Olanzapine Versus Placebo in Adolescents With Schizophrenia: A 6-Week, Randomized, Double-Blind, Placebo-Controlled Trial

LUDMILA KRYZHANOVSKAYA, M.D., PH.D., S. CHARLES SCHULZ, M.D., CHRISTOPHER MCDOUGLE, M.D., JEAN FRAZIER, M.D., RALF DITTMANN, M.D., PH.D., CAROL ROBERTSON-PLOUCH, D.V.M., THERESA BAUER, B.S., WEN XU, PH.D., WEI WANG, M.S., JANICE CARLSON, PH.D., AND MAURICIO TOHEN, M.D., DR.P.H.

ABSTRACT Objective: To assess olanzapines efficacy and tolerability in adolescents with schizophrenia. Method: One hundred seven inpatient and outpatient adolescents (olanzapine, n = 72, mean age 16.1 years; placebo, n = 35, mean age 16.3 years) with schizophrenia participated in this randomized (2:1), international, multisite, industry-sponsored trial. All patients met DSM-IV-TR criteria for schizophrenia, and they were treated for up to 6 weeks with flexible doses of olanzapine (2.5Y20.0 mg/day) or placebo. Last-observation-carried-forward mean changes from baseline to endpoint on the anchored version of the Brief Psychiatric Rating Scale for Children, Clinical Global Impression Scale-Severity of Illness, and Positive and Negative Syndrome Scale (PANSS) were assessed. Results: More olanzapine-treated versus placebotreated patients completed the trial (68.1% versus 42.9%, p = .020). Compared with placebo-treated patients, olanzapinetreated adolescents had significantly greater improvement in Brief Psychiatric Rating Scale for Children total (p = .003), Clinical Global Impressions Scale-Severity of Illness (p = .004), PANSS total (p = .005), and PANSS positive scores (p = .002). Olanzapine-treated patients gained significantly more baseline-to-endpoint weight (4.3 kg versus 0.1 kg, p < .001). Significantly more olanzapine-treated versus placebo-treated patients gained 7% or greater of their body weight at any time during treatment (45.8% versus 14.7%, p = .002). Prolactin and triglyceride mean baseline-to-endpoint changes were significantly higher in olanzapine-treated versus placebo-treated adolescents. The incidence of treatment-emergent significant 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 increases in weight, triglycerides, uric acid, most liver function tests, and prolactin were observed during olanzapine treatment. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(1):60Y70. Key Words: schizophrenia, olanzapine, efficacy, tolerability. Clinical trial registration informationVOlanzapine Versus Placebo in the Treatment of Adolescents With Schizophrenia. URL: http:// www.clinicaltrials.gov . Unique identifier: NCT00051298.

Approximately 20% to 40% of adults with schizophrenia experience their first psychotic break before the age of 19 years.1,2 Past research demonstrates a significant
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, McLean Hospital, 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

lag between symptom onset and initiation of antipsychotic treatment, which may affect the course of the disease later.2 Schizophrenia in adolescents is similar to
participation in the study; Richard Risser for statistical assistance; Svetlana Dominguez for editorial assistance; and the Adolescent Working Group for managing the study. Correspondence to Ludmila A. Kryzhanovskaya, M.D., Ph.D., Lilly Research Laboratories, Indianapolis, IN 46285-6156; e-mail: kryzhanovskayalu@ lilly.com 0890-8567/09/4801-00602008 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/CHI.0b013e3181900404

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the disorder in adults,2 although it can be associated with more severe symptoms2Y5 and a poorer prognosis.4,6 Risperidone and aripiprazole are currently approved to treat 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 schizophrenia available in the published literature.9,10 Although the efficacy and safety of atypical antipsychotics in adults has been well established,10,11 their efficacy and tolerability in adolescents differ from that of adults,4,8,11 including 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 not been established in adolescents in controlled trials. The efficacy and tolerability of atypical antipsychotics seem to differ in some respects from adolescents compared with adults, and the fact that adolescents may have an increased susceptibility to these adverse events,14 the importance of adolescent data is clear. This article presents data from a randomized double-blind, placebocontrolled trial of olanzapine (2.5Y20.0 mg/day) in adolescents with schizophrenia.
METHOD Study Patients Participants in this study were male and female adolescents ages 13 to 17 years with schizophrenia of the paranoid, disorganized, catatonic, undifferentiated, and residual types (DSM-IV-TR; diagnosis was confirmed by the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime [KSADS15]). Patients were both inpatients and outpatients recruited from multiple sites in the United States (20 sites) and Russia (5 sites) from November 2002 to April 2005. Patients were able to perform all protocol-required examinations and were required to have a total score of 35 or higher on the anchored version of the Brief Psychiatric Rating Scale for Children (BPRS-C16) with a score of 3 or higher on at least one of the following BPRS-C items at enrollment and randomization: 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 within 30 days of the trial with a drug without regulatory approval for any indication; a documented olanzapine allergic reaction; a previous nonresponse to an adequate dose/duration of olanzapine treatment; potential safety concerns; pregnancy, nursing, or refusal to practice acceptable contraception (for females); acute/unstable medical conditions; current/expected use of any concomitant psychotropic medications (except for certain benzodiazepines and anticholinergics);

200 ng/mL or greater of baseline prolactin; clinically significant laboratory abnormalities; DSM-IV-TR substance dependence within 30 days (except nicotine and caffeine); and a current DSM-IV-TR diagnosis of a comorbid psychiatric or developmental disorder. Patients who were previously treated with clozapine and other atypical antipsychotics were included in the study. All patients and their parents/authorized legal representatives signed an informed consent before the patients participation 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 with olanzapine or placebo; and an optional 26-week open-label period with olanzapine. During the washout period, all previous antipsychotic drugs were tapered so that patients were free of all psychotropic medications for at least 2 days before randomization. Patients were randomly assigned in a 2:1 ratio to either olanzapine (2.5Y20.0 mg/day) or placebo nightly. The starting dose of olanzapine was 2.5 or 5.0 mg/day at the discretion of the investigator and could be increased (to a maximum dose of 20.0 mg/day) or decreased by an increment of 2.5 or 5.0 mg/ day at the investigators discretion. The dose was titrated to at least 10.0 mg/day by the third week, provided there were no tolerability concerns. Doses would continue to be increased to the highest tolerated dose, if there were no tolerability concerns. Dose adjustments were allowed at any time in any number of increments/decrements. Patients unable to tolerate the minimum dose (2.5 mg/day) were discontinued from the study. Patients who did not respond to therapy (nonresponse: <20% decrease in BPRS-C and Clinical Global Impressions-Severity of Illness [CGI-S] score Q3 after at least 3 weeks of treatment) were able to receive open-label olanzapine without completing the doubleblind period. The only psychotropic medications allowed during the trial were benzodiazepines (2 mg/day lorazepam equivalents were allowed for no more than 3 consecutive days during the trial) and anticholinergics (in doses of up to 2Y6 mg/day throughout the trial). Efficacy Measures The primary efficacy measure was the mean baseline-to-endpoint change in the investigator-rated BPRS-C16 total score. Secondary efficacy measures included baseline-to-endpoint changes on the CGI-S,17 Positive and Negative Syndrome Scale (PANSS),18 and the Overt Aggression Scale (OAS).19 In addition, changes on the CGIImprovement of Illness scale (CGI-I)17 were evaluated at endpoint. A secondary measure was patients response rate, defined a priori as a 30% or greater reduction in the BPRS-C total score from baseline to endpoint and a CGI-S score of 3 or lower (mildly ill) at the last measurement. Tolerability Measures Treatment-emergent adverse events, laboratory test results, vital signs, weight, electrocardiograms (ECGs), and extrapyramidal symptoms (EPS) were monitored. Laboratory tests included clinical chemistry, electrolytes, lipid profile, prolactin, urinalysis, and hematology panels. These tests were performed at protocol-specified time points, when clinically indicated, and any time a patient completed the double-blind period or discontinued from the study. Fasting (Q8 hours) glucose and lipids were collected at baseline and endpoint. Treatment-emergent high and low laboratory values were defined as a change from low or normal at any time before randomization to high or low, respectively, at any time after baseline.

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Treatment-emergent high prolactin was defined using Tietz reference ranges (female subjects, 3.2Y20.0 ng/mL; male subjects, 2.8Y11 ng/mL).20 Lipid categories were adolescent specific and were defined as follows: total cholesterol, normal to borderline (<170 to Q170 and <200 mg/dL), normal to high (<170 to Q200 mg/dL), and borderline to high (Q170 and <200 to Q200 mg/dL); lowdensity lipoproteins, normal to borderline (<110 to Q110 mg/dL), normal to high (<110 to Q130 mg/dL), and borderline to high (Q110 and <130 to Q130 mg/dL); high-density lipoproteins, normal to low (965 to <35 mg/dL), and borderline to low (Q35 and <65 to <35 mg/dL); and triglycerides, normal to borderline (<90 to Q90 and 9130 mg/dL), normal to high (<90 to Q130 mg/ dL), and borderline to high (Q90 and e130 to 9130 mg/dL). Glucose categories were defined using American Diabetes Association criteria21 and National Cholesterol Education Program22 criteria, respectively. Elevations in alanine aminotransferase (ALT) were examined in the following ranges: less than one, three, and five times the upper limit of the laboratory reference range at baseline to greater than one, three, and five times the upper limit of the laboratory reference range, respectively. Vital signs were monitored at each visit; height was measured at baseline, weeks 1 and 4, and the 6-week endpoint or study discontinuation visit. Weight was measured at each visit. Electrocardiogram was recorded at enrollment and the 6-week endpoint or study discontinuation visit. QT interval was corrected using Bazett and Fridericia formulae for adolescents with less than 60 bpm and 60 bpm or greater at baseline, respectively. EPS were assessed by observation and administration of the Simpson-Angus Scale,23 the Barnes Akathisia Scale,24 and the Abnormal Involuntary 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 continuous tolerability data. Categorical data were analyzed using a Fisher exact test, and a mixed-model repeated-measures analysis of covariance was used to analyze the change in the BPRS-C total score from baseline to each postbaseline visit and included the terms for baseline, visit, country, therapy, and therapy by visit. Time-to-event analyses were performed using a log-rank test. The last-observationcarried-forward method was used to analyze mean changes from baseline to endpoint. For potentially clinically important categorical changes in vital signs and ECGs, baseline was defined as the last observation before randomization. For treatment-emergent categorical analyses, treatmentemergent adverse events, laboratory abnormalities, and EPS scale ratings, baseline was defined as the enrollment and randomization visits. Treatment-by-country interactions and heterogeneity across countries were tested at the 0.10 level; all other analyses were tested using a two-sided ! level of .05. SAS software version 8.2 (SAS Institute Inc., Cary, NC) was used to perform all statistical analyses. RESULTS Baseline Patient Characteristics

baseline characteristics (Table 1). The mean age was 16.1 years (SD 1.3 years) for patients treated with olanzapine and 16.3 years (SD 1.6 years) for patients treated with placebo. The majority of patients were male subjects and white, and most had been treated previously with antipsychotics. Patients from both countries were almost equally represented.
Patient Disposition

Significantly more olanzapine-treated versus placebotreated patients completed the 6-week double-blind period (49/72 [68.1%] versus 15/35 [42.9%]; p = .020; odds ratio [OR] 2.8; 95% confidence interval [CI] 1.2Y6.5). Time to all-cause discontinuation was significantly longer for olanzapine-treated versus placebotreated patients ( p = .007; hazard ratio 0.5; 95% CI 0.2Y0.8). The 25th percentile for time for all-cause discontinuation was 29.5 days for olanzapine-treated patients and 20.0 days for placebo-treated patients. Significantly fewer olanzapine-treated versus placebotreated patients discontinued treatment because of lack of efficacy (10/72 [13.9%] versus 18/35 [51.4%], p < .001; OR 0.2; 95% CI 0.1Y0.4). The treatment groups 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 discontinuation of the five olanzapine-treated patients were all related to elevated liver enzyme activity, including increased ALT (n = 2), aspartate aminotransferase (n = 1), and transaminases (n = 1), and an abnormal liver function test (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 patients received benzodiazepines (21/72 [29.2%] versus 18/35 [51.4%], p = .033); there were no significant differences in the incidence of anticholinergic use (3/72 [4.2%] versus 2/35 (5.7%), p = .661). There were no significant differences between the treatment groups in the mean daily dose of benzodiazepines (olanzapine, 1.6 mg/day; placebo, 1.8 mg/day, p = .470 lorazepam equivalents) or the number of days of benzodiazepine treatment (olanzapine, 6.3 days; placebo, 7.4 days, p = .679).
Efficacy

A total of 107 patients were randomly assigned to olanzapine (n = 72) or placebo (n = 35; Fig. 1). The two treatment groups did not significantly differ on any

The olanzapine-treated versus placebo-treated patients had significantly greater last-observation-carried-forward

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OLANZAPINE FOR ADOLESCENT SCHIZOPHRENIA

improvements in BPRS-C scores from baseline to endpoint (j19.4 versus j9.3, effect size = 0.63, p = .003). This improvement became significant at week 2 ( p = .020) and continued to be significant through the end of double-blind treatment (week 3, p = .004; week 4, p = .023; week 5, p = .010; week 6, p = .015; Fig. 2). The data, stratified by country, demonstrated no significant interaction between treatment and country on the least squares mean change from baseline to endpoint on the BPRS-C (therapy and treatment interaction: p = .146; Russia: Y17.4 versus Y2.6, p = .003; United States: Y21.2 versus Y15.0, p = .258). The response rate did not significantly differ between olanzapine-treated and placebotreated adolescents in either country (Russia: 35.3% versus 18.8%, p = .328; United States: 39.5% versus 31.6%, p = .772). Several secondary measures of efficacy also showed significant improvement from baseline to endpoint (Table 2): olanzapine-treated versus placebo-treated patients had significantly greater improvements on PANSS total (Y21.3 versus Y8.8, p = .005; effect size =

0.6) and positive scores (Y6.6 versus Y2.7, p = .002; effect size = 0.66) and OAS physical aggression toward others subscale (Y0.1 versus 0.0, p = .019). Adolescents treated with olanzapine had statistically significantly greater improvements on the CGI-S (4.8Y3.7 [Y1.1] versus 4.9Y4.4 [Y0.5], p = .004); in addition, CGI-I endpoint scores significantly differed between the groups (2.7 versus 3.8, p < .001). The a prioriYdefined response rate did not differ significantly between olanzapine-treated and placebotreated adolescents (37.5% versus 25.7%, p = .278). There was no significant difference between the treatment groups in the time to response for either definition.
Tolerability

Treatment-emergent adverse events occurring at anytime during treatment in 5% or greater of olanzapinetreated patients included increased weight (30.6% versus 8.6%, p = .014), somnolence (23.6% versus 2.9%, p = .006), headache (16.7% versus 5.7%, p = .138), increased appetite (16.7% versus 8.6%, p = .376), sedation (15.3% versus 5.7%, p = .214), dizziness

Fig. 1 CONSORT flow diagram of patient disposition. CONSORT = Consolidated Standards of Reporting Trials.

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TABLE 1 Patient Characteristics and Severity of Illness at Baseline (N = 107) Treatment Group Variables Age, mean (SD; range), y Sex, male, n (%) Ethnic origin, n (%) White Hispanic African descent Other Country, n (%) United States Russia Age at onset, mean (SD), y Range, y <12 y, n (%) Q12 y, n (%) Previous antipsychotic use,b n (%) Aripiprazole Chlorpromazine Clozapine Haloperidol Levopromazine Olanzapine Piracetam (pericyazine) Quetiapine Risperidone Trifluoperazine Ziprasidone Patients with Q1 prior antipsychotic treatment Patients with no prior antipsychotic treatment BPRS-C total, mean (SD) CGI-S Score of 4Vmoderately ill, n (%) Score of 5Vmarkedly ill, n (%) Score of 6Vseverely ill, n (%) Score of 7Vextremely ill, n (%) PANSS total Positive Negative Olanzapine (n = 72) 16.1 (1.3; 13.0Y18.0) 51 (70.8) 52 (72.2) 2 (2.8) 17 (23.6) 1 (1.4) 38 (52.8) 34 (47.2) 12.5 (3.2) 5.0Y17.0 20 (27.8) 52 (72.2) 3 (4.2) 6 (8.3) 5 (6.9) 5 (6.9) 3 (4.2) 8 (11.1) 3 (4.2) 11 (15.3) 21 (29.2) 4 (5.6) 1 (1.4) 51 (70.8) 21 (29.2) 50.3 (10.0) 4.8 (0.7) 24 (33.3) 36 (50.0) 12 (16.7) 0 (0.0) 95.3 (14.1) 22.8 (5.2) 24.9 (5.6) Placebo (n = 35) 16.3 (1.6; 13.1Y18.0) 24 (68.6) 25 (71.4) 1 (2.9) 7 (20.0) 2 (5.7) 19 (54.3) 16 (45.7) 13.4 (2.8) 5.0Y17.0 7 (20.0) 28 (80.0) 3 (8.6) 2 (5.7) 4 (11.4) 6 (17.1) 3 (8.6) 3 (8.6) 3 (8.6) 3 (8.6) 16 (45.7) 2 (5.7) 5 (14.3) 30 (85.7) 5 (14.3) 50.1 (8.6) 4.9 (0.8) 11 (31.4) 16 (45.7) 7 (20.0) 1 (2.9) 95.5 (14.1) 22.7 (4.2) 24.8 (6.2) .894 .471 pa .536 .825 .656 V V V V 1.00 V V .175 V .385

.390 1.00 .470 .171 .390 1.00 .390 .542 .129 1.00 .014 .148

.902 .885 .969

Note: BPRS-C = Brief Psychiatric Rating Scale for Children; CGI-S = Clinical Global Impressions-Severity of Illness; PANSS = Positive and Negative Syndrome Scale. a Frequencies were analyzed using Fisher exact test; efficacy measures, using a type III sum of squares analysis-of-variance model that included the terms for country and therapy. b Totals do not add up to 100% because each patient may have been previously treated with more than one antipsychotic.

(8.3% versus 2.9%, p = .423), nasopharyngitis (5.6% versus 5.7%, p = 1.00), pain in extremity (5.6% versus 2.9%, p = 1.00), schizophrenia (5.6% versus 20.0%, p = 0.37), and vomiting (5.6% versus 11.4%, p = .434). No deaths were reported during the study.

Olanzapine-treated adolescents experienced significantly greater mean changes from baseline to endpoint in fasting triglycerides (41.6 mg/dL [SD 75.3 mg/dL] versus 4.4 mg/dL [51.4 mg/dL], p = .029) and uric acid (32.7 2mol/L [49.3 2mol/L] versus Y5.7

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Fig. 2 Visitwise least squares mean changes in Brief Psychiatric Rating Scale for Children (BPRS-C) scores from baseline to week 6 in olanzapine (2.5Y20.0 mg/ day) and placebo-treated patients. Olanzapine-treated adolescents experienced significantly greater improvements compared with placebo-treated adolescents starting at week 2 and continuing on through the acute period of treatment (p < .05). Ns; 3.5 days olanzapine = 72, placebo = 35. Week 1 olanzapine = 70, placebo = 34. Week 2 olanzapine = 69, placebo = 33. Week 3 olanzapine = 66, placebo = 30. Week 4 olanzapine = 57, placebo = 21. Week 5 olanzapine = 52, placebo = 18. Week 6 olanzapine = 50, placebo = 15. Least squares means and p values were derived from a mixed model, repeated measures analysis (MMRM) with the terms baseline, therapy, country, visit, and therapy * visit.

2mol/L [46.8 2mol/L], p < .001; Table 3). The incidence of treatment-emergent high triglycerides at any time was significantly higher in olanzapine-treated compared with placebo-treated patients (60.8% versus 25.0%, p = .006) but not significantly different at

endpoint (27.5% versus 16.7%, p = .392). There were no other significant differences in the incidence of abnormal glucose and lipids. There were no significant differences in the incidence of patients switching from a normal glucose or lipid category at baseline

TABLE 2 LOCF LS Mean Changes From Baseline to Endpoint in Secondary Efficacy Scores in Adolescents With Schizophrenia Treated With Olanzapine (2.5Y20.0 mg/day) or Placebo for 6 Weeks (N = 107) Olanzapine (n = 72)a Placebo (n = 35)a Efficacy Measure BPRS-C total PANSS total Positive Negative General psychopathology CGI-S CGI-Ic OAS total Verbal aggression Physical aggression toward objects Physical aggression toward self Physical aggression toward others Baseline 50.3 95.2 22.8 24.8 47.7 4.8 2.0 1.0 0.5 0.2 0.3 Change at Endpoint Y19.4 Y21.3 Y6.6 Y3.8 Y10.9 Y1.1 2.7 Y0.9 Y0.5 Y0.3 Y0.1 Y0.1 Baselinea 50.1 95.5 22.7 24.8 48.1 4.9 2.4 1.1 0.6 0.1 0.5 Change at Endpointb Y9.3 Y8.8 Y2.7 Y1.8 Y4.3 Y0.5 3.8 Y0.2 Y0.2 Y0.2 0.1 0.0 pb .003 .005 .002 .081 .004 .004 <.001 .051 .163 .256 .053 .019

Note: LOCF = last observation carried forward; LS = least squares; BPRS-C = Brief Psychiatric Rating Scale for Children; PANSS = Positive and Negative Syndrome Scale; CGI-S = Clinical Global Impressions-Severity of Illness Scale; CGI-I = Clinical Global ImpressionsImprovement Scale; OAS = Overt Aggression Scale. a For PANSS and OAS: olanzapine, n = 71; placebo, n = 35. b Changes from baseline were compared using a type III sum of squares analysis-of-covariance model that included terms for country, therapy, and baseline. The efficacy analyses included only those patients with both a baseline and at least one postbaseline measurement. c For the CGI-I, only the endpoint value was available. LS means and p values were derived from an analysis-of-variance model that included terms for country and therapy.

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Olanzapine Baseline Mean (SD; Range) 89.4 (10.4; 61.2Y115.2) 165.5 (36.7; 93.3Y293.0) 97.4 (31.7; 39.9Y227.9) 49.5 (12.4; 18.6Y83.6) 93.0 (39.9; 35.4Y209.1) 340.3 (60.0; 190.0Y482.0) 26.6 (45.6; 8.0Y399.0) 28.7 (70.0; 7.0Y597.0) 8.7 (6.2; 1.5Y46.0) 138.7 (105.4; 42.0Y763.0) 21.8 (14.7; 8.0Y116.0) 46.2 (3.8; 36.0Y55.0) 0.44 (0.03; 0.43Y0.51) 9.2 (0.8; 7.6Y11.2) 15.6 (12.3; 2.3Y65.8) 416.4 (15.6) 401.6 (13.5) 67.0 (13.3; 38.3Y100.2) 23.5 (4.6; 17.0Y40.7) 169.2 (11.0; 136.5Y187.0) 4.3 (3.3; Y2.7 to 14.5) 1.4 (1.2; Y1.3 to 5.5) 0.3 (1.6; Y5.0 to 11.0) Y0.5 (19.0) Y1.6 (14.2) 408.4 (19.5) 395.1 (16.0) 68.9 (16.9; 39.2Y116.1) 24.0 (6.1; 15.7Y45.3) 169.8 (11.0; 132.0Y186.4) 5.0 (33.1; Y215.0 to 116.0) 20.7 (61.5; Y118.0 to 380.0) Y1.7 (4.0; Y12.0 to 7.0) 10.7 (96.1; Y496.0 to 377.0) 7.0 (22.9; Y21.0 to 172.0) Y2.1 (3.5; Y11.0 to 8.0) Y0.02 (0.03; Y0.08 to 0.04) Y0.3 (0.5; Y1.7 to 1.1) 8.8 (17.9; Y49.9 to 73.5) 23.7 (9.0; 14.0Y56.0) 21.1 (14.9; 8.0Y80.0) 9.5 (4.7; 1.5Y21.0) 200.5 (226.0; 52.0Y1,305.0) 19.8 (9.4; 9.0Y52.0) 45.6 (3.1; 38Y52.0) 0.43 (0.04; 0.34Y0.53) 9.1 (0.7; 7.5Y10.9) 18.7 (16.2; 4.2Y64.8) 2.9 (10.5; Y23.4 to 32.4) 10.8 (21.3; Y41.4 to 82.0) 5.8 (20.1; Y35.6 to 65.0) Y3.1 (8.1; Y18.6 to 19.0) 41.6 (75.3; Y117.0 to 290.6) 32.7 (49.3; Y60.0 to 161.0) 92.8 (11.3; 61.2Y109.8) 162.8 (30.2; 106.8Y226.0) 98.2 (29.0; 44.9Y168.0) 46.0 (11.2; 31.7Y80.5) 93.9 (43.4; 44.3Y233.0) 336.9 (79.4; 196.0Y506.0) Mean Change at Endpoint (SD; Range) Baseline Mean (SD; Range) Placebo Mean Change at Endpoint (SD; Range) Y1.6 (9.7; Y19.8 to 16.2) 2.3 (20.1; Y36.0 to 46.8) 0.8 (19.2; Y27.1 to 37.2) 0.8 (11.6; 13.5Y41.8) 4.4 (51.4; Y163.9 to 90.4) Y5.7 (46.8; Y125.0 to 72.0) pa .073 .094 .301 .098 .029 <.001 Y3.8 (9.6; Y39.0 to 9.0) .135 Y5.9 (15.0; Y68.0 to 13.0) .015 2.0 (7.2; Y7.0 to 30.0) .001 Y59.6 (219.7; Y1242.0 to 77.0) .025 Y1.6 (7.0; Y20.0 to 18.0) .037 0.4 (2.4; Y6.0 to 4.0) <.001 0.00 (0.03; Y0.06 to 0.05) <.001 Y0.04 (0.4; Y1.1 to 0.9) .004 Y3.3 (14.8; Y51.2 to 24.2) .002 Y2.6 (16.3) 4.7 (15.9) 0.1 (2.8; Y6.4 to 7.3) Y0.1 (1.0; Y3.6 to 2.4) 0.3 (0.7; Y1.0 to 2.6) .637 .057 <.001 <.001 .940

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TABLE 3 LOCF Mean (SD) Changes from Baseline to Endpoint in Metabolic Parameters, Laboratory Values, Vital Signs, and Weight and Growth Measurements at Any Time During Treatment in Adolescents With Schizophrenia Treated With Olanzapine (2.5Y20.0 mg/day) or Placebo

Parameter

Fasting metabolic parametersb Glucose,c mg/dL Total cholesterol,c mg/dL LDL cholesterol,c mg/dL HDL cholesterol,c mg/dL Triglycerides,c mg/dL Uric acid,d 2mol/L Hepatic enzymesd AST, U/L ALT, U/L Bilirubin, total, mg/dL CPK, U/L GGT, U/L Albumin,d g/L Hematocritd Hemoglobind Prolactin,e 2g/L Corrected QT Bazett formula,f QT/ms Fridericia, QT/ms Growth and weight Weight,g kg BMI,g kg/m2 Height,g cm

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Note: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CPK = creatine phosphokinase; GGT = + glutamyltransferase; HDL = highdensity lipoprotein; LDL = low-density lipoprotein; LOCF = last observation carried forward. a Derived from a type III sum of squares analysis-of-variance model, with terms for country and therapy. b For all metabolic parameters (except uric acid), fasting samples were assessed. c Olanzapine, n = 55; placebo, n = 25. d Olanzapine, n = 70; placebo, n = 34. e Olanzapine, n = 64; placebo, n = 30. f Olanzapine, n = 63; placebo, n = 29; range not presented. g Olanzapine, n = 72; placebo, n = 34.

OLANZAPINE FOR ADOLESCENT SCHIZOPHRENIA

to an abnormal one at any time during treatment. Olanzapine-treated adolescents had significantly greater baseline-to-endpoint mean changes in prolactin (8.8 2g/L [17.9 2g/L] versus Y3.3 2g/L [14.8 2g/L], p = .002) and ALT compared with placebo-treated adolescents (20.7 U/L [65.1 U/L] versus Y5.9 U/L [15.0 U/L], p = .015; Table 3). Significantly more adolescents treated with olanzapine versus placebo developed treatment-emergent high prolactin at any time during treatment (81.0% versus 16.7%, p = .008). The frequency of treatment-emergent clinically significant elevations in ALT from less than five times the laboratory reference range to greater than five times the upper limit in olanzapine-treated patients was 8.7% (versus 0.0%, p = .174). From baseline to endpoint, olanzapine-treated patients gained significantly more weight (4.3 versus 0.1 kg, p < .001) and had significantly greater mean changes in body mass index (1.4 versus Y0.1, p < .001) compared with placebo-treated patients (Table 3). Significantly more olanzapine-treated patients gained 7% or greater of their baseline body weight (33/72 [45.8%]; 5/34 [14.7%], p = .002). Baseline-to-endpoint mean changes in blood pressure, pulse, Bazett or Fridericia corrected QT interval (Table 3), and other ECG measurements did not differ significantly between the groups. Olanzapine-treated and placebo-treated adolescents did not differ significantly in mean changes from baseline to endpoint on any of the three EPS measures, including the Simpson-Angus Scale total (p = .260), Barnes Akathisia Scale-global assessment of akathisia (p = .747), or the Involuntary Movement Scale nonglobal total (questions 1Y7, p = .897) scores. The number of patients treated with anticholinergics was not significantly different between the olanzapine and placebo treatment groups (4.2% versus 5.7%, p = .661). No adverse events pertaining to suicidal or selfinjurious behaviors were reported, and there was a trend of significantly greater improvement in the OAS total (p = .051) and the OAS physical aggression toward self scores (p = .053) for olanzapine-treated adolescents.

DISCUSSION

This is one of the few published double-blind placebo-controlled studies of an atypical antipsychotic in the treatment of adolescents with schizophrenia. On

most efficacy measures, olanzapine treatment led to significant improvement in schizophrenia symptoms. Comparisons of the response rates in these adolescents with adult data suggest that the response rate seen in adolescents in this study is lower than that of adults (38% versus 58% to 62% of adults with schizophrenia in a study of similar length and design).12 The response rate did not statistically significantly differ between the treatment groups, which may be explained by the large treatment response in the placebo-treated adolescents from the United States. However, the number of subjects recruited per site was much higher in the Russian sites compared with the U.S. sites and suggests that there may be differences between subjects enrolled in Russia and the United States. These site effects, although not statistically significant, may account for the observed differences in response rates for drug and placebo in the two countries. This may explain the differences seen between the patients of the two countries in terms of treatment response. Children and adolescents with schizophrenia typically have a poorer prognosis4,6 and more severe symptoms2Y5,8 than adults, which may explain the lower treatment response in children and adolescents.4,26 In the present study, patients had more severe symptoms than those typically seen in adults.12,13 The majority of adolescents in this study were considered at least markedly ill, based on their baseline CGI-S scores. Olanzapine treatment led to significant improvement in the PANSS total and positive scores but only numeric improvement in the PANSS negative scores. The latter finding is inconsistent with past research of olanzapine26Y28 and other atypical antipsychotics,3 which demonstrate significant improvement in negative symptoms. However, according to an open-label trial of olanzapine in children with schizophrenia, improvement in negative symptoms may not be evident until after 1 year of treatment.28 Weight gain was significantly more common and more pronounced in olanzapine-treated versus placebotreated adolescents, which is consistent with previous research.11,26Y30 Weight gain is commonly reported during olanzapine treatment in adults12,13; however, the rates of potentially clinically important weight gain (Q7% from baseline) in the present study and other studies in adolescents11,26Y30 are higher than those reported in adults (e.g., 46% in this analysis versus 12% in a 6-week adult study12). In this analysis,

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KRYZHANOVSKAYA ET AL.

olanzapine-treated adolescents gained 4.3 kg in 6 weeks, which is more than twice the weight gain (1.9 kg) reported in a 6-week trial of olanzapine in adults.13 This is consistent with previous research of olanzapine in adolescents, which demonstrated a 7.1-kg increase over 8 weeks31 and a 7.2-kg increase over 12 weeks.32 Overall, adolescents may be more susceptible to gaining weight during antipsychotic treatment than adults8,33 because adolescents have gained weight during treatment with antipsychotics that were considered Bweight neutral.[31,32 Because of the concern over lifestyle of patients with psychiatric disorders and the increases in weight seen in both adults and adolescents treated with olanzapine, attempts should be made to create a healthy lifestyle for these patients.14 These include reducing sugar intake, eating smaller meals more frequently, limiting saturated fat intake while increasing fiber intake, and increasing physical activity. Olanzapine-treated adolescents had greater mean changes in uric acid and fasting triglycerides, glucose, total cholesterol, and high-density lipoprotein cholesterol compared with placebo-treated adolescents, although only the changes in fasting triglycerides and uric acid were significantly higher in olanzapine-treated adolescents. Patients with early-onset schizophrenia may be at an increased risk for the cardiovascular complications of hypertriglyceridemia.34 Furthermore, increases in triglycerides have been correlated with changes in weight.35,37 Prolactin levels significantly increased from baseline to endpoint in olanzapine-treated versus placebotreated adolescents in this study and seemed to remain elevated during chronic treatment (Lilly data on file). Another study in children and adolescents has also reported increases in prolactin during treatment with olanzapine.36 The mean increases in olanzapine-treated adolescents in this analysis were greater than those reported in an adult trial of similar duration (8.8 2g/L in this analysis versus 2.9 2g/L in a previous study in adults37) and are lower than the mean changes reported in an 11.2-week study in adolescents (8.8 mg/L versus Y0.1 mg/L38). Changes in prolactin during olanzapine treatment may be smaller than with other antipsychotics,38 but longer term data are needed. The rates of hyperprolactinemia seen in this analysis of olanzapine-treated adolescents (81%) are higher than those previously reported in an open-label study in adolescents with psychoses (70%).36 This suggests that

adolescents may be more susceptible than adults to prolactin increases33; whereas in adults, olanzapine may alleviate these symptoms,35 patients ages 18 years or younger may have a greater risk for hyperprolactinemia.14 Some studies have shown that changes in prolactin may be especially important for adolescent patients because patients have reported treatment-emergent adverse events relating to sexual maturation and development 39,40 such as breast enlargement, galactorrhea,33 dysmenorrhea, and sexual dysfunction,30 although the clinical significance of elevated serum prolactin levels is unknown for most patients. Olanzapine-treated patients also experienced significantly greater mean changes in ALT, consistent with adult studies of olanzapine.12,13 In addition, five olanzapine-treated patients discontinued the study because of the elevated liver enzyme activity. There is scant literature concerning the changes in liver functioning in adolescents and children during treatment with antipsychotics. One study found that the elevations in ALT and aspartate aminotransferase that occurred during combination treatment with olanzapine and divalproex were significantly greater than the increases in either of the patients treated with olanzapine or divalproex.41 Concerning EPS, the mean changes on the three scales did not significantly differ between the groups, neither did the incidence of anticholinergic use. Extrapyramidal symptoms have not been typically reported as an adverse event during treatment with olanzapine.12,31,42 In fact, improvements in EPS have been observed during olanzapine treatment in patients who switched from typical antipsychotics.36 Nevertheless, EPS have been previously reported in nondouble-blind placebo-controlled studies of adolescents treated with both an atypical antipsychotic olanzapine9,28 and typical antipsychotics4,9 in adolescents. In one study, more than half of the adolescents treated with olanzapine, risperidone, or haloperidol had at least moderate EPS; and more than half were taking anticholingeric medicine.31 It is not clear why the results of this study differ from those of Sikich and colleagues.31 The children and adolescents in the Sikich study were markedly to severely ill (mean baseline CGIS: this study, 4.9; Sikich et al., 5.6), although the mean modal doses were comparable (this study, 11.1 mg/day; Sikich et al., 12.3 mg/day), and the studies were similar in duration (this study, 6 weeks;

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OLANZAPINE FOR ADOLESCENT SCHIZOPHRENIA

Sikich et al., 8 weeks). Adolescents may be particularly vulnerable to EPS33 because D2 receptor density is higher in this age group.43 This study has several limitations. The strict inclusion criteria may limit the generalizability of these results. In addition, the dosing regimen used in this study may not reflect olanzapine doses used in clinical practice: doses were slowly titrated, and few concomitant medications were allowed. Furthermore, adolescents treated with placebo who had a CGI-S score of 3 or higher (mild illness severity) at week 3 were allowed to move to the open-label olanzapine arm. This Bnonresponsive[ threshold was extremely low; therefore, patients who were mildly ill were switched to olanzapine open-label treatment. This could have biased the efficacy results in favor of olanzapine. Finally, the duration of the trial was relatively short (6 weeks); therefore, conclusions about the long-term efficacy and safety cannot be made. In conclusion, olanzapine treatment in adolescents with schizophrenia led to significant improvements on several measures of efficacy compared with placebo treatment. This finding is consistent with previous studies of olanzapine in adults with schizophrenia, although the response rate seems to be lower in adolescents. The types of adverse events in the olanzapine treatment group seemed to be similar to those in adults, although the magnitude of changes in weight and prolactin levels may be greater in adolescents. Careful consideration should be given when assessing the potential risks and benefits of olanzapine treatment for adolescents with schizophrenia.

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Disclosure: Drs. Kryzhanovskaya, Dittmann, Robertson-Plouch, Xu, Carlson, and Tohen, and Ms. Wang and Ms. Bauer are employees of Eli Lilly and Company. Dr. McDougle has served on the speakers bureau of Bristol-Myers Squibb, Janssen Pharmaceutica, and McNeil Pediatrics; served as a consultant for Eli Lilly, Hoffman-LaRoche, and Forest Research Institute; and received research grants from Bristol-Myers Squibb and Janssen Pharmaceutica. Dr. Schulz has served on the speakers bureaus of Eli Lilly, AstraZeneca, and Bristol-Myers Squibb; served as a consultant to Eli Lilly, AstraZeneca, and Vanda; received research support from Abbott, Eli Lilly, AstraZeneca, and MIND Institute; and received honoraria from AstraZeneca and Eli Lilly. Dr. Frazier has either served as a consultant to or has received research support from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Neuropharm, Otsuka American Pharmaceutical, and Pfizer. REFERENCES
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