Early Antipsychotic Response to Aripiprazole in Adolescents With Schizophrenia

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NEW RESEARCH

Early Antipsychotic Response to Aripiprazolein Adolescents With Schizophrenia: Predictive

Value for Clinical OutcomesChristoph U. Correll, M.D., Joan Zhao, Ph.D., William Carson, M.D., Ron Marcus, M.D.,

Robert McQuade, Ph.D., Robert A. Forbes, Ph.D., Raymond Mankoski, M.D.

Objective: In adults with chronic schizophrenia, most symptom decreases occur in the firstfew weeks of antipsychotic treatment, and nonresponse at week 2 predicts a later nonre-sponse. The trajectory of antipsychotic response and the predictive value of early anti-psychotic effects were investigated for ultimate outcome in adolescent schizophrenia, where

such data are still lacking. Method: This post hoc analysis of a 6-week, randomized,double-blinded trial of aripiprazole (n 196) versus placebo (n 98) evaluated if adolescents13 to 17 years old with schizophrenia exhibited substantial symptomatic improvement toaripiprazole in the first few treatment weeks and whether early response (ER) versus earlynonresponse (ENR) predicted clinically relevant outcomes. ER decreased at least 20% and ENRdecreased less than 20% in Positive and Negative Syndrome Scale (PANSS) total score at week2 (ER2/ENR2) or 3 (ER3/ENR3). Ultimate response decreased at least 40% in PANSSscore. Results: Nearly 50% of the PANSS decrease was achieved by week 2 and up to 75% byweek 3. ER2/ER3 subjects showed significantly greater improvement than ENR subjects inPANSS total score, PANSS positive and negative subscale scores, and functionally relevantoutcomes. In general, ER3 had better sensitivity, specificity, and positive and negativepredictive values than ER2 for predicting ultimate response. ER2 subjects were 8.8 times (95%confidence interval 4.019.4) and ER3 subjects were 8.6 times (95% confidence interval 4.516.6)more likely to achieve remission at week 6 (p < .0001) than ENR2 and ENR3 subjects,

respectively, although adverse events were similar. Conclusions: Like adults with chronicschizophrenia, adolescents with early-phase schizophrenia exhibited most symptomaticimprovement early during aripiprazole treatment, with week 3 improvements having the

best predictive power. Although requiring extension, these results may inform clinical de-cision making. Clinical trial registration informationAripiprazole in Adolescents withSchizophrenia, http://clinicaltrials.gov/, NCT00102063. J. Am. Acad. Child Adolesc. Psychiatry,2013;52(7):689698. Key Words: adolescent schizophrenia, antipsychotics, early response,remission, response prediction

A

bout one third of subjects with schizo-phrenia develop their first symptomsbefore reaching adulthood, with onset

of symptoms during adolescence being rela-tively common.1 Most affected individuals havesubstantial lifelong impairment and more than

50% require continuous support, whether livingin the community or in institutions.2 In addition,adolescent-onset schizophrenia is associated

with greater functional impairments than adult-onset schizophrenia.3,4 For these reasons, earlyrecognition and interventions are particularlyimportant.5

Antipsychotics are the mainstay of schizo-phrenia treatment, and their initiation should aimto balance efficacy, tolerability, and acceptability2

to minimize the risk of exposure to ineffectivetreatments and the occurrence of unnecessary orunacceptable adverse effects. Furthermore, earlyprediction of response to a given antipsychotic is

This article is discussed in an editorial by Dr. Linmarie Sikich onpage 677.

Clinical guidance is available at the end of this article.

Supplemental material cited in this article is available online.

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important,6,7 because long-term treatment is fun-damental to the management of schizophreniasymptoms, and time spent on ineffective treat-ment should be minimized. Recent evidence hasshown that in adults with chronic schizophrenia,

less than minimal treatment response at weeks 1to 3 predicts an ultimate nonresponse at studyendpoint with high predictive validity.8-15

Therefore, identifying adolescents with schizo-phrenia who may not respond to and/or remit ona chosen treatment could be a powerful tool thatenables clinicians to formulate treatment regi-mens that shorten the exposure to ineffectiveagents and that increase the likelihood ofachieving optimal symptomatic remission.

Clinical decision making usually tries tobalance efficacy and tolerability. Atypical anti-psychotics have been favored in the treatmentof adolescents with psychotic disorders,16 be-cause in adults and adolescents they are at leastas efficacious as typical antipsychotics3,16-20 andare associated with a decreased risk of devel-oping extrapyramidal symptoms (EPSs), adverseeffects to which pediatric subjects are particu-larly vulnerable.1,18,21-23 However, atypical anti-psychotics have been associated with differentdegrees of weight gain and metabolic abnor-malities, and pediatric subjects also seem to beparticularly vulnerable to these effects.20-22,24,25

Such safety concerns with atypical antipsy-

chotics have been highlighted through findingsfrom the Treatment of Early-Onset Schizo-phrenia Spectrum Disorders (TEOSS) study,20

although during maintenance treatment differ-ences to typical antipsychotics became lesspronounced.26 The decreased incidence of EPSsobserved with atypical antipsychotics as a classhas been associated with their binding affinityto dopamine-2 and their antagonist activity atserotonin-2A receptors. In addition, weight gainand metabolic abnormalities have been attrib-uted to several receptor systems, including theserotonin-2C, dopamine-2, and histaminer-

gic and cholinergic receptors.25,27 However, thereceptor-binding affinity varies among antipsy-chotics,28-30 which is likely the reason for differ-ences in adverse-effect profiles that have beensuggested as the main guiding principle formaking a treatment choice in the absence ofgeneral efficacy differences among most anti-psychotics in adults30,31 and in youths.21 Never-theless, in the event that early nonresponse(ENR) to a specific agent and in a given patient issufficiently predictive of ultimate nonresponse,

this individual response pattern can be used tomore precisely balance observed efficacy withtolerability effects.

Aripiprazole is a partial agonist of dopamine-2,dopamine-3, and serotonin-2A receptors.32-35

Together with olanzapine, paliperidone, quetia-pine, and risperidone, aripiprazole is approved bythe U.S. Food and Drug Administration for thetreatment of adolescents with schizophrenia.16,36

Although these agents have each demonstratedefficacy in at least one placebo-controlled trial,more information is needed to help refine thetreatment decision process to identify adolescentswith schizophrenia who may not respond and/orremit on a chosen treatment to shorten their ex-posure to ineffective agents and to increase thelikelihood of achieving optimal symptomaticremission. Therefore, the objective of the presentanalysis was to assess if, analogous to observa-tions in adults with chronic schizophrenia,adolescents receiving aripiprazole for the treat-ment of schizophrenia exhibit symptomatic de-creases early during treatment and whether earlyresponse (ER) versus ENR (at week 2 or 3 oftreatment) is a useful marker to predict relevantclinical outcomes at a later time point. To theauthors knowledge, this is the first such analysisfor any antipsychotic to be published on an ado-lescent population.

METHODStudy Design and SubjectsThis was a post hoc analysis of data from a phaseIII, multinational, multicenter, 6-week, randomized,double-blinded, placebo-controlled, fixed-dose trialinvestigating the efficacy of aripiprazole (10 or 30 mg)in adolescents with schizophrenia. Full details of thestudy design and inclusion and exclusion criteria have

been published previously.37

In brief, eligible subjects were adolescents 13 to17 years old with an Axis I primary diagnosis ofschizophrenia (DSM-IV).38 The diagnosis was con-firmed by a child psychiatrist at the time of screening,

using the Schedule for Affective Disorders andSchizophrenia for School-Age ChildrenPresent andLifetime Version,39 and subjects were required to havea baseline Positive and Negative Syndrome Scale(PANSS)40 total score of at least 70. Exclusion criteriaincluded a history or current diagnosis of mentalretardation, major depressive episodes, and schizo-affective disorder. Subjects also were excluded if 2previous trials of different antipsychotics had failed.

Prohibited medications, including mood stabilizers,antidepressants, and other psychotropics, were dis-continued at least 3 days before initiating treatment.

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Subjects were permitted to receive rescue medications(benzodiazepine or anticholinergic medications) dur-ing the study for relief of transient symptoms.

Written informed consent was obtained from allsubjects guardians or legal representatives and writtenassent was obtained from each adolescent subject. Theprotocol, procedures, consent, and assent statementswere approved by the institutional review board orethics committee of each participating center.

Efficacy AssessmentsThe primary efficacy endpoint was mean change from

baseline to week 6 (last observation carried forward[LOCF]) in the PANSS total score. Other efficacyoutcome measurements included the PANSS positiveand negative subscales, Clinical Global ImpressionsImprovement (CGI-I) scale, CGISeverity scale(CGI-S),41 Childrens Global Assessment Scale,42

and the Pediatric Quality of Life Enjoyment and

Satisfaction Scale.43

Safety AssessmentsSafety outcomes included frequency of adverse eventsand changes in weight and metabolic measurements.Drug-related movement disorders were assessed withthe Simpson-Angus Scale,44 the Barnes AkathisiaRating Scale,45 and the Abnormal Involuntary Move-ment Scale46 at every study week.

Statistical AnalysisThe focus of this study was to characterize and predictthe trajectory of treatment response to aripiprazole in

adolescents with schizophrenia. For the time course ofsymptomatic improvement, analyses were performedseparately for the 10-mg and the 30-mg arms becausethe time course of separation from placebo in the 2arms was different in the original study.37 However,

because the results of the predictive value of ERversus ENR were similar for the 10-mg and 30-mgdose arms, the 2 doses were combined in the anal-yses to lessen the complexity of the presented data.Although this was a placebo-controlled trial, as inprior analyses of adult studies, this report focuses onthe antipsychotic response pattern to inform treatmentdecisions.

For the purpose of this post hoc analysis, ER was

defined as a decrease of at least 20% in PANSS totalscore at study week 2 (ER2) or study week 3 (ER3).ENR was defined as a decrease less than 20% in PANSStotal score at study week 2 (ENR2) or study week 3(ENR3). Ultimate response (UR) was defined asa decrease in PANSS total score at study endpoint(week 6, LOCF) of at least 20% (UR20), at least 30%(UR30), or at least 40% (UR40). These cutoffs were used

because they had been used in prior studies, andbecause a decrease of at least 20% in the PANSS totalscore correlates roughly with minimally improvedon the CGI-I, whereas a decrease of at least 40% to 50%

corresponds to much improved on the CGI-I.47

Remission was defined cross-sectionally as a score ofno higher than 3 (mild or less) on the following 8PANSS items at the end of the study (LOCF afterweek 2 assessment), using the remission criteria byAndreasen et al.48: P1 (delusions), P2 (conceptualdisorganization), P3 (hallucinatory behavior), G9 (un-usual thought content), G5 (mannerisms/posturing),N1 (blunted affect), N4 (social withdrawal), and N6(lack of spontaneity/flow of conversation). For com-parisons with prior studies on this topic, the percent-ages of decrease in the total PANSS score usinguncorrected PANSS scores, i.e., without subtraction ofthe 30 points representing absent symptoms, werecalculated.

The ER and ENR groups were compared usingdescriptive statistics for patient demographics and

baseline characteristics and mixed models repeatedmeasures analyses to compare the ER and ENR groups

on the PANSS total, positive, and negative scores,CGI-S, CGI-I, Pediatric Quality of Life Enjoymentand Satisfaction Scale scores, and Childrens GlobalAssessment Scale scores. Odds ratios were calculat-ed for comparisons of endpoint response status(!20%, !30%, !40%, and !50% decreases in PANSStotal score) and cross-sectional remission at LOCFstudy endpoint beyond week 2 for the ER2 versusENR2 and the ER3 versus ENR3 groups.

Sensitivity, specificity, positive predictive value(PPV), and negative predictive value (NPV) wereevaluated to determine the accuracy of ER/ENR2 andER/ENR3 in predicting different levels of UR at week6 (LOCF) and to determine the accuracy of predicting

remission for the ER2 and ER3 groups.Moreover, receiver operating characteristic (ROC)

curves for ERs at weeks 2 and 3 with respect to de-crease in PANSS total score (predicting !20%, !30%,or !40% or at week 6) were calculated to determine thePANSS total score threshold at weeks 2 and 3 with the

best predictive power for UR at week 6.

RESULTSIn total, 302 adolescents with schizophrenia(1317 years old) participated in this 6-week,randomized, double-blinded, placebo-controlledtrial of aripiprazole versus placebo. Relevant data

were available for 196 subjects who received ari-piprazole 10 mg (n 99) or 30 mg (n 97) andhad a baseline PANSS total score of 94.0 and95.0, respectively. Overall, 32.7% (n 64) ach-ieved ER status at week 2, and 48.9% (n 96)achieved ER status at week 3. Baseline patientand illness characteristics of subjects with ER2/ENR2 and ER3/ENR3 to aripiprazole treatmentwere similar (Table 1).

Patient disposition has been described indetail previously.37 Overall, 83% of aripiprazole-

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treated subjects completed the study. The mainreasons for discontinuation for subjects receiv-ing aripiprazole were withdrawal of consent(4.0% and 11.8% for the 10-mg and 30-mg arms,respectively), adverse events (7.0% and 3.9%,respectively), and lack of efficacy (5.0% and1.0%, respectively).

Efficacy OutcomesSymptom decrease was greatest in the first 2 to 3weeks of treatment. By week 1, subjects in the

10-mg arm had attained 24% of the decrease thatthey ultimately achieved in their PANSS totalscore at week 6. These subjects attained decreasesof 51% by week 2 and 68% by week 3. Subjects inthe 30-mg arm exhibited 33% of their overalldecrease at week 1, a decrease of 49% by week 2,and a decrease of 75% by week 3. In the 2 arms,after week 3, incremental gains were less than15% for each subsequent week (Figure 1).

The decrease in PANSS total score was signif-icantly greater for ER2 versus ENR2 subjects from

week 1 to week 6 at each time point (Figure 2a).At week 6, PANSS total score changes were 41.6versus 22.0 (p < .0001; Table 2). Results weresimilar when using week 3 to determine ER status(Figure 2b), with endpoint decreases of 40.6versus 16.5 (p < .0001) for ER3 versus ENR3subjects, respectively (Table 2). Similar findingswere observed across each time point from week1 to week 6 for PANSS positive subscale scores(Figure S1, available online). Except for PediatricQuality of Life Enjoyment and Satisfaction Scale

overall score in the ER/ENR2 groups, all otherrelevant measurements of efficacy similarlydemonstrated highly statistically significant andclinically meaningful differences favoring ERversus ENR subjects (Table 2).

For subjects with an ER2, proportionsachieving UR at week 6 were 95.3% for UR20,82.8% for UR30, and 67.2% for UR40. For subjectswith an ER3, proportions achieving UR at week6 were 97.9%, 82.3%, and 61.5% for UR20,UR30, and UR40, respectively. UR rates were

TABLE 1 Baseline Demographic and Psychiatric Characteristics of Subjects With an Early Response Versus EarlyNonresponse at Study Week 2 or 3

Week 2 Week 3Aripiprazole Aripiprazole

(N 196) (N 196)

Early Nonresponder Early Responder Early Nonresponder Early Responder(n 132) (n 64) (n 100) (n 96)

Age (y), mean (SD) 15.5 (1.3) 15.5 (1.4) 15.5 (1.2) 15.4 (1.5)Race, n (%)

Caucasian 78 (59.0) 34 (53.1) 65 (65.0) 47 (48.9)Black/African American 20 (15.2) 8 (12.5) 13 (13.0) 15 (15.6)Asian 16 (12.1) 12 (18.8) 10 (10.0) 18 (18.8)Other 18 (13.6) 10 (15.6) 12 (12.0) 16 (16.7)

Ethnicity, n (%)Non-Hispanic/Latino 114 (86.4) 55 (85.9) 87 (87.0) 82 (85.4)

Weight (kg), mean (SD) 62.8 (15.7) 66.1 (20.9) 62.3 (14.4) 65.6 (20.4)BMI (kg/m2), mean (SD) 22.8 (4.7) 24.0 (6.7) 22.6 (4.6) 23.9 (6.2)Psychiatric characteristics

Disease duration (y), mean (SD) 1.3 (1.9) 1.5 (2.1) 1.5 (2.1) 1.3 (1.8)Age at onset (y), mean (SD) 14.2 (2.2) 14.1 (2.6) 14.1 (2.3) 14.2 (2.3)Onset before age 13 years, n (%) 19 (14.4) 11 (17.2) 15 (15.0) 15 (15.6)On any psychotropic treatment before

study entry, n (%)96 (72.7) 49 (76.6) 74 (74.0) 71 (74.0)

Used antipsychotic before studyentry, n (%)

61 (46.2) 37 (57.8) 41 (41.0) 57 (59.4)

PANSS total, mean (SD) 94.3 (15.6) 94.4 (15.8) 93.4 (15.9) 95.3 (15.3)PANSS positive, mean (SD) 22.8 (5.1) 22.8 (4.9) 22.9 (5.4) 22.7 (4.6)PANSS negative, mean (SD) 25.1 (6.6) 25.3 (6.2) 24.7 (6.0) 25.6 (7.0)CGI-S, mean (SD) 4.5 (0.7) 4.5 (0.8) 4.5 (0.7) 4.5 (0.7)

Note: Subjects with an early response showed a decrease of at least 20% from baseline to endpoint (last observation carried forward) in Positive and

Negative Syndrome Scale (PANSS) total score. BMI body mass index; CGI-S Clinical Global ImpressioneSeverity.

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significantly higher for ER than for ENR subjectsat each level of UR and for the 2 ER time points(Table 2).

Remission at study endpoint was achieved by55.6% (n 109/196) of subjects receiving aripi-prazole, 53.5% (n 53/99) in the 10-mg arm, and57.7% (n 56/97) in the 30-mg arm. ER2 subjectshad significantly higher rates of remission thanENR2 subjects (86.0% versus 41.0%; p < .0001).The same was true for ER3 versus ENR3 subjects

(80.0% versus 32.0%; p2-week) antipsychotic treatment in adolescentswith schizophrenia. Future studies with otherantipsychotics in youth with schizophrenia areneeded to better characterize the predictive valueof ER/ENR to antipsychotics in youth withearly-onset schizophrenia. &

Accepted May 1, 2013.

Dr. Correll is with the Zucker Hillside Hospital, Hofstra North ShoreLong Island Jewish School of Medicine, and Albert Einstein College ofMedicine. Drs. Zhao, Carson, McQuade, and Forbes are with OtsukaPharmaceutical Development and Commercialization. Dr. Marcus iswith Bristol-Myers Squibb. Dr. Mankoski is with Genzyme.

This study was supported by Bristol-Myers Squibb and Otsuka Phar-maceutical Co., Ltd.

Editorial support for the preparation of this manuscript was provided byOgilvy Healthworld Medical Education; funding was provided byBristol-Myers Squibb. The authors thank the participants and theirfamilies for their involvement in this study.

Disclosure: Dr. Correll has received grant or research support from theNational Institute of Mental Health, Bristol-Myers Squibb/Otsuka, theFeinstein Institute for Medical Research, Janssen/Johnson and Johnson,and the National Alliance for Research in Schizophrenia andDepression. He has served as a consultant to Actelion, Alexza, theAmerican Academy of Child and Adolescent Psychiatry, AstraZeneca,Bristol-Myers Squibb, Eli Lilly and Co., Genentech, the Gerson LehrmanGroup, IntraCellular Therapies, Lundbeck, Medavante, Medscape,Merck, National Institute of Mental Health, Janssen/Johnson and

Johnson, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva,

and Vanda. He has served on the speakers

bureau of Merck (non-promotional lectures only). He owns stock in Alexza. He has partici-pated in Continuing Medical Education article preparation forMedscape. He is a member of the Data Safety Monitoring Boardsfor Cephalon, Janssen/Johnson and Johnson, Lundbeck, Pfizer,Takeda, and Teva. Dr. Forbes is a former employee of Genentech.Dr. Mankoski is a former employee and stockholder of Bristol-MyersSquibb. Drs. Zhao, Carson, Marcus, and McQuade report nobiomedical financial interests or potential conflicts of interest.

Correspondence to Christoph U. Correll, M.D., Division of PsychiatryResearch, The Zucker Hillside Hospital, Glen Oaks, NY 11004;e-mail: [email protected]

0890-8567/$36.00/2013 American Academy of Child andAdolescent Psychiatry

http://dx.doi.org/10.1016/j.jaac.2013.04.018

REFERENCES1. Young CM, Findling RL. Pharmacologic treatment of adolescent

and child schizophrenia. Expert Rev Neurotherapeut. 2004;4:53-60.

2. Mattai AK, Hill JL, Lenroot RK. Treatment of early-onset schizo-phrenia. Curr Opin Psychiatry. 2010;23:304-310.

3. Sikich L. Efficacy of atypical antipsychotics in early-onset schizo-phrenia and other psychotic disorders. J Clin Psychiatry. 2008;69(suppl 4):21-25.

4. American Academy of Child and Adolescent Psychiatry. Practiceparameter for the assessment and treatment of children andadolescents with schizophrenia. J Am Acad Child AdolescPsychiatry. In press.

5. Bodnar M, Malla A, Joober R, Lepage M. Cognitive markers ofshort-term clinical outcome in first-episode psychosis. Br

J Psychiatry. 2008;19 3:297-304.6. Salimi K, Jarskog LF, Lieberman JA. Antipsychotic drugs for first-

episode schizophrenia: a comparative review. CNS Drugs. 2009;23:837-855.

7. Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onsethypothesis of antipsychotic action: a hypothesis tested and rejec-ted. Arch Gen Psychiatry. 2003;60:1228-1235.

8. Kinon BJ, Chen L, Ascher-Svanum H, et al. Predicting response toatypical antipsychotics based on early response in the treatment ofschizophrenia. Schizophr Res. 2008;102:230-240.

9. Correll CU, Malhotra AK, Kaushik S, McMeniman M, Kane JM.Early prediction of antipsychotic response in schizophrenia. Am

J Psychiatry. 2003;16 0:2063-2065.10. Leucht S, Busch R, Hamann J, Kissling W, Kane J. Early-onset

hypothesis of antipsychotic drug action: a hypothesis tested,confirmed and extended. Biol Psychiatry. 2005;57:1543-1549.

Clinical Guidance

In youth with multiepisode schizophrenia who haveless than minimal improvement despite a 3-week trialwith an adequately dosed antipsychotic agent withconfirmed adherence (e.g., supervised medicationingestion), a switch to another antipsychotic shouldbe considered, unless clear triggers for the psychosis(such as environmental, substances, [partial] non-adherence) exist that should be addressed first.

This suggested guidance for youth withschizophrenia is currently based on 1 aripiprazoletrial and needs to be considered in the context ofrecent American Academy of Child and AdolescentPsychiatry guidelines, which state that a 6-week trialof an adequately dosed antipsychotic should beconducted before switching to a different antipsy-chotic agent.4

Dosing/titration schedules need to be factored intothe timing of declaring whether a patient is an earlyresponder or nonresponder.

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mailto:[email protected]://dx.doi.org/10.1016/j.jaac.2013.04.018http://www.jaacap.org/http://www.jaacap.org/http://dx.doi.org/10.1016/j.jaac.2013.04.018mailto:[email protected]


10/13

11. Leucht S, Busch R, Kissling W, Kane JM. Early prediction ofantipsychotic nonresponse among patients with schizophrenia.

J Clin Psychiatry. 2007;68:352-360.12. Kinon BJ, Chen L, Ascher-Svanum H, et al. Early response

to antipsychotic drug therapy as a clinical marker of subse-quent response in the treatment of schizophrenia. Neuro-psychopharmacology. 2010;35:581-590.

13. Chang YC, Lane HY, Yang KH, Huang CL. Optimizing earlyprediction for antipsychotic response in schizophrenia. J ClinPsychopharmacol. 2006;26:554-559.

14. Ascher-Svanum H, Nyhuis AW, Faries DE, Kinon BJ, Baker RW,Shekhar A. Clinical, functional, and economic ramifications ofearly nonresponse to antipsychotics in the naturalistic treatment ofschizophrenia. Schizophr Bull. 2008;34:1163-1171.

15. Lin C, Chou L, Lin C, Hsu C, Chen Y, Lane HY. Earlyprediction of clinical response in schizophrenia patients re-ceiving the atypical antipsychotic zotepine. J Clin Psychiatry.2007;68:1522-1527.

16. Correll CU, Kratochvil CJ, March JS. Developments in pediatricpsychopharmacology: focus on stimulants, antidepressants, andantipsychotics. J Clin Psychiatry. 2011;72:655-670.

17. Fraguas D, Correll CU,Merchan-Naranjo J, et al. Efficacy andsafetyof second-generation antipsychotics in children and adolescentswith psychotic and bipolar spectrum disorders: comprehensivereview of prospective head-to-head and placebo-controlled com-

parisons. Eur Neuropsychopharmacol. 2011;21:621-645.18. Kumra S, Oberstar JV, Sikich L, et al. Efficacy and tolerability of

second-generation antipsychotics in children and adolescents withschizophrenia. Schizophr Bull. 2008;34:60-71.

19. Sikich L, Hamer RM, Bashford RA, Sheitman BB, Lieberman JA.A pilot study of risperidone, olanzapine, and haloperidol inpsychotic youth: a double-blind, randomized, 8-week trial. Neu-ropsychopharmacology. 2004;29:133-145.

20. Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison offirst- and second-generation antipsychotics in early-onset schizo-phrenia and schizo-affective disorder: findings from the Treatmentof Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study.Am J Psychiatry. 2008;165:1420-1431.

21. Correll CU. Antipsychotic use in children and adolescents: mini-mizing adverse effects to maximize outcomes. J Am Acad ChildAdolesc Psychiatry. 2008;47:9-20.

22. Correll CU. Assessing and maximizing the safety and tolerabilityof antipsychotics used in the treatment of children and adoles-

cents. J Clin Psychiatry. 2008;69(suppl 4):26-36.23. Correll CU, Kane JM. One-year incidence rates of tardive dyski-

nesia in children and adolescents treated with second-generationantipsychotics: a systematic review. J Child Adolesc Psycho-pharmacol. 2007;17:647-656.

24. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM,Malhotra AK. Cardiometabolic risk of second-generation anti-psychotic medications during first-time use in children andadolescents. JAMA. 2009;302:1765-1773.

25. De Hert M, Dobbelaere M, Sheridan EM, Cohen D, Correll CU.Metabolic and endocrine adverse effects of second-generationantipsychotics in children and adolescents: a systematic reviewof randomized, placebo controlled trials and guidelines for clinicalpractice. Eur Psychiatry. 2011;26:144-158.

26. Findling RL, Johnson JL, McClellan J, et al. Double-blind mainte-nance safety and effectiveness findings from the Treatment ofEarly-Onset Schizophrenia Spectrum (TEOSS) study. J Am AcadChild Adolesc Psychiatry. 2010;49:583-594; quiz 632.

27. Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs andobesity. Trends Mol Med. 2011;17:97-107.

28. Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone:receptor-binding properties and real-world psychiatric practice.

J Clin Psychiatry. 2003;64(suppl 19):6-12.29. Farah A. Atypicality of atypical antipsychotics. Prim Care

Companion J Clin Psychiatry. 2005;7:268-274.30. Correll CU. From receptor pharmacology to improved outcomes:

individualising the selection, dosing, and switching of antipsy-chotics. Eur Psychiatry. 2010;25(suppl 2):S12-S21.

31. KaneJM, CorrellCU. Past andpresent progress in thepharmacologictreatment of schizophrenia. J Clin Psychiatry. 2010;71:1115-1124.

32. Burris KD, Molski TF, Xu C, et al. Aripiprazole, a novel antipsy-chotic, is a high-affinity partial agonist at human dopamine D2receptors. J Pharmacol Exp Ther. 2002;302:381-389.

33. Tadori Y, Forbes RA, McQuade RD, Kikuchi T. Characterization ofaripiprazole partial agonist activity at human dopamine D

receptors. Eur J Pharmacol. 2008;597:27-33.34. Jordan S, Koprivica V, Dunn R, Tottori K, Kikuchi T, Altar CA.In vivo effects of aripiprazole on cortical and striatal dopami-nergic and serotonergic function. Eur J Pharmacol. 2004;483:45-53.

35. Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA. Theantipsychotic aripiprazole is a potent, partial agonist at the human5-HT(1A) receptor. Eur J Pharmacol. 2002;441:137-140.

36. Kuehn BM. FDA panel OKs 3 antipsychotic drugs for pediatricuse, cautions against overuse. JAMA. 2009;302:833-834.

37. Findling RL, Robb A, Nyilas M, et a l. A multiple-center,randomized, double-blind, placebo-controlled study of oral ari-piprazole for treatment of adolescents with schizophrenia. Am JPsychiatry. 2008;165:1432-1441.

38. American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders. 4th ed, text rev. Washington, DC:American Psychiatric Publishing; 2000.

39. Kaufman J, Birmaher B, Brent D, et al. Schedule for AffectiveDisorders and Schizophrenia for School-Age Children-Present and

Lifetime Version (K-SADS-PL): initial reliability and validity data.J Am Acad Child Adolesc Psychiatry. 1997 ;36:980-988.

40. Kay SR, Opler LA, Lindenmayer JP. Reliability and validity of thepositive and negative syndrome scale for schizophrenics. Psychi-atry Res. 1988;23:99-110.

41. Guy W. Clinical Global Impressions (CGI). ECDEU AssessmentManual for Psychopharmacology. US Department of Health,Education, and Welfare Publication (ADM) 76-338. Rockville, MD:National Institute of Mental Health; 1976; 218-222.

42. Shaffer D, Gould MS, Brasic J, et al. A Childrens Global Assess-ment Scale (CGAS). Arch Gen Psychiatry. 1983;40:1228-1231.

43. Endicott J, Nee J, Yang R, Wohlberg C. Pediatric Quality of LifeEnjoyment and Satisfaction Questionnaire (PQ-LES-Q): reliabilityand validity. J Am Acad ChildAdolesc Psychiatry.2006;45:401-407.

44. Simpson GM, Angus JW. A rating scale for extrapyramidal sideeffects. Acta Psychiatr Scand Suppl. 1970;212:11-19.

45. Barnes TR. A rating scale for drug-induced akathisia. Br JPsychiatry. 1989;154:672-676.

46. Guy W. Abnormal Involuntary Movement Scale (AIMS). USDepartment of Health Education and Welfare. ECDEU Assess-ment Manual for Psychopharmacology. Rockville, MD: NationalInstitute of Mental Health; 1976; 534-537.

47. Leucht S, Kane JM, Etschel E, Kissling W, Hamann J, Engel RR.Linking the PANSS, BPRS, and CGI: clinical implications. Neu-ropsychopharmacology. 2006;31:2318-2325.

48. Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR,Weinberger DR. Remission in schizophrenia: proposed criteriaand rationale for consensus. Am J Psychiatry. 2005;162:441-449.

49. Schimmelmann BG, Schmidt SJ, Carbon M, Correll CU. ARational, Evidence Informed Approach to Psychopharmacologyfor Adolescents with Early Onset, First Episode Psychoses. CurrOpin Psychiatry. 2013;26:219-230.

50. Gallego JA, Robinson DG, Sevy SM, et al. Time to treatmentresponse in first-episode schizophrenia: should acute treatmenttrials last several months? J Clin Psychiatry. 2011;72:1691-1696.

51. Derks EM, Fleischhacker WW, Boter H, Peuskens J, Kahn RS.Antipsychotic drug treatment in first-episode psychosis: shouldpatients be switched to a different antipsychotic drug after 2, 4, or6 weeks of nonresponse? J Clin Psychopharmacol. 2010;30:176-180.

52. Emsley R, Rabinowitz J, Medori R. Time course for antipsychotictreatment response in first-episode schizophrenia. Am J Psychi-atry. 2006;163:743-745.

53. Emsley R, Oosthuizen PP, Kidd M, Koen L, Niehaus DJ,Turner HJ. Remission in first-episode psychosis: predictor vari-ables and symptom improvement patterns. J Clin Psychiatry. 2006;67:1707-1712.

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FIGURE S1 Mean change from baseline to endpoint in Positive and Negative Syndrome Scale (PANSS) positivesubscale scores for subjects receiving aripiprazole treatment exhibiting (a) early response at week 2 (ER2) versus earlynonresponse at week 2 (ENR2) and (b) ER3 versus ENR3 by study week. Note: p< .0001 at each time point. Meanbaseline PANSS positive subscale scores for ER2 (aripiprazole): 22.8; ENR2 (aripiprazole): 22.8; ER3 (aripiprazole):22.7; ENR3 (aripiprazole): 22.9.

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FIGURE S2 Percentage of receiver operating characteristic curve results for early response (ER) to aripiprazole atweeks 2 and 3 predicting decreases of at least 20%, 30%, and/or 40% Positive and Negative Syndrome Scale (PANSS)total score at endpoint (week 6). Note: The distance between the red points and the perfect predictor points (0% on x axisand 100% on y axis) are very short, indicating that a decrease of at least 20% in PANSS total score carries goodpredictive capability for ultimate response similar to the exact optimal point.

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TABLE S1 Safety and Tolerability by Week for Subjects Achieving an Early Response Versus Early Nonresponse at Week2 or an Early Response Versus Early Nonresponse at Week 3

Week 2, n (%) Week 3, n (%)

ENR2 ER2 ENR3 ER3

(n

132) (n

64) (n

100) (n

96)Akathisia 13 (10) 4 (6) 10 (10) 7 (7)Restlessness 14 (11) 4 (6) 11 (11) 7 (7)Insomnia 17 (13) 6 (9) 13 (13) 10 (10)Nausea, vomiting 19 (14) 5 (8) 12 (12) 12 (13)Parkinsonian eventa 28 (21) 19 (30) 18 (18) 29 (30)Somnolence, sedation 22 (17) 12 (19) 16 (16) 18 (19)Weight gain !7% 6 (5) 3 (5) 5 (5) 4 (4)Weight change (kg) 0.2 0.0 0.3 0.1Mean change from baselineb

SAS 0.3 0.2 0.2 0.3BARS 0.1 0.0 0.1 0.0AIMS 0.2 0.2 0.1 0.2

Note: AIMS

Abnormal Involuntary Movement Scale; BARS

Barnes Akathisia Rating Scale; ER2

early response at week 2; ER3

early response atweek 3; ENR2 early nonresponse at week 2; ENR3 early nonresponse at week 3; SAS Simpson-Angus Scale.aParkinsonism event includes extrapyramidal disorder and tremor.bLast observation carried forward results.

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Early Antipsychotic Response to Aripiprazole in Adolescents With Schizophrenia