Current Psychopharmacology, 2012, 1, 117-121
117
Aripiprazole in Children and Adolescents with Schizophrenia E. Argyriou*, M. Petroggona, S. Charitaki, M. Belivanaki, G. Giannakopoulos and G. Kolaitis Department of Child Psychiatry, University of Athens Medical School, “Aghia Sophia” Children’s Hospital, Athens, Greece Abstract: Background: Aripiprazole is an atypical antipsychotic that was approved, relatively recently, for use in adolescents with schizophrenia. Objective: The aim was to discuss efficacy and tolerability issues of aripiprazole in adolescents suffering from schizophrenia. Method: A Medline search identified only three studies and one post hoc analysis for one of them, concerning the use of aripiprazole in adolescents with schizophrenia. Finally, one of the studies was excluded because of the small number of cases treated with aripiprazole. Results: Based on the clinical evidence, including data from two short-terms clinical trials and one post-hoc analysis of one of the abovementioned studies, aripiprazole seemed generally safe and well tolerated in children and adolescents. Aripiprazole at doses of 10 to 30 mg/day was more efficacious in ameliorating the symptoms (including hostility) of schizophrenia than was placebo. It was associated with low number and mild-to-moderate intensity of adverse events, and with no clinically relevant findings in ECGs, vital signs, and clinical laboratory tests. The most common adverse events were extrapyramidal disorder, somnolence, and tremor. Also aripiprazole is unlikely to be associated with hyperprolactinemia and clinically significant weight gain. Conclusion: Scant information exists to evaluate the use of aripiprazole in early-onset schizophrenia, due to the lack of published studies. The initial encouraging results provide further support and point out the necessity for systematic research on the efficacy and tolerability of aripiprazole in pediatric patients suffering from schizophrenia.
Keywords: Aripiprazole, adverse effects, children and adolescents, effectiveness, schizophrenia. INTRODUCTION Aripiprazole is the first in a new class of second-generation antipsychotics with a novel pharmacologic profile. It acts as a dopamine antagonist at hyperdopaminergic sites (e.g. mesolimibic system in schizophrenia) and as a dopamine agonist at hypodopaminergic sites (e.g. prefrontal cortex in schizophrenia) [1, 2]. More specifically, its pharmacologic profile includes a combination of partial-agonist activity at D2, D3 and 5-HT1A receptors, antagonist activity at 5-HT2A receptors, and moderate binding affinity for other receptors (histaminic, muscarinic) [3]. The Food and Drug Administration (FDA) first approved aripiprazole for the treatment of schizophrenia in adults in 2002. Recently aripiprazole was approved for the treatment of (1) acute manic or mixed episodes associated with bipolar I disorder in pediatric patients aged 10 to 17 years, (2) children and adolescents aged 6 to 17 years with irritability associated with autistic disorder and (3) schizophrenia in adolescents aged 13 to 17 years [4]. Clinical trials suggest that aripiprazole may be an effective and well-tolerated treatment in juvenile mania [5,6] but still, additional controlled studies are necessary. Because of the very small number of trials of aripiprazole conducted with child and adolescent patients, it is necessary *Address correspondence to this author at the Department of Child Psychiatry, University of Athens Medical School, “Aghia Sophia” Children’s Hospital, Thivon & Papadiamantopoulou, 115 27, Athens, Greece; Tel:/Fax: 0030 210 7473811; E-mail:
[email protected]
2211-5579/12 $58.00+.00
to extrapolate most evidence on drug efficacy from studies in adults [7]. However, it should be noted that children and adolescents show greater sensitivity to a range of antipsychotic-related adverse events including extrapyramidal side effects [8], weight gain, obesity, and metabolic syndrome [9, 10]. This partial dopamine agonist seems to be efficacious in the treatment of both positive and negative symptoms in acute and long-term treatment of schizophrenia in adults at doses of 10 to 30mg/ day [11, 12, 13]. Moreover, findings exist on the efficacy of aripiprazole to treat hostility symptoms in psychotic adults [14, 15]. Additionally, clinical studies suggest that adults treated with aripiprazole have low rates of common antipsychotic side effects, including extrapyramidal symptoms, tardive dyskinesia, weight gain, sedation, hyperprolactinemia, QTc prolongation, hyperglycemia, and hyperlipidemia [16]. The efficacy of aripiprazole against positive, negative and cognitive symptoms of schizophrenia and its tolerability may be explained by its above-mentioned combined activity in various receptors [3]. To our knowledge, there are no published reviews on the use of aripiprazole in the treatment of schizophrenia in pediatric populations. Given the scant literature on clinical efficacy and tolerability of aripiprazole in treating schizophrenia in children and adolescents, the current report tries to discuss these issues in order to help clinicians assess the appropriate therapeutic role of this agent.
© 2012 Bentham Science Publishers
118 Current Psychopharmacology, 2012, Volume 1, No. 2
Argyriou et al.
METHOD A Medline search (2001-September 2011) was conducted for clinical studies of aripiprazole in the treatment of schizophrenia in children and adolescents. The search terms were aripiprazole; schizophrenia; children; adolescents; treatment; side effects. The reference lists of identified articles were reviewed for additional relevant publications. All full study publications were included in the report. Finally, the included studies were two clinical trials [17,18] and one post-hoc analysis [19] concerning the trial of Findling et al., 2008 [18]. A long-term study [20] that compared the effectiveness and safety of antipsychotics in early onset psychoses was finally excluded, because the authors indicated that the small number of cases treated with aripiprazole, did not permit evaluation of all the parameters taken into account during the study. The studies included in this report are listed in Table 1. CLINICAL EFFECTIVENESS Findling et al. 2008 [17], studied the effectiveness of aripiprazole in pediatric patients by using the Clinical Global Impression-Severity of Illness (CGI-S) that rates illness severity and the Clinical Global Impression-Improvement Table 1.
(CGI-I) that rates change from the initiation (baseline) of treatment [21]. It was an open label sequential-cohort study in children and adolescents of 10-17 years old, concerning 21 individuals, 14 male 7 female, with mean age 12.2 years, 16 white and 4 black. Primary diagnosis was schizophrenia (n=1), bipolar disorder (n=12), Tourette syndrome (n=5), attention-deficit hyperactivity disorder and conduct disorder (n=1), obsessive-compulsive disorder (n=1), and pervasive developmental disorder (n=1). Aripiprazole was initiated at 2 mg/day then escalated every 2 days for up to 12 days using a forced titration scheme to achieve a maximum dose of 20, 25, or 30 mg/day. Scales were used before dosing on day 1 of dose-escalation (CGI-S only) and on days 1 and 14 of the fixed dose phase (patients received the maximum dose for each cohort for a further 14 days). Clinically meaningful improvement in mean CGI-S score was observed in all 3 cohorts (mean baseline CGI-S scores were 4.0, 3.7, and 3.5 in the 20-, 25-, and 30-mg/d cohorts, respectively). Amelioration continued during the variable length doseescalation (mean scores 3.1, 2.2, and 1.5, respectively), with generally further improvement during the fixed-dose phase, (mean scores 2.4, 2.3, and 1.2, respectively). Mean CGI-I scores were 2.3, 1.8, and 1.3, respectively, at the end of dose-escalation. By day 14 of the fixed-dose phase, the majority of patients' conditions were classified as "very
Characteristics of the Studies Included in the Report
Study
Findling et al., 2008
Samle Size N=21
Multicenter, openlabel, sequentialcohort,
Age; Gendre
Diagnoses
10-17 years (mean=12.2) Male=14 Female=7
Schizophrenia (N=1);
Assessment Scales CGI-S, CGI-I
Bipolar Disorder (N=12); Tourette Syndrome (N=5);
dose-escalation
Treatment
ADHD + Conduct Dis. (N=1); ObsessiveCompulsive Disorder (N=1);
N=302
13-17 years (mean=15.4)
Schizophrenia
20mg: one mild dystonic reaction;
20mg (N=8); 25mg (N=7);
25 mg: one acute dystonic reaction;
30mg (N=6);
30mg: well tolerated All AEs were mild to moderate Aripiprazole 10mg (N=100);
Male =171 Female=131
6-week, multiple center, randomized, double blind, placebo-controlled
Meaningful improvement in mean CGI score in all 3 cohorts; Generally well tolerated across all cohorts;
Aripiprazole
Pervasive Developmental Disorder (N=1) Findling et al., 2008
Outcomes
30mg (N=102)
PANSS, CGI, CGAS, PQLES-Q
Placebo (N=100)
Significantly greater improvement than placebo on the PANSS total, CGI and CGA-S score in both ARI doses Generally well tolerated and not dose limiting; low rate of discontinuation due to adverse events; 10mg/d: one acute dystonic reaction
Robb et al., 2010 Post-hoc analysis of data from a 6-week, multicenter, doubleblind, randomized, placebo-controlled study (Findling et al., 2008)
N=296
13-17 years (mean=15.5) Male =168 Female=128
Schizophrenia
Aripiprazole 10mg/d (N=99); 30mg/d (N=97); Placebo (N=98)
PANSS Hostility, PQLES-Q, CGAS
Both doses show statistically significant improvement versus placebo in the PANSS Hostility factor
Aripiprazole in Children and Adolescents with Schizophrenia
much improved" to "much improved" (mean scores 1.7, 2.0, and 1.3, respectively. Furthermore, Findling et al., 2008 [18] used the Positive and Negative Syndrome Scale (PANSS) that contains three subscales: positive syndrome, negative syndrome, general psychopathology [22] and Children’s Global Assessment Scale (CGAS), that provides a rating of functional impairment [23] to record the longitudinal course of illness and treatment response. This was a multicenter, randomized, double blind, placebo-controlled trial of 302 children aged 13-17 years (mean age 15.4). Among the 171 males, 111 were Caucasians, 19 African American, 18 Asian and 23 of other nationalities. Of the 131 females 69 were Caucasians, 17 African American, 25 Asian, 1 American Indian or Alaska native, 19 Hispanic/Latino ethnicity and 21 of other nationalities. The patients were divided in three groups: 100 patients received 10mg/day of aripiprazole, 102 received 30mg/day of aripiprazole and 100 received placebo for 6 weeks. In the placebo group the onset of the disease for 23 children was before the age of 13, while for 77 persons the onset was between 13-17 years old. In aripiprazole 10mg group, for 15 patients the onset was before 13 years old, whereas for 85 persons the disease started between 13-17 years. Finally, in aripiprazole 30mg group, first symptoms occurred before the age of 13 in 15 cases, although in 87 cases they appeared between 13-17 years. Assessments were performed at baseline and at weekly visits through day 42, for PANSS, while CGAS was completed at baseline and at the end of treatment. Using the Paediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) [24] assessed the quality of life and the satisfaction of the patients. Both "total score" and a separate "overall score" (as determined by one item on the questionnaire) were determined at screening and at day 42. Treatment with both doses of aripiprazole resulted in significantly greater improvement than placebo between baseline and the end of treatment on the PANSS total, PANSS positive symptom subscale, CGI-S, CGI-I and C-GAS. The 10-mg/day dose of aripiprazole also produced significantly greater results than placebo on the PANSS negative subscale. The treatment with the dose of 30mg/day resulted in significant improvement in negative symptoms at weeks 3 and 4 (p=0.05 and p=0.05, respectively) but not at the end of the study. At the week 1 visit, the 30-mg group demonstrated significantly greater improvement than the placebo group on the PANSS total, PANSS positive subscale, and CGI severity and improvement scales. CGI improvements scores showed progressive improvement over the course of the study, with significant differences from placebo in the 10-mg aripiprazole group observed at weeks 1, 5, and 6 (p=0.02, p=0.03, p=0.02, respectively) and in the 30-mg group at all scheduled postbaseline visits except week 2 (week 1: p=0.002; weeks 3-6: p=0.005, p=0.004, p=0.0002, p=0.0004, respectively). Similarly, CGI severity scores showed improvement from "moderately" / "markedly" ill at baseline (scores of 4.6, 4.5, and 4.6 for the placebo, 10-mg, and 30mg groups respectively) to "mildly" / "moderately" ill at week 6 (score of 3.7 for placebo, 3.3 for both 10-mg and 30mg groups). Significant differences between placebo and aripiprazole were observed in the 10-mg group at weeks 3, 5, and 6 (p=0.04, p=0.03, p=0.008, respectively) and in the 30mg group at all scheduled postbaseline visits except week 2
Current Psychopharmacology, 2012, Volume 1, No. 2 119
(week 1: p=0.03, weeks 3-6: p=0.003, p=0.02, p=0.004, p=0.002, respectively). The mean change from baseline in the score on the CGA-S at week 6 for both aripiprazole groups was significantly greater than the change with placebo. On the PQ-LES-Q both aripiprazole groups demonstrated significant improvement at the end of the study on the separate "overall score" item, but they did not show significant change from baseline on the 14-item "total score". In addition, the post hoc analysis [19] of data from the double-blind, randomized, placebo-controlled trial [18], measured hostility by using the Hostility factor score of the PANSS (studied at baseline and at end-point) and demonstrated that aripiprazole, at doses of 10 and 30 mg/day, is significantly more effective than placebo at improving Hostility factor scores in adolescents with schizophrenia. At the end point, both aripiprazole doses produced statistically significantly greater improvements than placebo in reducing hostility in adolescents with schizophrenia (10 mg/day, -3.0; 30 mg/day, -3.7; placebo, 2.1; t=1.97, degrees of freedom df = 288, p < 0.05 and t=2.68, df = 288, p< 0.05 vs placebo, respectively). Despite the limitations of the post hoc nature of this analysis, aripiprazole seems to be an effective treatment for hostility symptoms in adolescents with schizophrenia. TREATMENT-RELATED ADVERSE EFFECTS Aripiprazole treatment was generally well tolerated. There were no reports for suicides or deaths during the mentioned studies. Among the 302 subjects there were 44 non-completers (10 in the placebo group, 16 in the 10mg/day group, and 18 in the 30mg/day group) that left the randomized, double blind, placebo-controlled study. Out of the 44 patients that left the study, 7 withdrew due to lack of efficacy (1 in the placebo group, 5 in the 10mg/day group and 1 in the 30mg/day group), 13 withdrew because of adverse events (2 in the placebo group, 7 in the group taking 10mg/day of aripiprazole and 4 in the group taking 30mg/day), 21 withdrew consent (5 in the placebo group, 4 in the 10mg/day group and 12 in the), 1 person of the group taking placebo was lost during the follow-up and 2 patients (1 in the group of placebo and 1 in the 30mg/day group) withdrew for other reasons. The most common adverse events associated with discontinuation were psychotic disorder (N= 3) and schizophrenia (N=3). After a short time improvement in PANSS scores each of the six patients was withdrawn from the study because of an event precipitated by aggravation of symptoms associated with psychosis or schizophrenia. The most common adverse events associated with aripiprazole were extrapyramidal disorder (i.e. shakes, muscles stiffness, or other involuntary movements), somnolence and tremor. The incidence of these adverse events appeared to be consistently higher at the 30-mg dose than at the 10-mg dose. The rate of discontinuation due to adverse events was low in both aripiprazole groups and was comparable to the rate in the placebo group. One patient out of 100, in the 10-mg aripiprazole group, withdrew owing to the emergence of dystonia, which resolved 3 days later. A dose of 30 mg/day of aripiprazole was associated with a higher incidence of tremor and Parkinsonism but not with dystonic events, dyskinesia nor akathisia. Patients in the placebo group lost an average of 0.8 kg over the 6-week
120 Current Psychopharmacology, 2012, Volume 1, No. 2
treatment period, which was significantly different from the changes in the aripiprazole-treated patients, who either had no overall change in weight (10-mg group) or gained 0.2kg on average (30-mg group). Similarly, aripiprazole therapy was generally well tolerated across all cohorts of the dose escalation, openedlabel study. In the 20-mg/d cohort, 5 of 6 evaluated patients tolerated aripiprazole up to 20 mg, permitting initiation of the 25-mg/d cohort. The sixth patient experienced a mild dystonic reaction and was down-titrated to 15 mg/d on day 6 of the fixed-dose phase. In the 25-mg/d cohort, 4 of 5 evaluated patients tolerated aripiprazole up to 25 mg; the fifth patient discontinued on day 6 of the fixed-dose phase due to an acute dystonic reaction. All 6 patients in the 30mg/d cohort tolerated aripiprazole up to 30 mg. All adverse events were mild or moderate in intensity (headache, upper abdominal pain, dizziness). Generally, no clinically significant changes in ECG measures, including QTCB intervals were observed, in heart rate or blood pressure, in glucose or lipid measures and weight gain, while serum prolactin appeared decreased. It is necessary to make clear that no known suicides or deaths were reported during the specific studies and that no further clinical studies or case reports have identified adverse reactions to aripiprazole. DISCUSSION Our search revealed only two clinical trials and one posthoc analysis, concerning the use of aripiprazole in children and adolescents suffering from schizophrenia. Of the prementioned studies only one was randomized, double blind and placebo-controlled. Although, the first trial adds to our knowledge about tolerability and safety of aripiprazole in children and adolescents at doses up to 30 mg/day, only one patient of the studied group suffered from schizophrenia. Despite, the absence of long-term outcomes, aripiprazole at doses of 20, 25, and 30 mg/ day seemed well tolerated in pediatric patients with psychiatric disorders. Aripiprazole was more efficacious in positive and negative symptoms of schizophrenia at doses of 10 and 30 mg/day than placebo. Both doses groups had statistically significant superiority on the amelioration of positive symptoms at the end of the study, and a statistically significant difference from placebo was noticed in the 10-mg/day group. The 30-mg aripiprazole dose was superior to placebo at the 3rd and 4th week, but not at the last observation. Additionally, patients with a "moderately" to "markedly" severe baseline illness showed clinically meaningful improvement. Both doses groups demonstrated statistically significant improvement compared to placebo, and the difference from placebo was numerical greater for the 30-mg group than for the 10-mg group at all meetings, except that of 2nd week. Functioning, as well as, quality of life appeared significantly improved in all groups treated with aripiprazole, than in the placebo group. Moreover, aripiprazole appeared to be efficacious for hostility symptoms in adolescents suffering from schizophrenia, although the limitations of the post-hoc nature of the analysis. Younger and first-episode patients are more sensitive to both therapeutic and adverse effects of antipsychotic drugs. So, it is really important to mention that treatment with aripiprazole was not associated with clinically significant
Argyriou et al.
changes in vital signs, ECG parameters, clinical laboratory values, weight gain, and prolactin concentration in plasma. Furthermore, a meta-analysis [25] on the efficacy, safety and tolerability of antipsychotic drugs included three clinical trials: Findling et al., 2008 [18] concerning aripiprazole, Haas et al., 2009 [26] concerning risperidone, and Kryzhanovskaya et al., 2009 [27] concerning olanzapine. The results revealed that treatment with 10 mg of aripiprazole daily was related to the lowest incidence of extrapyramidal symptoms and didn’t show significant weight gain, while 30 mg/ day of aripiprazole was connected with a higher incidence of tremor and Parkinsonism but not with dystonic events, dyskinesia nor akathisia. The most commonly reported adverse effects were extrapyramidal disorder, somnolence, and tremor and they were low in number and their intensity was mild to moderate. While, head-to head comparisons of atypicals antipsychotics vs typicals in adolescents with schizophrenia have shown that the efficacy against psychotic symptoms is similar, there were differences in tolerability and their side effects profile. Atypicals reduce the risk of extra pyramidal side effects but they can cause weight gain, hyperlipidemia, sedation, hypersalivation, seizures and hyperprolactinemia [7]. Comparatively to other antipsychotics, aripiprazole is not associated with weight gain, high levels of prolactin, ECG changes or severe extrapyramidal side effects and seems to be effective in both positive and negative psychotic symptoms but still additional long-term comparative studies are necessary. This is the first report, to our knowledge, trying to investigate the efficacy and tolerability of aripiprazole in adolescents with schizophrenia and focus on its potential therapeutic benefits. To conclude, aripiprazole seems to be efficacious in both positive and negative symptoms of adolescent-onset schizophrenia, although the data are really limited, because of the very small number of trials of antipsychotics conducted with pediatric patients. Regarding its low association with adverse events, aripiprazole can be considered as a very promising treatment of psychotic symptoms in adolescents. This initial encouraging result indicates that additional short- and long-term randomized, placebo-controlled clinical trials are needed to compare aripiprazole to placebo and to other atypical antipsychotics. Further systematic research is highly recommended in order to thoroughly evaluate the efficacy of aripiprazole in the treatment of youths with schizophrenia. ACKNOWLEDGEMENT No acknowledgments are due. CONFLICT OF INTEREST No conflicts of interest concerning the topics of this article. REFERENCES [1]
Burris KD, Molski TF, Xu C, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 2002; 302: 381-389.
Aripiprazole in Children and Adolescents with Schizophrenia [2]
[3] [4]
[5]
[6]
[7] [8]
[9]
[10] [11]
[12]
[13]
[14]
[15]
Current Psychopharmacology, 2012, Volume 1, No. 2 121
Horacek J, Bubenikova-Valesova V, Kopecek M, et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 2006; 5: 389-409. Hirose T, Uwahodo Y, Yamada S, et al. Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile. J Psychopharmacol 2004; 18: 375-383. Abilify. Bristol-Myers Suibb Company/Otsuka America Pharmaceutical Inc, Aripiprazole (Abilify) Prescribing Information. Princeton NJ: Bristol-Myers Squibb Co & Otsuka America Pharmaceutical, Inc, 2007. Biederman J, McDonell M, et al. Aripiprazole in the treatment of pediatric bipolar disorder: a systematic chart review. CNS spectrums 2005; 10-2: 141-148. Barzman D, DelBello M, et al. The effectiveness and tolerability of aripiprazole for pediatric bipolar disorders: a retrospective chart review. J Child & Adolescent Psychopharmacology 2004; 14: 593600. Rutter M, Bishop D, Pine DS, Scott S, Stevenson J, Taylor E, Thapar A. Rutter’s Child and Adolescent Psychiatry. 5th ed. Blackwell Publishing Limited 2008; 737-758. Kumra S, Jacobsen LK, Lelane M, et al. Case series: Spectrum of neuroleptic-induced movement disorders and extrapyramidal sideeffects in childhood-onset schizophrenia. JAACAP 1998b; 37: 221227. Ratzoni G, Gothelf D, Brand-Gothelf A, et al. Weight gain associated with olanzapine and risperidone in adolescent patients: A comparative prospective study. JAACAP 2002; 41: 337-343. Correll CU, Carlson HE: Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. JAACAP 2006; 45: 771-791. Cutler AJ, Marcus RN, Hardy SA, et al. The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia. CNS Spectr 2006; 11: 691-702. Pigott TA, Carson WH, Saha AR, et al. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study. J Clin Psychiatry 2003; 64: 1048-1056. Chrzanowski WK, Marcus RN, Torbeyns A, et al. Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine. Psychopharmacology (Berl) 2006; 189: 259-266. Janicak PG, Glick ID, Marder SR, et al. The acute efficacy of aripiprazole across the symptom spectrum of schizophrenia: A pooled post hoc analysis from 5 short-term studies. J Clin Psychiatry 2009; 70: 25-35. Volavka J, Czobor P, Citrome L, et al. Efficacy of aripiprazole against hostility in schizophrenia and schizoaffective disorder: Data
Received: September 9, 2011
[16]
[17]
[18]
[19]
[20]
[21]
[22] [23]
[24] [25]
[26]
[27]
from 5 double-blind studies. J Clin Psychiatry 2005; 66: 13621366. Marder SD, McQuade RD, Stock E, et al. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res 2003; 61: 123-136. Findling RL, Kauffman RE, Sallee FR, et al. Tolerability and pharmacokinetics of aripiprazole in children and adolescents with psychiatric disorders. An open-label, dose-escalation study. J Clin Psychopharmacology 2008; 28: 441-446. Findling RL, Robb A, Nyilas M, et al. A multiple-center, randomized, double-blind, placebo controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Amer J Psychiatry 2008; 165: 1432-1441. Robb AS, Carson WH, Nyilas MD, et al. Changes in positive and negative syndrome scale-derived hostility factor in adolescents with schizophrenia treated with aripiprazole: Post hoc analysis of randomized clinical trial data. J Child & Adol Psychopharmacology 2010; 20: 33-38. Cianchetti C, Ledda MG. Effectiveness and safety of antipsychotics in early onset psychoses: a long–term comparison. Psychiatry Research 2011: 10.1016: 1-8. Guy W. Early Clinical Drug Evaluation Unit (ECDEU) Assessment Manual for Psychopharmacology. Revised. NIMH Publication DHEW Publication No ADM 76-338. Rockville, MD: National Institute of Mental Health; 1976. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bulletin 1987; 13: 261-276. Shaffer D, Gould MS, Brasic J, et al. A children’s global assessment scale (CGAS). Archives of General Psychiatry 1983; 40: 1228-1231. Endicott J, Nee J, Yang R, Wohlberg C. Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q): reliability and validity. JAACAP 2006; 45: 401-407. Ardizzone I, Nardecchia F, Marconi A, et al. Antipsychotic Medication in Adolescents Suffering from Schizophrenia: A MetaAnalysis of Randomized Controlled Trials. Psychopharmacology Bulletin 2010; 43(2): 45-66. Haas M, Eerdekens M, Kushner S, et al. Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-blind study. Br J Psychiatry 2009; 194:158-64. Kryzkonovskaya l, Schulz SC, McDougle C, et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial. JAACAP 2009; 48:60-70.
Revised: December 5, 2011
Accepted: December 30, 2011
