Am J Psychiatry 164:10, October 2007 1547

Article

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This article is featured in this month’s AJP Audio and is discussed in an editorial by Dr. McClellan on p. 1462.

Olanzapine Versus Placebo in the Treatment of Adolescents With Bipolar Mania

Mauricio Tohen, M.D., Dr.P.H.

Ludmila Kryzhanovskaya, M.D., Ph.D.

Gabrielle Carlson, M.D.

Melissa DelBello, M.D., M.S.

Janet Wozniak, M.D.

Robert Kowatch, M.D.

Karen Wagner, M.D., Ph.D.

Robert Findling, M.D.

Daniel Lin, Ph.D.

Carol Robertson-Plouch, D.V.M.

Wen Xu, Ph.D.

Ralf W. Dittmann, M.D., Ph.D.

Joseph Biederman, M.D.

Objective: The purpose of this study wasto evaluate the efficacy and safety ofolanzapine for the treatment of acutemanic or mixed episodes associated withbipolar disorder in adolescents.

Method: A 3-week multicenter, parallel,double-blind, randomized placebo-con-trolled trial was conducted at 24 sites inthe United States and two sites in PuertoRico. The participants were outpatientand inpatient male and female adoles-cents 13–17 years of age with an acutemanic or mixed episode. Subjects re-ceived either olanzapine (2.5–20 mg/day[N=107]) or placebo (N=54). The meanchange from baseline to endpoint in theYoung Mania Rating Scale total score wasthe primary outcome measure.

Results: The mean baseline-to-endpointchange in the Young Mania Rating Scaletotal score was significantly greater forpatients receiving olanzapine relative to

patients receiving placebo, and a greaterproportion of olanzapine-treated pa-tients met response and remission crite-ria (44.8% versus 18.5% and 35.2% versus11.1%, respectively). The mean baseline-to-endpoint weight change was signifi-cantly greater for patients receiving olan-zapine relative to patients receiving pla-cebo (3.7 kg versus 0.3 kg), and theincidence of treatment-emergent weightgain ≥7% of baseline was higher for olan-zapine-treated patients (41.9% versus1.9%). The mean baseline-to-endpointchanges in prolactin, fasting glucose,fasting total cholesterol, uric acid, andthe hepatic enzymes aspartate transami-nase and alanine transaminase were sig-nificantly greater in patients treated witholanzapine relative to patients receivingplacebo.

Conclusions: Olanzapine was effectivein the treatment of bipolar mania in ado-lescent patients. Patients treated witholanzapine, however, had significantlygreater weight gain and increases in thelevels of hepatic enzymes, prolactin, fast-ing glucose, fasting total cholesterol, anduric acid.

(Am J Psychiatry 2007; 164:1547–1556)

Bipolar disorder is a devastating condition with an es-timated prevalence of 0.1%–2% among adolescents (1–3).The prevalence of bipolar disorder in adults has been re-ported to be as high as 3.9% in the United States (4). Signif-icant morbidity is associated with adolescent bipolar dis-order, with wide-reaching negative consequences such aspoor academic performance, disruptions in family socialrelations, substance abuse, hospitalizations, and a highrate of mortality because of suicide (3, 5–8).

A number of open-label, prospective studies have ex-amined pharmacological treatments for children and ado-lescents with bipolar mania (9–16); however, the lack ofadequately powered controlled trials has made it difficultto evaluate their effectiveness and safety. In one placebo-controlled trial, treatment with oxcarbazepine was notmore effective than placebo (17). In another placebo-con-trolled trial, which examined treatment with topiramate,

results were inconclusive, in part because of a limitedsample size (18). A small, double-blind, placebo-con-trolled study found that quetiapine in combination withdivalproex was more effective for the treatment of adoles-cent bipolar mania compared with divalproex alone (19).We conducted a double-blind, placebo-controlled, ran-domized trial to examine the safety and efficacy of olanza-pine in the treatment of bipolar mania in adolescents.

MethodThis randomized, double-blind, placebo-controlled trial was

conducted from November 2002 to May 2005 in the United States(24 sites) and Puerto Rico (two sites). Study settings included uni-versity medical centers, outpatient clinics, and private practices.

Patients

The study enrolled 161 male and female patients 13–17 years ofage (Figure 1). All subjects met diagnostic criteria for manic or

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mixed bipolar episodes (with or without psychotic features) ac-cording to the Diagnostic and Statistical Manual for Mental Dis-orders, Fourth Edition-Text Revision (DSM-IV-TR 2000) and con-firmed with the Kiddie Schedule for Affective Disorders andSchizophrenia for School-Aged Children—Present and LifetimeVersion (20). Subjects were inpatients and outpatients with a totalscore ≥20 on the Adolescent Structured Young Mania Rating Scale(21). Exclusion criteria included prior nonresponse to olanzapine,treatment within the previous 30 days with an experimental med-ication that was not available for clinical use, serious suicidal risk,clinically significant abnormal laboratory values at baseline,DSM-IV-TR substance dependence (except nicotine and caffeine)within the past 30 days, or treatment with a long-lasting neuro-leptic within 14 days prior to randomization.

Concomitant use of benzodiazepines/hypnotics was allowed(≤2 mg lorazepam equivalents/day, not to exceed 3 consecutivedays). Episodic use of anticholinergics was also permitted (2–6mg/day) to treat extrapyramidal symptoms. However, prophylac-tic use was not permitted. Psychostimulant use was permitted aslong as the same dose was maintained for at least 30 days prior torandomization and was not altered during the study.

Written informed consent was obtained from patients andtheir legal guardians prior to participation in the study. Theappropriate ethics review boards approved the study beforerecruitment.

Study Design

The study consisted of the following three periods: period I,screening/washout of 2–14 days; period II, 3-week double-blind,

acute treatment with two assessments during the first week ofdouble-blind therapy and weekly thereafter; and period III, 26-week open-label olanzapine treatment. Only results pertaining tothe 3-week double-blind period are presented in this article.

All previous mood stabilizers or antimanic drugs were taperedduring washout to ensure that patients were free of these medica-tions for at least 2 days before randomization. Antidepressantshad to be discontinued at least 7 days prior to randomization,with the exception of monamine oxidase inhibitors (at least 14days prior to randomization) and fluoxetine (at least 5 weeks priorto randomization). To ensure patient safety, hospitalization forthe primary study condition was allowed at the discretion of theinvestigator.

During the double-blind period, patients were randomly as-signed in a 2:1 ratio to receive olanzapine (2.5–20.0 mg/day) orplacebo. A 2:1 ratio was chosen for ethical reasons to minimizethe exposure of acutely manic patients to placebo. Patients in theolanzapine group received a starting dosage of 2.5 mg/day or 5.0mg/day, which could subsequently be increased by 2.5 mg/day or5.0 mg/day increments at the investigator’s discretion. Patients ineither study group who did not adequately respond to treatmentafter at least 10 days could enter the 6-month open-label olanza-pine phase at the investigator’s discretion without breaking previ-ous double-blind assignment. All patients entering the open-la-bel phase initially received a 2.5 mg/day or 5 mg/day dose ofolanzapine, which could subsequently be increased up to 20 mg/day. No additional medications were allowed during the open-la-bel phase. A nonresponse was defined in the protocol as having a<20% reduction in the Young Mania Rating Scale total score rela-tive to baseline and a Clinical Global Impressions—Bipolar Ver-sion severity of mania score >3. All 16 patients receiving placeboand 10 of the 12 olanzapine-treated patients who discontinuedbecause of a lack of efficacy entered the open-label phase.

Assessments

The primary efficacy variable was the mean change from base-line to endpoint in the Young Mania Rating Scale total score. Ateach scheduled visit, Young Mania Rating Scale assessments wereobtained from both the patient and parent/legal guardian; onitems in which scores were discrepant between assessments, themore severe score was used. Secondary efficacy variables in-cluded baseline-to-endpoint changes on the Young Mania RatingScale individual items; Clinical Global Impressions—Bipolar Ver-sion overall, severity of mania, or depression subscales (22); Chil-dren’s Depression Rating Scale—Revised (23); Attention DeficitHyperactivity Disorder (ADHD) Rating Scale-IV—Parent Version(24); and Overt Aggression Scale (25). Additional efficacy mea-sures included rates of response (≥50% decrease in the Young Ma-nia Rating Scale total score from baseline to endpoint) and remis-sion (Young Mania Rating Scale total score ≤12 at endpoint). Theincidence of switch to depression (Clinical Global Impressionsdepression score ≤3 at baseline and ≥4 at any time during thedouble-blind phase) was also assessed.

The efficacy of olanzapine in patients with distinct illness char-acteristics or comorbidities was investigated further in the follow-ing subgroups: comorbid ADHD or oppositional defiant disorder,mania type, rapid cycling (as defined by DSM-IV), psychotic fea-tures, and age of onset. The Kiddie Schedule for Affective Disor-ders and Schizophrenia for School-Aged Children—Present andLifetime Version was used to determine a current or lifetime his-tory of ADHD or oppositional defiant disorder.

Safety was assessed by evaluating between-group differencesfor treatment-emergent adverse events and changes (mean and/or categorical) in vital signs, electrocardiogram (ECG) findings,laboratory values, or extrapyramidal symptoms from baseline toendpoint or at any time. Fasting (≥8 hours) glucose and lipid pa-rameters were collected at randomization and at endpoint. Treat-

FIGURE 1. Flow Diagram of Patient Progress Through theStudy

Enrolled (N=161)

Randomly assigned toolanzapine (N=107)

Randomly assigned toplacebo (N=54)

Completed acute phase(N=85, 79.4%)

Completed acute phase(N=35, 64.8%)

Discontinued (N=22, 20.6%):Lack of efficacy

(N=12, 11.2%)Adverse event (N=3, 2.8%)Patient decision/personal

conflict (N=4, 3.7%)Physician decision

(N=1, 0.9%)Other (N=2, 1.9%)

Discontinued (N=19, 35.2%):Lack of efficacy

(N=16, 29.6%)Adverse event (N=1, 1.9%)Patient decision/personal

conflict (N=1, 1.9%)Criteria not met/

noncompliance (N=1, 1.9%)

Not enrolled (N=53):Protocol entry criteria not met (N=37)Patient or guardian withdrew consent

(N=10)Unable to contact patient (N=2)Personal conflict or other patient

decision (N=1)Sub-investigator decision (N=1)Noncompliance (N=1)Patient did not return (N=1)

Patients enteredin study (N=214)

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ment-emergent categorical changes in lipid parameters were de-fined using National Cholesterol Education Program AdultTreatment Panel III criteria, changes in glucose parameters usingAmerican Diabetes Association criteria, and changes in prolactinparameters using both sex and age norm data (females: 4–12years=2.6–21.0 ng/ml, 12–14 years=2.5–16.9 ng/ml, 14–18 years=4.2–39.0 ng/ml; males: 4–12 years=2.6–21.0 ng/ml, 12–14 years=2.8–24.0 ng/ml, 14–18 years=2.8–16.1 ng/ml). Criteria for othertreatment-emergent abnormal laboratory values were definedusing Covance reference ranges. Extrapyramidal symptoms wereassessed using the Simpson-Angus Scale (26), the Barnes Akathi-sia Scale (27), and the Abnormal Involuntary Movement Scale(28). All adverse events were recorded as actual terms and codedto Medical Dictionary for Regulatory Activities terms. Study med-ication compliance was assessed at each visit by direct question-ing and study drug accountability.

Statistical Methods

All patient data were analyzed on an intent-to-treat basis. Base-line frequencies were compared using Fisher’s exact test. Baselinemeans were compared by analysis of variance (ANOVA) withtreatment and country as the independent factors for the contin-uous data. Exact Mann-Whitney-Wilcoxon test was used to com-pare baseline means when the distributions of the residual errorswere not normal.

For analysis of last-observation-carried-forward mean changefrom baseline to endpoint, patients with baseline and at least onepostbaseline measurements were included in the analysis.Changes in continuous efficacy data were analyzed using analysisof covariance (ANCOVA) models, which included terms for base-line Young Mania Rating Scale total score, country, and treatment.All reported Young Mania Rating Scale, Clinical Global Impres-sions—Bipolar Version, Children’s Depression Rating Scale—Re-vised, ADHD Rating Scale-IV, and Overt Aggression Scale meanchange scores represent least squares means. Analysis of visit-wiseYoung Mania Rating Scale total scores used a mixed-effects modelrepeated-measures method, which included independent factorsfor baseline, therapy, country, visit, and therapy-by-visit interac-tion. Estimates of effect size for rates of response and remissionusing relative risk and number needed to treat were calculatedwith corresponding 95% confidence intervals (CIs). Time to re-

sponse and remission of mania were calculated using the Kaplan-Meier technique. Mean baseline-to-endpoint changes for contin-uous safety measures were analyzed using ANOVA models, whichincluded terms for country and treatment. Estimates of treatmenteffects on weight gain ≥7% of baseline and abnormally high pro-lactin levels were calculated using number needed to harm.

All tests of hypotheses used a two-sided alpha=0.05, whereastreatment-by-subgroup interactions used alpha=0.10 (SAS soft-ware version 8.2, SAS Institute Inc., Cary, N.C.). No statistical ad-justments were made for multiple comparisons of secondary orsafety measures. For safety measures, adjustments for multiplecomparisons would have made the requirement for statistical sig-nificance too stringent, potentially introducing type II errors andmissing small but clinically meaningful safety signals.

Results

A total of 161 patients were randomly assigned to re-ceive olanzapine (N=107) or placebo (N=54). There wereno statistically significant group differences in baselinedemographic characteristics (Table 1).

A significantly greater number of patients receiving pla-cebo relative to olanzapine-treated patients discontinuedbecause of lack of efficacy (29.6% versus 11.2%, p=0.007).Three patients treated with olanzapine (increased heartrate, elevated hepatic enzymes, and weight gain) and onepatient receiving placebo (pregnancy) discontinued be-cause of an adverse event.

The mean modal dose of olanzapine during the double-blind period was 10.7 mg/day (SD=4.5), and the meandaily dose was 8.9 mg. No significant group differenceswere observed in the incidence of benzodiazepine use(olanzapine: 12.1% versus placebo: 7.4%, p=0.426) ormean daily dose (olanzapine: 1.44 mg [SD=1.53] versusplacebo: 2.05 mg [SD=1.66], p=0.227); however, the pla-cebo group received benzodiazepines for longer periodsof time (10.0 days [SD=6.98] versus 2.85 days [SD=3.53], p=

TABLE 1. Baseline Patient and Illness Characteristics

Characteristic

Group

pOlanzapine PlaceboN Mean SD N Mean SD

Age (years) 107 15.1 1.3 54 15.4 1.2 0.250a

Age at onset of illness (years) 106 10.9 3.3 54 11.5 3.1 0.331a

Total lifetime number of previous episodesMania 92 2.1 5.0 46 4.4 9.0 0.190b

Depression 92 1.6 2.8 50 4.0 8.3 0.027b

Mixed 81 1.2 3.7 46 3.9 9.4 0.090b

Total cumulative hospitalizations (months) 34 0.9 1.2 9 1.4 2.5 0.927b

Time since last hospitalization (days) 55 145.4 310.3 21 361.0 540.9 0.168b

Length of current episode (days) 106 309.8 749.1 54 237.2 542.2 0.515b

Total N % Total N % pCurrent episode

Mixed 107 61 58.9 54 25 46.3 0.136c

Rapid cycling 96 25 26.0 48 5 10.4 0.031c

Psychotic features 106 22 20.8 54 7 13.0 0.281c

Current or previous diagnosis of ADHD 105 45 42.9 54 13 24.1 0.024c

Current or previous diagnosis of oppositional defiant disorder

106 37 34.9 54 12 22.2 0.107c

Sex (male) 107 61 57.0 54 24 44.4 0.13c

Race (Caucasian) 107 71 66.4 54 41 75.9 0.247c

a Type III sum of squares from ANOVA model adjusted for country and therapy.b Exact Mann-Whitney-Wilcoxon text.c Fisher’s exact test.

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0.019). Rates of anticholinergic medication use did not dif-fer significantly between the olanzapine and placebogroups (4.7% versus 0%, p=0.169).

Efficacy

The mean baseline to last-observation-carried-forwardendpoint change in the Young Mania Rating Scale totalscore was significantly greater for the olanzapine grouprelative to the placebo group (–17.65 versus –9.99, p<0.001;effect size=0.84). The olanzapine group also had signifi-cantly greater mean changes in Clinical Global Impres-sions—Bipolar Version overall (–1.63 versus –0.99,p<0.001) and Clinical Global Impressions—Bipolar Ver-sion severity of mania (–1.73 versus –1.05, p<0.001) scoresrelative to the placebo group. Inclusion of study site as anindependent factor in the statistical model did not signifi-cantly alter the results of the analyses. Furthermore, whenbaseline factors for which significant baseline differenceswere observed (i.e., number of previous depressive epi-sodes, rapid cycling, current diagnosis of ADHD) were in-cluded in the ANCOVA model, outcomes of the analyseswere not significantly altered.

Statistically significant separation between the olanzap-ine and placebo groups was observed at the 1-week timepoint and onward, but not at the ½-week time point. Themean baseline to last-observation-carried-forward end-point improvements in nine out of 11 individual YoungMania Rating Scale items scores showed significantlygreater statistical difference in the olanzapine group rela-tive to the placebo group (Table 2). The mean improve-ments from baseline to last-observation-carried-forwardendpoint also showed significantly greater statistical dif-ference for patients receiving olanzapine compared with

patients receiving placebo on a number of secondary effi-cacy scales (Table 2).

Rates of response and remission were significantlyhigher for olanzapine patients relative to placebo patients(response: 48.6% versus 22.2%, p=0.002, relative risk=2.19,95% CI=1.28–3.74, number needed to treat=3.80, 95% CI=2.44–8.54; remission: 35.2% versus 11.1%, p=0.001, relativerisk=3.17, 95% CI=1.43–7.04, number needed to treat=4.14, 95% CI=2.74–8.53). Visit-wise response rates areshown in Figure 2. Times-to-reach response and remis-sion criteria were significantly shorter for patients receiv-ing olanzapine compared with patients receiving placebo(response: p=0.003; remission: p=0.002, log-rank test).

The incidence of switch to depression did not differ sig-nificantly between the two study groups (olanzapine:8.2%; placebo: 14.3%, p=0.480; Fisher’s exact test), andthere was no significant difference in the time to switch todepression. Furthermore, mean changes from baseline toendpoint in scores from scales of depressive symptom se-verity did not differ significantly between olanzapine andplacebo subjects.

Subgroup Analyses

Mean changes from baseline to endpoint in the YoungMania Rating Scale total score did not differ significantlybetween patients receiving olanzapine and patients re-ceiving placebo for any of the subgroups (no significanttherapy-by-subgroup interactions) (Table 3). For the sub-groups of patients with psychotic features and rapid cy-cling, treatment group differences were not significant,but the sample populations were small.

Concomitant psychostimulant use (yes: N=25; no: N=134) did not differentially affect changes in Young ManiaRating Scale scores (yes: –12.94 versus –6.73; no: –18.06versus –10.19; therapy-by-psychostimulant use: p=0.959).

Safety

Adverse events. The incidence of treatment-emergentadverse events reported with a frequency ≥5% was signifi-cantly higher in the olanzapine group for appetite in-crease, weight increase, and somnolence and sedationitems. During the double-blind study period, four seriousadverse events occurred in three olanzapine-treated pa-tients (two patients experienced exacerbation of bipolardisorder and one patient had decreased neutrophil countand decreased white blood cell count); none occurred inthe placebo group. No deaths occurred during the study.

Vital signs and weight. Significantly greater baseline-to-endpoint increases in supine systolic blood pressure(3.61 [SD=10.40] versus –2.28 [SD=11.26], p=0.001), supinepulse (9.51 [SD=14.53] versus –0.67 [SD=12.52], p<0.001),and standing pulse (8.90 [SD=16.72] versus –1.35 [SD=14.52], p<0.001) were observed in the olanzapine group rel-ative to the placebo group. Mean baseline-to-endpoint in-creases in weight (3.66 kg [SD=2.18] versus 0.30 kg [SD=1.67], p<0.001) and body mass index (1.18 [SD=0.85] versus

FIGURE 2. Response Rates by Visit Defined as ≥50% Reduc-tion From Baseline to Endpoint in the Young Mania RatingScale Total Score

a Denotes statistically significant differences between treatmentgroups (p<0.05).

80

60

40

20

0.5 1.0 1.5 2.0 2.5 3.00

Pati

en

ts W

ho

Resp

on

ded

(%

)

Time (weeks)

Olanzapine (N=105)

Placebo (N=54)

a

a a

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0.02 [SD=0.62], p<0.001) were significantly greater in theolanzapine group relative to the placebo group. Visit-wisechanges in body weight and body mass index are shown inFigure 3. The incidence of treatment-emergent weight gain≥7% of baseline was significantly higher in the olanzapinegroup relative to the placebo group (41.9% versus 1.9%,p<0.001; number needed to harm=2.5, 95% CI=1.99–3.34).

Metabolic parameters. Significantly greater baseline-to-endpoint increases were observed in the olanzapinegroup relative to the placebo group for fasting glucose(0.15 mg/dl [SD=0.58] versus –0.21 mg/dl [SD=0.21], p=0.002) and fasting total cholesterol (0.37 mg/dl [SD=0.61]versus 0.03 mg/dl [SD=0.75], p=0.010). Using AmericanDiabetes Association and National Cholesterol EducationProgram criteria for glucose and lipid parameters, respec-tively, there were no significant differences between theolanzapine and placebo groups in the incidence of treat-ment-emergent abnormal fasting glucose or lipids at anytime during treatment, although the incidence of treat-ment-emergent normal to borderline-abnormal triglycer-ides was higher (15.4% versus 0%, p=0.028) (Table 4). How-ever, using Covance reference ranges for total cholesterol,

high-density lipoprotein cholesterol, and triglycerides, theincidents of treatment-emergent abnormally high valuesat any time were significantly higher for the olanzapinegroup relative to the placebo group (total cholesterol:19.1% versus 2.1%, p=0.004; high-density lipoprotein cho-lesterol: 10.9% versus 0.0%, p=0.016; and triglycerides:49.1% versus 14.8%, p=0.003).

Prolactin and other laboratory values. Me a n b a se -line-to-endpoint increases in prolactin were significantlygreater in the olanzapine group relative to the placebogroup (females: 15.38 ng/ml [SD=13.73] versus 2.67 ng/ml[SD=8.60], p<0.001; males: 11.50 ng/ml [SD=9.50] versus0.66 ng/ml [SD=3.06], p<0.001). The incidence of treat-ment-emergent abnormally high levels of prolactin wassignificantly higher in patients receiving olanzapine com-pared with patients receiving placebo (females: 25.7% ver-sus 0%, p=0.007, number needed to harm=3.89, 95% CI=2.49–8.90; males: 62.5% versus 5%, p<0.001, numberneeded to harm=1.74, 95% CI=1.35–2.45). Mean baseline-to-endpoint increases in hepatic enzymes were signifi-cantly greater in the olanzapine group relative to the pla-cebo group (aspartate transaminase: 7.41 [SD=20.95] ver-

TABLE 2. Change in Symptom Severity Scores From Baseline to Endpoint

Scale

Group

p

Olanzapine Placebo

Baseline (N=107)Change From Baseline

to Endpoint Baseline (N=54)Change From Baseline

to EndpointMean SD N Mean Mean SD N Mean

Young Mania Rating Scale Total score

33.08 6.55 105 –17.65 32.04 6.23 54 –9.99 <0.001

Elevated mood 2.79 0.99 105 –1.4 2.74 0.78 54 –0.69 <0.001Increased motor activity/

energy2.95 0.90 105 –1.21 2.80 0.76 54 –0.51 <0.001

Sexual interest 1.14 1.08 105 –0.72 1.33 1.13 54 –0.58 0.249Sleep 2.42 1.08 105 –1.98 2.30 1.19 54 –1.26 <0.001Irritability 5.48 1.32 105 –2.32 5.28 1.37 54 –1.4 0.004Speech (rate and amount) 5.14 1.53 105 –2.96 4.69 1.66 54 –1.37 <0.001Language thought disorder 2.24 0.58 105 –1.18 2.11 0.66 54 –0.71 <0.001Content 3.41 2.29 105 –2.08 3.11 2.13 54 –1.35 0.019Disruptive-aggressive

behavior4.84 1.37 105 –2.1 4.74 1.58 54 –1.18 0.006

Appearance 1.18 1.05 105 –0.61 1.24 1.10 54 –0.14 <0.001Insight 1.49 1.39 105 –0.96 1.70 1.37 54 –0.77 0.268

Clinical Global Impressions Bipolar VersionSeverity overall 4.81 0.71 105 –1.63 4.83 0.75 54 –0.99 <0.001Severity of mania 4.81 0.69 105 –1.73 4.81 0.75 54 –1.05 <0.001Severity of depression 3.12 1.59 105 –0.89 2.65 1.60 54 –0.80 0.533

Children’s Depression Rating Scale—Revised total score

40.43 15.60 100 –8.37 35.77 15.35 53 –9.50 0.508

ADHD Rating Scale-IV—Parent Version total score

29.03 13.84 99 –9.69 25.28 11.84 50 –6.33 0.048

Hyperactivity-impulsivity subtotal score

13.84 6.81 100 –5.29 11.56 5.39 50 –2.87 0.008

Inattention subtotal score 15.21 8.02 99 –4.43 13.67 7.49 51 –3.62 0.388Overt Aggression Scale total

score6.34 3.67 100 –3.60 5.73 2.94 52 –1.90 <0.001

Verbal aggression total score 2.74 1.31 100 –1.43 2.73 1.21 52 –0.75 0.004Physical aggression toward

self total score0.84 1.12 100 –0.54 0.58 0.85 52 –0.36 0.071

Physical aggression toward others total score

1.18 1.20 100 –0.65 1.00 1.1252

–0.23 0.010

Physical aggression toward objects total score

1.58 1.14 100 –0.99 1.42 1.02 52 –0.63 0.026

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sus –1.62 [SD=5.74] U/liter, p=0.002; alanine transaminase:19.53 [SD=50.23] versus –1.28 [SD=8.60] U/liter, p=0.003).The incidence of treatment-emergent abnormally highlevels of aspartate transaminase and alanine transaminaseat any time was significantly higher in patients receivingolanzapine compared with patients receiving placebo (as-partate transaminase: 22.4% versus 2.0%, p<0.001; alaninetransaminase: 33.7% versus 2.1%, p<0.001, number neededto harm=14.96, 95% CI=7.59–507.42). Increases in uric acidwere significantly greater in the olanzapine group relativeto the placebo group (21.04 µmol/liter [SD=52.39] versus0.60 µmol/liter [SD=56.97], p=0.026).

ECG. Mean baseline-to-endpoint increases in heart ratewere significantly greater in patients receiving olanzapinecompared with patients receiving placebo (9.80 bpm [SD=

12.46] versus –3.61 bpm [SD=10.38], p<0.001). Meanchange from baseline to endpoint in Fridericia-adjustedQTc interval did not differ significantly between the olan-zapine and placebo groups (2.28 msec [SD=15.64] versus1.62 msec [SD=14.84], p=0.808).

Extrapyramidal Symptoms. No significant differenceswere observed between the two study groups on the Ab-normal Involuntary Movement Scale (olanzapine, –0.10[SD=0.71] versus placebo, 0.00 [SD=0.19], p=0.289), Simp-son-Angus (olanzapine, 0.02 [SD=0.93] versus placebo, –0.02 [SD=0.14], p=0.769), or Barnes scales (olanzapine, –0.04 [SD=0.44] versus placebo, 0.06 [SD=0.60], p=0.264).

Suicidality. One report of treatment-emergent suicidalideation occurred in the olanzapine group, but there wereno reports of suicide attempt or self-injurious behavior.

TABLE 3. Mean Change From Baseline to Endpoint in Young Mania Rating Scale Total Scores for Subtypes of AdolescentPatients

Subtype

Group

ComparisonOlanzapine Placebo

N

Baseline Mean Change From

Baseline to Endpoint N

Baseline Mean Change From

Baseline to Endpoint p

Effect Size

Subtype-By-Treatment pMean SD Mean SD

Mania typePure 44 34.50 5.63 –17.44 29 33.10 5.20 –11.85 0.19 0.58 1.60Mixed 61 32.05 7.00 –19.66 25 30.80 7.15 –9.96 <0.001 1.10 1.60

Psychotic featuresYes 20 35.40 6.45 –7.71 7 34.14 7.24 –0.46 0.111 0.73 0.739No 85 32.53 6.49 –18.07 47 31.72 6.09 –10.15 <0.001 0.88 0.739

ADHDPresent 45 33.27 7.4 –19.48 13 33.62 6.93 –10.54 0.003 0.98 0.615Absent 58 32.76 5.90 –17.86 41 31.54 5.99 –10.16 <0.001 0.89 0.615

Oppositional defiant disorderPresent 36 34.11 6.49 –17.90 12 32.17 7.36 –10.21 0.028 0.78 0.962Absent 68 32.43 6.54 –17.23 42 32.00 5.96 –9.86 <0.001 0.83 0.962

Rapid cyclingYes 24 33.50 7.07 –13.67 5 30.60 4.22 –7.32 0.271 0.56 0.885No 71 32.97 6.48 –18.75 43 32.51 6.56 –11.11 <0.001 0.90 0.885

Age at onset≤12 years 68 31.82 6.53 –15.99 29 32.55 6.65 –7.50 <0.001 0.59013–17 years 36 35.50 6.04 –18.75 25 31.44 5.77 –12.20 0.018 0.590

FIGURE 3. Weight Gain of Subjects Over the 3-Week Period

70

68

64

66

62

Weig

ht

(kg)

0.0 0.5 1.0 1.5 2.0 2.5 3.0

28

26

24

22

BM

I

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Time (weeks)

Olanzapine (N=105)

Placebo (N=54)

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Discussion

Although the use of antipsychotic agents for bipolar ma-nia in adolescents has increased markedly (29), to ourknowledge this is the first adequately powered placebo-controlled study to evaluate the safety and efficacy of anyantipsychotic agent in this patient population.

Patients treated with olanzapine experienced greater re-ductions in the severity of affective symptoms relative topatients receiving placebo, as reflected by the significantlygreater mean decreases in Young Mania Rating Scale total,Clinical Global Impressions—Bipolar Version overall se-verity, and Clinical Global Impressions—Bipolar Versionseverity of mania scores. Furthermore, the greater efficacyof olanzapine relative to placebo was evident across mostof the subgroups of patients analyzed.

The present study is distinguished from previous investi-gations of treatments for adolescent bipolar mania, which,for the most part, were not placebo-controlled, involvedsmall patient populations, and allowed use of concomitantmedications. These differences, however, preclude mean-ingful comparisons of treatment efficacy with findingsfrom studies in adolescents previously reported in the liter-ature. The efficacy of olanzapine for the treatment of bipo-lar mania in adults has been examined in two double-blind, placebo-controlled studies (30, 31), and findingsfrom these studies may provide useful points of compari-son. However, these comparisons should also be temperedby an acknowledgment of potentially important differ-ences, such as starting (2.5 mg versus 10 or 15 mg) andmean daily (8.9 mg versus 14.9 or 16.4 mg) doses of olanza-pine and study duration (3 versus 4 weeks in one study).

The rates of study completion among adolescent pa-tients treated with olanzapine were notably higher com-pared with corresponding rates among adult patients

(79.4% versus 61.4% and 61.8%), while discontinuationrates because of lack of efficacy were lower (11.2% versus28.6% and 27.3%) (30, 31). A point difference of 7.66 inmean baseline-to-endpoint change in the Young ManiaRating Scale score was observed between adolescent pa-tients receiving olanzapine or placebo, with a correspond-ing effect size of 0.84, compared with 0.46 and 0.53 in theadult studies (28, 29). The response rates observed in ado-lescent patients (olanzapine: 48.6%; placebo: 22.2%) arecomparable with those reported by Tohen et al. in onestudy (30) (olanzapine: 48.6%; placebo: 24.2%) in adult pa-tients, but somewhat lower for both the olanzapine groupand the placebo group in another study (31) (olanzapine:64.8%; placebo: 42.9%). It should be noted, however, thatthe latter study was 4 weeks in duration, which may ac-count in part for the higher response rates.

Significant differences were observed between patientstreated with olanzapine and patients receiving placebo re-garding mean baseline-to-endpoint changes in fastingglucose and total cholesterol. Based on the Covance refer-ence ranges, the incidents of treatment-emergent abnor-mally high levels of fasting total cholesterol, high-densitylipoprotein cholesterol, and triglycerides were signifi-cantly higher for patients receiving olanzapine relative topatients receiving placebo. Increases in prolactin levelswere observed in adolescents but not in the adult studies(30, 31). Increased prolactin levels have been reported pre-viously during treatment with various typical and atypicalantipsychotics in children and adolescents (32–34), and ithas been suggested that adolescents may be more suscep-tible to treatment-emergent elevations in prolactin (35);however, the health impact of elevated prolactin is still un-clear. The incidence of treatment-emergent abnormallyhigh aspartate transaminase and alanine transaminase

TABLE 4. Incidence of Treatment-Emergent Abnormal Glucose and Lipid Parameters at Any Time in Adolescents WithBipolar Mania Treated With Olanzapine (2.5–20.0 mg/day) or Placebo

Parameter and Category

Group

Olanzapine Placebo

pan/N % n/N %Glucose

Normal (<126 mg/dl) to high (≥126 mg/dl) 1/81 1.2 0/39 0 1.00Cholesterol

Normal (<200 mg/dl) to high (>240 mg/dl) 1/75 1.3 0/34 0 1.00Borderline (between 200 and 240 mg/dl) to high (>240 mg/dl) 0/3 0 0/3 0Normal (<100 mg/dl) to borderline (between 100 and 160 mg/dl) 15/75 20.0 1/34 2.9 0.020

Low-density lipoprotein cholesterolNormal (<100 mg/dl) to high (≥160 mg/dl) 0/50 0 0/26 0Borderline (between 100 and 160 mg/dl) to high (≥160 mg/dl) 2/24 8.3 0/8 0 1.00Normal (<100 mg/dl) to borderline (between 100 and 160 mg/dl) 14/50 28.0 6/26 23.1 0.786

High-density lipoprotein cholesterolNormal (≥40 mg/dl) to low (>40 mg/dl) 6/51 11.8 5/32 15.6 0.742

TriglyceridesNormal (<150 mg/dl) to high (>200 mg/dl) 5/65 7.7 0/30 0 0.176Normal (<150 mg/dl) to extreme high (>500 mg/dl) 0/65 0 0/30 0Borderline (between 150 and 200 mg/dl) to high (≥200 mg/dl) 0/5 0 0/3 0Borderline (between 150 and 200 mg/dl) to extreme high (≥500 mg/dl) 0/5 0 0/3 0Normal (<150 mg/dl) to borderline (between 150 and 200 mg/dl) 10/65 15.4 0/30 0 0.028

a American Diabetes Association reference ranges for abnormal versus normal changes in fasting glucose and National Cholesterol EducationProgram reference ranges for abnormal versus normal changes in fasting glucose.

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values at any time during the double-blind period was sig-nificantly higher in adolescent patients treated with olan-zapine relative to adolescent patients receiving placebo.Similar increases in alanine transaminase values havebeen observed in adult patients treated with olanzapine(30, 31), although they appear to be asymptomatic andtransient in nature (36). It is, however, uncertain whether asimilar transient course occurs in adolescent patients.Furthermore, the long-term consequences of these in-creases in liver enzymes in adolescents are unclear.

Weight gain has been documented previously in adultpatients suffering from bipolar mania treated with olanza-pine; however, mean weight gain was greater in this groupof adolescent patients (adolescents: 3.66 kg; adults:1.65 kg[30] and 2.11 kg [31]). Age-related differences in weightgain during treatment with atypical antipsychotics havebeen reported elsewhere (37–40), with a greater suscepti-bility observed among children and adolescents; however,the reasons are not yet understood. The need to recognizeand develop mitigation strategies around issues of weightgain and potential metabolic dysregulation has been high-lighted in a recent review of atypical antipsychotic medica-tions in adolescent patients (41). The significant weightgain observed during this short, 3-week trial raises con-cerns about potential negative consequences of prolongedtreatment with olanzapine, particularly in the proportionof patients who experienced rapid weight increase. Forthese patients, other options should be considered de-pending on the efficacy and tolerability of alternative treat-ments. A risk-benefit ratio or likelihood of help or harm de-rived from number-needed-to-harm and number-needed-to-treat estimates around weight gain and treatment re-sponse (2.50/3.80=0.66) suggests that although the proba-bility of responding is good, the probability of gainingweight is even greater. In the absence of data from long-term studies with olanzapine or other treatments, the risk-benefit ratio over longer treatment periods remains to bedetermined in this patient population.

There were several limitations to this study. The trialcharacterizes only a brief window in the course of treat-ment for bipolar disorder and was designed to balancethe need for a reasonable time interval to determine effi-cacy and safety with ethical concerns of treating patientsexperiencing an acute manic episode with placebo. Fur-thermore, an option to discontinue the double-blindphase and enter the open-label phase after 10 days wasprovided out of safety concerns for patients who did notrespond to treatment, which may have accounted for thesignificantly higher discontinuation rate among patientsreceiving placebo.

The benefits of olanzapine for the treatment of acutemanic episodes in adolescents should be consideredwithin the context of its safety profile as observed in thisstudy. Changes in several parameters identified as risk fac-tors for cardiovascular disease and diabetes were ob-served in adolescent patients treated with olanzapine.

Overall, the types of adverse events appeared to be similarto those reported in adults, although weight, metabolic,and prolactin changes may be greater in adolescents.However, given its short duration, this trial cannot answerquestions regarding the long-term safety or efficacy ofolanzapine in the adolescent population.

Received Nov. 27, 2006; revisions received Feb. 28 and April 20,2007; accepted April 24, 2007 (doi: 10.1176/appi.ajp.2007.06111932).From Lilly Research Laboratories, Indianapolis; McLean Hospital, Har-vard Medical School, Belmont, Mass.; Stony Brook University School ofMedicine, Stony Brook, N.Y.; University of Cincinnati College of Medi-cine, Cincinnati; Massachusetts General Hospital, Harvard MedicalSchool, Boston; University of Texas Medical Branch, Galveston, Tex.;Case Western Reserve University, Cleveland; and the Department ofChild and Adolescent Psychosomatics, University of Hamburg, Ger-many. Address correspondence and reprint requests to Dr. Tohen, LillyResearch Laboratories, Lilly Corporate Center, Indianapolis, IN 46285;m.tohen@lilly.com (e-mail).

Drs. Tohen and Kryzhanovskaya are employees and shareholderswith Eli Lilly. Dr. Carlson reports affiliations with Eli Lilly, Otsuka,Shire, Janssen, Bristol-Myers Squibb, Sanofi-Aventis, Cephalon, andNIMH. Dr. DelBello has served as a consultant and has received re-search support from Eli Lilly; she has received research support fromand served as a consultant and speaker for AstraZeneca; she hasserved as a consultant for and received research support fromJohnson and Johnson and Pfizer; she has served as a speaker forGlaxoSmithKline, and she has received research support from Shire.Dr. Wozniak has served as a consultant for Pfizer and Shire Pharma-ceuticals; she has received research funding from Eli Lilly and NIMH;and she has served on the speaker's bureaus of Eli Lilly and Janssen;her spouse has served on the speaker's bureaus of Cephalon, SanofiAventis, Sepracor, GlaxoSmithKline, and Takeda; he has served onthe advisory boards of Pfizer, GlaxoSmithKline, Sepracor, Schwarz-Pharma, Takeda, and Boehringer-Ingelheim; and he has received re-search support from Pfizer, GlaxoSmithKline, UCB Pharma, Boe-hringer-Ingelheim, and Schwarz-Pharma. Dr. Kowatch has receivedresearch support from Bristol-Myers Squibb, Stanley Research Foun-dation, NIMH, and NICHD; he has served as a consultant/advisoryboard member for Creative Educational Concepts, Child and Adoles-cent Bipolar Foundation, and Abbott; he has served as Editor of Cur-rent Psychiatry; and he has served on the speaker's bureaus of Astra-Zeneca and Abbott. Dr. Wagner has received research support fromNIMH; and she has served as a consultant and advisory board mem-ber for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, EliLilly, Forest Laboratories, Janssen, Novartis, Otsuka, Pfizer, SanofiAventis, and Solvay. Dr. Findling has received research support, actedas a consultant, and/or served on a speaker’s bureau for Abbott, As-traZeneca, Bristol-Myers Squibb, Celltech Medeva, Cypress Bio-sciences, Forest, GlaxoSmithKline, Johnson and Johnson, Eli Lilly, NewRiver, Novartis, Otsuka, Pfizer, Sanofi-Aventis, Sepracore, Shire,Solvay, Supernus Pharmaceuticals, and Wyeth. Drs. Lin, Robertson-Plouch, and Xu are employed by Eli Lilly. Dr. Dittmann is an em-ployee and shareholder with Eli Lilly. Dr. Biederman has received re-search support from and has served as a speaker or advisory boardmember for Shire, Eli Lilly, Pfizer, McNeil Abbott, Bristol-MyersSquibb, New River Pharmaceuticals, Cephalon, Janssen, Novartis,UCB Pharma, AstraZeneca, Forest Laboratories, GlaxoSmithKline,and Neurosearch; he has also received research support from theStanley Medical Institute, Lilly Foundation, Prechter Foundation,NIMH, NICHD, and NIDA.

Sponsored by Eli Lilly and Company.

The authors thank Stephen Ganocy, Ph.D., and Joseph Calabrese,M.D. (Case Western Reserve School of Medicine and the UniversityHealth and Hospital System, Cleveland), for conducting an indepen-dent data analysis with access to the raw data set for the results ofthis study. Drs. Ganocy and Calabrese received no compensation orfunding for conducting the independent academic analyses of theresults. The authors also thank Svetlana Dominguez for her technicaland editorial assistance.

This trial was registered at www.ClinicalTrials.gov in Nov. 2002 un-der the identifier NCT00050206. The primary outcome measure,

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mean change from baseline to endpoint in Young Mania Rating Scaletotal score, was defined in the protocol prior to the start of the trial.A detailed description of the study design and results has been pro-vided at www.clinicalstudyresults.org under the identifier 4360.

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