JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 21, Number 3, 2011

ª Mary Ann Liebert, Inc.
Pp. 207–212
DOI: 10.1089/cap.2010.0139

A Placebo-Controlled Pilot Study of Adjunctive Olanzapine

for Adolescents with Anorexia Nervosa

Vivian Kafantaris, M.D.,1–3 Ellen Leigh, Ph.D.,4 Stanley Hertz, M.D.,5 Alison Berest, M.A.,1
Janet Schebendach, Ph.D.,6 Wendy Meyer Sterling, M.S.,7 Ema Saito, M.D.,1 Suzanne Sunday, Ph.D.,2,3
Claudine Higdon, M.D.,1 Neville H. Golden, M.D.,8 and Anil K. Malhotra, M.D.1–3

Abstract
Objective: The objective of this study was to explore whether the addition of olanzapine versus placebo increases weight gain
and improves psychological symptoms in adolescents with anorexia nervosa-restricting type who are participating in a
comprehensive eating disorders treatment program.
Methods: Twenty underweight females participated in this 10-week, double-blind, placebo-controlled pilot study of olan-
zapine. The primary efficacy measure was change in percentage of median body weight measured at baseline and weeks 5 and
10. Secondary efficacy measures included clinician-rated and self-reported measures of psychological functioning measured
at 2-week intervals and eating disorder symptoms measured at baseline and weeks 5 and 10 as well as laboratory assessments
(including indirect calorimetry), which were also performed at baseline and weeks 5 and 10. A mixed models approach to
repeated measures analysis of variance was utilized to detect any treatment-by-time interaction.
Results: Fifteen of 20 enrolled females (median age, 17.1 years; range, 12.3–21.8 years; mean body mass index, 16.3)
completed this 10-week pilot study. Change in % median body weight did not differ between the treatment groups at midpoint
or end of study. Both groups gained weight at a similar rate and had similar improvements in eating attitudes and behaviors,
psychological functioning, and resting energy expenditure. A trend of increasing fasting glucose and insulin levels was found
only in the olanzapine group at week 10.
Conclusions: These preliminary findings do not support a role for adjunctive olanzapine for underweight adolescent females
with anorexia nervosa-restricting type who are receiving standard care in an eating disorder treatment program (clinical
trials.gov; no. NCT00592930).

Introduction ventions examined thus far have had minimal success in re-
ducing acute symptoms (Walsh et al. 2006) and improving

A norexia nervosa-restricting type (AN-R) is characterized

by restricted eating, perceptual distortions in body image,
and intense fears of becoming overweight. The morbidity of
this illness includes nutritional deficiencies, electrolyte and
acid–base imbalances, dehydration, cardiac dysrrhythmias, and
a hypometabolic state secondary to malnutrition (Kaye 2008).
In adolescents, there may be significant growth retardation,
pubertal delay, and reduction in peak bone mass. The mortality
rate is between 6% and 18% (Theander 1985), with half the
deaths resulting from suicide. Psychopharmacological inter-
long-term outcome (Bulik et al. 2007). Recent pharmacological
targets include the 5-hydroxytryptamine (5-HT) system.
The 5-HT neuronal systems contribute to modulation of appetite,
motor activity, mood, and obsessional and impulse control. Drugs
that act on the 5-HT system, such as the second-generation anti-
psychotic medication olanzapine, may have some efficacy in the
treatment of AN (Kaye et al. 2005).
We wanted to explore whether a contributing factor to the
olanzapine-induced weight gain seen in other patient populations
was a reduction in resting energy expenditure (REE) and altered

This study took place at the Division of Child and Adolescent Psychiatry at Schneider Children’s Hospital of the North Shore-Long Island Jewish
Health System, New Hyde Park, New York (now known as Cohen Children’s Medical Center).
1
Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York.
2
Hofstra North Shore-LIJ School of Medicine at Hofstra University, Hempstead, New York.
3
Department of Biostatistics, The Feinstein Institute for Medical Research, Manhasset, New York.
4
Medford, Massachusetts.
5
Private Practice, Roslyn, New York.
6
New York State Psychiatric Institute, New York, New York.
7
Department of Adolescent Medicine, Cohen Children’s Medical Center, New Hyde Park, New York.
8
Department of Adolescent Medicine, Stanford University School of Medicine, Palo Alto, California.

207
208
metabolism of energy substrates, including carbohydrate, protein,
and fat, as measured by the Respiratory Quotient (RQ). We
hypothesized that REE during the course of nutritional rehabilita-
tion would be lower than expected in the olanzapine-treated group
(Schebendach et al. 1997; Graham et al. 2005; Sharpe et al. 2005).
We also wanted to explore whether olanzapine may be efficacious
in ameliorating body image distortion.
To assess feasibility, as well as to gather preliminary data on
efficacy and safety measures, a sample size of 20 females with AN-
R was chosen for this randomized, parallel-group, 10-week, dou-
ble-blind, placebo-controlled pilot study of adjunctive olanzapine.
We hypothesized that adjunctive treatment with olanzapine, in
comparison to placebo, (1) increases weight gain as measured by
change in percentage of mean body weight (% MBW) in under-
weight adolescents with AN-R and (2) increases glucose and in-
sulin levels, but is otherwise safe and well tolerated, (3) decreases
associated eating disorder symptoms, and (4) decreases REE and
substrate utilization (RQ).
Methods
Study participants
All females receiving treatment for AN at our medical center’s
Eating Disorder Treatment Program for adolescents over a 4-year
period were screened for eligibility. Participants could be inpa-
tient, those attending day hospital, or outpatients at study entry.
Females between 12 and 21 years of age with a primary diagnosis
of AN-R as determined by the Eating Disorder Examination
(EDE) (Fairburn and Cooper 1993) or Eating Disorder Not
Otherwise Specified if the sole criterion not met was 3 months of
amenorrhea were eligible to participate. Patients were excluded if
they met criteria for past or current binge/purge type in an attempt
to increase homogeneity in this small sample. At our center,
pharmacotherapy for the binge-purge subtype tended to consist of
selective serotonin reuptake inhibitors, prescribed off-label,
whereas the AN-R group was felt to be more resistant to available
treatments. Patients were also excluded if they were judged to be a
serious suicidal risk, had prior treatment with olanzapine, or were
not on a stable medication regimen for 8 weeks prior to study
entry. After a full explanation of the study, patients over age 18
signed an informed consent document approved by our medical
center’s institutional review board. Patients under age 18 gave
written assent and a parent or guardian gave written consent. All
participants received individualized medical care, nutritional
management, and psychological treatment consisting of individ-
ual, group, family, and multifamily group therapy at our center’s
eating disorders program. Intensity of treatment was determined
by the eating disorders clinical team. Inpatients were treated on an
adolescent medicine unit of a children’s hospital and attended the
day-hospital program on weekdays. Day-hospital patients at-
tended the program on weekdays and had three meals and two
snacks supervised by staff. Outpatients generally had weekly
visits with an adolescent medicine physician, a nutritionist, and a
psychotherapist experienced in treating eating disorders and did
not attend the eating disorder program’s group or family therapy
sessions. Changes in the intensity of care provided were structured
such that participants could move through varying levels of care
based on their clinical needs as determined by the eating disorders
treatment team. Typically, treatment intensity was decreased
when weight gain goals set by the clinical team were met so that
inpatients were ‘‘stepped down’’ to day hospital and then to out-
patient treatment.
KAFANTARIS ET AL.
Study procedures
The research pharmacist randomly assigned participants to re-
ceive olanzapine or matching placebo using a computer-generated
table for inpatients or outpatients. Randomization was stratified by
inpatient versus day hospital or outpatient status at study entry.
Study and treatment personnel were blinded to treatment assign-
ment. Olanzapine or matching placebo started with a 2.5 mg single
oral dose in the evening or at bedtime for 1 week. The daily dose
was increased by 2.5 mg each week to a target dose of 10 mg/day by
week 4. Dosage was decreased if intolerable side effects occurred.
Medication adherence was assessed by participants’ self-report and
by olanzapine serum levels drawn at weeks 5 and 10. The olan-
zapine levels were stored in a freezer and sent to Eli Lilly for
analysis after all subjects completed the study.
Measurements
The primary efficacy measure was % MBW at weeks 0 (base-
line), 5, and 10. Participants were weighed in a hospital gown and
underwear after voiding and prior to eating in the morning. Body
mass index (BMI) was calculated from height and weight using the
following formula: BMI ¼ weight (in kilograms) divided by the
height (in meters) squared. Median BMI was defined as the 50th
percentile of BMI for age and gender using the 2000 CDC growth
curves for children and adolescents (Kuczmarski et al. 2000). %
MBW was defined as measured BMI divided by median BMI and
multiplied by 100.
Tolerability of medication was assessed weekly by the research
psychiatrist by physical examination including blood pressure and
pulse obtained in the sitting and standing positions and by assess-
ment of extrapyramidal symptoms. After a physical exam and pa-
tient interview, the occurrence and intensity of adverse effects were
recorded on the Treatment Emergent Side Effects Scale (TESS)
Symptom Intensity Catalog (Guy 1976), a 48-item structured ad-
verse events scale. Laboratory measures included fasting glucose,
fasting insulin, complete blood counts, and electrocardiogram at
weeks 0, 5, and 10. Electrocardiograms were interpreted by a con-
sulting pediatric cardiologist who was blind to group assignment.
Changes in general psychiatric symptoms were assessed at weeks
0, 2, 4, 6, 8, and 10 by the research psychiatrist, using clinician-
administered rating instruments, including the Hamilton Depression
Rating Scale (HDRS) (Williams 1988) and the Brief Psychiatric
Rating Scale (Woerner et al. 1988). Eating disorder symptoms were
assessed by the EDE (Fairburn and Cooper 1993) and the Yale-
Brown-Cornell-Eating Disorder Scale (YBC-EDS) (Mazure et al.
1994); both instruments were administered by an experienced li-
censed doctoral-level clinical psychologist at weeks 0, 5, and 10. The
EDE is a semistructured interview schedule that assesses a patient’s
eating disorder symptoms. The four subscale scores (Restraint,
Eating Concern, Weight Concern, and Shape Concern) represent an
average of items included in that category. A total or global score
comprised of an average of the four subscales is also recorded. The
YBC-EDS assesses the severity of the eating disorder. The scale
contains 19 individual items, 2 global severity items, and 1 reliability
item. Two parallel sets of four symptom items are grouped to gen-
erate a Preoccupation Subtotal and a Ritual Subtotal, which are
combined to report a Total score. A fourth group of six items forms a
Motivation to Change Total spanning both eating-related preoccu-
pations and rituals. Higher scores indicate more pathology.
To explore whether olanzapine was helpful in ameliorating body
image distortion, a body image assessment adapted from the work
by Williamson et al. (1987, p. 466) was administered at baseline
OLANZAPINE VS. PLACEBO IN ANOREXIA
and weeks 5 and 10. The adaptation consisted of presenting nine
numbered silhouettes ranging from emaciated (1) to obese (9) on a
single sheet of paper. Participants were asked to answer the fol-
lowing four questions: (1) ‘‘Which do you think is ideal for oth-
ers?’’; (2) ‘‘Which do you think is ideal for yourself?’’; (3) ‘‘Which
one do you think you look like now?’’; and (4) ‘‘Which one do you
feel you look like now?’’
REE and RQ were measured after a 12–14-hour overnight fast,
using an open circuit, flow-through, ventilated-hood computerized
indirect calorimeter (Datex Deltatrac II; Sensor Medics, Anaheim
CA). Patients remained awake and in a supine position throughout
the study. The calorimeter was calibrated to a known gas prior to
measurement, and oxygen consumption (VO2) and carbon dioxide
(VCO2) production were measured over a 30-minute period. Cal-
culation of REE and RQ were made by the onboard computer of the
calorimetry system. Studies were conducted at weeks 0, 5, and 10.
Data analytic methods
The demographic variables of age, weight, height, days inpa-
tient, days in day hospital, and days in outpatient treatment were
compared between the two treatment groups using two-sample
t-tests. BMI, % MBW, physiological data, adverse events as rated on
the TESS, eating disorder symptoms, and general psychological
symptoms were examined using repeated measures analysis of var-
iance with a mixed models approach to determine whether the
treatment groups behaved differently across the time points (i.e., the
treatment group-by-time interaction). A priori pairwise comparisons
examining changes across treatments between the groups were
conducted using t-tests. All analyses were of intention-to-treat type.
Results
Of the 94 eligible participants identified from consecutive ad-
missions to our eating disorder treatment program, 74 (78.7%)
declined study participation, greatly prolonging the time needed to
recruit our 20 participants (Fig. 1). The most common reasons cited
for declining to participate were not wanting to gain any weight or
wanting to gain weight without the use of medication. Enrolled
participants did not differ in age mean, BMI, or % MBW from those
who declined.
The 20 enrolled patients had a mean age of 17.1 years (range,
12.3–21.8 years) and a mean BMI of 16.4 (SD, 1.2; range, 13.4–
18.2). Ethnicity reflected the eating disorder treatment population
at our medical center and did not differ between the treatment arms.
Sixteen (80%) of the participants were Caucasian, 2 (10%) were
Asian, and 1 (5%) each was Hispanic or Black. Fourteen partici-
pants met full Diagnostic and Statistical Manual of Mental Dis-
orders, 4th edition (American Psychiatric Association 1994),
criteria for AN-R; the remaining six participants met all criteria
except for 3 months of amenorrhea and were evenly distributed
across the two treatment groups. At study entry, nine were inpa-
tients, six were day-hospital patients, and five were attending the
eating disorders outpatient clinic weekly.
There were no significant differences between the placebo and
olanzapine groups at baseline in age in years (18.10  2.04 vs.
16.41  2.20, t ¼ 1.78, p ¼ 0.09, df ¼ 18), weight in pounds
(92.20  8.11 vs. 94.77  8.66, t ¼ 0.66, p ¼ 0.52, df ¼ 18), or
height in inches (63.87  3.10 vs. 62.80  2.61, t ¼ 0.85, p ¼ 0.40,
df ¼ 18). However, when taken together to calculate % MBW,
these small differences between groups resulted in a significantly
lower mean % MBW for the placebo group at baseline. To correct
for this difference in % MBW, the initial repeated measures anal-
209
190 Screened
96
Ineligible
94
Eligible
74
Declined
20
Randomized
10 10
Active Placebo
3 Early
Termination: 2 Early
1 sedation Termination:
2 stopped 1 hypomania
medication 7 8 1 weight loss
Completers Completers
FIG. 1. Study participant flow.
ysis of variances of all other variables contained the covariate of
‘‘% MBW’’ in all analyses. In each case, it did not significantly
enter the model and was dropped from the final results presented in
Table 1.
Fifteen of our 20 enrolled patients (75%) completed this 10-
week pilot study. The reasons for noncompletion differed between
the groups. Three participants (15%) assigned to olanzapine
treatment withdrew consent prior to the week 5 assessment, citing
dissatisfaction with medication treatment, whereas the two non-
completers from the placebo arm were removed by the investiga-
tors for clinical worsening (Fig. 1). The mean daily dose of active
olanzapine at week 10 was 8.5 mg. Five of seven (71.4%) partici-
pants assigned to the olanzapine arm had detectable serum olan-
zapine levels at weeks 5 and 10. No participants assigned to placebo
treatment had detectable olanzapine levels. During their study
participation, there were no significant differences between the
placebo and olanzapine treatment groups in the mean number of
days of inpatient treatment (5.9  11.1 vs. 3.0  5.0), day hospital
(22.6  15.4 vs. 20.9  16.4), or outpatient treatment (33.6  21.7
vs. 31.2  22.5).
Mean % MBW improved in both treatment arms, as indicated by
a significant main effect of time, with 10 weeks differing signifi-
cantly from baseline (t ¼ 2.68, p ¼ 0.01). Contrary to our hy-
pothesis, adding olanzapine vs. placebo to a comprehensive eating
disorder treatment program did not further improve mean % MBW
at any time point in the intention-to-treat analyses (Table 1). Si-
milar results were obtained when dropouts and nonadherers to
olanzapine treatment were excluded from the analyses.
On the clinician-administered TESS, there were no significant
group-by-time interactions for any of the items, including increased
appetite, drowsiness, increased motor activity, rigidity, tremor,
dystonia, akathisia, or dyskinesia.
The group-by-time interactions approached statistical signifi-
cance for fasting glucose (F(2,45) ¼ 2.99, p ¼ 0.06) and fasting
210 KAFANTARIS ET AL.

Table 1. Metabolic Variables Over Time by Group

Placebo Olanzapine
Main effect Main effect Group-by-time
Mean  SD n Mean  SD n of time of group interaction

Body mass index (BMI) F(2, 45) ¼ 4.28, F(1, 45) ¼ 3.02, F(2, 45) ¼ 0.12,
Week 0 16.0  1.5 10 16.9  0.6 10 p ¼ 0.02 p ¼ 0.09 p ¼ 0.89
Week 5 17.0  1.7 9 17.8  1.4 7
Week 10 17.7  1.8 8 18.1  2.0 7
% MBW F(2, 45) ¼ 3.85, F(1, 45) ¼ 8.29, F(2, 45) ¼ 0.13,
Week 0 75.7  7.3 10 82.7  4.4 10 p ¼ 0.03 p ¼ 0.006 p ¼ 0.88
Week 5 80.5  7.9 9 86.6  5.3 7
Week 10 3.5  8.8 8 88.1  8.8 7
Glucose, mg/dL F(2, 45) ¼ 0.55, F(1, 45) ¼ 0.38, F(2, 45) ¼ 2.99,
(reference range: 70–99) p ¼ 0.58 p ¼ 0.38 p ¼ 0.06
Week 0 79.2  5.7 10 74.8  6.6 10
Week 5 74.0  6.3 9 76.3  3.5 7
Week 10 74.0  7.7 8 81.6  12.0 7
Insulin, mIU/mL F(2, 39) ¼ 1.90, F(1, 39) ¼ 1.80, F(2, 39) ¼ 2.61,
(reference range: 3.0–17) p ¼ 0.16 p ¼ 0.19 p ¼ 0.09
Week 0 4.7  3.1 10 4.0  2.6 10
Week 5 7.0  5.2 8 5.1  2.9 6
Week 10 4.2  1.0 6 20.8  33.8 5
Resting energy expenditure, F(2, 45) ¼ 1.56, F(1, 45) ¼ 0.32, F(2, 45) ¼ 0.11,
kcal/24 hours p ¼ 0.22 p ¼ 0.58 p ¼ 0.90
Week 0 927.0  86.9 10 972.0  40.8 10
Week 5 1007.8  63.4 9 1027.1  170.5 7
Week 10 1020.0  93.5 8 1021.4  287.8 7

MBW ¼ mean body weight.

insulin (F(2,39) ¼ 2.61 p ¼ 0.09). Given that we had specific
hypotheses that fasting glucose and insulin levels would be ele-
vated at week 10 compared with baseline for the olanzapine group
but not for the placebo group and that the two treatment groups
would differ at week 10, we conducted those pairwise contrasts. At
week 10, the olanzapine group had significantly elevated glucose
levels when compared with the placebo group (t ¼ 2.02,
p ¼ 0.05). The change from baseline to week 10 approached sig-
nificance for the olanzapine group (t ¼ 1.90, p ¼ 0.06) but was not
significant for the placebo group (t ¼ 1.51, p ¼ 0.14). With respect
to insulin levels, the olanzapine group had significantly elevated
levels at week 10 compared with their baseline levels (t ¼ 2.73,
p ¼ 0.009) and compared with the placebo group at week 10
(t ¼ 2.44, p ¼ 0.02). Baseline vs. week 10 was not different for the
placebo group (t ¼ 0.10, p ¼ 0.92).
Measures of metabolic recovery (REE and RQ) and cardiac
function (ECG) did not differ between treatment arms (Table 1).
On both measures of general psychopathology (HDRS and the
Brief Psychiatric Rating Scale), the placebo group had elevated
scores, indicating greater psychopathology, when compared with the
olanzapine group at baseline; however, the group-by-time interac-
tions were not significant. On measures of specific eating behaviors
and attitudes (EDE and YBC-EDS), there was a significant im-
provement over time for both treatment groups on the YBC-EDS
Preoccupations score and the EDE Restraint score only, but no sig-
nificant group-by-time interactions. There were also no significant
group, time, or group-by-time effects for the body image assessment.
Discussion
This is the first placebo-controlled study in adolescents of the
adjunctive use of olanzapine for the treatment of AN-R. It is also
the only placebo-controlled, longitudinal study in antipsychotic-
naive AN-R patients to explore the effects of olanzapine on REE.
Contrary to our hypotheses, the addition of olanzapine vs. pla-
cebo did not result in further increases in % MBW when added to
a comprehensive eating disorder treatment program for adoles-
cents with AN-R and did not contribute to improvements in general
psychopathology assessments or eating attitudes or behavior. Both
treatment groups experienced some improvement over time on
measures of specific eating attitudes and behaviors as indicated by
the decline in EDE Restraint and YBC-EDS Preoccupation scores.
However, participants did not improve on many eating disorder
symptoms. The persistence of the rituals, shape, eating and weight
concerns, and body image distortion coupled with low motivation
to change these attitudes and behaviors may place these young
women at high risk for relapse.
There were no immediate safety concerns associated with the
use of olanzapine in this 10-week study. However, the increases in
mean fasting glucose and insulin levels on olanzapine relative to
placebo, especially given the similarities in the amount of weight
gained by both groups, suggest a direct metabolic effect of olan-
zapine and the need for close monitoring during its long-term use.
These findings add to a growing body of evidence associating
olanzapine with increases in fasting glucose levels, including in
adolescents (Tohen et al. 2007).
The results of this study do not support an olanzapine-induced
decrease in REE as a contributing mechanism for weight gain. For
both treatment groups, REE, percentage of predicted REE, and RQ
improved throughout treatment. However, both groups were at a
low body weight at the end of this 10-week study and, as expected,
(Schebendach et al. 1997) remained hypometabolic.
To our knowledge, only two comparable placebo-controlled
trials of olanzapine for the treatment of AN have been published to
OLANZAPINE VS. PLACEBO IN ANOREXIA 211

date, and both have involved adult populations. One found an effect Conclusions
for olanzapine on rate of weight gain (Bissada et al. 2008) and
The lack of support for olanzapine’s efficacy relative to placebo
the other did not (Brambilla et al. 2007). Our results are mostly
in the context of our comprehensive treatment setting, coupled with
consistent with Brambilla and colleagues’ outpatient study of 30
concerns regarding increases in insulin and glucose, dissuaded us
adults with AN who were randomly assigned to have olanzapine vs.
from pursuing a larger placebo-controlled study of adjunctive
placebo added to standardized cognitive-behavioral therapy. Si-
olanzapine for adolescents with AN-R at our setting.
milar to our results, they found no difference in weight trajectory
between treatment groups as well as no benefit in symptoms spe-
cific to eating disorder pathology. Unlike our findings, they did find Clinical Significance
a benefit of olanzapine in improving symptoms of depression as
Recruitment into pharmacological studies in this population
measured by the HDRS. However, in their analyses of AN sub-
continues to be a challenge (Halmi et al. 2005; Halmi 2008). The
groups (AN-R and AN binge-purge type), they suggested that the
high rate of study refusal, withdrawal, and nonadherence to med-
positive effects for olanzapine were found primarily in the binge-
ication treatment across studies indicate that pharmacotherapy is
purge group.
not perceived as a desirable modality of treatment by many patients
Our results contrast those of Bissada and colleagues (2008) in-
with AN. These factors limit the sample size and generalizability of
volving treatment of 34 adults in a day-hospital setting. They re-
the studies that are conducted. Assessing and addressing factors
ported that the olanzapine-treated group gained weight at a
related to treatment nonadherence using cognitive and behavioral
significantly greater rate relative to placebo and that a greater
techniques may allow for greater acceptance of pharmacological
proportion of olanzapine-treated patients achieved their target BMI
treatments.
of 18.5. Their study design, 10-week duration of treatment and
mean dose of olanzapine administered, was similar to ours, but they
included both restricting (n ¼ 16) and binge-purge (n ¼ 18) types of Disclosures
AN. No examination of response by clinical subtype was reported.
Eli Lilly had no access to the data and were not involved in data
Given the findings of Brambilla et al. (2007), the results by Bissada
analysis or in the preparation of this manuscript. Dr. V. Kafantaris
et al. may also have been driven by the responses of the binge-purge
has received investigator-initiated research support in the form of
subjects.
donation of medication from GlaxoSmithKline, donation of med-
Strengths of this study include its double-blind, placebo-
ication and matching placebo from Astra Zeneca, Eli Lilly, Janssen,
controlled design and the use of a comprehensive eating disorder
and Pfizer, and research funding from Pfizer for an unrelated, NIH-
treatment program for all participants that provided continuity of
funded study. Dr. S. Hertz has been on the speakers’ bureau for Eli
care across treatment settings up to age 21. Other strengths include
Lilly, Pfizer, and Forest. Dr. N. Golden is a co-investigator on a
laboratory measures such as fasting glucose and insulin levels,
study examining bone mineral density in adolescent girls, funded
serum olanzapine levels, indirect calorimetry, and comprehensive
by TEVA Pharmaceuticals. There is nothing to disclose that might
assessment of specific eating disorder symptomatology, including a
pose a conflict of interest for the present study. Dr. A.K. Malholtra
measure to assess body image distortion, along with general psy-
is or has been a consultant to Eli Lilly, Merck, Janssen, BMS, and
chopathology measures.
Vanda Pharmaceuticals. E. Leigh, Ph.D., Alison Berest, M.A.,
The impact of including 18–21-year-olds treated in our center is
J. Schebendach, Ph.D., W.M. Sterling, M.S., E. Saito, M.D., C.
not clear. Given the more positive results from the two adult patient
Higdon, M.D., and S. Sunday, Ph.D., have no institutional or cor-
samples, it is also possible that younger patients are less responsive
porate/commercial relationships that might pose a conflict of in-
to olanzapine than are adults.
terest.
Limitations of this pilot study include the small sample size,
resulting in some baseline differences between groups despite
randomization, and the potential self-selection of patients who Acknowledgments
were motivated to gain weight. Our ability to detect any added
The authors thank Victor Fornari, M.D., for his ongoing support
benefit of adjunctive olanzapine may also have been undermined
and guidance and Tameka Fraser for her expert assistance in
by the efficacy of the psychosocial and nutritional treatments all
manuscript preparation. This study was supported by an investi-
participants received, including the opportunity to transition be-
gator-initiated grant from Eli Lilly. Eli Lilly also supplied olan-
tween inpatient, day-hospital, and outpatient settings, as needed.
zapine and matching placebo tablets and analyzed the blinded,
Although randomization was stratified by inpatient versus out-
de-identified serum samples for olanzapine levels.
patient status at study entry and the groups did not differ in the
intensity of treatment received, their transitioning between these
three settings may have added to the variance in the rates of References
weight gain and further diminished the study’s ability to detect
American Psychiatric Association. Diagnostic and Statistical Manual
olanzapine’s effects. Future studies that include binge-purge type of Mental Disorders, 4th ed. Washington, DC: American Psychia-
and limit participation to outpatients may be better able to detect tric Association; 1994.
olanzapine’s benefits, if any. Bissada H, Tasca G, Barber AM, Bradwejn J: Olanzapine in the
The high study refusal rate among eligible patients was a treatment of low body weight and obsessive thinking in women
noteworthy challenge and is consistent with other reports in the with anorexia nervosa: A randomized, double-blinded, placebo-
literature wherein more than half the eligible participants de- controlled trial. Am J Psychiatry 165:1281–1288, 2008.
clined study enrollment (e.g., Bissada et al. 2008). Our 75% Brambilla F, Segura Garcia C, Fassino S, Abbate Daga G, Favaro A,
retention rate in a pharmacotherapy study for AN is comparable Santonastaso P, Ramaciotti C, Bondi E, Mellado C, Borriello R,
to other published studies (Halmi et al. 2005; Bissada et al. Monteleone P: Olanzapine therapy in anorexia nervosa: Psycho-
2008). biological effects. Int Clin Psychopharmacol 22:197–204, 2007.
212
Bulik CM, Berkman ND, Brownley KA, Sedway JA, Lohr KN: An-
orexia nervosa treatment: A systematic review of randomized
controlled trials. Int J Eat Disord 40:310–320, 2007.
Fairburn CG, Cooper Z: The eating disorders examination. In: Binge
Eating: Nature, Assessment, and Treatment. Edited by C.G. Fair-
burn, G.T. Wilson. NY: Guilford Press; 1993; pp. 317–360.
Graham KA, Perkins DO, Edwards LJ, Barrier RC, Jr., Lieberman JA,
Harp JB: Effect of olanzapine on body composition and energy
expenditure in adults with first-episode psychosis. Am J Psychiatry
162:118–123, 2005.
Guy W (ed): ECDEU Assessment Manual for Psychopharmacology,
revised. Rockville, MD: U.S. Department of Health, Education and
Welfare publication (ADM); 1976.
Halmi KA: The perplexities of conducting randomized, double-blind,
placebo-controlled treatment trials in anorexia nervosa patients. Am
J Psychiatry 165:1227–1228, 2008.
Halmi KA, Agras WS, Crow S, Mitchell J, Wilson GT, Bryson SW,
Kraemer HC: Predictors of treatment acceptance and completion in
anorexia nervosa. Arch Gen Psychiatry 62:776–781, 2005.
Kaye WH: Neurobiology of anorexia and bulimia nervosa. Physiol
Behav 94:121–135, 2008.
Kaye WH, Frank GK, Bailer UF, Henry SE: Neurobiology of AN:
Clinical implications of alterations of the function of serotonin and
other neuronal systems. Int J Eat Disord 37:S15–S19, 2005.
Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal
KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL: CDC
growth charts: United States. Adv Data (314):1–27, 2000.
Mazure CM, Halmi KA, Sunday SR, Romano SJ, Einhorn AM: The
Yale-Brown-Cornell Eating Disorder Scale: development, use, re-
liability and validity. J Psychiatry Res 28:425–445, 1994.
Schebendach J, Golden NH, Jacobson MS, Hertz S, Shenker IR: The
metabolic responses to starvation and refeeding in adolescents with
anorexia nervosa. Ann NY Acad Sci 817:110–119, 1997.
KAFANTARIS ET AL.
Sharpe JK, Byrne NM, Stedman TJ, Hills AP: Resting energy ex-
penditure is lower than predicted in people taking atypical anti-
psychotic medication. J Am Diet Assoc 105:612–615, 2005.
Theander S: Outcome and prognosis in anorexia nervosa and bulimia:
Some results of previous investigations, compared with those of a
Swedish long-term study. J Psychiatry Res 19:493–508, 1985.
Tohen M, Kryzhanovskaya L, Carlson G, DelBello M, Wozniak J,
Kowatch R, Wagner K, Findling R, Lin D, Robertson-Plouch C:
Olanzapine versus placebo in the treatment of adolescents with
bipolar mania. Am J Psychiatry 164:1547–1556, 2007.
Walsh BT, Kaplan AS, Attia E, Olmstead M, Parides M, Carter JC,
Pike KM, Devlin MJ, Woodside B, Roberto CA, Rockert W:
Fluoxetine after weight restoration in anorexia nervosa: A ran-
domized controlled trial. JAMA 295:2605–2612, 2006.
Williams JBW: A structured interview guide for the Hamilton De-
pression Rating Scale. Arch Gen Psychiatry 45:742–747, 1988.
Williamson DA, Kelley ML, Cavell TA, Prather RC: Eating and
elimination disorders. In: Handbook of Assessment in Childhood
Psychopathology: Applied Issues in Differential Diagnosis and
Treatment Evaluation. Edited by C.L. Frame, J.L. Matson. NY:
Plenum; 1987; pp. 461–487.
Woerner MG, Manuzza S, Kane JM: Anchoring the BPRS: An aid to
improved reliability. Psychopharmacol Bull 24:112–117, 1988.
Address correspondence to:
Vivian Kafantaris, M.D.
Division of Psychiatry Research
The Zucker Hillside Hospital
75-59 263rd St.
Glen Oaks, NY 11004
E-mail: vkafanta@nshs.edu