Clinical Phillipa J.

Hay
Anglica M. Claudino

Psychopharmacology of Eating
Disorders: A Research Update
Abstract: The paper presents a critical review (with search date 2010) of the major psychotropic medications assessed in
eating disorders, namely antipsychotics, antidepressants, mood-stabilizing medications, anxiolytic and other agents.
The evidence of efcacy of drug treatments is mostly weak or moderate. In addition, attrition rates are usually higher
than for psychotherapies. However, there is support for use of antidepressants, particularly high-dose uoxetine in
bulimia nervosa, and anticonvulsants (topiramate) for binge-eating disorder. Low-dose antipsychotic medication
may be clinically useful as adjunct treatment in acute anorexia, particularly where there is high anxiety and obsessive
eating-related ruminations and failure to engage, but more trials are needed. Drug therapies such as topiramate
and anti-obesity medication may aid weight loss in obese or overweight patients with binge-eating disorder; however,
common or potentially serious adverse effects limit their use.

(Reprinted with permission from the International Journal of Neuropsychopharmacology 2012; 15:209222)

INTRODUCTION are distinct in being underweight and hence in a star-

vation state. In the clinic obesity is extremely common

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Eating disorders comprise anorexia nervosa, bulimia in patients with BED and in community surveys
nervosa, binge-eating disorder (BED) and eating dis- (e.g. Hudson et al. 2007) over 40% with BED are
order not otherwise specied (EDNOS) (APA, 2000). obese with body mass index (BMI) .30. Those
Lifetime prevalence estimates in the community are with BED may also be at increased risk of meta-
0.6% for are anorexia nervosa, 1.0% for bulimia bolic syndrome over and above risk due to obesity
nervosa, and 2.8% for BED (Hudson et al. 2007). alone (Hudson et al. 2010). Other non-specic
Both birth-cohort estimates (Hudson et al. 2007) and psychiatric features such as anxiety or mood dis-
sequential population surveys (Hay et al. 2008) sug- turbance, obsessionality and impulsivity are also
gest an increase in disorders of recurrent binge eating common. Treatments are thereby multi-dimensional
in recent years. Eating disorders are characterized by comprising psychotherapy, nutritional rehabilita-
disordered eating behaviours together with cognitive tion, sometimes medical resuscitation and the judi-
schema of self-view being unduly inuenced by body cious use of psychotropic and other medication
image or weight and shape concerns and extreme pre- (Treasure et al. 2010).
occupation with thoughts of food and eating (APA, The present paper reviews the use of psycho-
2000). Disordered eating behaviours include binge pharmacological agents in eating disorders. The
eating (uncontrolled eating of inappropriately large focus of research (and hence this review) has been on
amounts of food), subjective binging on smaller food the three well-described diagnostic groups of an-
quantities, severe dietary restriction, and weight con- orexia nervosa, bulimia nervosa and BED, as efcacy
trol behaviours such as vomiting, use of diuretics or for pharmacotherapy for EDNOS is largely un-
laxatives and driven exercise. The latter behaviours known. It is also acknowledged that the treatment of
are also used as compensation for the recurrent binge anorexia nervosa is particularly poorly studied with
eating typical of bulimia nervosa. In BED there is rigorous systematic reviews consistently concluding
similar recurrent overeating without compensation. there is little evidence for any therapy (e.g. Lock &
All eating disorders have known physical as well as Fitzpatrick, 2009). The major groups of antipsycho-
psychological morbidity. People with anorexia nervosa tic, antidepressant, mood-stabilizing and anxiolytic

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 HAY AND CLAUDINO

non-randomized trials where there were no RCTs of

Main Classes of Medica-
Table 1. an agent or where they were of relevance in presaging
tion Use in Anorexia Nervosa RCTs. It should be noted that these latter studies
Tested in at Least One Ran- are at high risk of bias and should be read as indicative
domized Controlled Trial (RCT) of putative effects and not as substantive evidence of
Medication Clinical effects RCT (n) efcacy.
Antipsychotic
First generation ANTIPSYCHOTIC MEDICATIONS
Pimozide Inconsistent vs. placebo 1
Antipsychotic medication use is largely conned
Sulpiride Inconsistent vs. placebo 1
to people with anorexia nervosa. It is thought an-
Second generation tipsychotics act by targeting dopaminergic and/or
Amisulpride Greater weight gain vs. 1 serotinergic dysfunction (Connan & Stanley, 2003;
antidepressants
Kaye et al. 1999). Clinically, antipsychotics are used
Olanzapine Greater reduction in 1 to reduce extreme beliefs regarding body image and
ruminations vs.
chlorpromazine eating-related disturbed thoughts such as intense ru-
Greater weight gain and 2 minations about food, pseudo-hallucinations as well
reduction psychological as the hyper-arousal and agitation found when people
distress vs. placebo are confronted with weight gain (Powers & Santana,
Antidepressant 2004; Taylor & McAskill, 2000). Paradoxically, in
Amitriptyline Inconsistent greater weight 2 anorexia nervosa, they may not consistently promote
gain vs. placebo weight gain (McKnight & Park, 2010), despite this
Clomipramine No significant effects vs. 1 being a common side-effect in normal weight people
placebo with other psychiatric illnesses such as schizophrenia
Fluoxetine Reduced relapse after 1 (e.g. Chwastiak et al. 2009).
weight gain vs. placebo First-generation antipsychotics such as chlorprom-
No reduced relapse after 1
weight gain when azine were found to cause severe adverse effects such
added to cognitive as convulsions and Parkinsonism. In addition as sum-
behaviour therapy vs. marized in Table 1, there was inconsistent evidence
cognitive behaviour from RCTs regarding the efcacy of tested agents
therapy such as pimozide and sulpiride, in placebo-controlled
trials (Vandereycken, 1984; Vandereycken & Pierloot,
1982). However, there have been a number of prom-
agents are presented rst, followed by less com- ising trials of the second-generation antipsychotics
monly used agents and a discussion of issues in the olanzapine and quetiapine, following case-series
management of comorbid weight disorder. Com- reports in all age groups by Bosanac et al. (2005),
prehensive information on medications used in the Court et al. (2010), Duncan & del Dotto (2007),
treatment of complications of starvation and poor Leggero et al. (2010) and Powers et al. (2007).
nutrition is found in the text by Birmingham & In these studies low doses (e.g. 15 mg/d olanzapine,
Treasure (2010). Literature for the present review 100400 mg/d quetiapine) were commonly used.
was sourced from recent extensive searches conducted There is also one case report supporting the use of
by either or both authors for the purposes of Cochrane aripipazole in three patients with bulimia nervosa
Library and Clinical Evidence and other reviews as well as eight with anorexia nervosa (Trunko et al.
(Claudino et al. 2006; Hay & Claudino, 2010a,b; 2010). In this series, the three patients with bulimia
Treasure et al. 2010; search date 2009) and updated nervosa had or previously had low weight. However,
to June 2010 for this report with a Pubmed search there are few RCTs.
using the terms anorexia nervosa or bulimia nervosa OneRCTcomparedlow-dose(50mg/d)amisulpride
or BED and therapy or treatment. Also searched (a D2 and D3 receptor antagonist at higher doses,
were reference lists of the following systematic pre-synaptic antagonism at lower doses) to uox-
reviews: Brownley et al. 2007; Bulik et al. 2007 and etine (mean dose 28 mg/d) and to clomipramine
Shapiro et al. 2007. Studies were selected for inclusion, (mean dose 57.69 mg/d) in 35 in-patients with
rst, if they met a level of evidence that minimized risk anorexia nervosa attending a weight restoration
of bias as in the above reviews, i.e. were randomized programme for 12 wk. Those given amisulpride
controlled trials (RCTs) with completion rates at had signicantly greater weight gain but other illness
least 50%, or a systematic review of RCTs. Second, features did not differ between groups (Ruggiero et al.
we included studies of case series or case reports or 2001).

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A systematic review (search date 2009) reported there are high rates, up to 50%, of lifetime comorbid
on three RCTs testing olanzapine, a 5-HT2/D2 re- depression and bulimia nervosa (Hudson et al. 2007).
ceptor antagonist, vs. placebo or other antipsychot- However, the efcacy of antidepressant treatment in
ic for anorexia nervosa (McKnight & Park, 2010). bulimia nervosa appears independent of effects on mood
The rst RCT compared it to chlorpromazine added and is more likely related to augmentation of satiety
to standard care in 15 anorexia nervosa patients mechanisms and subsequent reduction in binge eating
(Mondraty et al. 2005). In this trial (which was not (see below) (Goldstein et al. 1999; Walsh et al. 2000).
blinded), olanzapine (mean dose 10 mg/d) showed Claudino et al. (2006) conducted a systematic re-
greater efcacy in reducing anorexic ruminations view of efcacy of antidepressants in acute phase an-
compared to 50 mg/d chlorpromazine. Brambilla et al. orexia nervosa. Only four small RCTs were identied,
(2007) compared olanzapine (2.5 mg for 1 month, three of the tricyclic antidepressants (TCAs) ami-
5 mg for 2 months) to placebo as an adjunctive triptyline (Biederman, et al. 1985; Halmi, et al. 1986)
treatment with cognitive behaviour psychotherapy and clomipramine (Lacey & Crisp, 1980), and one
(CBT) in 30 anorexia nervosa outpatients. Olanzapine of the selective serotonin reuptake inhibitor (SSRI)
was reported to increase weight gain, and reduce de- uoxetine (Attia et al. 1998). Halmi et al. (1986)
pressive symptoms and aggressiveness compared to randomized 72 inpatients to amitriptyline, cyprohep-
placebo, but only for patients of the binge-purge type. tadine or placebo treatment groups. They reported
Finally, Bissada et al. (2008) compared olanzapine a small statistically signicant effect in decreasing the
combined with a day-hospital treatment for 10 wk to time to achieve target weight for both drug groups.
placebo in 34 anorexia nervosa participants. Those The three other acute-phase trials found no sig-
taking olanzapine showed a greater rate of increase in nicant differences in symptom response or weight
weight (achieving target BMI earlier) and improve- gain between active and placebo groups. In addi-
ment of obsessive symptoms. While completion rates tion, cardiovascular risk with tricyclic drugs limits
were high (82%), 55% of eligible patients declined their use in this patient group (Biederman et al.
to be randomized, indicating a potential problem 1985; Halmi et al. 1986). While the doses of anti-
of low acceptance of olanzapine by people with an- depressant used in these trials were low and the
orexia nervosa. duration of treatment was short, the consistency of
These few RCTs suggest a role for low-dose second- negative ndings does not provide support for their
generation antipsychotics in reducing psychological use. There is little evidence for other classes of an-
distress particularly in the re-feeding phase of anorexia tidepressants, although a case report for mirtazepine

PUBLICATIONS
INFLUENTIAL
nervosa treatment. However, there may be problems (which has noradrenergic and serotonergic activity)
with patient acceptance. Larger trials of efcacy are is promising. In this report mirtazepine aided weight
needed, particularly of quetiapine and aripiprazole gain and mood in a 50-yr-old woman with a history of
which may be less sedating and better tolerated as food restriction since her adolescence (Safer et al. 2011).
they are putatively less likely to cause severe weight It has been postulated that the lack of efcacy of
gain feared by patients. At present there are no trials serotonergic drugs in the acute phase of anorexia
of efcacy in other eating disorders and thus no spe- nervosa may be related to low levels of serotonin
cic indication for their use in recognized guidelines metabolites in cerebrospinal uid (e.g. as found by
(APA, 2006; NICE, 2004; RANZCP, 2004). Jimerson et al. 1992) due to poor dietary intake of
the serotonin precursor tryptophan. However, a
ANTIDEPRESSANTS AND LIKE small RCT that compared uoxetine 1 nutritional
MEDICATIONS supplements with uoxetine 1 placebo nutritional
supplements found that the former did not improve
In both anorexia nervosa and bulimia nervosa the physiological effects of chronic under-nutrition
there is putative rationale for the use of antidepres- or appear to enhance the efcacy of drugs (Barbarich
sants. In anorexia nervosa shared inheritance with et al. 2003). More recent ndings using positron
depression (Strober et al. 2000; Wade et al. 2000), emission tomography (PET) imaging by Bailer et al.
neurobiological, most notably serotonin dysfunction (2007) suggest that there may be a better response
(Kaye et al. 1998, 2005) and concurrent depressive to medication for those with restricting type an-
and obsessional psychopathology (Godart et al. 2007; orexia vs. those with bulimic type because of a
Kaye et al. 2004) have suggested a role for anti- differential serotonin receptor-binding activity.
depressant treatment. In addition a recent meta- A body of work summarized in Kaye (2008) now
analysis (Lee & Lin, 2010) has supported there supports the view that there is a poor response to
being a specic genetic variant of the serotonin antidepressants because of adverse effects of star-
transporter gene promoter found in people with an- vation in the 5-HT1A receptor and in extracellular
orexia nervosa (but not bulimia nervosa). Similarly, 5-HT concentrations.

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 HAY AND CLAUDINO

Two double-blind RCTs have tested uoxetine for reduction in appetite and weight, and the use of
patients following acute treatment weight restora- uoxetine has superseded TCAs (Fichter et al. 1991;
tion (Kaye et al. 2001; Walsh et al. 2006). The rst Fluoxetine Bulimia Nervosa Collaborative Study
small trial (n 5 35) found signicantly more patients Group, 1992; Goldstein et al. 1999; Romano et al.
on uoxetine had reduced relapse, namely, they main- 2002). The SSRI antidepressant, uoxetine, is thus
tained an adequate weight and symptom reduction the only medication recommended by leading guide-
during the 1-yr follow-up after hospital discharge lines for bulimia nervosa (APA, 2006), and it is at a high
compared to the control group. However, attrition dose of 60 mg/d. Lower doses were less efcacious
was very high in the placebo group (84% vs. 37% in in this patient group (Fluoxetine Bulimia Nervosa
the treatment group), and for most the decision to Collaborative Study Group, 1992; Goldstein et al.
terminate the study was based on symptoms in- 1995). Clinicians may note that further analyses of
dicating a relapse. A second larger trial of 93 patients these two studies by Sysko et al. (2010) reported
(Walsh et al. 2006) did not nd adding uoxetine attaining early response (more than 60% reduction
to CBT helped prevent relapse (dened as BMI fall- in binge eating or vomiting frequency in the rst
ing to #16.5 kg/m2 and/or worsening of anorexic 3 wk of treatment) was strongly predictive of eventual
symptoms, development of major clinical problems treatment response.
or suicidal ideation). In addition a well-designed Strong evidence of the efcacy of other SSRI agents
RCT (n 5 122 randomized; Halmi et al. 2005) is still lacking, but in clinical practice they may be
was inconclusive as there was an unacceptably high considered for patients that do not respond well to
rate of attrition (73%) in participants randomized uoxetine. There are three similar and very small
to a uoxetine (60 mg/d) arm compared to CBT randomized placebo-controlled trials of citalopram
arm (57% attrition) or combination arm (59%). (Milano et al. 2005a), sertraline (Milano et al. 2004),
Thus, antidepressant use is supported neither in and uvoxamine (Milano et al. 2005b), which were
the acute nor maintenance phases of anorexia ner- supportive for efcacy of all three SSRIs. In addition,
vosa treatment. a small (n 5 27) single blinded trial comparing u-
The situation is very different for use of anti- oxetine and citalopram found no differences in out-
depressants in bulimia nervosa where there are a comes, but the attrition rate was moderately high
number of RCTs (see Table 2), systematic reviews (Leombruni et al. 2006). However, a later study from
and meta-analyses that have consistently supported the same group (Giaquinto et al. 2006) compared the
a range of classes of agents, namely TCAs, SSRIs and three SSRIs in the treatment of bulimia nervosa and
monoamine oxidase inhibitors (MAOIs) in reducing found sertraline (100 mg/d) associated with a very
binge eating and vomiting and improving mood small reduction in binge eating and purging com-
and anxiety symptoms (Bacaltchuk & Hay, 2003; pared to uvoxamine or uoxetine. Finally, as shown
Hay & Claudino, 2010a). Specic SSRIs evalu- on Table 2, most agents only have one RCT pub-
ated include uoxetine, citalopram, sertraline and lished and it is also likely there is publication bias
uvoxamine. (Bacaltchuk & Hay, 2003). A large (n 5 300) neg-
In Bacaltchuk & Hay (2003) pooled data from 24 ative trial of 150300 mg uvoxamine remains pub-
RCTs found that bulimic behaviours had reduced lished only in secondary reports (Corcos et al. 1996;
by up to 70% in the short-term (mean 8 wk); how- Freeman, 1998).
ever, pooled abstinence rates were less than 20% Inconclusive and lower levels of evidence are avail-
when antidepressants were used without any con- able with drugs that act on the noradrenergic system.
current psychosocial intervention. Moreover, Agras Based on ndings from earlier studies that tested drugs
et al. (1992) found that one-third of the 25% of with noradrenergic effects, on the involvement of the
patients who were abstinent at the end of treatment noradrenergic system in the regulation of hunger and
relapsed over time. In contrast, a small number of satiety, and on existing connections between sero-
relapse-prevention studies have reported an effect of tonergic and noradrenergic pathways in the cen-
continuing pharmacotherapy (Fichter et al. 1996; tral nervous system, two small uncontrolled trials of
Romano et al. 2002), although these ndings should reboxetine, a selective noradrenaline reuptake in-
be viewed with caution due to high attrition (around hibitor, have reported positive ndings (El-Giamal
90% at 1 yr follow-up in Romano et al. 2002). et al. 2000; Fassino et al. 2004). Two small un-
Attrition is also high in most trials (around 40%) controlled studies of milnacipran, a selective serotonin
of single pharmacological treatments, in part because and noradrenaline reuptake inhibitor, have suggested
of side-effects but also probable patient preference a trend towards reduction binge eating (El-Giamal
for non-pharmacological therapies. There does, how- et al. 2003; Noma et al. 2008).
ever, appear to be better acceptability for SSRIs. Finally, bupropion is an antidepressant that blocks
This may be because of their short-term effects on reuptake of noradrenaline and dopamine. It was

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Table 2. Main Classes of Medication Use in Bulimia Nervosa Tested in at

Least One Randomized Controlled Trial (RCT)
Medication Clinical effects RCT (n)
Tricyclic antidepressants
Imipramine Bulimic symptom reduction vs. placebo 1
Less reduction binge eating vs. cognitive behaviour therapy (CBT) and 1
less reduction binge eating vs. combined CBT and imipramine and
no significant difference when combined with CBT vs. CBT alone
Desipramine Symptom reduction vs. placebo 2
No significant symptom reduction vs. CBT and no reduction binge 1
eating vs. combined CBT and desipramine and no significant
difference when combined with CBT vs. CBT alone
Monoamine oxidase inhibitors
Phenylzine Bulimic symptom reduction vs. placebo 2
Isocarboxacid Bulimic symptom reduction vs. placebo 1
Brofaromine Bulimic symptom reduction vs. placebo 1
Moclobemide Bulimic symptom reduction vs. placebo 1
Selective serotonin reuptake inhibitors
Fluoxetine Reduced bulimic symptoms at 60 (but not 20)mg/d vs. placebo 3
Reduced relapse but high attrition at 60 mg/d vs. placebo 1
No significant differences in outcome vs. CBT and no reduction binge 3
eating vs. combined CBT and fluoxetine and no significant difference
when combined with CBT vs. CBT alone or nutritional counselling
No differences in outcome vs. citalopram 1
Citalopram Reduced bulimic symptoms vs. placebo 1
Sertraline Reduced bulimic symptoms vs. placebo 1
Poorer reduction in symptom vs. fluvoxamine or fluoxetine 1
Fluvoxamine Reduced bulimic symptoms vs. placebo 1
Reduced relapse at 150 mg/d vs. placebo 1
Other

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Mianserin Bulimic symptom reduction vs. placebo 1
Trazodone Bulimic symptom reduction vs. placebo 1
Bupropion Reduced bulimic symptoms vs. placebo but high seizure rates 1
preclude its use
Topiramate Reduced bulimic symptoms and greater weight loss vs. placebo 2
Naltrexone Inconsistent reduction bulimic symptoms vs. placebo 2

found superior to placebo at reducing binge eating Antidepressants are considered to have a role in
and purging episodes in one trial of 55 bulimia the treatment of BED based on their efcacy in
nervosa participants (Horne et al. 1988). However, reducing binge-eating in patients with bulimia ner-
it is contraindicated for people with bulimia nervosa vosa (Bacaltchuk & Hay, 2003) and on the high rate
due to the high rates (7.2%) of generalized tonic- of comorbid major depressive disorder in patients with
clonic seizures found in this RCT. BED (Fontenelle et al. 2003; Javaras et al. 2008). As
There have been a number of RCTs comparing shown on Table 3, two TCAs [imipramine (Laederach-
antidepressants in combination with CBT (the Hofmann et al. 1999) and desipramine (Agras et al.
present rst-line treatment for bulimia nervosa; 1994)] and several SSRIs, such as uvoxamine, sertra-
APA, 2006; NICE, 2004) with inconsistent results. line, uoxetine and citalopram (Arnold et al. 2002;
When pooled in meta-analyses (Bacaltchuk et al. Devlin et al. 2005; Grilo et al. 2005a; Hudson et al.
2001; NICE, 2004) ndings suggest that (a) drug- 1998; McElroy et al. 2000, 2003a,b; Pearlstein et al.
alone treatments have consistently less efcacious 2003) have been evaluated in RCTs of BED. These
binge-eating abstinence rates than when combined trials have been small (n 5 85 or fewer), and most short-
with CBT, and (b) dropout rates in the antide- term (mean duration of 10 wk, all ,20 wk) (Claudino
pressant arms of such trials are high (more than 50% et al. 2010). Early trials reported consistent reductions
in some studies). in binge-eating frequency but more recently two trials

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Main Classes of Medication Usea in Binge-Eating Disorder

Table 3.
(BED) Tested in at Least One Randomized Controlled Trial (RCT)
Medication Clinical effects RCT (n)
Tricyclic antidepressants
Imipramine BED symptom and weight reduction combined with dietary 1
counseling vs. placebo and dietary counseling
Desipramine No greater BED symptom reduction or weight loss when 1
combined with cognitive behaviour therapy (CBT) and
behavioural weight loss (BWL)
Selective serotonin reuptake inhibitors
Fluoxetine Inconsistent reduced binge eating and improved weight 2
control vs. placebo
Less BED symptom reduction but not less weight loss 1
vs. fluoxetine 1 CBT
Citalopram Reduced binge eating and improved weight control vs. placebo 1
Sertraline Reduced binge eating and improved weight control vs. placebo 1
Fluvoxamine Inconsistent reduced binge eating and improved weight vs. placebo 2
Escitalopram No significant reduction binge eating but improved weight vs. placebo 1
Other
Atomoxetine BED symptom and weight reduction vs. placebo 1
Topiramate Reduced BED symptoms and greater weight loss vs. placebo 2
When combined with CBT reduced BED symptoms and 1
weight vs. CBT alone
Zonisamide Reduced bulimic symptoms and greater weight loss vs. placebo 1
Orlistat When combined with BWL or guided self-help CBT reduced BED 2
symptoms and greater weight loss vs. placebo
a
Sibutamine has not been included here because of safety concerns and its subsequent withdrawal from the market in North America, Europe and other
countries including Australia in 2010.

with a longer duration of 1620 wk that compared 50200 mg/d sertraline (mean loss 5.4 kg in 6 wk)
uoxetine to placebo (Devlin et al. 2005; Grilo et al. (McElroy et al. 2000). Only citalopram (McElroy
2005a) found uoxetine ineffective in reducing binge et al. 2003a,b) has been found to have a greater
eating or weight. efcacy in reducing depressive symptoms than pla-
Stefano et al. (2008) reported a meta-analysis of cebo in studies, but most trials have included pa-
seven pooled studies (six with SSRIs and one with tients with low baseline scores in depression scales
imipramine) involving a total of 300 patients, whereby (Appolinario & McElroy, 2004). More recently,
there was greater remission of binge-eating episodes escitalopram (mean dose 25.5 mg/d) in a RCT was
at the end of trials in the groups that received antide- associated with greater weight loss than in the pla-
pressants compared to the placebo groups (40.5% vs. cebo group, but effects on binge remission were
22.2%). Another meta-analysis (Reas & Grilo, 2008) weaker (Guerdjikova et al. 2008).
found SSRIs were associated with signicantly Venlafaxine, a selective serotonin and noradren-
increased binge-eating remission rates compared aline reuptake inhibitor, has been tested in only
to placebo (n 5 335, n 5 7 studies, RR 0.81, 95% an uncontrolled open trial of 35 obese/overweight pa-
CI 0.700.94) indicating that non-remission tients with BED. Results showed a signicant reduc-
rates are reduced by 19% with this class of anti- tion in binge-eating episodes and weight (Malhotra
depressant. et al. 2002). One case study has also reported good
With regard to overweight problems, a common effects for duloxetine (another combined serotonin
and problematic comorbidity, weight loss has been and noradrenalin reuptake inhibitor) in a patient
modest in most studies and no differences in weight with treatment-refractory BED (Bernardi & Pallanti,
loss were found in the meta-analysis of Stefano et al. 2010). RCTs are needed to evaluate the efcacy of
(2008). Reas & Grilo (2008) reported a modest these agents.
effect on weight loss with SSRIs compared to pla- Some agents with pharmacological actions similar
cebo in meta-analysis. One trial of sertraline was to antidepressants have been trialed in BED. A short,
found to lead to clinically signicant weight loss: placebo-controlled RCT tested atomoxetine, a highly

464 Fall 2014, Vol. XII, No. 4 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY
 HAY AND CLAUDINO

selective norepinephrine reuptake inhibitor with anorexia nervosa was supportive of greater weight
weight loss properties, in 40 obese patients with gain in the active group (Gross et al. 1981). However,
BED. Atomoxetine was associated with greater im- this early study was never followed by more sub-
provement in binge-eating behaviours and weight stantive trials. Of more contemporary interest are
loss and was reasonably tolerated (McElroy et al. anticonvulsant drugs such as topiramate, which have
2007a), but to date these ndings have not been been studied in a range of mental health conditions
replicated. (Arnone, 2005) and been considered to be possibly
Sibutramine is an anti-obesity agent that is a se- useful in eating disorders for their anti-impulsivity
lective serotonin and noradrenaline inhibitor that and weight-losing effects (Ben-Menachem et al. 2003;
may induce weight loss by enhancing satiety and Li et al. 2005; McElroy et al. 2007b).
preventing the fall in energy expenditure that usu- Following promising case series (Barbee, 2003) a
ally follows weight loss. Sibutramine at a dose of double-blind, placebo-controlled RCT has supported
15 mg/d has been tested against placebo in two the efcacy of topiramate (Hedges et al. 2003a;
12-wk RCTs (Appolinario et al. 2003; Milano et al. Hoopes et al. 2003b) for bulimia nervosa patients.
2005c) and one 24-wk trial (Wiley et al. 2008) of In this trial, those treated with topiramate had sig-
BED. In these trials and a meta-analysis (Reas & nicantly greater reductions in mean weekly binge
Grilo, 2008) sibutramine was associated with signi- and/or purge days than those on placebo (44.8% vs.
cantly reduced binge eating and weight loss compared 10.7% for placebo) and also greater weight loss with
to placebo. However, attrition was high (Wiley et al. topiramate (1.8 kg, compared to the placebo group
2008), a high placebo response (also found by e.g. mean increase of 0.2 kg). Nickel et al. (2005) also
Pearlstein et al. 2003) was noted, and those more likely found that topiramate (250 mg/d) over a 10-wk
to have a placebo response had less severe symptoms at period signicantly reduced binge/purge frequency,
baseline (Jacobs-Pilipski et al. 2007). More impor- weight and improved health-related quality of life
tantly, safety issues related to increased cardiovascular compared to a placebo condition in 60 participants.
events in obese people with high cardiovascular risk However, although reportedly well tolerated, many
have been reported (James et al. 2010) and in 2010 patients in the topiramate arm experienced cognitive
sibutramine was withdrawn from the market in the impairment and neurological symptoms such as
USA, Europe and other countries. paresthesia. Other problems include the report of
RCTs of combination approaches of antidepres- very high congenital malformation rates in women
sants with CBT have suggested little advantage over taking topiramate for epilepsy, which may limit its

PUBLICATIONS
INFLUENTIAL
CBT alone in reducing binge eating (Agras et al. 1994; acceptability and use in young women with eating
Devlin et al. 2005; Grilo et al. 2005a), but there may disorders (Hunt et al. 2008).
be positive effects for increased weight loss beyond the Two double-blind RCTs have tested topiramate
effects of psychotherapy (Agras et al. 1994; Laederach- against placebo in obese patients with BED. The rst
Hofmann et al. 1999) or antidepressants alone (Ricca study enrolled 61 subjects for a 14-wk treatment
et al. 2001). Two recent combination trials, which (median dose 213 mg/d) (McElroy et al. 2003b).
lasted 16 wk (Grilo et al. 2005a) and 20 wk (Devlin The second larger multi-centre trial (McElroy et al.
et al. 2005), used a four-cell design to compare CBT 2007b) with 394 patients lasted 16 wk and used
1 uoxetine, CBT 1 placebo, uoxetine, and pla- a median dose of 300 mg/d. In these two trials,
cebo. These studies did not report any increase of topiramate reduced binge frequency, increased binge
treatment efcacy when uoxetine was added to remission and weight loss, and improved psy-
CBT. However, when eating psychopathologies were chological comorbidity. Longer-term efcacy of
analysed, results were better in the groups treated topiramate was tested in a 42-wk, open-label ex-
with CBT than in the groups treated only with drugs. tension (McElroy et al. 2004) of the rst trial with
For example, greater binge remission (but not greater 35 patients. Patients maintained reduced binge-
weight loss) was found in the group treated with eating frequency and weight loss in the subsequent
uoxetine and CBT than in the one treated with open phase, and patients on placebo also showed
medication alone (Grilo et al. 2005a). improvements when given topiramate in the open
phase. However, this study had high attrition and
MOOD-STABILIZING AGENTS adverse effects during the two phases, possibly be-
cause of the rapid increase of doses and the inclusion
Mood-stabilizing agents such as lithium and an- of patients with psychiatric comorbidity (McElroy
ticonvulsant drugs have not had a large role in the et al. 2003b, 2004).
treatment of eating disorders. A very small (n 5 16) One RCT (McElroy et al. 2006) has compared
placebo-controlled RCT of lithium treatment (mean another anticonvulsant zonisamide (mean endpoint
plasma level 1.0 6 0.1 mequiv./1) in acute-phase dose of 436 mg/d over 16 wk) to placebo in 60 obese

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 HAY AND CLAUDINO

women with BED. Although it was more effective Increasing evidence suggests that the ventromedial
than placebo in reducing binge-eating frequency and lateral regions of the hypothalamus and the ar-
and weight, zonisamide had considerable side-effects cuate nucleus play a signicant role in the regulation
and was poorly tolerated. An open trial over 1 yr of of appetite, and it argues high levels of glutamate
52 patients (30 with sub-threshold disorder) also may lead to appetite dysregulation through glutamate-
reported an advantage in binge-eating reduction induced neurotoxic effects mediated by N-methyl-
and weight loss when zonisamide was added to D-aspartate (NMDA) receptors (Hermanussen &
CBT (Ricca et al. 2009). However, attrition was high Tresguerres, 2003). Memantine is a low-to-moderate-
(50%) in the drug-treated group. In a meta-analysis afnity non-competitive NMDA receptor antagonist
(Reas & Grilo, 2008) of results from anti-epileptic that in one open-label trial of 16 overweight BED
trials (n 5 515) (McElroy et al. 2003a,b, 2006, participants (Brennan et al. 2008; exible dose of
2007a,b), large effects were reported for binge remis- 520 mg/d) decreased binge-eating frequency and
sion and weight loss (RR 0.63, 95% CI 0.510.78; obsessive features of binge eating, but not weight.
WMD 24.6 kg, 95% CI 25.36 to 23.79, re-
spectively) with a non-remission risk reduction of 37%. ANTI-OBESITY AGENTS
Finally a double-blind, multicentre RCT compared
the effects of topiramate (mean dose of 206 mg/d) The high rates of comorbidity of obesity and
with placebo when combined with CBT in 73 pa- BED has lead to interest in the use of anti-obesity
tients with BED. Those in the combined drug and agents in this group. Their use is supported by two
CBT arm had higher rates of binge-eating remission factors: their effects on the reduction of appetite or
(83.8% vs. 61.1%) and weight loss (26.8 kg vs. 20.9 kg) increase in satiety, thus their possible effects on binge-
in the 21 wk compared to the CBT-alone arm eating behaviours, and their promotion of weight loss,
(Claudino et al. 2007). Adverse effects were, how- as BED is frequently associated with obesity or over-
ever, more common in the topiramate group. weight (Appolinario & McElroy, 2004).
Sibutramine, a selective serotonin and noradren-
ANXIOLYTIC AND OTHER AGENTS aline inhibitor has been discussed above. Two RCTs
have tested the use of orlistat, a lipase inhibitor,
Anxiolytic drugs such as benzodiazepines are some- against placebo, in combination with a mildly reduced-
times used in anorexia nervosa (de Zwann & Roerig, calorie diet of 24 wk (89 obese patients with BED)
2003) but there are no RCTs testing their use. (Golay et al. 2005) or combined to a CBT-based
Steinglass et al. (2007) tested D-cycloserine (a glu- guided self-help manual for 12 wk (50 patients)
tamate partial agonist) in a very small study of 14 (Grilo et al. 2005b). After 24 wk, patients taking
patients (nine with anorexia nervosa) which was part orlistat showed greater mean weight loss (27.4% vs.
of evaluating an exposure (to food) therapy. Results 22.3%) as well as a greater reduction of eating-
were mixed and food intake was not enhanced. disorder symptoms, compared to those taking placebo
The opiate antagonist naltrexone has been trialled (Golay et al. 2005). Grilo et al. (2005b) reported better
in eating disorders based on the premise that some results in the orlistat group for both, binge remission
eating-disorder behaviours (specially binge eating) (64% vs. 36%) and clinically signicant weight loss
are addictive-like behaviours. Results of clinical (.5% from baseline weight: 36% vs. 8%), although
trials with naltrexone in bulimia nervosa are con- only weight loss was kept at the 3-month follow-up.
icting. Mitchell et al. (1989) reported negative A recent meta-analysis of comparative effect sizes
results in their low-dose naltrexone cross-over study for treatments of BED combined results of 38 studies
with 16 normal-weight women with bulimia ner- of RCTs and uncontrolled studies and pooled all
vosa, whereas Marrazzi et al. (1995a) found signif- types of pharmacotherapy, as well as psychotherapies
icant reductions in binge/purge symptoms during in computing comparative effect sizes (Vocks et al.
naltrexone treatment in all patients (n 5 19) with 2010). The paper supported the above ndings,
bulimic symptoms (anorexia nervosa of the bulimic namely signicant albeit modest effect sizes of 1.19
subtype or bulimia nervosa) in a double-blind pla- (95% CI 0.881.49, 11 studies, 212 participants)
cebo, cross-over study. Experimental studies suggest for binge-eating reduction and for weight loss 0.50
naloxone, also an opioid antagonist, may have a role (95% CI 0.150.85, three studies, 77 participants)
in reducing binge eating in BED (Drewnowski et al. but less impact on changes in eating-disorder cogni-
1995; Marrazzi et al. 1995b) but there are no RCTs tions. Psychotherapy had larger effect sizes supporting
as yet. Baclofen, a centrally acting g-amino-butyric it as rst-line treatment over pharmacotherapy.
acid B (GABA-B) receptor agonist has also shown However, the analysis was problematical in that
promise in reducing binge eating at 60 mg/d in a different forms of both psychotherapy and phar-
small case series (Broft et al. 2007). macotherapy were pooled.

466 Fall 2014, Vol. XII, No. 4 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY
 HAY AND CLAUDINO

CONCLUSIONS Disorders, 3rd edn (pp. 10971222). Arlington, VA: American Psychiatric
Association.
Appolinario JC, Bacaltchuk J, Sichieri R, Claudino AM, et al. (2003). A randomized,
Psychotherapies such as CBT or family therapy double-blind, placebo-controlled study of sibutramine in the treatment of binge
are treatments of choice for eating disorders but eating disorder. Archives of General Psychiatry 60, 11091116.
Appolinario JC, McElroy SL (2004). Pharmacological approaches in the treatment
pharmacotherapies have an important role in specic of binge eating disorder. Current Drug Targets 5, 301307.
disorders, albeit with a moderate to weak evidence Arnold LM, McElroy SL, Hudson JI, Welge JA, et al. (2002). A placebo-controlled,
base. Strongest evidence is for antidepressants, par- randomized trial of fluoxetine in the treatment of binge-eating disorder. Journal of
Clinical Psychiatry 63, 10281033.
ticularly high-dose uoxetine in bulimia nervosa, and Arnone D (2005). Review of the use of topiramate for treatment of psychiatric
anticonvulsants (topiramate) or anti-obesity agents disorders. Annals of General Psychiatry 4, 5.
Attia E, Haiman C, Walsh BT, Flater SR (1998). Does fluoxetine augment the
(sibutramine) for BED. In addition, attrition rates are inpatient treatment of anorexia nervosa? American Journal of Psychiatry, 155,
usually higher than for psychotherapies. Low-dose 548551.
antipsychotic medication may be clinically useful Bacaltchuk J, Hay P (2003). Antidepressants vs. placebo for people with bulimia
nervosa. Cochrane Database of Systematic Reviews. Issue 1, Art. No. CD003391.
as adjunct treatment in acute anorexia, particularly Bacaltchuk J, Hay P, Trefiglio R (2001). Antidepressants vs. psychological treat-
where there is high anxiety and obsessive eating- ments and their combination for bulimia nervosa. Cochrane Database of System-
atic Reviews. Issue 1, Art. No. CD003385.
related ruminations and failure to engage, but more Bailer U, Frank G, Henry S, Price J, et al. (2007). Serotonin transporter binding after
trials are needed. Drug therapies such as topiramate recovery from eating disorders. Psychopharmacology (Berlin) 195, 315324.
and anti-obesity medication may aid weight loss in Barbarich NC, McConaha CW, Halmi KA, Gendall K, et al. (2003). Use of nutritional
supplements to increase the efficacy of fluoxetine in the treatment of anorexia
obese or overweight patients with BED; however, nervosa. International Journal of Eating Disorders 35, 1015.
common or potentially serious adverse effects limit Barbee JG (2003). Topiramate in the treatment of bulimia nervosa with comorbid
mood disorders: a case series. International Journal of Eating Disorders 33, 468472.
their use and it is thought the placebo response may Ben-Menachem E, Axelsen M, Johanson EH, Stagge A, et al. (2003). Predictors of
be high in this disorder. weight loss in adults with topiramatetreated epilepsy. Obesity Research 11, 556562.
The mechanisms of effects of pharmacological Bernardi S, Pallanti S (2010). Successful duloxetine treatment of a binge eating
disorder: a case report. Journal of Psychopharmacology 24, 12691272.
therapies in eating disorders also need further study. Biederman J, Herzog DB, Rivinus TM, Harper GP, et al. (1985). Amitriptyline in the
While putative action is through modulation of do- treatment of anorexia nervosa. Journal of Clinical Psychopharmacology 5, 1016.
pamine and serotonin, central pathway regulation of Birmingham CL, Treasure J (2010). Medical Management of Eating Disorders,
2nd edn. Cambridge: Cambridge University Press.
other neurotransmitters such as noradrenaline also Bissada H, Tasca GA, Barber AM, Bradwejn J (2008). Olanzapine in the treatment
occurs. This is a developing eld as exemplied of low body weight and obsessive thinking in women with anorexia nervosa:
a randomized, double-blind, placebo-controlled trial. American Journal of Psy-
by Kaye and colleagues (Kaye, 2008) whose work chiatry 165, 12271228.
has found limbic system dopaminergic dysregulation Bosanac P, Norman T, Burrows G, Beumont P (2005). Serotonergic and dopami-
that persists after anorexia nervosa recovery and nergic systems in anorexia nervosa: a role for atypical antipsychotics? Australian
and New Zealand Journal of Psychiatry 39, 146153.
Frieling et al. (2010) who propose a new hypothesis

PUBLICATIONS
INFLUENTIAL
Brambilla F, Garcia CS, Fassino S, Daga GA, et al. (2007). Olanzapine therapy in
of dopaminergic (dys-) regulation, namely that a hy- anorexia nervosa: psychobiological effects. International Clinical Psychopharma-
cology 22, 197204.
perdopaminergic state in acutely ill anorexia nervosa Brennan BP, Roberts JA, Fogarty KV, Reynolds KA, et al. (2008). Memantine in the
leads to counter-regulatory mechanisms that in re- treatment of binge eating disorder: an open-label, prospective trial. International
covery result in reduced dopaminergic activity. Kaye Journal of Eating Disorders 41, 520526.
Broft AI, Spanos A, Corwin RL, Mayer L, et al. (2007). Baclofen for binge eating: an
and colleagues (2008) also postulate in an inherent open-label trial. International Journal of Eating Disorders 40, 687691.
serotonergic dysregulation that contributes to a dys- Brownley KA, Berkman ND, Sedway JA, Lohr KN, et al. (2007). Binge eating
disorder treatment: a systematic review of randomized controlled trials. Interna-
phoria which is partially relieved by food restriction, tional Journal of Eating Disorders 40, 337348.
albeit that the malnourished state impedes the bi- Bulik CM, Berkman ND, Brownley KA, Sedway JA, et al. (2007). Anorexia nervosa
ological activity of serotonergic antidepressants. Stud- treatment: a systematic review of randomized controlled trials. International
Journal of Eating Disorders 40, 310320.
ies of antidepressant use in bulimia nervosa also Chwastiak LA, Rosenheck RA, McEvoy JP, Stroup TS, et al. (2009) The impact of
support specic actions on satiety separate to mood obesity on health care costs among persons with schizophrenia. General Hospital
Psychiatry 31, 17.
modulation, and future research elucidating mech-
Claudino A, Hay P, Lima MS, Bacaltchuk J, et al. (2006). Antidepressants for anorexia
anisms of action will help guide more rationale nervosa. Cochrane Database of Systematic Reviews. Issue 1, Art. No. CD004365.
developments in the pharmacotherapy of these Claudino AM, Bacaltchuk J, Hay PJ (2010). Pharmacotherapy for eating disorders. In:
Paxton S, Hay P (Eds), Treatment Approaches for Body Dissatisfaction and Eating
disorders. Disorders: Evidence and Practice (pp. 184216). East Hawthorn: IP Communications.
Claudino AM, de Oliveira IR, Appolinario JC, Cords TA, et al. (2007). Randomized,
double-blind, placebo-controlled trial of topiramate plus cognitive-behavior ther-
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