REVIEW ARTICLE

What Potential Role Is There for Medication

Treatment in Anorexia Nervosa?

Scott J. Crow, MD1* ABSTRACT

James E. Mitchell, MD2,3
James D. Roerig, PharmD,
BCPP2,3
Kristine Steffen, PharmD2,3
Objective: To review selected issues
regarding the development of drug treat-
ments for anorexia nervosa (AN).
Method: The existing pharmacotherapy
literature for AN is reviewed, and the the-
oretical and practical considerations are
discussed.
Results: A very wide variety of drugs
have been examined in AN, generally
with negative results. There are a num-
ber of potential reasons for this finding,
including compliance, nutritional defi-
cits, selection of the wrong targets or the
wrong outcome measures, use of mono-
therapy, lack of animal models, or factors
intrinsic to AN.
Conclusion: Pharmacotherapy pro-
vides little benefit in the treatment of AN
at present. Several strategies might lead
to the identification of more effective
agents, including new measurement
strategies, identification of novel phar-
macologic targets, and consideration of a
clinical trials network. V C 2008 by Wiley
Periodicals, Inc.
Keywords: anorexia nervosa; medi-
cation; antidepressant; antipsychotic
(Int J Eat Disord 2009; 42:1–8)

of agents has been examined with mixed but

Introduction
Medications play a major role in the treatment of
many psychiatric disorders. They are, arguably, the
main intervention for treating individuals with
schizophrenia1 and bipolar illness,2 and they are
central to the treatment of unipolar depression3
and anxiety disorders.4–6 In addition, there is
increasing interest in the use of medications in the
treatment of chemical dependency.7
By contrast, thus far medication treatments play
a much less prominent role in eating disorders
treatment, where nutritional treatment and psy-
chotherapy are of primary importance. There is
some evidence for benefit from pharmacologic
treatments for bulimia nervosa (BN) and binge eat-
ing disorder (BED). In the case of BN, in the United
States there is an FDA-indicated drug, fluoxetine.
For anorexia nervosa (AN), the use of medication is
much less established. An unusually diverse variety
Accepted 3 June 2008
*Correspondence to: Scott Crow, MD, Department of Psychiatry,
University of Minnesota Medical School, F282/2A West, 2450 River-
side Avenue, Minneapolis, MN 55454-1495.
E-mail: crowx002@umn.edu
1
Department of Psychiatry, University of Minnesota Medical
School, Minneapolis, Minnesota
2
Neuropsychiatric Research Institute, Fargo, North Dakota
3
School of Medicine and Health Sciences, University of North
Dakota, Fargo, North Dakota
Published online 6 August 2008 in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/eat.20576
VC 2008 Wiley Periodicals, Inc.
mostly discouraging results. Recently, following di-
vergent reports regarding the efficacy of fluoxetine
for AN relapse prevention, Walsh and colleagues
reported the results of a large, well-controlled, and
carefully conducted trial in which fluoxetine pro-
vided no benefit.8 In summary, at present, there is
no convincing evidence of efficacy for any drug
treatment for AN in either the acute or chronic
phase of the illness; AN is one of the few psychiatric
disorders of which this may be said.
This lack of efficacious or effective agents is par-
ticularly surprising in light of the extensive attention
given to understanding the pharmacology of food
intake and body weight regulation in recent years.
While much of this attention has focused on obesity
treatment and thus may be of little direct benefit for
AN, there has also been substantial interest in the
treatment of undesired weight loss and cachexia
(albeit mostly in the areas of cancer and HIV dis-
ease). Below, we will briefly review the current status
of pharmacologic treatments for AN, examine
potential reasons why such treatments have not
proven helpful, and consider potential future strat-
egies for identifying effective pharmacologic agents.
Current Status of Pharmacologic
Treatments for Anorexia Nervosa
At this point, a number of trials have examined
potential medication treatments for AN. The agents

International Journal of Eating Disorders 42:1 1–8 2009 1

CROW ET AL.

studied in randomized controlled trials of pharma- TABLE 1. Medications studied previously for
AN treatment
cotherapy are listed in Table 1. An even larger
group of case series, case reports, and open trials Controlled Trials Case Series/Open Trials
exists, and these are also summarized in Table 1. Fluoxetine8–13
Quetiapine14
Several features of this body of work are notable. Sulpiride15 Haloperidol16
Most importantly, the randomized controlled trials Cisapride17,18 Olanzapine19–27
Zinc28 Paroxetine29,30
have involved agents from roughly 9 or 10 different Amitriptyline31,32 Fluoxetine33–41
therapeutic classes (depending on whether one Cyproheptadine31 Fluvoxamine36,42
wishes to subdivide the antidepressants). The Pimozide43 Sertraline36,44,45
Clonidine46 Tramadol47
uncontrolled trials involve a still more diverse array Nortriptyline12 Amisulpiride39
of drugs. Second, among the controlled trials, the Clomipramine48 Clomipramine30,39
results have been mixed but mostly negative.68,69 Lithium49 Citalopram50–52
Tetrahydrocannabinol53 Venlafaxine38
The few positive controlled trials have employed Olanzapine Growth Hormone54
zinc,28 amitriptyline and cyproheptedine (in one Testosterone55
trial each:31), and fluoxetine (in one trial:70). Third, Ethyl-eicosapentenoatae56
Risperidone57,58
as is usually true in psychopharmacology, the Isocarboxazid59
length of trials conducted falls far short of the Imipramine60
duration of typical clinical treatment. This is partic- Lithium61
Carbamazepine61
ularly true in the case of AN, where treatment is Dexamethasone62
often of long duration and the risk of relapse is Amitriptyline63
substantial. Fourth, choices of medication for treat- Nandrolone64
Naltrexone65
ment trials have been at least partially theory- L-dopa
66

driven; this stands in contrast to a number of Glycerol67

important, serendipitous discoveries in other areas
of psychopharmacology, including lithium and val-
proic acid for bipolar disorder, monoamine oxidase
inhibitors for depression, and phenothiazines for
schizophrenia.
Why have Medications not been
More Useful?
There are many potential reasons why medications
have not been more useful in the treatment of AN.
The first of these is the issue of compliance. Com-
pliance with pharmacologic treatments is a major
roadblock to treatment across all of medicine, and
is at least as much a problem within psychophar-
macology as in any other field. Medication compli-
ance probably is a particularly prominent problem
in AN treatment, since there are likely few other
instances where symptoms are as ego syntonic and
thus as likely to lead to poor medication compli-
ance (though similar problems can be encountered
in mania/hypomania and sometimes schizophre-
nia). This also suggests that even the willingness to
participate in therapeutic trials involves a bias. Two
important issues relating to compliance are clearly
demonstrated in a recently reported trial of cogni-
tive behavioral therapy (CBT) versus fluoxetine ver-
sus the two in combination.9 In this trial, compli-
ance with medication alone was poor with a much
lower rate of trial completion in the medication
only arm (27%) as compared to the CBT or CBT
plus medication arm (43 and 41%, respectively).
Thus, it appears that pharmacologic treatments for
AN may require coadministration with psychother-
apy to have a reasonable likelihood of achieving
compliance and even in that situation the adher-
ence/completion rates are disappointingly low.
Also, in this trial, the rate of attrition at the begin-
ning of treatment in the medication arm was par-
ticularly high, suggesting that a number of subjects
who initially indicated a willingness to receive ei-
ther medication and/or psychotherapy were in fact
unwilling to consider pharmacotherapy alone, and
when given that assignment, left the study.
A second potential explanation for poor medica-
tion response in AN is the starvation state that
accompanies this illness. The impact of starvation
on every organ system in the body has been very
well documented [for example see Ref. 71]. These
nutritional effects undoubtedly impact the brain as
demonstrated by studies of neuroimaging and cog-
nition.72 Such nutritional deficits might render the
brain without the nutrients needed to synthesize
adequate amount of neurotransmitters required for
medication response. Limited attempts thus far to
provide these potentially missing substances have
proven generally unsuccessful, however.10 Perhaps
this result is not surprising: in spite of the severe
nutritional deficits in AN and the obvious altera-
tions in attitudes, perceptions and behaviors

2 International Journal of Eating Disorders 42:1 1–8 2009


related to weight and eating, most brain functions
appear grossly intact. Nutritional disturbances
severe enough to impede drug response would
seem likely to impair many other cognitive func-
tions too, although this remains speculative.
Similarly, whether rates of receptor turnover or
synaptogenesis are altered by starvation is uncer-
tain. As discussed by Barbarich et al.,73 noninvasive
exploration of the central nervous system has only
been feasible for approximately the last decade
with brain imaging. Therefore, much work is yet to
be done to characterize the aberrations associated
with AN. Mazer et al.74 state that in humans, synap-
togenesis occurs from midgestation until 2 years of
age. However, Connan et al.75 discuss that AN onset
in the peripubertal time period may have signifi-
cant consequences in terms of scarring from the
disorder. These authors refer to previous research
which has shown that during adolescence, an im-
portant phase of central synaptogenesis and prun-
ing occurs which are thought to affect the integra-
tion of emotion and cognition76; McGivern et al.77
Connan et al.75 suggest that the limbic system may
be especially susceptible to negative effects of mal-
nutrition during this time. Depletion of serotonin is
also thought to affect protein components neces-
sary for synapse production.74 The majority of the
work evaluating serotonin depletion has been per-
formed in animals during the gestational or neona-
tal periods,74 so it is unclear whether it generalizes
to adolescent or adult populations. Despite this, it
is still interesting to note, as reviewed by Barbarich
et al.,73 patients with AN have been found to have
lower cerebral spinal fluid (CSF) concentrations of
the serotonin metabolite 5-HIAA during the acute
phase of the illness, which has been postulated to
reflect a consequence of starvation. Interestingly,
as this review also points out, CSF 5 HIAA has been
demonstrated to be elevated following a period
of long-term recovery in AN. Such persisting
changes—in terms of either neuronal structure and
function or neurotransmitter levels—could explain
why pharmacotherapy has yielded little benefit for
AN patients even following weight restoration.
A third potential contributor to lack of efficacy is
that studies thus far have consistently involved
pharmacologic monotherapy. This stands some-
what in contrast to studies of obesity where com-
binations have been tried, and is in contrast to
bipolar disorder, where combinations have been
frequently used. An example in obesity would be
previous work examining the combination of phen-
termine and fenfluramine.78 In this classic study,
the combination of serotonergic and noradrenergic
agents for the treatment of obesity appeared to be
International Journal of Eating Disorders 42:1 1–8 2009
ROLE OF MEDICATION IN ANOREXIA NERVOSA
more effective than previous studies of single
agents. It has become increasingly clear that the
control of eating behavior is complex and the sys-
tems involved are highly redundant.79 This may
explain why pharmacologic (and for that matter,
behavioral) attempts to modify weight have been
relatively unsuccessful, and also why the use of
treatment approaches affecting more than one
neurotransmitter system theoretically may be more
effective. If this is true in obesity, it may be similarly
true in starvation: targeting multiple neurotrans-
mitter systems may be more likely to change eating
behavior. Of course, in obesity or bipolar illness,
some clear evidence for efficacy for monotherapy
with several agents already existed, unlike AN.
Another possible reason why pharmacologic
treatments for AN have not been shown to be suc-
cessful is because researchers have either selected
the wrong outcome measures and/or the wrong
treatment targets. In most studies, weight has been
a main outcome measure (either by itself or as part
of a composite outcome) even though many would
argue that cognitive outcomes are at least as im-
portant. Furthermore, the outcome focus has been
on weight and eating behavior, but studies examin-
ing risk for developing disordered eating have
tended to focus on temperamental variables and
psychological variables not directly related to eat-
ing behavior. If critical risk and maintenance fac-
tors for AN involve variables not directly related to
eating, pharmacologic treatments aimed at directly
changing eating might be predicted to be of limited
value.
There is a relative lack of good animal models for
AN. Some possible models have been put forward:
for example, activity-based anorexia in rats80 or
thin sow syndrome.81 These models likely do not
lend themselves to efforts at developing drugs tar-
geting psychological variables; but if any aspects of
effective treatment will involve direct approaches
to weight, physical activity, or eating behavior then
these currently available models might be useful.
Some attempts have already been made in this
regard, using agents such as clonidine,82 olanza-
pine,83 and leptin84 Another issue which has prob-
ably worked against finding effective medications
is the limited attention to the treatment of this
illness that pharmaceutical companies have
provided. Pharmaceutical manufacturers have con-
ducted extensive studies on acute and mainte-
nance treatments of many psychiatric illnesses but
very little of this has occurred in AN. Several factors
might have contributed to this pattern, including
the (incorrectly) perceived relative rarity of this ill-
ness, the stigma related to eating disorders, and
3
CROW ET AL.
perhaps the perception of a high degree of risk in
conducting AN trials related to medical instability
and possible death.
A final potential explanation to consider is that
AN may be one form of psychopathology which
simply is not responsive to pharmacologic treat-
ment. This would set it apart from BN, BED, and
most of the common Axis I psychopathologies.
However, if this were true, it might suggest that a
history of AN might be a predictor of medication
nonresponse in BN trials. The majority of BN medi-
cation trials have not examined history of AN as an
outcome predictor, but in those which have prior
AN has not predicted eventual outcome.85–88 Also,
one must bear in mind that the same might have
been said 20 years ago of pharmacologic treatment
for obsessive-compulsive disorder (OCD); prior to
the advent of clomipramine and the SSRIs, consis-
tently effective drug treatments for OCD had not
been identified, although many had been tried.
How Might Medications
Be Useful for AN?
Considering how medications might prove to be
effective in AN treatment necessarily involves a
consideration of what the goals of medication
treatment should be. A fundamental question is
whether medications are conceived of as eliminat-
ing the illness in its entirety or providing adjunctive
treatment for specific symptoms or manifestations.
Examples of each approach can be found in psy-
chopharmacology. For example, the typical goal of
panic disorder treatment is complete resolution of
all panic symptoms and any associated agorapho-
bia. On the other hand, in some conditions where
anxiety is prominent, medications such as benzo-
diazepines are used to diminish anxiety without
necessarily assuming that anxiety would be elimi-
nated completely. Identifying targets for pharmaco-
logic treatment would be greatly aided with an
improved understanding of both the phenomenol-
ogy and underlying pathophysiology of AN.89
Weight gain is an objectively measurable and
obviously necessary outcome goal. The perception
of weight gain as a direct goal of pharmacotherapy
for AN undoubtedly contributes to the problem of
noncompliance frequently encountered clinically.
Attempts to target weight gain as a direct goal also
must address the issue of whether changing weight
without changing cognition represents a truly suc-
cessful and lasting strategy, which seems unlikely.
4 International Journal of Eating Disorders 42:1 1–8 2009
An approach more likely to be successful might
involve identifying and modifying other specific
target symptoms, with the ultimate goal of facilitat-
ing nutritional rehabilitation and psychotherapy.
For example, recent interest has been turned to the
idea of conditioned fear learning in AN.90 Anxiety
might represent one major factor that interferes
with refeeding and which, if at least partially ame-
liorated pharmacologically, might greatly facilitate
response to other sorts of treatment. Also, cognitive
rigidity, perfectionism, and obsessionality might
lend themselves to such treatment approaches. If
these factors are part of the core pathophysiology
of AN, then treatments aimed at these might be
more than simply adjunctive.
Strategies for Finding Effective
Medications for AN
Finding effective pharmacologic treatments will
likely involve substantially revising the strategies
used heretofore. New measurement techniques,
new potential target symptoms, and eventually per-
haps new pharmacologic targets based on evolving
knowledge of the molecular pathophysiology of the
illness will all be needed.
If effective drug treatments for AN will ultimately
focus on eating behaviors and weight, then feeding
laboratory measures (a technology which already
exists and clearly is a feasible tool) as well as mea-
surement of weight will be useful in supporting
treatment development efforts. Feeding laboratory
measures might be more sensitive in the detection
of treatment effects than traditional trial outcome
measures. However, if other target symptoms are
selected, then several steps are required. First, criti-
cal target symptoms for AN need to be clearly iden-
tified. Second, effective metrics for those factors,
preferably ones sensitive to both short-term and
long-term change, must be developed. This would
greatly aid development since it might allow for the
pilot testing of medications in a relatively brief pe-
riod of time. Such brief trials could be extremely
useful as compared to traditional, longer term
studies of 6 months to 1 year focusing largely on
weight. Long, formal trials require a large number
of subjects and extensive observation. Recruitment
for these studies is difficult91 and resource inten-
sive, which in turn greatly undermines our ability
to examine larger number of medications over a
shorter period of time.
In addition to identifying new behavioral targets,
the possibility exists that evolving work on the neu-

rochemical basis of AN might provide potential
specific pharmacologic targets. This approach has
been proposed in other areas, such as the treat-
ment of nicotine dependence and schizophrenia.
Recently, discussion of the limitations of the phar-
macological treatment of schizophrenia has
occurred.92 This discussion was generated by the
realization that limited progress in pharmacother-
apy for this disorder has occurred over the 50 plus
years since the first agent was identified. Also, at
the same time, the pharmaceutical industry was
spending large sums of money on developing
compounds similar to existing drugs rather than
exploring innovative strategies for new drug devel-
opment.93,94 These discussions led to the develop-
ment of the Measurement and Treatment Research
to Improve Cognition in Schizophrenia (MATRICS)
project. This effort brought together representa-
tives from industry, government, and academia to
develop new preclinical approaches to drug devel-
opment and new drug targets on which to focus
future efforts. In this particular example cognitive
deficits of schizophrenia were identified as having
a major impact on the outcome and functioning of
individuals with this disease. Although pharmaco-
therapy for schizophrenia is far more developed
than for AN, there are certain similarities to the
schizophrenia treatment situation. The prevalence
of AN and schizophrenia are similar at approxi-
mately 1–2%. Currently the drug treatment for AN
does not significantly affect the acute or long term
outcome, and the outcome of AN treatment is far
less than desired.
One consideration in reviewing pharmacological
treatment is that no drugs that are used in psychia-
try are disease-modifying agents. They simply
lessen symptoms regardless of the diagnosis of the
patient. Thus, as in the MATRICS project, the iden-
tification of symptoms that have the most rele-
vance to functioning and outcome is essential. The
participants in the project then had to identify
accurate and reliable methods of evaluating those
symptoms so as to quantify the effects of interven-
tions or probes such as pharmacological agents.
Parallel to this effort, the pathophysiology associ-
ated with the symptoms is explored. Finally,
through the joint effort of academia, industry and
the FDA potential molecular interventions are to be
identified and evaluated for efficacy.
Recently much work has been published regard-
ing the exploration of various system alterations in
acutely ill and recovered AN subjects. These studies
include evaluations of the serotonin metabolite,
5HIAA,95 the dopamine metabolite, HVA,96 the
serotonin receptors 5-HT2A and 5-HT1A,97–100 the
International Journal of Eating Disorders 42:1 1–8 2009
ROLE OF MEDICATION IN ANOREXIA NERVOSA
serotonin transporter,101,102 dopamine D2/D3 re-
ceptors,103 and fMRI studies of the insula.104 Thus,
a greater understanding of the alteration of neuro-
nal systems in AN is being achieved. As this body of
knowledge grows the identification of the pathol-
ogy associated with specific symptoms is possible.
Drug targets can then be identified, and molecular
entities to interface with these targets can be
explored. The MATRICS project is a large and com-
plicated endeavor involving multiple groups of
individuals with diverse expertise. However, it may
serve as a useful model for other areas of inquiry
such as AN pharmacotherapy.
Finally, modifications to the existing clinical trial
system might be very useful in facilitating medica-
tion discovery. While AN is not uncommon, recruit-
ment into trials has historically been difficult.
While this poses many practical problems, chief
among them for medication development is that
the challenges of recruitment at a single site or
small number of sites slow the pace at which in-
formation becomes available and diminish the
number of potential agents that can be studied.
The development of a coordinated network of sites
conducting AN pharmacology trials with standar-
dized assessments and clinical procedures would be
extremely useful in speeding such drug discovery.
Summary
To date, pharmacotherapy research for AN has
been extensive (at least in terms of variety of agents
examined), yet effective agents have not been iden-
tified. Numerous factors may contribute, including
compliance, selection of target symptoms and
pharmacologic targets, nutritional factors, use of
monotherapy, lack of industry interest or factors
intrinsic to AN. Strategies to remedy this problem
might include developing new treatment targets,
new measurement strategies, and new mechanisms
or networks for conducting trials.
References
1. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL,
Perkins DO, et al. Practice guideline for the treatment of
patients with schizophrenia, second edition. Am J Psychiatry
2004;161(2 Suppl):1–56.
2. American Psychiatric Association. Practice guideline for the
treatment of patients with bipolar disorder (revision). Am J
Psychiatry 2002;159(4 Suppl):1–50.
3. American Psychiatric Association. Practice guidelines for the
treatment of patients with major depressive disorder, second
edition. 2000;157(4 Suppl):1–45.
5
CROW ET AL.
4. American Psychiatric Association. Practice guidelines for the
treatment of patients with obsessive-compulsive disorder.
2007;164(7 Suppl):1–56.
5. American Psychiatric Association. Practice guideline for the treat-
ment of patients with panic disorder. 1998;155(5 Suppl):1–34.
6. Ursano RJ, Bell C, Eth S, Friedman M, Norwood A, Pfefferbaum
B, et al. Practice guideline for the treatment of patients with
acute stress disorder and posttraumatic stress disorder. Am J
Psychiatry 2004;161(11 Suppl):3–31.
7. Kleber HD, Weiss RD, Anton RF Jr, George TP, Greenfield SF,
Kosten TR, et al. Treatment of patients with substance use dis-
orders, second edition. American Psychiatric Association. Am J
Psychiatry 2007;164(4 Suppl):5–123.
8. Walsh BT, Kaplan AS, Attia E, Olmsted M, Parides M, Carter JC,
et al. Fluoxetine after weight restoration in anorexia nervosa:
A randomized controlled trial. JAMA 2006;295:2605–2612.
9. Halmi KA, Agras WS, Crow S, Mitchell J, Wilson GT, Bryson SW,
et al. Predictors of treatment acceptance and completion in
anorexia nervosa: Implications for future study designs. Arch
Gen Psychiatry 2005;62:776–781.
10. Barbarich NC, McConaha CW, Halmi KA, Gendall K, Sunday SR,
Gaskill J, et al. Use of nutritional supplements to increase the
efficacy of fluoxetine in the treatment of anorexia nervosa. Int
J Eat Disord 2004;35:10–15.
11. Attia E, Haiman C, Walsh BT, Flater SR. Does fluoxetine aug-
ment the inpatient treatment of anorexia nervosa? Am J Psy-
chiatry 1998;155:548–551.
12. Brambilla F, Draisci A, Peirone A, Brunetta M. Combined
cognitive-behavioral, psychopharmacological and nutritional
therapy in eating disorders. II. Anorexia nervosa–binge-
eating/purging type. Neuropsychobiology 1995;32:64–67.
13. Kaye WH, Frank GK, Meltzer CC, Price JC, McConaha CW,
Crossan PJ, et al. Altered serotonin 2A receptor activity in
women who have recovered from bulimia nervosa. Am J Psy-
chiatry 2001;158:1152–1155.
14. Powers PS, Bannon Y, Eubanks R, McCormick T. Quetiapine in
anorexia nervosa patients: An open label outpatient pilot
study. Int J Eat Disord 2007;40:21–26.
15. Vandereycken W. Neuroleptics in the short-term treatment of
anorexia nervosa. A double-blind placebo-controlled study
with sulpiride. Br J Psychiatry 1984;144:288–292.
16. Cassano GB, Miniati M, Pini S, Rotondo A, Banti S, Borri C,
et al. Six-month open trial of haloperidol as an adjunctive
treatment for anorexia nervosa: A preliminary report. Int J Eat
Disord 2003;33:173–177.
17. Stacher G, Bergmann H, Wiesnagrotzki S, Kiss A, Schneider C,
Mittelbach G, et al. Intravenous Cisapride accelerates delayed
gastric emptying and increases antral contraction amplitude
in patients with primary anorexia nervosa. Gastroenterology
1987;792:1000–1006.
18. Szmukler GI, Young GP, Miller G, Lichtenstein M, Binns DS. A
controlled trial of cisapride in anorexia nervosa. Int J Eat Dis-
ord 1995;17:347–357.
19. Boachie A, Goldfield GS, Spettigue W. Olanzapine use as an ad-
junctive treatment for hospitalized children with anorexia
nervosa: Case reports. Int J Eat Disord 2003;33:98–103.
20. Brambilla F, Monteleone P, Maj M. Olanzapine-induced weight
gain in anorexia nervosa: Involvement of leptin and ghrelin
secretion? Psychoneuroendocrinology 2007;32:402–406.
21. Dennis K, Le Grange D, Bremer J. Olanzapine use in adolescent
anorexia nervosa. Eat Weight Disord 2006;11:e53–e56.
22. Ercan ES, Copkunol H, Cykoethlu S, Varan A. Olanzapine treat-
ment of an adolescent girl with anorexia nervosa. Hum Psy-
chopharmacol 2003;18:401–403.
23. Hansen L. Olanzapine in the treatment of anorexia nervosa. Br
J Psychiatry 1999;175:592.
6 International Journal of Eating Disorders 42:1 1–8 2009
24. La Via MC, Gray N, Kaye WH. Case reports of olanzapine
treatment of anorexia nervosa. Int J Eat Disord 2000;27:363–
366.
25. Mehler C, Wewetzer C, Schulze U, Warnke A, Theisen F, Ditt-
mann RW. Olanzapine in children and adolescents with
chronic anorexia nervosa. A study of five cases. Eur Child Ado-
lesc Psychiatry 2001;10:151–157.
26. Mondraty N, Birmingham CL, Touyz S, Sundakov V, Chapman
L, Beumont P. Randomized controlled trial of olanzapine in
the treatment of cognitions in anorexia nervosa. Australas Psy-
chiatry 2005;13:72–75.
27. Malina A, Gaskill J, McConaha C, Frank GK, Lawson RH, Scholar
L, et al. Olanzapine treatment of anorexia nervosa: A retro-
spective study. Int J Eat Disord 2003;33:234–237.
28. Birmingham C, Goldner E, Bakan R. Controlled trial of zinc
supplementation in anorexia nervosa. Int J Eat Disord
1994;15:251–255.
29. Heiden A, De Zwaan M, Frey R, Presslich O, Kasper S. Paroxe-
tine in a patient with obsessive-compulsive disorder, anorexia
nervosa and schizoptypal personality disorder. J Psychiatry
Neurosci 1998;23:179–180.
30. Strobel M, Warnke A, Ruth M, Schulze U. Paroxetine versus clo-
mipramine in female adolescents suffering from anorexia
nervosa and depressive episode: A retrospective study on tol-
erability, reasons for discontinuing the antidepressant treat-
ment and different outcome measurements. Z Kinder Jugen-
psychiatr Psychother 2004;32:279–289.
31. Halmi KA, Eckert E, LaDu TJ, Cohen J. Anorexia nervosa. Treat-
ment efficacy of cyproheptadine and amitriptyline. Arch Gen
Psychiatry 1986;43:177–181.
32. Biederman J, Herzog DB, Rivinus TM, Harper GP, Ferber RA,
Rosenbaum JF, et al. Amitriptyline in the treatment of
anorexia nervosa: A double-blind, placebo-controlled study.
J Clin Psychopharmacol 1985;5:10–16.
33. Corwin J, Connelly S, Paz S, Schwartz M, Wirth J. Chart review
of rate of weight gain in eating disorder patients treated with
tricyclic antidepressants or fluoxetine. Prog Neuropsychophar-
macol Biol Psychiatry 1995;19:223–228.
34. Ferguson JM. Treatment of an anorexia nervosa patient with
fluoxetine. Am J Psychiatry 1987;344:1239.
35. Gwirtsman HE, Guze BH, Yager J, Gainsley B. Fluoxetine treat-
ment of anorexia nervosa: An open clinical trial. J Clin Psychia-
try 1990;51:378–382.
36. Holtkamp K, Konrad K, Kaiser N, Ploenes Y, Heussen N, Grzella
I, et al. A retrospective study of SSRI treatment in adolescent
anorexia nervosa: Insufficient evidence for efficacy.
J Psychiatric Res 2005;39:303–310.
37. Kaye WH, Gwirtsman HE, George DT, Ebert MH. Altered sero-
tonin activity in anorexia nervosa after long-term weight resto-
ration. Does elevated cerebrospinal fluid 5-hydroxyindoleace-
tic acid level correlate with rigid and obsessive behavior? Arch
Gen Psychiatry 1991;48:556–562.
38. Ricca V, Mannucci E, Paionni A, Di Bernardo M, Cellini M,
Cabras PL, et al. Venlafaxine versus fluoxetine in the treatment
of atypical anorectic outpatients: A preliminary study. Eat
Weight Disord 1999;4:10–14.
39. Ruggiero GM, Laini V, Mauri MC, Clemente A, Lugo F, Mantero
M, et al. A single blind comparison of amisulpride, fluoxetine
and clomipramine in the treatment of restricting anorectics.
Prog Neuropsychophramacol Biol Psychiatry 2001;25:1049–
1059.
40. Strober M, Freeman R, DeAntonio M, Lampert C, Diamond J.
Does adjunctive fluoxetine influence the post-hospital course
of restrictor-type anorexia nervosa? A 24-month prospective,
longitudinal followup and comparison with historical controls.
Psychopharmacol Bull 1997;33:425–431.

41. Strober M, Pataki C, Freeman R, DeAntonio M. No effect of ad-
junctive fluoxetine on eating behavior or weight phobia dur-
ing the inpatient treatment of anorexia nervosa: An historical
case-control study. J Child Adolesc Psychopharmacol 1999;9:
195–201.
42. Rey Sanchez F, Sanchez Inglesias S, Samino Aguado FJ, Lorenzo
Bragado MJ, Perez U. Fluvoxamine: An alternative pharmaco-
logical treatment in anorexia nervosa. Revista de Psiquiatria
Infanto-Juvenil 1993;2:111–117.
43. Vandereycken W, Pierloot R. Pimozide combined with behav-
ior therapy in the short-term treatment of anorexia nervosa. A
double-blind placebo-controlled cross-over study. Acta Psy-
chiatr Scand 1982;66:445–450.
44. Frank GK, Kaye WH, Marcus MD. Sertraline in underweight
binge eating/purging-type eating disorders: Five case reports.
Int J Eat Disord 2001;29:495–498.
45. Santonastaso P, Frederici S, Favaro A. Sertraline in the treat-
ment of restricting anorexia nervosa: An open controlled trial.
J Child Adolesc Psychopharmacol 2001;11:143–150.
46. Casper RC, Schlemmer RF Jr, Javaid JI. A placebo-controlled
crossover study of oral clonidine in acute anorexia nervosa.
Psychiatry Res 1987;20:249–260.
47. Mendelson SD. Treatment of anorexia nervosa with tramadol.
Am J Psychiatry 2001;158:963–964.
48. Lacey JH, Crisp AH. Hunger, food intake and weight: The
impact of clomipramine on a refeeding anorexia nervosa pop-
ulation. Postgrad Med J 1980;56 (Suppl 1):79–85.
49. Gross HA, Ebert MH, Faden VB, Goldberg SC, Nee LE, Kaye WH.
A double-blind controlled trial of lithium carbonate primary
anorexia nervosa. J Clin Psychopharmacol 1981;1:376–381.
50. Bergh C, Eriksson M, Lindenberg G, Sodersen P. Selective
serotonin reuptake inhibitors in anorexia. Lancet 1996;348:
1459.
51. Calandra C, Guilino V, Inserra I, Giufridda A. The use of
citalopram in an integrated approach in the treatment of eat-
ing disorders: An open study. Eat Weight Disord 1999;4:207–
210.
52. Fassino S, Leombruni P, Daga GA, Brustolin A, Migliaretti G,
Cavallo F, et al. Efficacy of citalopram in anorexia nervosa: A
polit study. Eur Neuropsychol 2002;12:453–459.
53. Gross H, Ebert MH, Faden VB, Goldberg SC, Kaye WH, Caine ED,
et al. A double-blind trial of delta 9-tetrahydrocannabinol in
primary anorexia nervosa. J Clin Psychopharmacol 1983;3:
165–171.
54. Hill K, Bucuvalas J, McClain C, Kryscio R, Martini RT, Alfaro MP,
et al. Pilot study of growth hormone administration during
the refeeding of malnourished anorexia nervosa patients. J
Child Adolesc Psychopharmacol 2000;10:3–8.
55. Miller KK, Greico KA, Kilbanski A. Testosterone administration
in women with anorexia nervosa. J Clin Endocrinol Metab
2005;90:1428–1433.
56. Ayton AK, Azaz A, Horrobin DF. Rapid improvement of severe
anorexia nervosa during treatment with ethyl-eicosapentae-
noate and micronutrients. Eur Psychiatry 2004;19:317–319.
57. Fisman S, Steele M, Short J, Byrne T, Lavallee C. Case study: An-
orexia nervosa and autistic disorder in an adolescent girl. J Am
Acad Child Adolesc Psychiatry 1996;35:937–940.
58. Newman-Toker J. Risperidone in anorexia nervosa. J Am Acad
Child Adolesc Psychiatry 2000;39:941–942.
59. Kennedy SH, Piran N, Garfinkel PE. Monoamine oxidase inhibi-
tor therapy for anorexia nervosa and bulimia: A preliminary
trial of biocarboxazid. J Clin Psychopharmacol 1985;5:279–
285.
60. Mumford PR, Tazrlow G, Gerner R. An experimental analysis of
the interaction of chemotherapy and behavior therapy in ano-
rexia nervosa. J Nerv Ment Disord 1984;172:228–231.
International Journal of Eating Disorders 42:1 1–8 2009
ROLE OF MEDICATION IN ANOREXIA NERVOSA
61. Hudson JI, Pope HG, Jonas JM, Yurgelun-Todd D. Treatment of
anorexia nervosa with antidepressants. J Clin Psychopharma-
col 1985;5:17–23.
62. Gordon CM, Emans SJ, DuRant RH, Mantzoros C, Grace E,
Harper GP, et al. Endocrinologic and psychological effects of
short-term dexamethasone in anorexia nervosa. Eat Weight
Disord 2000;5:175–182.
63. Moore DC. Amitriptyline therapy in anorexia nervosa. Am J
Psychiatry 1977;134:1303–1304.
64. Tec L. Nandrolone in anorexia nervosa. JAMA 1974;229:1423.
65. Luby ED, Marrazzi MA, Kinzie J. Case reports—Treatment of
chronic anorexia nervosa with opiate blockade. J Clin Psycho-
pharmacol 1987;7:52–53.
66. Johanson AJ, Knorr NJ. L-DOPA as Treatment for Anorexia
Nervosa. New York: Raven Press, 1977.
67. Caplin H, Ginsburg J, Beaconsfield P. Glycerol and treatment of
anorexia nervosa. Lancet 1973;1:319.
68. Bulik CM, Berkowitz RI, Brownley KA, Sedway JA, Lohr KN. Ano-
rexa nervosa treatment: A systematic review of randomized
controlled trials. Int J Eat Disord 2007;40:310–320.
69. Zhu AJ, Walsh BT. Pharmacologic treatment of eating disor-
ders. Can J Psychiatry 2002;47:227–234.
70. Kaye WH, Nagata T, Weltzin TE, Hsu LK, Sokol MS, McConaha
C, et al. Double-blind placebo-controlled administration of
fluoxetine in restricting- and restricting-purging-type anorexia
nervosa. Biol Psychiatry 2001;49:644–652.
71. Keys A, Brozek J, Henschel A, Mickelsen O, Taylor HL. The Biol-
ogy of Human Starvation. Minneapolis: The University of Min-
nesota Press, 1950.
72. Frank GK, Bailer UF, Wagner HS, Kaye WH. Neuroimaging stud-
ies in eating disorders. CNS Spectr 2004;9:539–548.
73. Barbarich NC, Kaye WH, Jimerson D. Neurotransmitter and
imaging studies in anorexia nervosa: New targets for treat-
ment. Curr Drug Targets CNS Neurol Disord 2003;2:61–72.
74. Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-
Azmitia P. Serotonin depletion during synaptogenesis leads to
decreased synaptic density and learning deficits in the adult
rat: A possible model of neurodevelopmental disorders with
cognitive deficits. Brain Res 1997;760:68–73.
75. Connan F, Murphy F, Connor SE, Rich P, Murphy T, Bara-Carill
N, et al. Hippocampal volume and cognitive function in ano-
rexia nervosa. Psychiatry Res 2006;146:117–125.
76. Benes FM. Brain development. VII. Human brain growth spans
decades. Am J Psychiatry 1998;155:1489.
77. McGivern RF, Andersen J, Byrd D, Mutter KL, Reilly J. Cognitive
efficiency on a match to sample task decreases at the onset of
puberty in children. Brain Cogn 2002;50:73–89.
78. Weintraub M, Sundaresan PR, Madan M, Schuster B, Balder A,
Lasagna L, et al. Long-term weight control study. I (weeks 0 to
34). The enhancement of behavior modification, caloric
restriction, and exercise by fenfluramine plus phentermine
versus placebo. Clin Pharmacol Ther 1992;51:586–594.
79. Crow S, Brown E. Investigational drugs for eating disorders.
Expert Opin Investig Drugs 2003;12:491–499.
80. Dixon DP, Ackert AM, Eckel LA. Development of, and recovery
from, activity-based anorexia in female rats. Physiol Behav
2003;80:273–279.
81. Treasure JL, Owen JB. Intriguing links between animal be-
havior and anorexia nervosa. Int J Eat Disord 1997;21:307–
311.
82. Rieg TS, Aravich PF. Systemic clonidine increases feeding and
wheel running but does not affect rate of weight loss in rats
subjected to activity-based anorexia. Pharmacol Biochem
Behav 1994;47:215–218.
83. Hillebrand JJ, van Elburg AA, Kas MJ, van Engeland H, Adan
RA. Olanzapine reduces physical activity in rats exposed to
7
CROW ET AL.
activity-based anorexia: Possible implications for treatment of
anorexia nervosa? Biol Psychiatry 2005;58:651–657.
84. Hillebrand JJ, Koeners MP, de Rijke CE, Kas MJ, Adan RA. Lep-
tin treatment in activity-based anorexia. Biol Psychiatry
2005;58:165–171.
85. Hughes PL, Wells LA, Cunningham CJ, Ilstrup DM. Treating
bulimia with desipramine. A double-blind, placebo-controlled
study. Arch Gen Psychiatry 1986;43:182–186.
86. Pope HG Jr, Keck PE Jr, McElroy SL, Hudson JI. A placebo-con-
trolled study of trazodone in bulimia nervosa. J Clin Psycho-
pharmacol 1989;9:254–259.
87. Walsh BT, Gladis M, Roose SP, Stewart JW, Stetner F, Glassman
AH. Phenelzine vs placebo in 50 patients with bulimia. Arch
Gen Psychiatry 1988;45:471–475.
88. Walsh BT, Hadigan CM, Devlin MJ, Gladis M, Roose SP. Long-
term outcome of antidepressant treatment for bulimia nerv-
osa. Am J Psychiatry 1991;148:1206–1212.
89. Roerig JL, Mitchell JE, Steffen KJ. New targets in the treatment of
anorexia nervosa. Expert Opin Investig Drugs 2005;9:135–151.
90. Strober M. Pathologic fear conditioning and anorexia nervosa:
On the search for novel paradigms. Int J Eat Disord 2004;35:
504–508.
91. McDermott C, Agras WS, Crow SJ, Halmi K, Mitchell JE, Bryson
S. Particpant recruitment for an anorexia nervosa treatment
study. Int J Eat Disord 2004;35:33–41.
92. Stover EL, Brady L, Marder SR. New paradigms for treatment
development. Schizophr Bull 2007;33:1093–1099.
93. United States Government Accountability Office. New Drug De-
velopment: Science, Business, Regulatory, and Intellectual
Property Issues Cited as Hampering Drug Development Efforts.
Washington, DC: United States Government Accountability
Office, 2006.
94. Owens J. 2006 drug approvals: Finding the niche. Nat Rev
Drug Discov 2007;6:99–101.
95. Kaye WH, Frank GK, Bailer UF, Henry SE. Neurobiology of ano-
rexia nervosa: Clinical implications of alterations of the func-
tion of serotonin and other neuronal systems. Int J Eat Disord
2005;37(Suppl):S15–S19; discussion S20–S21.
8 International Journal of Eating Disorders 42:1 1–8 2009
96. Kaye WH, Frank GK, McConaha C. Altered dopamine activity af-
ter recovery from restricting-type anorexia nervosa. Neuropsy-
chopharmacology 1999;21:503–506.
97. Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Mathis CC,
et al. Exaggerated 5-HT1A but normal 5-HT2A receptor activity
in individuals ill with anorexia nervosa. Biol Psychiatry 2007;
61:1090–1099.
98. Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Weissfeld L,
et al. Altered brain serotonin 5-HT1A receptor binding after re-
covery from anorexia nervosa measured by positron emission
tomography and [carbonyl11C]WAY-100635. Arch Gen Psychia-
try 2005;62:1032–1041.
99. Frank GK, Kaye WH, Meltzer CC, Price JC, Greer P, McConaha C,
et al. Reduced 5-HT2A receptor binding after recovery from
anorexia nervosa. Biol Psychiatry 2002;52:896–906.
100. Goethals I, Vervaet M, Audenaert K, Jacobs F, Ham H, Van de
Wiele C, et al. Differences of cortical 5-HT2A receptor binding
index with SPECT in subtypes of anorexia nervosa: Rela-
tionship with personality traits? J Psychiatr Res 2007;41:455–
458.
101. Kuikka JT, Tammela L, Karhunen L, Rissanen A, Bergstrom KA,
Naukkarinen H, et al. Reduced serotonin transporter binding
in binge eating women. Psychopharmacology (Berl) 2001;155:
310–314.
102. Tauscher J, Pirker W, Willeit M, de Zwaan M, Bailer U, Neu-
meister A, et al. [123I] beta-CIT and single photon emission
computed tomography reveal reduced brain serotonin trans-
porter availability in bulimia nervosa. Biol Psychiatry 2001;
49:326–332.
103. Frank GK, Bailer UF, Henry SE, Drevets W, Meltzer CC, Price JC,
et al. Increased dopamine D2/D3 receptor binding after recov-
ery from anorexia nervosa measured by positron emission to-
mography and [11c]raclopride. Biol Psychiatry 2005;58:908–
912.
104. Wagner A, Aizenstein H, Mazurkewicz L, Fudge J, Frank GK,
Putnam K, et al. Altered insula response to taste stimuli in
individuals recovered from restricting-type anorexia nervosa.
Neuropsychopharmacology 2008;33:513–523.