (5 mo)
2b) CBT gSH + Placebo (5 mo)
b) BWL (6 mo)
Volume 43 Number 1

BMI ¼ body mass index; BWL ¼ behavioral weight loss; CBT ¼ cognitive-behavior therapy; F ¼ female; FUP ¼ follow-up; gSH ¼ guided self-help; NA ¼ data not
available; sh ¼ self-help; W ¼ white.
* An additional N ¼ 39 obese patients without binge-eating disorder were also randomized to the treatments. The reader is referred to the publication for findings
which notably included binge-eating disorder status as a significant predictor and moderator of outcomes.37
y
Rapid response defined as 65% reduction in binge eating after 1 month of treatment.
z
Sibutramine was dosed at 15 mg/d until market withdrawal and replaced by orlistat 120 mg/3 × day.

treatment conditions, with olanzapine showing a
marginally significant advantage over placebo.
Findings of Combined Treatments for BN
Findings of RCTs testing combination treatments
with tricyclic antidepressants, appetite suppressants,
and SSRI antidepressants are presented in the
following sections (Table III).
Tricyclic Antidepressants
Existing evidence suggests there is no advantage for
adding tricyclic antidepressants to individual CBT or
intensive group psychotherapy. In one of the first
additive trials for BN, Mitchell et al27 investigated
imipramine in 171 patients with BN, randomly
allocating participants into imipramine only, placebo,
a combination of intensive group psychotherapy and
imipramine, and intensive group therapy + placebo.
All 3 active treatment conditions improved binge
eating and compensatory behaviors significantly more
than the placebo condition; however, the addition of
imipramine to group therapy showed no additional
effect over adding placebo (except for some
significant effects on reducing associated depression
and anxiety symptoms).
Agras et al,16 in an RCT with 71 patients with BN
randomized to 5 conditions, including a 16- and 24-
week treatment duration, found that 16 weeks of
individual CBT, and the combination of
CBT + desipramine, were superior to desipramine
alone in reducing binge eating and purging. At 24
weeks of treatment, the combined treatment was
superior, with binge abstinence rates of 70%, versus
55% and 42% for CBT-alone and medication,
respectively. High rates of attrition and relapse
affected those receiving medication after both 16 and
24 weeks, indicating the benefit of CBT to prevent
relapse after discontinuation of medication.
Leitenberg et al,19 in an RCT with 21 patients with
BN, compared the effectiveness of CBT-alone,
desipramine-alone, and a combination of
CBT + desipramine. The authors suggested that CBT
alone seemed more effective than desipramine and
that the combination was not superior to CBT alone.
Importantly, this study relied on partial analyses
performed with just 21 patients because the trial was
discontinued due to the high dropout rate and the
ineffectiveness of desipramine; between-group
comparisons at posttreatment were not possible.
January 2021
D.L. Reas and C.M. Grilo
Appetite Suppressants
Fahy et al,17 in an 8-week RCT with 43 women with
BN, failed to detect any significant differences between
the CBT + D-fenfluramine (45 mg/d) and
CBT + placebo groups. Overall, a rapid reduction in
symptoms occurred during the first 4 weeks of
treatment, but analyses revealed no differences
between treatment conditions to suggest any additive
therapeutic effect for adding D-fenfluramine to CBT.
SSRI Antidepressants
Fluoxetine is the sole medication approved for the
treatment of BN by the US Food and Drug
Administration (FDA). Although fluoxetine has
shown efficacy for BN,40,41 the evidence base
regarding the effectiveness of combining fluoxetine
with CBT or other psychotherapies is less clear.
Within an inpatient setting, Fichter et al26 found little
benefit to adding fluoxetine to an inpatient
behavioral psychotherapy program. Forty
hospitalized patients with BN were randomized to
receive fluoxetine or placebo in combination with the
intensive inpatient care for a period of 5 weeks (plus
a 2-week baseline and washout period). Overall,
although eating-disorder symptoms improved
significantly, the fluoxetine and placebo conditions
did not, suggesting no additive benefit.
Goldbloom et al,18 in a 16-week RCT, randomized
a total of 76 women with BN to receive fluoxetine,
CBT, or CBT + fluoxetine. All 3 treatment conditions
produced clinically meaningful improvements in
bulimia-related outcomes. Analyses comparing
treatment conditions revealed that CBT + fluoxetine
was significantly superior to fluoxetine alone, and
that CBT alone did not differ from CBT + fluoxetine.
Analyses were limited by a high dropout rate,
especially in the combined condition (ie, 43.8%).
Beumont et al25 tested an 8-week trial of intensive,
individually delivered nutritional counseling with and
without fluoxetine (60 mg/d) in 67 women with BN.
Overall, both treatment conditions were associated
with significant acute improvements in binge eating
and vomiting frequency, but the fluoxetine and
placebo conditions did not differ significantly.
Analyses of 20-week follow-up data after finishing/
discontinuing the 8-week treatments revealed
significantly different patterns: for the
fluoxetine + nutrition group, the proportion of binge-
25
26

Clinical Therapeutics
Table III. Main findings from randomized controlled trials investigating combined psychotherapy and pharmacotherapy for bulimia nervosa (BN).
Study Treatment Condition Attrition Purging Frequency Binge-Eating Depression Abstinence/
Frequency Remission
Agras et al (1992)16 Pre-, 16, 24, 32 wk: Pre-, 16, 24, and 32 wk: NA Purge abstinence,
16 wk:
a) SSRI 16 a/b) 17% a) 9.7 to 4.7 to 5.0 to a) 5.5 to 3.5 to 3.7 to a/b) 33%e
6.2c,d,e 6.2c,d,e
b) SSRI 24 c/d) 4% b) 6.3 to 3.9 to 2.9 to b) 5.9 to 3.4 to 2.7 to c/d) 64%e
3.4c,d,e 3.3c,d,e
c) CBT + SSRI 16 c) 8.3 to 2.6 to 2.7 to c) 7.5 to 2.4 to 2.1 to e) 48%a,b,c,d
3.2a,b 3.2c,d,e
d) CBT + SSRI 24 d) 11.7 to 1.2 to 1.7 to d) 9.3 to 1.7 to 2.3 to Binge abstinence, 16
1.1a,b 1.0a,b and 32 wk:
e) CBT 24 e) 10.1 to 1.7 to 2.7 to e) 8.7 to 1.5 to 2.8 to a/b) 35, 42e
2.2a,b 2.5a,b c/d) 65, 70e
e) 50, 55a,b,c,d

Beumont et al Pre-, 8, and 20 wk: Pre-, 8, and 20 wk: HAM-D: Binge-abstinence at

(1997)25 8 wk and FUP:
a) Nutritional counseling + placebo a) 30% a) 7.3 to 2.3 to 2.3 a) 6.1 to 1.2 to 1.9 a) 11.8 to 6.8 a) 61.5%, 60.9%
b) Nutritional counseling + SSRI b) 50% b) 8.8 to 1.2 to 2.5 b) 10.1 to 1.6 to 2.2 b) 11.0 to 5.3 b) 69.6%, 35.7%

Fahy et al (1993)17 At pre- and 16 wk: At pre- and 16 wk: MADRS:

a) CBT + D-fenfluramine a) 0% a) 6.2 to 3.2 a) 6.6 to 3.4 a) 13.1 to 8.7 8-wk: 54%
b) CBT + placebo b) 9.4% b) 7.8 to 3.8 b) 5.1 to 2.4 b) 13.0 to 9.3 16-wk: 74%

Fichter et al (1991)26 NA At pre- and post: HAM-D: EDI Bulimia

a) Inpatient psychotherapy + SSRI a) 0.0% a) 5.6 to 30 a)13.3 to 8.3 a) 10.2 to 3.0
b) Inpatient b) 0.0% b) 8.9 to 6.60 b) 14.1 to 11.1 b) 9.9 to 4.0
psychotherapy + placebo

Goldbloom et al Percent reduction: Percent reduction: BDI: Percent abstinent

(1997)18 from
Volume 43 Number 1

vomiting + BE:
a) CBT a) 33.3% a) 79.2%b a) 80% a) 18.4 to 13.8 a) 43%
b) SSRI b) 39.1% b) 37.4%a,c b) 70% b) 16.3 to 13.6 b) 17%
c) CBT + SSRI c) 56.9% c) 82.4%b c) 87% c) 14.8 to 7.5 c) 25%
January 2021

Table III. (Continued )

Study Treatment Condition Attrition Purging Frequency Binge-Eating Depression Abstinence/

Frequency Remission
Jacobi et al (2002)24 BDI: Percent abstinent
from vomiting, BE
at 1-year FUP:
a) CBT a) 42% a) 16.4 to 28.5 to 11.3 a) 17.4 to 13.5 to 8.9 a) 16.8 to 10.9 a) 20%, 40%
b) SSRI b) 25% b) 22.7 to 37.9 to 15.5 b) 20.5 to 34.9 to 12.7 b) 16.0 to 14.4 b) 13%, 38%
c) CBT + SSRI c) 33% c) 15.3 to 14.7 to 21.6 c) 9.0 to 13.5 to 14.8 c) 17.2 to 13.9 c) 11%, 11%
Percent reduction, Percent reduction,
posttreatment: posttreatment:
a) 52% a) 42%
b) 35% b) 46%
c) 32% c) 50%

Leitenberg et al Mean frequency vomiting EAT mean score: IDD: Percent abstinent
(1994)19 at pre-, end, and 6-mo from vomiting,
FUP: posttreatment:
a) CBT a) 14% a) 9.3 to 0.3 to 0.9* a) 41.6 to 14.7* to 12.6* a) 27.5 to 8.2 to 8.8* a) 71.4% (5 of 7)
b) Desipramine b) 57% b) 9.2 to 8.2 to 7.2 b) 55.7 to 47.0 to 41.0 b) 32.0 to 21.0 to 21.0 b) 0%
c) CBT + desipramine c) 28% c) 7.1 to 1.7 to 1.7* c) 62.6 to 26.4* to 36.8 c) 36.2 to 18.2* to 19.8 c) 57.1% (4 of 7)

Mitchell et al Mean frequency Mean frequency BE, pre HAMD-D, preepost: EDI global score, pre
(1990)27 vomiting, preepost: epost: epost:
a) Placebo a) 16.1% a)10.0 to 9.9b,c,d a) 8.0 to 7.8b,c,d a)10.9 to 9.7b,c,d a) 68.9 to 64.0b,c,d
b) Imipramine b) 32.6% b) 8.6 to 4.7c,d b) 7.3 to 3.7c,d b) 11.6 to 7.0c,d b) 67.4 to 49.6c,d
c) Intensive group therapy + placebo c) 14.7% c) 13.2 to 1.3a,b c) 9.2 to 1.0a,b c) 9.5 to 4.2a,b c) 60.9 to 28.5c,d
d) Intensive group d) 25.0% d) 9.6 to 1.0a,b d) 8.4 to 0.7a,b d) 11.0 to 2.3a,b d) 66.1 to 26.2b,c,d
therapy + imipramine

Mitchell et al Percent reduction at Percent reduction at HAM-D scores, pre: Percent abstinent

D.L. Reas and C.M. Grilo

(2001)22 endpoint and FUP: endpoint and FUP: from vomiting + BE
a) Placebo a) 5.5% a) 22.8% and 21.8% a) 32.4% and 26.9% a) 10.9 a) NA
b) Fluoxetine b) 0.0% b) 52.8% and 46.1% b) 50.3% and 43.4% b) 8.85 b) 16%
c) shCBT + placebo c) 0.0% c) 50.2% and 31.5% c) 59.7% and 35.4% c) 10.1 c) 24%
d) shCBT + Fluoxetine d) 5.8% d) 66.7% and 67.7% d) 66.8% and 61.6% d) 8.1 d) 26%

(continued on next page)

27
 Table III. (Continued )
28

Clinical Therapeutics
Study Treatment Condition Attrition Purging Frequency Binge-Eating Depression Abstinence/
Frequency Remission
Mitchell et al Frequency BE at pre-, Frequency compensatory BDI: Percent remitted (no
(2011)20 post-, and FUP: pre-, post-, and FUP: longer meeting
DSM criteria) at
end of treatment
and FUP:
a) CBT a) 19% a) 27 to 4 to 10 a) 44 to 12 to 15 a) 17.9 to 12.3 to 13.3 a) 57% and 44%
b) Stepped-care b) 25% b) 27 to 8 to 3 b) 43 to 19 to 5 b) 17.5 to 12.7 to 12.1 b) 52% and 32%

Walsh et al (1997)21 34% overall Frequency: Frequency: BDI: Percent abstinent

from
vomiting + BE:

a) CBT-SSRI a) 10.8 to 1.1e a) 7.3 to 0.95e a) 10.9 to 4.4 a) 48%

b) CBT-placebo b) 10.8 to 5.6d b) 7.2 to 2.56d b) 11.7 to 6.8 b) 20%
c) SPT-SSRI c) 10.6 to 5.5 c) 7.9 to 3.6 c) 15.9 to 6.7 c) 9%
d) SPT-Placebo d) 11.9 to 7.5b d) 6.2 to 3.3b d) 14.3 to 10.2 d) 14%
e) Medication e) 10.5 to 3.7a e) 8.3 to 2.6a e) 14.5 to 8.2 e) 21%

Walsh et al (2004)23 BDI: Percent abstinent

from
vomiting + BE:
a) Placebo a/b) 66.6% a) 17.3 to 12.5 a) 15.5 to 9.9 a) 18.4 to 15.9 a/b) 9.5%
b) Fluoxetine alone c/d) 71.4% b) 18.3 to 11.2 b) 16.6 to 8.1 b) 18.4 to 10.4 c/d) 12.2%
c) Placebo + gSH c) 20.7 to 10.3 c) 20.70 to 10.1 c) 19.6 to 17.2
d) Medication + gSH d) 19.3 to 17.2 d) 17.9 to 13.9 d) 19.7 to 12.5

BDI ¼ Beck Depression Inventory; BE ¼ binge eating; CBT ¼ cognitive-behavioral therapy; DSM ¼ Diagnostic and Statistical Manual of Mental Disorders; EAT ¼ Eating
Attitudes Test; EDI ¼ Eating Disorders Inventory; FUP ¼ follow-up; gSH ¼ guided self-help; HAM-D ¼ Hamilton Depression Inventory; IDD ¼ Inventory to Diagnose
Depression; NA ¼ data not available; NS ¼ not significant; SPT ¼ supportive psychotherapy; SSRI ¼ selective serotonin reuptake inhibitor; sh ¼ self-help.
Subscripts denote significant group differences between treatments.
Asterisk indicates a significant difference of p < .05.
Volume 43 Number 1

eating abstinent patients fell from 69.6% to 35.7%,
whereas for placebo + nutritional counseling group,
the proportion of abstinent patients remained fairly
constant at ~61%. Noteworthy was the high rate of
attrition from the study (50% and 30% for
fluoxetine and placebo, respectively) by the 20-week
follow-up.
Walsh et al,21 in a complex RCT design,
investigated: (1) how a psychodynamically oriented
supportive therapy compared with CBT; (2) whether
a 2-stage medication intervention, in which fluoxetine
was provided if desipramine (first medication used)
was found ineffective or poorly tolerated, would
improve the outcomes of a psychological treatment;
and (3) whether a combination of medication plus
psychological treatment (CBT + medication or
supportive therapy + medication) was superior to
medication alone. Analyses revealed that CBT was
significantly more effective than supportive
psychotherapy in improving binge eating and
purging. Second, combining CBT with antidepressant
medication was superior to medication alone. Third,
combining supportive psychotherapy with medication
conferred no additional benefit to medication. The
study did not include a psychotherapy-only group,
and thus a direct comparison of CBT with and
without medication was not possible.
Jacobi et al,24 in one of the few BN trials with a 12-
month follow-up, tested fluoxetine only, CBT, and
their combination. All treatment conditions led to
significant improvements in symptoms, although
abstinence rates were highest in the CBT condition,
both at posttreatment and at the 1-year follow-up.
Adding fluoxetine conferred no greater benefit in the
reduction of binge eating and purging than CBT
delivered alone. Caution is warranted when
interpreting the reported outcomes given the high
rates of attrition across the treatment conditions and
especially for the CBT condition.
Mitchell et al22 tested the effectiveness of self-help
CBT and fluoxetine in an RCT with 91 women with
BN randomized to 1 of 4 conditions: fluoxetine only,
placebo, self-help CBT + fluoxetine, or self-
CBT + placebo. The investigators reported that
abstinence rates did not differ significantly across
active treatment conditions (16% for fluoxetine, 26%
for self-help + fluoxetine, 24% for self-help
CBT + placebo, and “not available” for placebo),
although those who received self-help + fluoxetine
January 2021
D.L. Reas and C.M. Grilo
had the greatest reduction in the frequency of
vomiting episodes.
Walsh et al,23 in a 2-site trial, tested the effectiveness
of self-help CBT and fluoxetine in an RCT with 91
women with BN randomized to 1 of 4 conditions:
fluoxetine only, placebo, self-help CBT + fluoxetine,
or self-CBT + placebo. This RCT was performed in
primary care settings with generalist clinicians
delivering the interventions. Attrition was highly
problematic, with two thirds of the participants
dropping out of the study; completer rates were
33.3% for the fluoxetine groups and 28.6% for the
self-help groups. Rates of remission were poor at
8.8% overall, with no significant differences across
the 4 treatment conditions.
Mitchell et al,20 in a multisite trial with 293
patients with BN, compared “standard CBT” versus
a “stepped-care” approach by using an adaptive
treatment strategy; both treatment conditions
integrated pharmacotherapy with fluoxetine in the
case of nonresponse. Participants in the “standard
CBT” group received standard individual (20
sessions) CBT; a subset of patients who were
predicted to be nonresponders after 6 sessions
(defined as <70% reduction in purging) had
fluoxetine (60 mg/d) added to their treatment.
Participants in the stepped-care arm were started
with guided self-help CBT, with fluoxetine (60 mg/d)
added for those predicted to be nonresponders after
6 sessions, followed by standard individual CBT for
6 months for those who failed to achieve abstinence
by week 18; fluoxetine, if used, was continued until
the 1-year follow-up. Analyses revealed that the 2
treatment conditions did not differ significantly on
abstinence rates at posttreatment but the stepped-
care condition was superior to the standard CBT at
the 1-year follow-up. For the “at-risk” participants
(ie, nonresponders at session 6), the stepped-care
approach (which included the addition of fluoxetine)
enhanced outcomes at the end of treatment. The
authors noted that the guided self-help CBT (which
was delivered by less experienced clinicians) plus the
addition of fluoxetine for nonresponders seemed as
effective as the traditional individual standard
CBT + fluoxetine. Importantly, the effectiveness of
individual components within the sequences (ie, the
addition of fluoxetine) could not be examined
because there was no comparison condition and
because participants were randomized to the overall
29
 Clinical Therapeutics
treatment arms and not to fluoxetine treatments
within the arms.
Findings of Combined Treatments for BED
Findings of RCTs testing combination treatments
for BED with antidepressant, weight loss, and
antiepileptic medications are presented in the
following sections (Table IV).
Two open-label trials testing the additions of 3
antidepressants to CBT/BWL treatments for BED
reported little-to-no additive effects. Agras et al30
performed the first additive/sequential treatment
study for BED with 108 women randomized to one
of three 9-month treatment conditions: BWL, CBT
followed by BWL, and CBT followed by BWL with
the addition of the antidepressant desipramine (open-
label unblinded). The combined/additive condition
with desipramine did not significantly enhance binge-
eating outcomes, although a statistically significant
(albeit clinically meaningless) weight loss was
observed. Ricca et al32 performed an open-label
comparative trial in which 108 patients (men and
women) with BED were randomized to one of five 6-
month treatment conditions: CBT, CBT + fluoxetine,
CBT + fluvoxamine, fluoxetine, or fluvoxamine.
Analyses revealed that both antidepressant
monotherapies were significantly inferior to CBT
conditions (either alone or with addition of
antidepressants) and that neither SSRI antidepressant
significantly enhanced CBT outcomes.
Double-blind placebo-controlled RCTs have
provided further strong evidence indicating little-to-
no advantage for adding antidepressant medications
to either CBT or BWL. Laederach-Hofmann et al,31
in a placebo-controlled double-blind RCT with 31
patients with BED, found that adding imipramine to
a treatment with diet + supportive counseling failed
to enhance binge-eating outcomes relative to adding
placebo but was associated with statistically
significantly greater weight loss (−2.2 kg vs 0.2 kg).
Two double-blind RCTs testing fluoxetine in
combination designs yielded convergent findings that
adding this SSRI antidepressant did not significantly
improve outcomes produced by either BWL34 or
CBT.35 Specifically, Devlin et al34 found that adding
fluoxetine to BWL failed to significantly enhance
reductions in binge-eating frequency or abstinence
rates, eating-disorder psychopathology, or weight loss
but did produce greater reductions in depression
30
scores relative to adding placebo. In contrast, adding
CBT to BWL significantly enhanced binge-eating
outcomes (eg, abstinence rates of 62% vs 33%,
respectively).
Devlin et al,42 in their 24-month follow-up analyses,
reported that the addition of CBT to BWL (but not
fluoxetine) was associated with significantly greater
reductions in frequency of binge eating and
abstinence rates; neither CBT nor fluoxetine
enhanced weight losses, whereas fluoxetine enhanced
depression outcomes. Grilo et al35 reported that the
addition of fluoxetine did not significantly enhance
CBT on any outcome measure, whereas CBT (with
either fluoxetine or placebo) was significantly
superior to both fluoxetine and placebo (which did
not differ significantly from one another) on binge-
eating abstinence rates (ie, 50% and 61% vs 29%
and 30%, respectively). Similar patterns of significant
differences were reported for frequency of binge
eating and reductions in eating-disorder
psychopathology and depression; weight loss,
however, was minimal and did not differ significantly
across treatments.
Grilo et al,43 in their 12-month follow-up analyses
after the completion of treatments, reported that
CBT + fluoxetine and CBT + placebo did not differ
significantly from one another but both were both
significantly superior to monotherapy with fluoxetine
on most outcomes. Collectively, such findings
indicate the significantly superior durability of CBT
relative to fluoxetine and that adding fluoxetine
versus placebo to CBT had no long-term advantage
for binge eating outcomes following treatment
completion.
Double-blind placebo-controlled RCTs have
generally reported little-to-no advantage for adding
the 2 weight-loss medications that have been tested
to date to either CBT or BWL for BED, although
some findings suggest they may enhance weight loss,
albeit very modestly. RCTs have examined
orlistat,29,36,37 an FDA-approved weight-loss
medication that works locally in the gut to block fat
absorption, and sibutramine,39 a centrally acting
agent that was FDA approved and then withdrawn
from the market.
Golay et al,29 in an RCT with 89 patients with BED
comorbid with obesity, compared adding orlistat
versus placebo to a reduced-calorie diet (some
guidance but did not appear to be a behavioral [or
Volume 43 Number 1
January 2021

Table IV. Main findings from randomized controlled trials investigating combined psychotherapy and pharmacotherapy for binge-eating disorder
(BED).
Study Treatment Attrition % % Binge Binge-Eating Weight Loss Depression Eating Pathology
Condition Abstinent Frequency
Agras et al Binge days, weekly: Weight loss (kg): BDI: TFEQ Disinhibition:
(1994)30
a) BWL only a) 27 a) 19, 14 a) 4.5 to 1.5 to 2.0 a) 3.7 to 4.2 a) 12.9 to 11.6 to 11.3 CBT/BWL-D > BWL
only at wk 24
b) CBT/BWL b) 17 b) 37, 28 b) 4.4 to 1.2 to 1.7 b) 1.6 to 0a b) 13.5 to 12.7 to 8.9
c) CBT/BWL-D c) 23 c) 41, 32 c) 5.1 to 0.9 to 1.5 c) 6.0 to 4.8b c) 13.7 to 10.8 to 7.8

Laederach- NA Binge episodes, Weight loss (kg): HAM-D: NA

Hoffman et weekly:
al (1999)31
a) Counseling a) 6 a) 7.1 to 5.3 to 7.2 a) 0.2 to 2.2 a) 21.3 to 16.0 to 19.2
b) Imipramine b) 7 b)7.1 to 2.5 to 4.1 b) 2.2 to 5.1a b) 22.6 to 9.8a to 12.6a

Ricca et al NA Binge episodes, BMI: BDI: EDE:

(2001)32 monthly:
a) CBT a) 15 a) 18 to 8.0 to 8.0d,e Significantly reduced at a) 22 to 14 to 14 a) 3.8 to 3.4 to 3.3d,e
posttreatment and
FUP for CBT,
CBT + FLX, and
CBT + FLV but not for
the FLX and FLV
groups
b) CBT + FLX b) 27 b) 17 to 6.0 to 7.0d,e b)17 to 11 to 11 b) 3.8 to 2.7 to 2.7d,e
c) CBT + FLV c) 22 c) 18.0 to 8.0 to c) 22 to 10 to 10 c) 4.0 to 2.7 to 2.6d,e
8.0d,e
d) FLX only d) 24 d) 20.0 to 19.0 to d) 20 to 15 to 16 d) 3.4 to 3.8 to 3.9
21.0
e) FLV only e) 27 e) 20.0 to 18.0 to e) 21 to 14 to 14 e) 3.8 to 3.8 to 3.8
18.0

D.L. Reas and C.M. Grilo

Note: Significantly
reduced EDE total
for CBT, CBT-FLX,
and CBT-FLV but
not for the FLX and
FLV groups.
Greatest reduction
for CBT-FLV. No
31

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32

Clinical Therapeutics
Table IV. (Continued )

Study Treatment Attrition % % Binge Binge-Eating Weight Loss Depression Eating Pathology
Condition Abstinent Frequency
additional
improvement at
FUP
Devlin et al Main effect for Monthly, preepost: Weight (kg) at preepost: BDI, preepost: At posttreatment, no
(2005, CBT: significant
2007)34,42 treatment effects
for TFEQ, BES, or
BSQ
a) FLX a) 31 62% vs 33% a) 16.4 to 4.9 a) 113.8 to 111.9 a) 14.5 to 7.5 At FUP, FLX showed
advantage to
placebo for TFEQ
restraint (p ¼ 0.03)
b) Placebo b) 48 No main effect for b) 15.4 to 6.0 b) 113.5 to 111.1 b) 15.6 to 10.6
FLX:
c) CBT c) 40 52% vs 41% c) 17.1 to 3.7 c) 116.5 to 114.6 c) 13.9 to 8.4
d) CBT + FLX d) 25 d) 16.1 to 2.2 d) 116.9 to 112.8 d) 16.9 to 6.3
All given in addition to Note: At Note: At posttreatment Note: At posttreatment
group BWL posttreatment and and FUP, no and FUP, advantage to
2-y FUP, the significant main effects FLX vs placebo
addition of CBT to for either CBT or (p < 0.05)
BWL significantly medication
enhanced assignment
reduction in binge
frequency and
remission
(p < 0.001)

Golay et al Binge episodes, % loss, IBW: BDI, preepost: EDI total:

(2005)29 weekly:
a) Orlistat/diet a) 11 a) 77 a) 5.4 to 1.0 a) 7.4% loss a) 10.8 to 8.2 a) 68.0 to 50.0
b) Placebo/diet b) 29 b) 71 b) 6.2 to 1.7 b) 2.3% lossa b)13.6 to 11.6a b) 64.9 to 58.4a
Volume 43 Number 1

Note: % no longer
meeting BED
criteria

Grilo et al Binge episodes, % achieving 5% loss: BDI: EDE-interview global:

(2005)29 monthly:
a) Orlistat + CBT gSH a) 24 a) 64, 52 a) 16.4 to 3.2 to 3.4 a) 36%, 32% a) 17.1 to 10.1 to 9.9 a) 3.2 to 2.1 to 2.2
January 2021
Table IV. (Continued )

Study Treatment Attrition % % Binge Binge-Eating Weight Loss Depression Eating Pathology
Condition Abstinent Frequency
b) Placebo + CBT gSH b) 20 b) 36,a 52 b) 13.5 to 3.6 to 2.8 b) 8%,a 8%a b) 20.6 to 14.7 to 14.6 b) 3.2 to 2.4 to 2.3

Grilo et al Binge episodes, Weight loss (lb) at BDI: EDE global:

(2005, monthly EDE-Q: posttreatment and
2012)35,43 FUP:
a) FLX -only a) 22 a) 22, 4 a) 17.9 to 10.4 to a) 4.8 to 1.5 a) 16.9 to12.6 to 12.9 a) 3.9 to 3.1 to 3.3
10.4
b) Placebo b) 15 b) 26, NA b)13.2 to 7.2 c) 5.0 to 9.8 b) 18.7 to 11.7 b) 3.5 to 2.6
c) CBT + placebo c) 21 c) 61,a,b 36a c)16.6 to 2.3 to 4.6a,b d) 5.6 to 4.1 c) 16.5 to 7.4a to 11.4 c) 3.8 to 2.1 to 2.7a,b
d) CBT + FLX d) 23 d) 50,a,b 27a d)16.5 to 4.3 to d) 20.2 to 8.3 to 11.2 d) 4.0 to 2.2 to 2.4a,b
4.6a,b

Claudino et al Binge episodes, Weight loss (kg): BDI: BES:

(2007)28 weekly:
a) CBT+topiramate a) 19 a) 84 a) 4.2 to 0.0 a) 6.8 kg a)16.8 to 10.9 a) 27.2 to 7.5
b) CBT + placebo b) 28 b) 61a b) 3.4 to 0.3 b) 0.9 kga b) 15.9 to 9.2 b) 26.5 to 8.6

Ricca et al NA Binge episodes, BMI (kg/m2): BDI: EDE-Q global:

(2009)33 monthly:
a) CBT a) 33 a) 5.0 to 2.0 to 3.0 a) 39.2 to 38.4 to 38.9 a) 19.5 to 14.5 to 17.5 a) 2.8 to 2.6 to 2.7
b) CBT + zonisamide b) 50 b) 5.0 to 2.0 to 2.0a b) 38.4 to 36.7a to 36.5a b) 20 to 16 to 16.0 b) 2.8 to 2.1a to 2.2a

Grilo and NA BMI (kg/m2): BDI: EDE global:

White
(2013)37
a) BWL+ orlistat a) 30 a) 60, 50 a) 39.0 to 37.9 to 37.6 a) 22.9 to 11.4 to 10.3 a) 2.5 to 1.6 to 1.5
b) BWL+ placebo b) 25 b) 70, 50 b) 37.2 to 36.0 to 36.7a b) 25.7 to 17.1 to 20.9 b) 2.7 to 2.0 to 1.9

Grilo et al Binge episodes, BMI (kg/m2): BDI: EDE global:

(2014)39 monthly:

D.L. Reas and C.M. Grilo

a) Sibutramine a) 27 a) 39, 19, 19 a) 22.4 to 5.0 to 4.9 a) 39.4 to 38.4c,d to 38.7 a) 12.8 to 7.9 to 9.7 to a) 2.4 to 1.7 to 1.9 to
to 5.8 to 39.3 10.1 1.8
b) Placebo b) 15 b) 30, 41, 37 b) 21.1 to 5.3 to 5.7 b) 39.3 to 39.6c,d to b) 13.6 to 9.6 to 8.7 to b) 2.6 to 2.1 to 1.8 to
to 6.7 38.8to 39.5 7.5 1.8
c) shCBT + placebo c) 12 c) 24, 40, 40 c) 14.6 to 6.4 to c) 36.5 to 35.9a,b to 35.3 c)17.0 to 9.8 to10.3 to c) 2.5 to 1.7 to 1.7
3.6a,b to 4.9 to 35.4 10.5 to1.6
d) shCBT + sibutramine d) 16 d) 23, 50, 42 d)16.9 to 3.6 to 3.9 d) 37.8 to 35.6a,b to 36.0 d)14.0 to 9.3 to 9.8 to d) 2.5 to 1.8 to 1.6 to
to 3.0 to 36.5 10.3 1.6
33

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Clinical Therapeutics

lifestyle] weight loss intervention). Analyses revealed

a) 17.8 to 1.7 to 1.9 a) 37.5 to 35.7 to 35.2 to a) 14.0 to 10.0 to 9.1 to a) 2.6 to 1.8 to 1.7 to

BDI ¼ Beck Depression Inventory; BES ¼ Binge Eating Scale; BMI ¼ body mass index; BSQ ¼ Body Shape Questionnaire; BWL ¼ behavioral weight loss; D ¼
desipramine; CBT ¼ cognitive-behavioral therapy; EDE ¼ Eating Disorder Examination-Questionnaire; EDI ¼ Eating Disorders Inventory; FLV ¼ fluvoxamine;
FLX ¼ fluoxetine; FUP ¼ follow-up; gSH ¼ guided self-help; HAM-D ¼ Hamilton Depression Inventory; IBW ¼ ideal body weight; NA ¼ data not available.
no significant differences between the addition of
Eating Pathology

orlistat versus placebo to diet on proportion of

to 1.7 to 1.6
patients no longer meeting BED criteria (77% vs

b) 20.2 to 2.7 to 3.8 b) 39.4 to 36.9 to 37.3 to b) 15.3 to 8.9 to 8.8 to b) 2.7 to 1.8
EDE global:

71%, respectively) nor on the frequency of binge

1.7 eating, which was reduced substantially in both
treatment conditions. In contrast, adding orlistat to
diet was associated with significantly greater weight
loss than adding placebo (−7.4% vs −2.3%,
Depression

respectively).
Grilo et al,36 in an RCT with 50 patients with BED
comorbid with obesity, found that adding orlistat to
9.4

8.2

guided self-help CBT was associated with

BDI:

significantly greater binge-eating abstinence rates than

adding placebo at posttreatment (64% vs 36%,
respectively) but not at 3-month follow-up after
Weight Loss

b) 5.8 to 5.2 to 5.0

a) 5.1 to 5.1 to 3.4

discontinuing treatments (52% vs 52%). In contrast,

Weight loss (%)
BMI (kg/m2):

adding orlistat was associated with significantly

greater rates of attaining 5% weight loss at both
35.9

37.3

posttreatment (36% vs 8%) and at 3-month follow-

up (32% vs 8%).
Grilo and White,37 in an RCT with 89 Latinx
Binge-Eating

patients with obesity (40 with BED and 39 without

Frequency
Binge episodes,

BED), tested the addition of orlistat versus placebo

monthly:

(double-blind) to BWL treatments delivered in

to 2.4

to 2.4

individual sessions over 4 months, with a 6-month

Subscripts denote significant group differences between treatment conditions.

follow-up after finishing treatments. Notably, this

RCT was performed at a community mental health
Abstinent

b) 66.5, 33.3,
% Binge

a) 74.4, 38.2,

center serving economically/educationally

disadvantaged Latinx patients in Spanish in a “real-
44.7

41.1

world” urban setting. Analyses revealed significant

reductions in eating-disorder psychopathology,
depression, and weight loss. Overall, adding orlistat
Attrition %

to BWL did not enhance outcomes; however, BED

significantly moderated weight-loss outcomes: adding
b) 12.5
a) 2.6

orlistat to BWL enhanced weight loss in those

TFEQ ¼ Three-Factor-Eating-Questionnaire.

patients without BED but not among those with

BED. Analyses with the subgroup of 40 patients with
BED revealed binge-eating abstinence rates of 65% at
Treatment
Condition

posttreatment and 50% at 6-month follow-up.

a) BWL standard

b) Stepped-care

Grilo et al,39 in a placebo-controlled double-blind

RCT conducted in a primary care setting with 104
Table IV. (Continued )

patients with BED comorbid with obesity, tested the

effectiveness of self-help CBT and sibutramine, alone
and in combination. Patients were randomized to one
(2020)38,44

of four conditions (sibutramine only, placebo, self-

Grilo et al
Study

help CBT + sibutramine, or self-CBT + placebo)

delivered for 4 months and were followed up for 12
months after completing/discontinuing treatments.

34 Volume 43 Number 1

Analyses revealed that binge-eating abstinence rates
did not differ significantly across treatments, and the
treatments differed little in frequency of binge eating,
eating-disorder psychopathology, and depression. In
contrast, sibutramine was associated with
significantly greater weight loss at posttreatment;
however, weight re-gain occurred in patients who
had received sibutramine, and by the 6- and 12-
month follow-ups, weight loss was no longer
significantly different across groups.
Grilo et al38,44 tested the effectiveness of an adaptive
stepped-care treatment versus BWL in 191 patients
with BED and comorbid obesity. Patients were
randomized to either BWL (standard treatment;
n ¼ 39) or to stepped-care (n ¼ 152) for 6 months
and were followed up 6 and 12 months after
completing/discontinuing the treatments. Within
stepped-care, after 1 month of BWL, patients were
stratified according to treatment response. Patients
achieving a rapid response (defined as a 65%
reduction in binge eating) were randomized to a
weight-loss medication (sibutramine or orlistat) or to
placebo (double-blind). Nonrapid responders were
switched from BWL to guided self-help CBT; in
addition, they were randomized to either weight-loss
medication or placebo for the remaining 5 months.
Analyses revealed that, overall, BWL and stepped-
care did not differ in binge-eating abstinence rates
(74.4% vs 66.5%), percent weight loss (5.1% vs
5.8%), or secondary outcomes of depression or
eating-disorder psychopathology. Within stepped-
care, weight-loss medication enhanced certain
outcomes. Weight-loss medication significantly
enhanced binge-eating abstinence and frequency
outcomes among nonresponders to BWL and weight-
loss outcomes among both responders and
nonresponders to BWL. Analyses of 12-month
follow-up data44 revealed that, overall, the binge-
eating improvements and weight losses produced by
BWL and stepped-care did not differ significantly and
that within stepped-care, the medication and placebo
conditions did not differ.
Two RCTs have tested antiepileptic medications in
combination with CBT for BED.28,33 Ricca et al,33 in
an unblinded open-label RCT with 52 patients with
(subthreshold and threshold) BED, reported that
adding zonisamide to CBT for 24 weeks was
associated with significantly greater reductions than
January 2021
D.L. Reas and C.M. Grilo
CBT (alone) in eating-disorder psychopathology,
depression, and BMI at posttreatment. At the 12-
month follow-up, patients who had received
zonisamide plus CBT had significantly greater
reductions in binge-eating frequency than those
treated with CBT alone, along with significantly
greater reductions in 1 of 6 eating-disorder measures
and anxiety (but not depression) scores. Ricca et al
also reported analyses suggesting that both treatment
conditions had significant reductions in BMI at
posttreatment and that patients receiving CBT, but
not zonisamide + CBT, regained weight during the
12-month follow-up.
Claudino et al,28 in a placebo-controlled double-
blind RCT with 73 patients with BED, tested the
addition of topiramate versus placebo with 21 weeks
of CBT. Analyses revealed that topiramate, compared
with placebo, was associated with significantly
greater binge-eating abstinence rates (84% vs 61%,
respectively; using 1-week endpoint data) and
significantly greater weight loss (−6.8 kg vs −0.9 kg).
Analyses comparing topiramate and placebo
combinations with CBT revealed no statistically
significant differences in reductions in binge-eating
frequency, eating-disorder psychopathology, or
depression.
DISCUSSION AND CONCLUSIONS
Because many patients do not derive sufficient
benefits from the available monotherapies for eating
disorders, the present review evaluated RCTs testing
combined pharmacological and psychological
treatments to inform clinical practice and future
treatment research. In contrast to the public health
significance of eating disorders, the scope of
research performed on the utility of combining
treatments is limited overall and particularly in
recent years for AN and BN.
We identified a total of only 28 RCTs testing
combined interventions for eating disorders. This
RCT literature is characterized by substantial
methodological limitations, particularly for the AN
and BN trials, included high attrition, small sample
sizes, limited diversity of patient groups, and dearth
of data after the completion of treatments. Overall,
RCTs testing combined pharmacological plus
psychological treatments for eating disorders have
yielded mostly nonsignificant findings. For AN, 3 of
35
 Clinical Therapeutics
the 4 RCTs reported no significant advantage for
combining treatments, and the fourth RCT14
reported a statistically significant albeit clinically
modest advantage. For BN, 10 of the 12 RCTs
reported no significant advantage for combining
treatments; 2 RCTs22,23 found that combining
fluoxetine with specific psychological treatments
enhanced outcomes relative to medication-only but
not relative to the psychological treatments only. For
BED, of the 12 RCTs, only 2 (both with antiseizure
medications)28,33 significantly enhanced both binge-
eating and weight outcomes, and only 2 (with
orlistat, a weight-loss medication)29,36 enhanced
weight loss, albeit very modestly, but not binge-
eating outcomes.
Future research should examine whether treatments
found to be effective in specialty clinics can be
effectively delivered in generalist or more diverse
settings. Of 3 relevant RCTs, one found that
evidence-based treatments for BED could be
effectively delivered even in community clinics served
disadvantaged patients.37 However, 2 found that
evidence-based treatments for BED39 and BN23 were
largely ineffective when delivered by generalist
clinicians in primary care settings.
Future research should focus on testing additive
benefits of medications with relevant mechanisms of
action to available effective psychological
interventions. For example, there are 3 FDA-
approved weight-loss medications (phentermine/
topiramate, naltrexone/bupropion, and liraglutide)
that could be considered for the treatment of BED,
either alone or in combination with psychological/
behavioral interventions. Similarly, ongoing research
is testing the utility of combining
lisdexamphetamine,45,46 the sole FDA-approved
medication for BED, with CBT (NCT03924193). It is
important to note that at the present time, there are
no FDA-approved medications indicated specifically
for AN, only one (fluoxetine) for BN, and only one
(lisdexamphetamine) for BED, and as such, any use
of other medicines for the treatment of eating
disorders is “off-label.”
Future RCTs testing additive effects should use
innovative adaptive designs38 to evaluate ways to
combine and sequence treatments to improve
outcomes among nonresponders and to enhance
outcomes among responders to initial interventions.
Future RCTs should also examine patient factors that
36
might predict or moderate outcomes given the dearth
of available empirical data on predictors/moderators
of treatment outcomes.47 For AN, there is no
available evidence on patient variables to guide the
prescription of specific psychological versus
pharmacological versus combined treatments. For
BN, one study found that greater depression
predicted more rapid response to CBT than to
supportive, psychodynamically oriented therapy and
to antidepressant pharmacotherapy than placebo48;
such findings might suggest the utility for considering
combining treatments in cases with greater
depression. For BED, one study found that
overvaluation of shape/weight (a specific body image
cognitive feature of eating disorders) significantly
moderated treatment outcomes: patients with high
overvaluation were significantly more likely to
improve if receiving CBT than medication alone.49
Such findings suggest the utility of combining CBT
rather than relying on medication monotherapy if
treating patients with BED with high levels of
overvaluation of shape/weight. In the only study with
data to test for predictors/moderators of combination
treatments, Lydecker and Grilo50 found that
psychiatric comorbidity was associated with greater
ED psychopathology throughout treatment but did
not significantly moderate outcomes attained with
CBT, BWL, or combined pharmacological plus
psychological treatments. Such findings, which
challenge clinical perspectives that comorbidity
indicates need for combination treatments, require
further research.
Future clinical practice and research also build on a
treatment process known as “rapid response,” which
has been found to be a reliable prognostic predictor
of outcomes for BN and BED. Early rapid response
to treatment reliably predicts better outcomes for
both psychological and pharmacological treatments
among patients with BN48 and with BED.51e53
Research with BED has found that failing to have a
rapid response to initial treatments, particularly to
pharmacotherapies51,52 or to behavioral weight
loss,53 is a signal to consider the need to either
switch treatments or to add medications.38 Finally,
research should include longer term studies to
determine optimal treatment duration, include follow-
up assessments to identify both the differential
durability of treatments and periods of risk for
relapse43 and whether to discontinue medications.54
Volume 43 Number 1

DISCLOSURES
The authors report that they have no financial or other
conflicts of interest with respect to the content of this
paper.
No academic, pharmaceutical, or industry entity of
any kind influenced this review study or the
preparation of this report in any manner. The NIH
had no role or influence on the content of the paper
nor does the content reflect the views of the NIH.
ACKNOWLEDGMENTS
Dr. Grilo was supported, in part, by National Institutes
of Health (NIH) grants R01 DK49587, R01
DK114075, and R01 DK112771.
Dr. Grilo reports several broader interests that did
not influence this research or paper. These interests
include: consultant to Sunovion and Weight
Watchers; honoraria for lectures, CME activities, and
presentations at scientific conferences; and royalties
from Guilford Press and Taylor & Francis Publishers
for academic books.
Dr. Reas was responsible for conceptualization,
methodology, validation, investigation, writing drafts,
editing, and final review, visualization. Dr. Grilo was
responsible for conceptualization, methodology,
validation, investigation, writing drafts, editing, and
final review, visualization.
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Address correspondence to: Deborah L. Reas, PhD, Regional Department
for Eating Disorders, Division of Mental Health and Addiction, Oslo
University Hospital, Oslo, Norway. E-mail: deborah.lynn.reas@ous-hf.no
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