07-12-1900bissada.fm

Olanzapine in the Treatment of Low Body Weight and
Obsessive Thinking in Women With Anorexia Nervosa:
A Randomized, Double-Blind, Placebo-Controlled Trial
Hany Bissada, M.D.
Objective: Anorexia nervosa is associ-
Giorgio A. Tasca, Ph.D.
Results: Compared with placebo, olanza-
antipsychotic, is known to result in weight pine resulted in a greater rate of increase Ann Marie Barber, M.A.
gain in other patient populations. The ob- jective of this trial was to assess the effi- body mass index, and a greater rate of de- Jacques Bradwejn, M.D.
ences in adverse effects were observedbetween the two treatment conditions.
Conclusions: These preliminary results
suggest that olanzapine may be safely
Method: The study was a double-blind,
placebo-controlled, 10-week flexible dose trial in which patients with anorexia ner- Replication, in the form of a large multi- either olanzapine plus day hospital treat- (Am J Psychiatry 2008; 165:1281–1288)
Anorexia nervosa is a serious debilitating illness that the psychological symptoms (particularly food obses- affects 0.5% of women ages 15–24 (1). Anorexia nervosa is sions) that perpetuate the patient’s resistance to weight manifested as food restriction, a relentless pursuit of thin- ness caused by an obsessive fear of being fat, and a dis- Olanzapine is an atypical antipsychotic with a seroto- torted body image of a delusional proportion that causes nin-dopamine antagonist profile and a reported side ef- the patient to vehemently deny the seriousness of their fect of weight gain. According to Tollefson et al. (15), the obvious state of emaciation. The severe weight loss, asso- side effect of weight gain is significantly more common ciated medical complications, psychological morbidity, among individuals with a low baseline body mass index.
and chronic course of the illness result in anorexia nervosa In addition to the desired weight gain effect, olanzapine having the highest mortality rate among all psychiatric may have some antiobsessive and antidepressant proper- ties (16). Such properties would be very beneficial to pa- Extended hospitalizations, which can restore weight to tients with the restricting subtype of anorexia nervosa, emaciated individuals, are expensive and discouraged by whose obsessional traits are often a contributing factor to private medical insurance plans which are constantly their underlying psychopathology (17). The antidepres- pressuring for shorter lengths of inpatient stay (3, 4). Thus, sant properties of olanzapine would be equally beneficial patients with anorexia nervosa frequently are discharged to those patients with the binge/purge subtype, whose as soon as medical stabilization is achieved, even though binging and purging behavior is often a coping mecha- they are still underweight, a situation likely to cause them nism to relieve dysphoric mood and psychic tension (17).
to fail in transitional day patient programs (5). While few Over the last few years, evidence supporting the use of rigorous controlled trials have been conducted, it appears olanzapine in the treatment of anorexia nervosa has accu- that pharmacological treatments, including selective sero- mulated (reviewed in reference 18). Olanzapine has been tonin reuptake inhibitors (SSRIs) (6–9) and standard neu- reported in 22 case reports, two retrospective studies (18), roleptics (10–13), as well as psychological treatments (14) and two open trials (19, 20) to be clinically beneficial in administered during weight restoration, have not been anorexia nervosa in terms of facilitating weight gain and predictably effective in increasing the rate of weight gain reducing the obsessive pursuit of thinness and associated (thus shortening the length of hospital stay) or in reducing anxiety observed in these patients. Little of the literature, This article is featured in this month’s AJP Audio, is the subject of a CME course (p. 1365),
and is discussed in an editorial by Dr. Halmi (p. 1227).
Am J Psychiatry 165:10, October 2008 OLANZAPINE IN ANOREXIA NERVOSA
however, is based on clinical trials, which led La Via et al.
Inclusion criteria required all participants to attend the day (21) to recommend a controlled trial to demonstrate the hospital program for eating disorders. This program is publicly efficacy of olanzapine in anorexia nervosa. A randomized, funded and exists within the department of psychiatry of The Ot-tawa Hospital. The program is modeled on the Toronto General controlled trial of olanzapine versus chlorpromazine was Hospital’s eating disorders program (25) and shares a number of conducted (22); however, the treatment arms were not features with other day hospitals, including supervised meals blinded. Although the two treatment conditions did not and group therapy (26). The program accommodates up to eight differ in weight gain, patients receiving olanzapine experi- patients with moderate to severe eating disorder pathology. Pa- enced a reduction in anorexic rumination (22). Recently, a tients attend the program 4 days a week, from 9:00 a.m. to 6:00p.m., for 12 to 14 weeks. In a naturalistic study with a separate randomized, double-blind, placebo-controlled trial of sample of women with anorexia nervosa, this program demon- olanzapine in the treatment of anorexia nervosa (23) was strated positive outcomes for weight restoration and in eating conducted using repeated measures analysis of variance disorder attitudes and behaviors, depression, and interpersonal (ANOVA), an analytic approach to longitudinal data with known disadvantages (24). No statistically significant dif- After complete description of the study to participants, written informed consent was obtained prior to enrollment in the trial.
ference in weight gain between the treatment and placebo The study was approved by the hospital research ethics board and conditions was found. When the sample was stratified by registered at www.ClinicalTrials.gov.
anorexia nervosa subtype, however, the increase in body Measures
mass index was significantly greater among those partici-pants with the binge/purge subtype of anorexia nervosa Body weight and height were assessed on a calibrated balance beam scale (Health-o-meter 402KL, Alsip, Ill.). Height was mea- receiving olanzapine. Olanzapine demonstrated signifi- sured at the beginning of the study. Body mass index was calcu- cant improvements in depression, anxiety, obsessive- lated by dividing weight in kilograms by height in meters squared.
compulsiveness, and aggressiveness compared with pla- Anxiety and depression were measured using the full scales of cebo. Taken as a whole, the literature suggests that olanza- the Personality Assessment Inventory (28), a self-report measure.
pine has positive effects on psychological symptoms asso- Each scale has 24 items that assess anxiety and depression interms of cognitive, affective, and physiological domains. Scale ciated with anorexia nervosa, but its effect on weight gain scores were transformed into T scores based on a normative pop- ulation mean of 50 and a standard deviation of 10, with higher The present study was designed to evaluate the effect of scores representing greater depression or anxiety. These scales olanzapine on weight gain in patients with anorexia ner- have been shown to have excellent psychometric properties in aneating disorder population (29).
vosa. A secondary objective was to evaluate the antiobses- Obsessions and compulsions were rated by a clinician using sive, anticompulsive, antianxiety, and antidepressant the 10-item Yale-Brown Obsessive Compulsive Scale (30). This properties of the medication, which would be beneficial in scale provides a measure of the severity of symptoms of general improving treatment outcomes for patients with anorexia obsessions and compulsions that is not influenced by the type of nervosa. This 10-week randomized, double-blind, pla- obsessions or compulsions. Five items each are summed for the cebo-controlled trial of olanzapine in anorexia nervosa in- obsessions and compulsions scales, with higher scores indicatinggreater severity of symptoms. These scales have excellent psycho- volved patients attending an intensive day hospital metric properties (30), and the measure differentiates eating dis- program for eating disorders 4 days per week. We hypoth- order groups from a normative population (31). Yale-Brown Ob- esized that olanzapine plus participation in the day hospi- sessive Compulsive Scale assessments were conducted by two tal program would result in 1) a greater rate of weight gain, clinicians who initially rated the patients separately and then 2) a shorter time to achievement of a healthy target weight, came to a consensus when ratings differed.
and 3) a greater positive change in depression, anxiety, ob- Procedure
sessions, and compulsions compared with placebo.
No clinical trial of olanzapine in anorexia nervosa had been pub- lished when the present study began; therefore, the work of Tollef- son and colleagues (16) on olanzapine in the treatment of schizo-phrenia was used to estimate the number of participants required.
Based on their results, a large effect size (d=1) was expected. For ad- Participants
equate power (0.80) and with alpha set at 0.05 (one-tailed), it was Eligible participants were recruited from patients referred to the estimated that a total of 28 participants were required.
eating disorders program at The Ottawa Hospital by a family phy- Potential participants received a diagnostic interview con- sician or psychiatrist between September 2000 and April 2006. All ducted by two independent clinicians, a psychiatrist and a psy- participants met DSM-IV criteria for anorexia nervosa (restricting chologist. Agreement between the two assessors was required for or binge/purge subtype), including a body mass index ≤17.5 kg/ a diagnosis of anorexia nervosa. To further assess the accuracy of m2. Secondary amenorrhea, however, was not required. Exclusion diagnosis, written reports, with diagnostic conclusions and pa- criteria were active suicidal intent, comorbid substance abuse dis- tient-identifying data removed, were reviewed by a blind expert.
order, bipolar disorder, schizophrenia or any other psychotic dis- There was 100% agreement between the blind assessment and order, organic brain syndromes or dissociative disorders, preg- the original diagnosis of anorexia nervosa, including 100% agree- nancy, and failure to use effective contraception if sexually active.
Participants were required to remain free from psychotropic med- Patients who met inclusion criteria and agreed to participate ication for a 2-week period prior to beginning the study medica- were randomly assigned to either the olanzapine plus day hospi- tion. Of the 147 patients who were approached, 34 met criteria, tal condition or placebo plus day hospital condition. Randomiza- agreed to participate, and were enrolled in the trial.
tion was stratified according to anorexia nervosa subtype (re- Am J Psychiatry 165:10, October 2008 BISSADA, TASCA, BARBER, ET AL.
FIGURE 1. CONSORT Diagram
stricting or binge/purge). Stratified block randomization was Statistical Analyses
completed by an independent statistician using a computer ran- Hierarchical linear modeling (32), which is a mixed-effects ran- dom number generator. A card indicating group assignment was dom regression approach, was used to model growth curve prepared for each successive participant and placed in a sealed change trajectories for each patient’s body mass index across the opaque envelope with the stratum identified on the outside. An 13 weeks of the trial while controlling for anorexia nervosa sub- independent hospital pharmacist retained these envelopes un- type. Growth curves allow for the assessment of the differential opened and in sequence until provided with the identity and an- rate or rapidity of increase in body mass index across treatment orexia nervosa subtype of each new participant. All study person- conditions. Hierarchical linear growth models (mixed-effects nel and participants were blind to treatment assignment for the models) for weekly body mass index and random blood glucoselevel measurements were as follows: duration of the study. Only the pharmacist was aware of group as- signment. A log was kept in case of a medical emergency that re- Level 2: π0=β00 + β01(condition) + β02(pretreatment score) + quired the treatment team to be unblinded, but it was not used.
β03(subtype) + u0 and π1=β10 + β11(condition) + β12(pretreat- Medication was delivered from the pharmacy to the day hospital program and dispensed by the psychiatrist responsible for pa- where Y refers to body mass index across patient and time, β10 is tient care, who was also blind to group assignment. The olanza- the average growth parameter across weeks and patients, and pine and placebo tablets were indistinguishable in appearance to β11(condition) refers to the difference in growth parameters be- both participants and study personnel.
The duration of the study was 13 weeks. After a 2-week baseline Outcomes on psychological variables (depression, anxiety, ob- period, olanzapine or placebo was administered for 10 weeks sessions, and compulsions) were also assessed using mixed-ef-fects growth models, but with random intercepts and fixed slopes, (weeks 3–12 of the study). Olanzapine was prescribed according while controlling for the respective pretreatment levels and for to a flexible dose regimen, starting at the minimum dose of 2.5 anorexia nervosa subtype. Mixed-effects models to assess pre- to mg/day and titrated slowly by increments of 2.5 mg/week to a posttreatment change in psychological variables were as follows: maximum dose of 10 mg/day. Weight was measured once a week Level 1: Y=π0 + π1(time) + e for 13 weeks. Assessment of psychological variables (depression, Level 2: π0=β00 + β01(condition) + β02(pretreatment score) + anxiety, obsessions, and compulsions) occurred during the first β03(subtype) + u0 and π1=β10 + β11(condition) + β12(pretreat- baseline week (week 1) and posttreatment (week 13).
Am J Psychiatry 165:10, October 2008 OLANZAPINE IN ANOREXIA NERVOSA
TABLE 1. Demographic Characteristics of Women With Anorexia Nervosa Approached to Participate in a 10-Week Random-
ized Trial of Olanzapine Versus Placebo While Attending Day Hospital Treatment
a Median family income range is reported (in Canadian dollars).
where Y refers to the psychological variable across patient and clined. Of the 34 patients enrolled in the study, 16 were time (pre- to posttreatment), β10 is the average growth parameter randomly assigned to the olanzapine plus day hospital for patients, and β11(condition) refers to the difference in growth condition and 18 were randomly assigned to the placebo parameters between treatment conditions. plus day hospital condition. Two women dropped out of Growth curve modeling is the preferred method of assessing longitudinal or repeated measurement data (24, 33) because it the olanzapine plus day hospital condition: one patient avoids the restrictive assumptions of repeated measures ANOVA, was not ready for treatment and left the day hospital pro- and one can make use of all available data without either imputa- gram, and the second patient subsequently expressed an tion of missing data or listwise deletion of data (34). This avoids unwillingness to take any psychotropic medication. Four parameter biases inherent in last observation carried forwardmethods (35).
patients dropped out of the placebo plus day hospital con- Kaplan-Meier survival curves were analyzed to compare study dition: three left because they were not ready for treat- conditions in mean time to achievement of weight restoration ment, and the other was asked to leave because of contin- (defined as a body mass index ≥18.5 kg/m2). A survival analysis ued substance use, which was against program rules. The was conducted on all participant data, with right censoring ap- proportion of drop-outs was similar across conditions plied to data of those individuals who withdrew from the study.
The analysis controlled for anorexia nervosa subtype. Chi-square tests were conducted to compare the percentage of patients in Demographic characteristics at baseline for the two each condition who dropped out of treatment.
treatment conditions and of those patients who declined toparticipate are presented in Table 1. Patients enrolled in the study were similar to eligible individuals who declined toparticipate (N=42) in both age (F=2.25, df=1, 74, p=0.14) and All data were normally distributed, and there was no ev- body mass index (F=0.18, df=1, 74, p=0.67). The proportion idence of univariate or multivariate outliers at any of the of patients within each subtype of anorexia nervosa was time points. Type I error rates were set at p<0.05 per test.
also similar across patients enrolled in the study and those Although one-tailed tests were conducted, a similar pat- who declined to participate (χ2=1.00, df=1, p=0.32).
tern of results was obtained with two-tailed tests. Hence,only the two-tailed tests are reported.
The mean dose of olanzapine over the 10-week treat- ment period for study completers (N=14) was 6.61 mg/day Treatment Implementation and Subject
Characterization
Treatment Adherence
During the data collection period, 147 female patients meeting criteria for anorexia nervosa were referred for To monitor treatment adherence, weekly urine samples treatment (Figure 1). Of these, 71 patients were excluded: were collected and analyzed at an independent laboratory.
eight patients met one or more exclusion criteria and 63 Urine samples were screened by automated high pressure otherwise eligible patients refused treatment in the day liquid chromatography using a system for broad spectrum hospital program. Reasons for refusing to participate in drug screening (Bio-Rad REMEDi HS, Hercules, Calif.).
the program included conflict with school or work sched- The method detects olanzapine and its principle metabo- ules, prohibitive geographic location (i.e., too far to travel), lites, N-desmethyl olanzapine and 2-hydroxymethyl olan- and refusal to agree to intensive treatment. Of the remain- zapine. Laboratory results indicated that all participants ing 76 eligible patients, 34 agreed to participate and 42 de- were compliant throughout the trial.
Am J Psychiatry 165:10, October 2008 BISSADA, TASCA, BARBER, ET AL.
TABLE 2. Weekly Body Mass Index Measurements of Women With Anorexia Nervosa by Treatment Condition
a Weeks 1 and 2=baseline period; week 13=posttreatment period. Medications were administered during weeks 3–12.
b Weight was not recorded for one participant.
c Weight was not recorded for two participants.l Adverse Effects
FIGURE 2. Comparison of Treatment Conditions in Time to
Achievement of Target Body Mass Index (18.5 kg/m2)a
There were no serious adverse side effects (e.g., extrapy- ramidal symptoms, excessive sleepiness, dizziness, or ga-lactorrhea) reported or found during weekly medical ex- aminations. Blood glucose levels were randomly tested each week in all patients. There was no evidence of im-paired glucose tolerance or de novo development of diabe- tes mellitus in any participant. Mixed-model regressiongrowth curves indicated no difference between conditions hieving T
in overall blood glucose levels (β00= –0.20; t=1.18, df=32, p=0.25) and no difference in the rate of change in blood glu- cose levels across weeks (β10= –0.03; t=1.22, df=32, p=0.23).
tion Not Ac
Weight Gain
Mean body mass index measurements per week are pre- Weeks Since R andom Assignment
sented in Table 2. As suggested by Singer and Willett (33), a Kaplan-Meier survival curves analysis indicated a significant differ- individual empirical growth plots were examined visually, ence between groups (Mantel-Cox test: χ2=5.31, df=1, p=0.02).
and these indicated that a linear model would best repre-sent the data. Furthermore, 95% of the within-subject Psychological Symptoms Associated With
growth variance was accounted for by a linear model.
Anorexia
Growth curve change trajectories indicated that all pa- Psychological outcomes according to treatment condi- tients, including those receiving placebo and those receiv- tion, both pre- and posttreatment, are presented in Table ing olanzapine, showed significant increases in body mass 3. Mixed-effects model analyses of pre- to posttreatment index across the 13 weeks of the trial (β change on the Personality Assessment Inventory indi- 32, p<0.001). However, patients receiving olanzapine cated a significant decrease in depression (β10= –15.79; t= showed a greater rate of increase in body mass index 4.23, df=57, p<0.001) and anxiety (β10= –6.96; t=2.46, df=57, p=0.02) across both treatment conditions. However, across weeks compared with patients receiving placebo comparison of the two conditions showed no differences (β11= –0.06; t= –2.25, df=31, p=0.03).
in change in depression scores (β11=8.28; t=1.52, df=55, p= Survival analysis comparing treatment conditions in 0.13) or anxiety scores (β11=2.82; t=0.60, df=55, p=0.55).
time to achievement of target body mass index (18.5 kg/ Mixed-effects model analyses of pre- to posttreatment m2) was conducted. Of the total sample, 55.6% of patients change on the Yale-Brown Obsessive Compulsive Scale in- receiving placebo and 87.5% of patients receiving olanza- dicated a significant decrease in obsessions (β10= –4.25; t= pine achieved weight restoration (Mantel-Cox test: χ2= 3.20, df=57, p=0.003) and compulsions (β10= –3.36; t=3.79, 5.42, df=1, p=0.02). For the olanzapine group, the mean df=57, p=0.001) across both treatment conditions. Com- survival time was 8.06 weeks (SE=0.68, 96% CI=6.74–9.39).
parison of the two conditions indicated that olanzapine For the placebo group, the mean survival time was 10.06 resulted in greater positive change in obsession scores weeks (SE=0.67, 95% CI=8.75–11.36) (Figure 2).
than placebo (β11=4.20; t=2.37, df=55, p=0.02). No differ- Am J Psychiatry 165:10, October 2008 OLANZAPINE IN ANOREXIA NERVOSA
TABLE 3. Pre- and Posttreatment Psychological Outcomes of Women With Anorexia Nervosa by Treatment Condition
a Mixed-effects model analyses of pre- to posttreatment change on the Personality Assessment Inventory indicated a significant decrease in depression (p<0.001) and anxiety (p=0.017); however, there were no differences between treatment conditions on these variables (all p val-ues >0.13).
b Mixed-effects model analyses of pre- to posttreatment change on the Yale-Brown Obsessive Compulsive Scale indicated a significant decrease in obsessions (p=0.003) and compulsions (p=0.021). Olanzapine resulted in greater positive change in obsession scores than placebo (p=0.02); however, there were no differences between treatment conditions in change in compulsion scores.
ences in change in compulsion scores were evident be- Some researchers and clinicians have expressed con- tween conditions (β11=0.60; t=0.45, df=55, p=0.70).
cern that atypical antipsychotic medications, includingolanzapine, may increase the risk of developing diabetes Discussion
mellitus, particularly type II diabetes (37–39). However,this concern is primarily related to the long-term treat- The results provide preliminary evidence to address the ment of patients with schizophrenia, who have a high inconsistency in the literature concerning the effects of prevalence of obesity and related medical disorders (38, olanzapine on weight gain in anorexia nervosa. By using 40). No serious side effects or adverse medical effects, modern analytic techniques for repeated measurement such as impaired glucose tolerance or de novo diabetes data (i.e., hierarchical linear modeling and survival analy- mellitus, were noted in the present study.
sis), we demonstrated that treatment with olanzapine re- There are a number of limitations to this study. First, be- sulted in greater and more rapid weight gain than placebo cause this is a clinical trial of a pharmacological treatment, in a sample of patients with anorexia nervosa attending a it is required that olanzapine demonstrate effects over and day hospital treatment program for eating disorders. Fur- above an already effective psychological treatment. This thermore, the robustness of this conclusion is supported potential constraint on the effect size of olanzapine may by the similarity in the results from the two different ana- have reduced the power of the analyses. Conversely, there lytic approaches to the data, i.e., hierarchical linear mod- is the possibility that psychological treatment may have eling and survival analysis. This suggests that olanzapine enhanced compliance with the olanzapine treatment. The was helpful to patients in achieving target body mass in- impact of psychological treatment on the effect size of dex more quickly. This bodes well for patients requiringmore comprehensive treatment for anorexia nervosa, be- olanzapine treatment is unknown. Second, the power of cause researchers have found that early response to treat- the analyses was already modest given the small sample ment is a predictor of positive outcomes in individuals size. Thus, some potentially clinically meaningful differ- with an eating disorder (36). Earlier response to treatment ences may have failed to reach statistical significance.
may also help to reduce the length of stay for expensive in- However, as demonstrated by the number of patients re- patient treatments for anorexia nervosa.
fusing treatment during this trial, recruiting a large sampleof willing patients with anorexia nervosa is a challenge that Both the placebo plus day hospital and olanzapine plus day hospital conditions resulted in improvements in de- has long impeded treatment research with this population.
pression, anxiety, and obsessive and compulsive symp- Likely, this issue will necessitate a large multicenter trial.
toms over the period of this trial. This is similar to results Although these results may be considered preliminary and reported in a previous study with a different sample dem- require replication, the present study remains one of the onstrating the effectiveness of day hospital treatment for largest of its kind. Third, over half of the patients ap- anorexia nervosa (27). Hence, a sizable amount of change proached for this study refused to participate. This reduces in psychological symptoms was likely attributable to day the generalizability of the results to patients with anorexia hospital treatment alone. In addition, there was promising nervosa who are willing to accept pharmacological and in- evidence of additional treatment effects of olanzapine for tensive day treatments in order to enhance weight gain. A obsessive symptoms. This suggests that the suspected an- fourth limitation is that there is no follow-up data. The pro- tiobsessive properties of olanzapine may confer added vision of olanzapine was viewed as a time-limited en- benefit to women with anorexia nervosa, whose obses- hancement to current treatment. The lack of follow-up sional traits may be debilitating and a hindrance to posi- limits what can be said about the long-term impact of olanzapine on weight gain and obsessive symptoms.
Am J Psychiatry 165:10, October 2008 BISSADA, TASCA, BARBER, ET AL.
The results of the present study suggest that olanzapine 10. Dally PJ, Sargant W: A new treatment of anorexia nervosa. Br is likely useful in increasing the rate of weight gain and in reducing time to achievement of weight restoration 11. Dally P, Sargant W: Treatment and outcome of anorexia ner- among patients with anorexia nervosa. There was also ev- 12. Vandereycken W, Pierloot R: Pimozide combined with behav- idence of the potential for olanzapine to reduce obsessive iour therapy in the short-term treatment of anorexia nervosa: symptoms among patients with anorexia nervosa. The a double-blind placebo-controlled cross-over study. Acta Psy- variance outcomes from this study may be useful in pro- viding sample size estimates for future trials. Furthermore, 13. Vandereycken W: Neuroleptics in the short-term treatment of anorexia nervosa: a double-blind placebo-controlled study the results clearly demonstrate the value in undertaking with sulpiride. Br J Psychiatry 1984; 144:288–292 future randomized, placebo-controlled, multicenter stud- 14. Wilson GT, Grilo CM, Vitousek KM: Psychological treatment of ies of longer duration and with follow-up and a larger pop- eating disorders. Am Psychol 2007; 62:199–216 ulation to more definitively assess the effectiveness and 15. Tollefson GD, Beasley CM Jr, Tran PV, Street JS, Krueger JA, safety of olanzapine in the treatment of anorexia nervosa.
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Supported by a grant from Eli Lilly. The authors thank Dr. D. William Cameron for comments on previous drafts of this manuscript, Dr.
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