Effectiveness of aripiprazole in adolescents and young adults with schizophrenia spectrum disorders:...

Brief Report

Effectiveness of aripiprazole in adolescents andyoung adults with schizophrenia spectrumdisorders: comparison of first-episode to

recurrent psychosisYu-Shu Huang,1,2 Chin-Bin Yeh,3 Ching-Shu Tang,4 Chih-Ken Chen,2,5 Wen-Jiun Chou,2,4

Miao-Chun Chou,2,4 Yu-Yu Wu,1,2 Shing-Yi Liang1,2 and Liang-Jen Wang2,5

1Department of Child Psychiatry andSleep Center, Chang Gung MemorialHospital, 2School of Medicine, ChangGung University, Taoyuan, 3Departmentof Psychiatry, Division of Child andAdolescent Psychiatry, Tri-Service GeneralHospital, National Defense MedicalCenter, Taipei, 4Department of Child andAdolescent Psychiatry, Chang GungMemorial Hospital – Kaohsiung MedicalCenter, Chang Gung University College ofMedicine, Kaohsiung, and 5Departmentof Psychiatry, Chang Gung MemorialHospital at Keelung, Keelung, Taiwan

Corresponding author: Dr Liang-JenWang, Department of Psychiatry, ChangGung Memorial Hospital at Keelung,No.200 Avenue 208 Ji-Jin 1st Raod,Keelung 204, Taiwan. Email:wangliangjen@gmail.com

Received 8 June 2011; accepted 7 April2012

Abstract

Aims: The study aims to determinethe clinical outcomes of aripiprazoletreatment in adolescents and youngadults with schizophrenia spectrumdisorders.

Methods: This was a 24-week, obser-vational, prospective study. Patientswith schizophrenia spectrum disor-ders were prescribed a daily dose of5 mg to 30 mg of aripiprazole. Effec-tiveness was assessed by the changefrom baseline in psychotic symptomsand quality of life.

Results: Forty-two patients with amean age of 18.1 � 3.7 years were

recruited. Eighteen were experiencingthe first episode of psychosis (FEP),whereas the remaining 24 were non-FEP. Psychotic symptoms, but notquality of life, improved globally frombaseline scores by the endpoint of thestudy (effect size = 0.44). Comparedwith non-FEP patients, FEP patientshad greater improvements (effectsize = 0.45) in some clinical outcomedimensions during the 24-weekaripiprazole treatment.

Conclusion: We observed significantimprovements of medium effect sizesin psychotic symptoms of patientswith schizophrenia spectrum disor-ders within a naturalistic clinicalsetting, especially for FEP patients.

Key words: adolescent, antipsychotic, early intervention, effectiveness,first-episode psychosis.

INTRODUCTION

Patients with early-onset psychosis exhibit a chroniccourse of illness and severe functional impair-ments.1 Patients in a first episode of psychosis (FEP)demonstrated higher relative rates of therapeuticresponse and symptom remission with treatment,compared with patients with multiple prior epi-sodes.2 Therefore, FEP represents a critical stageof illness during which the effectiveness of thera-peutic interventions can affect patients’ long-termoutcomes.3

Aripiprazole is a new antipsychotic agent with aunique pharmacological profile that works as apartial agonist at the dopamine D2 and serotonin5-HT1A receptor, and as an antagonist at the

serotonin 5-HT2A receptor.4 Nowadays, aripiprazolehas been demonstrated to be effective for child andadolescent patients with psychotic disorders,5 andfor FEP patients.6–9 Nevertheless, there is as yet nopublished study that investigates the differencesin effectiveness between patients with FEP andpatients with recurrent psychosis, particularly inadolescent and young adult patients.

Thus, this study aimed at surveying the clinicaloutcomes of aripiprazole treatment in adolescentsand young adults with schizophrenia spectrumdisorders, including their psychotic symptomsand quality of life. In addition, we investigated thepossible influences on these clinical outcomes bycomparing patients with FEP with those withrecurrent psychosis.

Early Intervention in Psychiatry 2012; ••: ••–•• doi:10.1111/j.1751-7893.2012.00379.x

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METHODS

Participants

Eligible patients with schizophrenia spectrum dis-orders at an outpatient hospital department wereselected for this study if they: (i) were aged between12 and 25 years old; (ii) were diagnosed with schizo-phrenia, schizoaffective disorder or psychotic disor-der not otherwise specified in the Diagnostic andStatistical Manual of Mental Disorders, FourthEdition after being assessed with the Mini Interna-tional Neuropsychiatric Interview10; (iii) had a Clini-cal Global Impression-Severity scale (CGI-S) score�3 at the screening visit; and (iv) were either drugnaïve or have received a previous antipsychotictreatment. The data for this report were obtainedfrom four investigator sites in Taiwan. The study wasconducted in accordance with the local ethics andregulatory requirements for each site. The purposeof the study was adequately explained to all partici-pants, and informed consent was gathered asrequired by local regulations at the start of thisstudy. If the patient’s age was under 18 years, theconsent of their guardians was further required.

Participants were classified into those sufferingfrom FEP or recurrent psychosis (non-FEP). Patientswho met the following criteria were defined as FEP:(i) a period of less than 1 year between the first onsetof psychotic symptoms and study recruitment; and(ii) no history of psychiatric ward admission. Therest of the patients who did not conform to thesecriteria were regarded as non-FEP.

Study design

This was a 24-week, non-randomized, observa-tional, prospective study. The participants were pre-scribed commercially available aripiprazole withinthe dose range of 5 to 30 mg per day. To ensure thatthe study reflected real-life clinical practice, thedosage prescribed was at the discretion of the psy-chiatrists. Concurrent psychotherapy and otherconcomitant antipsychotic drugs were not allowedduring the study period. Follow-up of patientsoccurred at outpatient clinics in various hospitals,and the style of treatment was comparable acrossinvestigator sites.

Outcome measures

Clinical outcome assessments were made at base-line, week 4, week 8, week 12, week 16 and week 24.The primary efficacy assessment was administeredby the psychiatrist during each visit with the CGI-S11

and the Brief Psychiatric Rating Scale (BPRS).12

Moreover, quality of life was assessed using the briefversion of the World Health Organization Quality ofLife Scale (WHOQOL-BREF).13

Statistical analysis

The data were analysed with the statistical softwarepackage SPSS, version 16 (SPSS Inc., Chicago, IL,USA). A two-tailed value of P < 0.05 was consideredstatistically significant. Variables are presented aseither mean � standard deviation or frequency. Thecategorical variables were tested with chi-squaretest or Fisher’s exact test, and the continuous vari-ables were analysed by t-test. In examining the lon-gitudinal data, efficacy analysis was performed onthe basis of the intention-to-treat principle. Missingdata were accounted for by using the last observa-tion carried forward method. Differences betweenthe FEP and non-FEP groups were investigatedusing the linear mixed model analysis to examinethe extent of change in the scores of the outcomemeasures during the 24 weeks. Patients’ gender, age,previous antipsychotic drug treatment and theirduration of illness were set as covariates. An analysisof the effect size was done using the softwarepackage G-Power 3.1 (Heinrich-Heine-Universität,Düsseldorf, Germany), based on the settings of 80%power, P = 0.05 and sample size = 42.

RESULTS

A total of 42 Taiwanese subjects (mean age:18.1 � 3.7 years) with schizophrenia spectrumdisorders were enrolled into the study. Primarydiagnoses included schizophrenia (n = 30),schizoaffective disorder (n = 2) and psychotic disor-der not otherwise specified (n = 10). The meandosage of aripiprazole at the endpoint was8.3 � 4.6 mg day-1. Of the total sample, 18 partici-pants (42.9%) were experiencing their FEP, whereasthe remaining 24 participants (57.1%) had at leastone previous episode of psychosis before theircurrent episode (non-FEP). The sociodemographicdata and symptoms at baseline of the FEP and non-FEP groups are contrasted and summarized inTable 1. Fifteen patients (35.7%) discontinued pre-maturely because of lack of efficacy (n = 4), adverseevents (n = 5), withdrawal of consent (n = 3) or lossof follow-up (n = 3).There were no significant differ-ences between the two groups in the rate of studycompletion or in the average dosage of aripiprazoleat the end of treatment.

Significant improvements, with an effect sizeof 0.44, were observed in the CGI-S (t = 5.38,P < 0.001), BPRS total scores (t = 6.70, P < 0.001),

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BPRS positive symptoms (t = 6.70, P < 0.001), BPRSnegative symptoms (t = 5.48, P < 0.001) and BPRSgeneral symptoms (t = 5.66, P < 0.001) of all partici-pants following aripiprazole treatment for 24 weeks.With regard to quality of life, significant improve-ments in the WHOQOL-BREF were only experi-enced in the domain of psychological health(t = -2.78, P = 0.032), and not in the areas of physicalhealth, social relationships and environment.Figure 1 demonstrates the trend for score changesrelative to baseline in the CGI-S and BPRS scoresbetween FEP and non-FEP patients during the24-week study period. After controlling for patients’gender, age, previous antipsychotic drug treatmentand their duration of illness, significant interactionbetween groups and time, with an effect size of 0.45,was found in the CGI-S (F = 7.41, P = 0.008) and theBPRS general score (F = 5.67, P = 0.022).

DISCUSSION

Patients in our study showed substantial improve-ments of median effect sizes, in global psychoticsymptoms, as observed by the CGI-S and the BPRS,during the 24-week aripiprazole treatment. Thesefindings generally converge with those in previousinternational studies.14,15 Regarding quality of life,significant improvement was only experienced inthe domain of psychological health, as measuredby the WHOQOL-BREF, for all patients in thisstudy. In the past, some researchers have reportedthat patients with psychotic disorders presented

improved quality of life under aripiprazole treat-ment.16,17 However, there were variability acrossthese studies in the time intervals for measure-ments, the population of study and the sample size,which might account in part for the inconsistentresults thus far.

In this study, aripiprazole produced a bettertreatment effect in some outcome dimensionsfor adolescent and young adult patients with FEPcompared with non-FEP patients. Other studiesdemonstrated similar findings,18–20 especially duringthe first year of starting antipsychotic treatment.21

Poorer treatment response in patients with recur-rent psychosis might be associated with putativeneurobiological processes in brain changes duringthe course of illness.22 FEP patients, especially ado-lescents and young adults among the FEP sufferers,might have a critical opportunity to benefit fromearly therapeutic interventions.23

There are some methodological limitations tothis study. First, this was an open-label, non-randomized study, and thus, placebo effects, ratingbias or reporting bias could not be excluded.Second, the classification of FEP or non-FEP in thisstudy was based on the duration between diseaseonset and recruitment into this study. However,schizophrenia spectrum disorders could developinsidiously, and it is sometimes difficult to deter-mine the exact onset of illness. Third, the samplesize of our study was not sufficiently large, whichwas further tempered by a substantial attritionrate. This did reduce the statistical power of ouranalyses. Lastly, the treatment procedure was not

TABLE 1. Sociodemographic and clinical baseline characteristics

Total (n = 42) FEP (n = 18) Non-FEP (n = 24) P value

Gender (male), n (%) 25 (59.5) 10 (55.6) 15 (62.5) 0.650Previous antipsychotic treatment, n (%) 28 (66.7) 7 (38.9) 21 (87.5) 0.002Age (year) 18.1 (3.7) 16.9 (3.5) 18.9 (3.7) 0.086Age of onset of psychotic symptoms (year) 16.2 (3.3) 16.1 (3.7) 16.3 (3.1) 0.887Body mass index 21.9 (0.8) 20.0 (0.9) 23.2 (1.2) 0.055CGI-Severity 4.0 (0.9) 4.2 (0.7) 3.9 (1.0) 0.363BPRS

Total score of 18 items 49.4 (12.8) 47.9 (11.5) 50.5 (13.8) 0.521Positive symptoms 20.6 (6.6) 19.8 (6.1) 21.1 (7.1) 0.538Negative symptoms 13.5 (4.4) 12.4 (3.4) 14.3 (4.9) 0.179General symptoms 15.4 (4.8) 15.7 (5.3) 15.1 (4.5) 0.724

WHOQOL-BREFPhysical health 21.1 (4.8) 22.3 (4.5) 20.2 (4.9) 0.195Psychological health 16.8 (5.0) 16.8 (4.2) 16.8 (5.6) 0.963Social relations 11.9 (2.6) 11.9 (3.1) 11.8 (2.2) 0.955Environment 29.1 (6.3) 28.6 (5.4) 29.4 (7.0) 0.692

Data are given as mean (SD) except where indicated otherwise.BPRS, Brief Psychiatric Ratings Scale; CGI, Clinical Global Impression; FEP, patients with first episode of psychosis; SD, standard deviation; WHOQOL–BREF,the brief version of the World Health Organization Quality of Life Scale.

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standardized, so there was a possible confoundingeffect from varying aripiprazole dosages or con-comitant medications. Furthermore, a portion ofpatients had received a previous antipsychotictreatment, but we did not gather details about whenour participants first received these treatments.Therefore, the duration of untreated psychosis, apotential predictor of the clinical outcomes forpsychosis, could not be identified in this study.

In conclusion, our study showed that aripiprazoleled to clinical improvements, with median effectsizes, in the global psychotic symptoms of adoles-cents and young adults with schizophrenia spec-trum disorders in a naturalistic clinical setting.Patients with FEP had greater benefits from arip-iprazole treatment in some dimensions of clinicaloutcome, compared with those with non-FEP. Thismay be a helpful reference for early interventionwith adolescents and young adults with schizophre-nia spectrum disorders in clinical practice.

ACKNOWLEDGEMENTS

This study was sponsored by the Chang GungMedical Research Project (CMRPG270051) and

Otsuka, Taiwan. Ted Knoy is appreciated for hiseditorial assistance.

REFERENCES

1. Mala E. Schizophrenia in childhood and adolescence. NeuroEndocrinol Lett 2008; 29: 831–6.

2. Robinson DG, Woerner MG, Alvir JM et al. Predictors of treat-ment response from a first episode of schizophrenia orschizoaffective disorder. Am J Psychiatry 1999; 156: 544–9.

3. Salimi K, Jarskog LF, Lieberman JA. Antipsychotic drugs forfirst-episode schizophrenia: a comparative review. CNSDrugs 2009; 23: 837–55.

4. McGavin JK, Goa KL. Aripiprazole. CNS Drugs 2002; 16:779–86; discussion 87–8.

5. Greenaway M, Elbe D. Focus on aripiprazole: a review of itsuse in child and adolescent psychiatry. J Can Acad ChildAdolesc Psychiatry 2009; 18: 250–60.

6. Takahashi H, Oshimo T, Ishigooka J. Efficacy and tolerabilityof aripiprazole in first-episode drug-naive patients withschizophrenia: an open-label trial. Clin Neuropharmacol2009; 32: 149–50.

7. Lee HY, Ham BJ, Kang RH et al. Trial of aripiprazole in thetreatment of first-episode schizophrenia. Psychiatry ClinNeurosci 2010; 64: 38–43.

8. Docherty JP, Baker RA, Eudicone J et al. Effect of aripiprazoleversus haloperidol on PANSS Prosocial items in early-episodepatients with schizophrenia. Schizophr Res 2010; 120: 199–203.

9. Josiassen RC, Shaughnessy RA, Filymer DM et al. Early inter-vention with second-generation antipsychotics in first-

FIGURE 1. Changes in scores of CGI-severity (a), BPRS total scores (b), BPRS positive symptoms (c), BPRS negative symptoms (d) andBPRS general symptoms (e) over time, relative to baseline, in patients with first-episode of psychosis (FEP) or recurrent psychosis(non-FEP). , FEP (n = 18); , non-FEP (n = 24).Numbers of cases that remained in the study at weeks 4, 8, 12, 16 and 24 inthe FEP group were 16, 15, 13, 13 and 12; and in the non-FEP group were 19, 18, 17, 15 and 15, respectively. BPRS, Brief PsychiatricRatings Scale; CGI, Clinical Global Impression.*P < 0.05, **P < 0.01 significance level for interaction between groups (FEP vs. non-FEP)and time.

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episode psychosis: results of an 8-week naturalistic study.Early Interv Psychiatry 2010; 4: 57–63.

10. Sheehan DV, Lecrubier Y, Sheehan KH et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the devel-opment and validation of a structured diagnostic psychiatricinterview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59(Suppl. 20): 22–33; quiz 4–57.

11. Guy W. ECDEU Assessment manual for psychopharmacology-revised. Department of Health, Education and Welfare, 1976.

12. Overall JE, Pfefferbaum B. The Brief Psychiatric Rating Scalefor children. Psychopharmacol Bull 1982; 18: 10–16.

13. The WHOQOL Group: Development of the World HealthOrganization WHOQOL-BREF quality of life assessment.Psychol Med 1998; 28: 551–8.

14. Glick ID, Mankoski R, Eudicone JM et al. The efficacy, safety,and tolerability of aripiprazole for the treatment of schizo-affective disorder: results from a pooled analysis of a sub-population of subjects from two randomized, double-blind,placebo-controlled, pivotal trials. J Affect Disord 2009; 115:18–26.

15. Janicak PG, Glick ID, Marder SR et al. The acute efficacy ofaripiprazole across the symptom spectrum of schizophrenia:a pooled post hoc analysis from 5 short-term studies. J ClinPsychiatry 2009; 70: 25–35.

16. Taylor D, Hanssens L, Loze JY et al. Preference of medicineand patient-reported quality of life in community-treatedschizophrenic patients receiving aripiprazole vs standard ofcare: results from the STAR study. Eur Psychiatry 2008; 23:336–43.

17. Aitchison KJ, Mir A, Shivakumar K et al. Costs and outcomesassociated with an aripiprazole add-on or switching open-label study in psychosis. J Psychopharmacol 2011; 25: 675–84.

18. Francey SM, Nelson B, Thompson A et al. Who needs antip-sychotic medication in the earliest stages of psychosis?A reconsideration of benefits, risks, neurobiology and ethicsin the era of early intervention. Schizophr Res 2010; 119:1–10.

19. Schennach-Wolff R, Jager M, Mayr A et al. Predictors ofresponse and remission in the acute treatment of first-episode schizophrenia patients–is it all about early response?Eur Neuropsychopharmacol 2011; 21: 370–8.

20. Kwon JS, Jang JH, Kang DH et al. Long-term efficacy andsafety of aripiprazole in patients with schizophrenia, schizo-phreniform disorder, or schizoaffective disorder: 26-weekprospective study. Psychiatry Clin Neurosci 2009; 63: 73–81.

21. Compton MT, Gordon TL, Goulding SM et al. Patient-levelpredictors and clinical correlates of duration of untreatedpsychosis among hospitalized first-episode patients. J ClinPsychiatry 2011; 72: 225–32.

22. Arango C, Moreno C, Martinez S et al. Longitudinal brainchanges in early-onset psychosis. Schizophr Bull 2008; 34:341–53.

23. Johannessen JO, Friis S, Joa I et al. First-episode psychosispatients recruited into treatment via early detection teamsversus ordinary pathways: course, outcome and healthservice use during first 2 years. Early Interv Psychiatry 2007;1: 40–8.

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