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Copyright @ 200
8
American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
Olanzapine Versus Placebo in Adolescents With Schizophrenia: A 6-Week, Randomized,Double-Blind, Placebo-Controlled Trial
LUDMILA KRYZHANOVSKAYA, M.D., P
H
.D., S. CHARLES SCHULZ, M.D.,CHRISTOPHER M
C
DOUGLE, M.D., JEAN FRAZIER, M.D., RALF DITTMANN, M.D., P
H
.D.,CAROL ROBERTSON-PLOUCH, D.V.M., THERESA BAUER, B.S., WEN XU, P
H
.D., WEI WANG, M.S., JANICE CARLSON, P
H
.D.,
AND
MAURICIO TOHEN, M.D., D
.P.H.
ABSTRACTObjective:
To assess olanzapine’s efficacy and tolerability in adolescents with schizophrenia.
Method:
One hun-dred seven inpatient and outpatient adolescents (olanzapine,
= 72, mean age 16.1 years; placebo,
= 35, mean age16.3 years) with schizophrenia participated in this randomized (2:1), international, multisite, industry-sponsored trial. Allpatients met
DSM-IV-TR 
criteria for schizophrenia, and they were treated for up to 6 weeks with flexible doses ofolanzapine (2.5
 Y 
20.0 mg/day) or placebo. Last-observation-carried-forward mean changes from baseline to endpoint ontheanchoredversionoftheBriefPsychiatricRatingScaleforChildren,ClinicalGlobalImpressionScale-SeverityofIllness,and Positive and Negative Syndrome Scale (PANSS) were assessed.
Results:
More olanzapine-treated versus placebo-treated patients completed the trial (68.1% versus 42.9%,
= .020). Compared with placebo-treated patients, olanzapine-treated adolescents had significantly greater improvement in Brief Psychiatric Rating Scale for Children total (
= .003),Clinical Global Impressions Scale-Severity of Illness (
= .004), PANSS total (
= .005), and PANSS positive scores (
=.002). Olanzapine-treated patients gained significantly more baseline-to-endpoint weight (4.3 kg versus 0.1 kg,
< .001).Significantly more olanzapine-treated versus placebo-treated patients gained 7% or greater of their body weight at anytime during treatment (45.8% versus 14.7%,
= .002). Prolactin and triglyceride mean baseline-to-endpoint changeswere significantly higher in olanzapine-treated versus placebo-treated adolescents. The incidence of treatment-emergentsignificant changes in fasting glucose, cholesterol, or triglycerides did not differ between the groups at endpoint,but significantly more olanzapine-treated patients had high triglycerides at any time during treatment.
Conclusions:
Olanzapine-treated adolescents with schizophrenia experienced significant symptom improvement. Significant increasesinweight,triglycerides,uricacid,mostliverfunctiontests,andprolactinwereobservedduringolanzapinetreatment.
J.Am.Acad. Child Adolesc. Psychiatry,
2009;48(1):60
 Y 
70.
Key Words:
schizophrenia, olanzapine, efficacy, tolerability. Clinicaltrial registration information
 V 
Olanzapine Versus Placebo in the Treatment of Adolescents With Schizophrenia. URL:
http:// www.clinicaltrials.gov 
. Unique identifier: NCT00051298.
 Approximately 20% to 40% of adults with schizophre-nia experience their first psychotic break before the ageof 19 years.
1,2
Past research demonstrates a significantlag between symptom onset and initiation of antipsy-chotic treatment, which may affect the course of the dis-ease later.
2
Schizophrenia in adolescents is similar to
 Accepted October 2, 2008.Drs. Kryzhanovskaya, Robertson-Plouch, Xu, Carlson, and Tohen, Ms. Bauer and Ms. Wang are with Eli Lilly and Company.Dr. Schulz is with the University of Minnesota Medical School. Dr. McDougle is with the Indiana University School of Medicine. Dr. Frazier is with the Cambridge Health Alliance, McLeanHospital, Harvard Medical School. Dr. Dittmann is with Eli Lilly and Company, Lilly Deutschland.This work was sponsored by Eli Lilly and Company.The authors thank the patients, their families, and the study investigators for  participation in the study; Richard Risser for statistical assistance; Svetlana Dominguez for editorial assistance; and the Adolescent Working Group for man-aging the study.Correspondence to Ludmila A. Kryzhanovskaya, M.D., Ph.D., Lilly Re-search Laboratories, Indianapolis, IN 46285-6156; e-mail: kryzhanovskayalu@ lilly.com
0890-8567/09/4801-0060
Ó
2008 by the American Academy of Child and Adolescent Psychiatry.DOI: 10.1097/CHI.0b013e3181900404
60
WWW.JAACAP.COM J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 48:1, JANUARY 2009
 
Copyright @ 200
8
American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
the disorder in adults,
2
although it can be associated withmoreseveresymptoms
2
 Y 
5
andapoorerprognosis.
4,6
Risperidone and aripiprazole are currently approved totreat schizophrenia in adolescents in the United States, whereas olanzapine is not yet approved. Despite this,antipsychotics are commonly prescribed.
7,8
Currently,there are few double-blind placebo-controlled trials of antipsychotics in children and adolescents with schizo-phreniaavailableinthepublishedliterature.
9,10
 Althoughthe efficacy andsafety ofatypical antipsychoticsin adultshas been well established,
10,11
their efficacy and toler-ability in adolescents differ from that of adults,
4,8,11
in-cluding a greater susceptibility to weight gain and motor adverse events.
8
Olanzapine is effective for treating the symptoms of schizophrenia,
12,13
but its efficacy and safety have notbeen established in adolescents in controlled trials. Theefficacy and tolerability of atypical antipsychotics seemto differ in some respects from adolescents compared with adults, and the fact that adolescents may have anincreased susceptibility to these adverse events,
14
theimportance of adolescent data is clear. This article pre-sents data from a randomized double-blind, placebo-controlled trial of olanzapine (2.5
 Y 
20.0 mg/day) inadolescents with schizophrenia.
METHOD
Study Patients
Participants in this study were male and female adolescents ages13 to 17 years with schizophrenia of the paranoid, disorganized,catatonic, undifferentiated, and residual types (
DSM-IV-TR 
; diag-nosis was confirmed by the Schedule for Affective Disorders andSchizophrenia for School-Age Children-Present and Lifetime [K-SADS
15
]). Patients were both inpatients and outpatients recruitedfrom multiple sites in the United States (20 sites) and Russia (5 sites)from November 2002 to April 2005. Patients were able to performall protocol-required examinations and were required to have a totalscore of 35 or higher on the anchored version of the Brief PsychiatricRating Scale for Children (BPRS-C
16
) with a score of 3 or higher onat least one of the following BPRS-C items at enrollment andrandomization: hallucinations, delusions, or peculiar fantasies. Administrators of the BPRS-C were trained and tested for interrater reliability (0.75 to qualify).Patients who met any of the following criteria were excluded:previous participation in a clinical trial of oral olanzapine; treatment within30daysofthetrialwithadrugwithoutregulatoryapprovalfor any indication; a documented olanzapine allergic reaction; previous nonresponsetoanadequatedose/durationofolanzapinetreat-ment; potential safety concerns; pregnancy, nursing, or refusal to prac-tice acceptable contraception (for females); acute/unstable medicalconditions; current/expected use of any concomitant psychotropicmedications (except for certain benzodiazepines and anticholinergics);200 ng/mL or greater of baseline prolactin; clinically significant labo-ratory abnormalities;
DSM-IV-TR 
substance dependence within 30days(exceptnicotineandcaffeine);andacurrent
DSM-IV-TR 
diagnosisofacomorbidpsychiatricordevelopmentaldisorder.Patientswhowerepreviouslytreated with clozapine and other atypical antipsychotics wereincluded in the study. All patients and their parents/authorized legalrepresentatives signed an informed consent before the patientsparticipation in the study.
Study Design and Medications
This study consisted of three periods: a 2- to 14-day screening and washout period; a 6-week, double-blind, acute period witholanzapine or placebo; and an optional 26-week open-label period with olanzapine. During the washout period, all previous anti-psychotic drugs were tapered so that patients were free of allpsychotropic medications for at least 2 days before randomization.Patients were randomly assigned in a 2:1 ratio to either olanzapine(2.5
 Y 
20.0 mg/day) or placebo nightly.The starting dose of olanzapine was 2.5 or 5.0 mg/day at thediscretion of the investigator and could be increased (to a maximumdose of 20.0 mg/day) or decreased by an increment of 2.5 or 5.0 mg/dayattheinvestigator’sdiscretion.Thedosewastitratedtoatleast10.0mg/daybythethirdweek,providedtherewerenotolerabilityconcerns.Doses would continue to be increased to the highest tolerated dose, if there were no tolerability concerns. Dose adjustments were allowed atany time in any number of increments/decrements. Patients unable totolerate the minimum dose (2.5 mg/day) were discontinued from thestudy. Patients who did not respond to therapy (nonresponse: <20%decrease in BPRS-C and Clinical Global Impressions-Severity of Illness [CGI-S] score
Q
3 after at least 3 weeks of treatment) wereable toreceive open-label olanzapine withoutcompleting the double-blind period. The only psychotropic medications allowed during thetrial were benzodiazepines (2 mg/day lorazepam equivalents wereallowed for no more than 3 consecutive days during the trial) andanticholinergics (in doses of up to 2
 Y 
6 mg/day throughout the trial).
Efficacy Measures
The primary efficacy measure was the mean baseline-to-endpointchange in the investigator-rated BPRS-C
16
total score. Secondary efficacy measures included baseline-to-endpoint changes on theCGI-S,
17
Positive and Negative Syndrome Scale (PANSS),
18
and theOvert Aggression Scale (OAS).
19
In addition, changes on the CGI-Improvement of Illness scale (CGI-I)
17
 were evaluated at endpoint. A secondary measure was patients’ response rate, defined a priorias a 30% or greater reduction in the BPRS-C total score from baselineto endpoint and a CGI-S score of 3 or lower (mildly ill) at thelast measurement.
Tolerability Measures
Treatment-emergent adverse events, laboratory test results, vitalsigns, weight, electrocardiograms (ECGs), and extrapyramidalsymptoms (EPS) were monitored. Laboratory tests included clinicalchemistry, electrolytes, lipid profile, prolactin, urinalysis, andhematology panels. These tests were performed at protocol-specifiedtime points, when clinically indicated, and any time a patientcompleted the double-blind period or discontinued from the study.Fasting (
Q
8 hours) glucose and lipids were collected at baseline andendpoint. Treatment-emergent high and low laboratory values weredefined as a change from low or normal at any time beforerandomization to high or low, respectively, at any time after baseline.
OLANZAPINE FOR ADOLESCENT SCHIZOPHRENIA 
 WWW.JAACAP.COM
61
 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 48:1, JANUARY 2009
 
Copyright @ 200
8
American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
Treatment-emergent high prolactin was defined using Tietz referenceranges (female subjects, 3.2
 Y 
20.0 ng/mL; male subjects, 2.8
 Y 
11ng/mL).
20
Lipid categories were adolescent specific and were de-fined as follows: total cholesterol, normal to borderline (<170 to
Q
170 and <200 mg/dL), normal to high (<170 to
Q
200 mg/dL),and borderline to high (
Q
170 and <200 to
Q
200 mg/dL); low-density lipoproteins, normal to borderline (<110 to
Q
110 mg/dL),normal to high (<110 to
Q
130 mg/dL), and borderline to high(
Q
110 and <130 to
Q
130 mg/dL); high-density lipoproteins,normal to low (
9
65 to <35 mg/dL), and borderline to low (
Q
35and <65 to <35 mg/dL); and triglycerides, normal to borderline(<90 to
Q
90 and
9
130 mg/dL), normal to high (<90 to
Q
130 mg/dL), and borderline to high (
Q
90 and
e
130 to
9
130 mg/dL).Glucose categories were defined using American Diabe-tes Association criteria 
21
and National Cholesterol EducationProgram
22
criteria, respectively. Elevations in alanine aminotrans-ferase (ALT) were examined in the following ranges: less than one,three, and five times the upper limit of the laboratory referencerange at baseline to greater than one, three, and five times theupper limit of the laboratory reference range, respectively. Vital signs were monitored at each visit; height was measured atbaseline, weeks 1 and 4, and the 6-week endpoint or study dis-continuation visit. Weight was measured at each visit. Electro-cardiogram was recorded at enrollment and the 6-week endpointor study discontinuation visit. QT interval was corrected using Bazett and Fridericia formulae for adolescents with less than 60bpm and 60 bpm or greater at baseline, respectively. EPS wereassessed by observation and administration of the Simpson-AngusScale,
23
the Barnes Akathisia Scale,
24
and the Abnormal Involun-tary Movement Scale.
25
Statistical Analyses
Data were analyzed on an intent-to-treat basis, with a two-sided
!
level of .05. An analysis-of-covariance model with the terms
country 
,
therapy 
, and
baseline 
was used to evaluate continuous efficacy data, whereas an analysis-of-variance model was used to evaluate contin-uous tolerability data. Categorical data were analyzed using a Fisher exact test, and a mixed-model repeated-measures analysis of co- variance was used to analyze the change in the BPRS-C total scorefrom baseline to each postbaseline visit and included the terms for 
baseline 
,
visit 
,
country 
,
therapy 
, and
therapy by visit 
. Time-to-eventanalyses were performed using a log-rank test. The last-observation-carried-forward method was used to analyze mean changes frombaseline to endpoint.For potentially clinically important categorical changes in vital signsand ECGs, baseline was defined as the last observation before ran-domization. For treatment-emergent categorical analyses, treatment-emergent adverse events, laboratory abnormalities, and EPS scaleratings, baseline was defined as the enrollment and randomization visits. Treatment-by-country interactions and heterogeneity acrosscountries were tested at the 0.10 level; all other analyses were testedusingatwo-sided
!
levelof.05.SASsoftwareversion8.2(SASInstituteInc., Cary, NC) was used to perform all statistical analyses.
RESULTS
Baseline Patient Characteristics
 A total of 107 patients were randomly assigned toolanzapine (
n
= 72) or placebo (
n
= 35; Fig. 1). The twotreatment groups did not significantly differ on anbaseline characteristics (Table 1). The mean age was16.1 years (SD 1.3 years) for patients treated with olan-zapine and 16.3 years (SD 1.6 years) for patients treated with placebo. The majority of patients were male sub- jects and white, and most had been treated previously  with antipsychotics. Patients from both countries werealmost equally represented.
Patient Disposition
Significantly more olanzapine-treated versus placebo-treated patients completed the 6-week double-blindperiod (49/72 [68.1%] versus 15/35 [42.9%];
p
= .020;odds ratio [OR] 2.8; 95% confidence interval [CI]1.2
 Y 
6.5). Time to all-cause discontinuation was sig-nificantly longer for olanzapine-treated versus placebo-treated patients (
 p
= .007; hazard ratio 0.5; 95% CI0.2
 Y 
0.8). The 25th percentile for time for all-causediscontinuation was 29.5 days for olanzapine-treatedpatients and 20.0 days for placebo-treated patients.Significantly fewer olanzapine-treated versus placebo-treated patients discontinued treatment because of lack of efficacy (10/72 [13.9%] versus 18/35 [51.4%],
 p
< .001; OR 0.2; 95% CI 0.1
 Y 
0.4). The treatmentgroups did not differ significantly in the percentage of patients discontinuing because of an adverse event(olanzapine, 5/72 [6.9%]; placebo, 0/35 [0.0%],
p
=.170). The reported adverse events that led to dis-continuation of the five olanzapine-treated patients wereall related to elevated liver enzyme activity, including increased ALT (
n
= 2), aspartate aminotransferase (
n
=1), and transaminases (
n
= 1), and an abnormal liver functiontest(
n
=1).The mean daily dose of olanzapine was 11.1 mg/day;the mean modal dose was 12.5 mg/day. Significantly fewer olanzapine-treated versus placebo-treated patientsreceived benzodiazepines (21/72 [29.2%] versus 18/35[51.4%],
p
= .033); there were no significant differencesin the incidence of anticholinergic use (3/72 [4.2%] versus 2/35 (5.7%),
p
= .661). There were no significantdifferences between the treatment groups in the meandaily dose of benzodiazepines (olanzapine, 1.6 mg/day;placebo, 1.8 mg/day,
p
= .470 lorazepam equivalents) or thenumberofdaysofbenzodiazepinetreatment(olanza-pine, 6.3days;placebo,7.4days,
p
=.679).
Efficacy
The olanzapine-treated versus placebo-treated patientshad significantly greater last-observation-carried-forward
KRYZHANOVSKAYA ET AL.
62
WWW.JAACAP.COM J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 48:1, JANUARY 2009

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