|Year : 2013 | Volume
| Issue : 5 | Page : 439-446
Antipsychotics in children and adolescents with schizophrenia: A systematic review and meta-analysis
Siddharth Sarkar, Sandeep Grover
Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||13-Apr-2013|
|Date of Decision||24-May-2013|
|Date of Acceptance||07-Jul-2013|
|Date of Web Publication||6-Sep-2013|
Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
Objective: To systematically review the efficacy and tolerability data of antipsychotics in children and adolescents with schizophrenia.
Materials and Methods: Pubmed, Google scholar and Psych Info were searched to identify studies published in peer-reviewed English language journals. All studies evaluating the efficacy of antipsychotics in children and adolescents with schizophrenia and having 3 or more participants were included. Of the studies identified, only randomized controlled trials were included in the meta-analysis. Data was analysed using effect size calculation as per Cohen's d. Fifty published studies were identified which reported use of antipsychotics in children and adolescents with schizophrenia. Of these, 15 randomized controlled studies were included in meta-analysis.
Results: Evidence suggests that both first generation antipsychotics (FGA) and second generation antipsychotics (SGAs) are better than placebo (effect size [ES] 2.948, confidence interval [CI] 1.368 to 4.528, sample size 31; and ES 0.454, CI 0.414 to 0.542, sample size 1308 respectively). However, FGAs seemed to be inferior to SGAs (ES -0.363, CI -0.562 to -0.163, sample size of 243) and clozapine is superior to all other antipsychotics (ES 0.848, CI 0.748 to 0.948, and sample size 85) in treatment of schizophrenia in children and adolescents. The extrapyramidal side effects are more common with FGAs while metabolic adverse effects are more common with SGAs.
Conclusion: FGAs and SGAs are effective in the treatment of children and adolescents with schizophrenia. Clozapine apparently is the most effective antipsychotic in this condition.
Keywords: Adolescents, antipsychotics, children, schizophrenia
|How to cite this article:|
Sarkar S, Grover S. Antipsychotics in children and adolescents with schizophrenia: A systematic review and meta-analysis. Indian J Pharmacol 2013;45:439-46
|How to cite this URL:|
Sarkar S, Grover S. Antipsychotics in children and adolescents with schizophrenia: A systematic review and meta-analysis. Indian J Pharmacol [serial online] 2013 [cited 2019 Jun 17];45:439-46. Available from: http://www.ijp-online.com/text.asp?2013/45/5/439/117720
| » Introduction|| |
Childhood onset schizophrenia presents a particular challenge as it is associated with poor prognosis when compared to adult onset schizophrenia. ,, However, treatment can significantly improve the course and outcome of schizophrenia in children and adolescents. Effective treatment of schizophrenia relies on the use of antipsychotics. Although a large data base is available for use of antipsychotics in adult population, the same cannot be applied to children and adolescents because pharmacodynamic and pharmacokinetic properties of mediations tend to differ between adults and children. 
Professional bodies have drafted practice parameters for treatment of schizophrenia in children and young persons. , These practice parameters suggest that pharmacotherapy forms the mainstay of the treatment options for such patients and recommend that second generation antipsychotics may be preferred but the side effects of these medications in the form weight gain and metabolic disturbances may be problematic. Hence, these guidelines caution and emphasize the need to monitor the treatment.
Prudent management of a case of schizophrenia in children and adolescents requires an informed reflection on the available research evidence about the efficacy of different pharmacological agents and the possible side effects. The current evidence of the role of antipsychotics in children and adolescents with schizophrenia is rather limited. This study attempts to carry out a systematic review and meta-analysis of studies which evaluated efficacy of various antipsychotics in the treatment of schizophrenia in children and adolescents. The secondary objective was to find out the tolerability of the antipsychotics in this population.
| » Materials and Methods|| |
Electronic searches were carried out using Pubmed, PsychInfo and Google Scholar with keywords of 'childhood onset', 'adolescent onset', children, adolescent, 'schizophrenia' and 'antipsychotic' (and names of individual antipsychotics) used in various combinations. The searches were carried out in December 2012 and 380 English language abstracts were identified. Further studies were identified from the cross references. Randomized controlled trials were included for meta-analysis.
Selection of Studies
Studies published in peer-reviewed English language journals with following inclusion criteria were included: efficacy/effectiveness trials of antipsychotics in children and adolescent, diagnosis of schizophrenia made in accordance to nosological system or through clinician's interview, age of patients less than 18 years of age at the time of entering into the trial and reporting outcome in any form of clinical efficacy measure. Studies which were published as part of conference proceedings only were not included. Meta-analysis was carried out on those randomized controlled studies with at least five subjects in each arm and had explicitly reported efficacy as a categorical or continuous variable of improvement.
Full texts of the relevant papers were obtained. Data was extracted and coded by two investigators independently (Siddharth Sarkar and Sandeep Grover). Information was extracted from the published papers pertaining to study characteristics (nature of the study, manner of randomization, blinding, duration of study, intention to treat analysis), demographic characteristics (number of subjects, age range or mean, gender distribution), clinical details (diagnoses, medication groups, efficacy measure, outcome, side effects). Discrepancies between the two investigators were resolved by mutual discussion and re-evaluation of the published paper. The studies were classified into two types: randomized controlled trials and non-randomized trial. The side effects reported in the studies were tabulated.
Effect sizes for the efficacy of antipsychotics were calculated. In studies which reported more than one outcome measure, the primary outcome measure was considered for calculation of effect size. In studies, which had not explicitly mentioned a primary efficacy variable, the proportion of patient's improved or first variable mentioned for efficacy was taken for analysis. The effect size is a measure of the effectiveness of an intervention and allows easy comparison of different studies. The greater the value of effect size, the greater is the efficacy. The confidence intervals of effect size tell about the impact of the findings of the study. Inferences should be drawn with caution if the confience intervals are large. Studies with large sample sizes usually have narrower confidence intervals. In this study, Cohen's d was used for calculation of effect sizes, which gives a robust measure for both categorical and continuous data.  For dichotomous variables of efficacy, logit method was used for deriving effect size and confidence intervals. In studies which had more than two groups, effect sizes were calculated for individual comparisons between different drugs or between a drug and placebo. Mean effect sizes and confidence intervals were calculated for comparison of first generation antipsychotic (FGA) versus placebo, second generation antipsychotic (SGA) versus placebo, FGA versus SGA, and clozapine versus other drugs.
Random effects model was used for computing the mean effect sizes. The random effects model has been shown to be superior to fixed effects model for computation in meta-analyses. , For assessing the heterogeneity, I 2 test was used. This measure expressed as a percentage reflects the degree of heterogeneity between the studies and makes comparison easier than Cochran's Q. It does not need to take into account the degrees of freedom for comparison of meta-analyses. 
| » Results|| |
In total 50 studies were identified which had evaluated at least one antipsychotic medication in children and adolescents with schizophrenia. Of these, 31 studies were excluded because they were open label or were retrospective studies (chart reviews) and case series [Table 1] and did not met the inclusion criteria for the metanalysis. These studies reported the usefulness of first generation antipsychotics (FGAs) as well as the second generation antipsychotics (SGAs). These studies evaluated amisulpiride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, thiothixene and ziprasidone. The sample sizes in these studies ranged from as low as 3 subjects to 390 subjects. A variety of instruments have been utilized to measure outcomes in these studies and improvements have been noted in variety of domains.
|Table 1: Non-randomized studies evaluating various antipsychotics in children and adolescents with schizophrenia|
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Efficacy in Randomized Controlled Trials
Out of 50 studies 19 had randomly assigned the patients to different treatment groups and had more than one treatment arm. Of these 19 studies, we couldn't lay our hands to one study Pool et al., (Haloperidol versus Placebo versus Loxapine). Data from two studies could not be utilized to calculate Cohen's d effect sizes (Realmuto et al., [thiothixine versus thioridazine], and Arango et al., [olanzapine versus quetiapine]). One follow up study  was not included in meta-analysis as patients in this study comprised the medication 'responders' of a previous study. Hence, meta-analysis was conducted on 15 randomized controlled trials [Table 2]. Studies which had more than 2 arms, effect sizes were calculated for all the comparisons reported in those studies. Of these 15 studies, all studies were double blind except one had used blinded raters. 
|Table 2: Randomized controlled studies of antipsychotics in children and adolescent with schizophrenia|
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Six of the studies included in the meta-analysis had at least one first generation antipsychotic (FGAs) arm. Some studies compared more than two drugs and a few studies compared efficacy of different dosing regimen for the same drug. Two studies compared FGAs with placebo and five studies compared SGAs with placebo. The sample sizes in the individual comparisons varied from 21 to 257. A variety of structured instruments have been utilized to report outcomes. These have commonly included Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI). The effect sizes for the various comparisons ranged from -0.999 to 2.948.
All the comparisons with placebo favored the antipsychotic arm with effect sizes ranging from 2.948 (haloperidol) to 0.128 (low dose paliperidone). Haloperidol had higher effect size in comparison to placebo followed by risperidone, olanzapine, paliperidone (medium dose), aripiprazole, quetiapine (higher dose), aripiprazole (lower dose), paliperidone (high dose), quetiapine (lower dose) and paliperidone (lower dose). The mean effect size for FGA versus placebo was 2.948 (based on a cumulative sample of 31 participants, confidence interval [CI] 1.368 to 4.528, I 2 = 0), while that of SGAs versus placebo was 0.454 (based on a cumulative sample of 1308 participants, CI 0.414 to 0.542, I 2 = 0.69). When SGAs were compared to FGAs, the meta-analysis revealed a mean effect size of -0.363, favoring SGAs (based on cumulative sample of 243, CI -0.562 to -0.163, I 2 = 48.2). When clozapine was compared with other antipsychotics the effect size was found to be 0.848 (based upon 85 participants, CI 0.748 to 0.948, I 2 = 0), suggesting that clozapine was more efficacious than other antipsychotics. The I 2 test of heterogeneity suggested that for comparison of FGA versus placebo, SGA versus placebo and clozapine versus other drugs, heterogeneity was minimal, though it was considerable in the comparison of SGAs versus FGAs. The forest plot of the included studies is shown in [Figure 1] and the funnel plot is depicted in [Figure 2].
A variety of side effects have been reported in studies evaluating antipsychotics in children with schizophrenia [Table 3]. The side effects encountered in greater frequency with a medication. Extrapyramidal symptoms were the most commonly side effects encountered with FGAs, while sedation and weight gain were seen more frequently with SGAs. Some of the studies reported changes in metabolic parameters, especially dyslipidemia and glucose intolerance with olanzapine and clozapine.
|Table 3: Side effects of medications observed in children and adolescents|
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| » Discussion|| |
The present metanalysis evaluates the available efficacy and tolerability data of the commonly used antipsychotics in children and adolescents with schizophrenia. It shows that that FGAs and second generation antipsychotics (SGAs) are better than placebo in the treatment of schizophrenia in children and adolescents. This is in congruence to the efficacy data in the adult population. , However it is important to note that the data base is very small compared to adults. Further the data of FGAs is limited to haloperidol, fluphenazine and molindone. It is also important to note that the exceptionally high efficacy of FGAs as suggested by big effect size in this meta-analysis is based upon only one study which had small sample size and evaluated the outcome in an ill defined manner. Hence, this finding may just be an aberration rather than truly representative of efficacy of FGAs.
The available evidence also suggests that SGAs are also superior to placebo in the treatment of schizophrenia in children and adolescents. The evidence base for this is much larger compared to that for FGAs and placebo. Among the different atypical antipsychotics the effect size of risperidone was more than that of quetiapine and aripiprazole. When FGAs were compared to SGAs, SGAs stood out better in terms of efficacy but the data base for this comparison is limited to only 243 subjects. Comparisons of FGAs and SGAs in adults subjects have also reported greater efficacy of some of the SGAs like olanzapine, risperidone and amisulpiride over FGAs. ,
The tests of heterogeneity reveal that comparisons of SGAs versus FGAs. The degree of heterogeneity in the efficacy data in these studies may be due to variety of the medications, different demographic compositions of the participants, sensitivity of the instruments used to measure efficacy and subtle differences in the methodology. The random effects model has been used for calculating the mean effect sizes which gives a better estimation when such heterogeneity is present.
As seen in adult population , findings of this meta-analysis also suggest that clozapine is better than other antipsychotics in head to head comparisons in children and adolescents too.
In terms of tolerability, data suggests that extrapyramidal symptoms are seen with FGAs as well as the SGAs, though more frequently with the FGAs. Evidence also suggests that SGAs are also associated with weight gain and derangement of metabolic parameters in children and adolescents too.
This meta-analysis and review of literature also bring forth some of the limitations of the existing literature with regard to use of antipsychotic medications in children and adolescents with schizophrenia. First, the evidence suggests that most of the data is limited to short term trials and there is dearth of long term studies evaluating the efficacy and tolerability of antipsychotics in children and adolescents. As most of the patients with schizophrenia require use of antipsychotics for longer periods, the short term efficacy data may not be useful in understanding the efficacy and most importantly adverse effects which occur over long term period. Second, most of the studies have been limited to small sample sizes. It is now well understood that studies which are underpowered to evaluate a particular outcome are less useful. Keeping this in mind, it can be said that many of the studies which have evaluated various antipsychotics in children and adolescents are underpowered. Third, most of the data which is available originates from the western countries. Studies in adults suggest that patients from different ethnic background sow varieties in response to different antipsychotics. Fourth, there is lot of heterogeneity in assessing the efficacy and use of primary outcome measure. Due to this comparison of different studies evaluating the same antipsychotic or different antipsychotics is difficult. Hence, there is an urgent need to conduct well designed long term studies with larger sample size, involving subjects of different ethnicity to have a better idea about efficacy and tolerability of antipsychotics in children and adolescents with schizophrenia.
The present meta-analysis has certain limitations which must be remembered while interpreting the results. Due to limited number of studies and incomparable reporting of demographic and clinical variables, sensitivity analysis was not conducted. Effect sizes of all the randomized controlled studies could not be calculated due to inadequate information from the published texts. The review relied upon the published articles and did not seek out unpublished material or use conference proceedings in analysis. Though a few studies may have been missed, there was a tendency to err towards including higher quality studies which have undergone rigorous peer review procedure. Most of the studies included are of short duration studies with low sample sizes. Variation in the drug dosages (both inter individual in a study as well as between studies) make the comparison difficult. Also outcome measures for reporting improvement have varied across studies, emphasizing caution while interpreting results.
To conclude, this meta-analysis suggests that at present the evidence base for use of antipsychotics in children and adolescents with schizophrenia is rather limited. However, the existing data suggests that both FGAs and SGAs are useful in managing the symptoms of schizophrenia in children and adolescents. Further the evidence suggests that SGAs may be better than FGAs and lend support to the recommendations made by the existing guidelines. , Clozapine is superior to other atypical antipsychotics and FGAs. Hence, patients who do not respond to other antipsychotic may be treated with clozapine.
| » References|| |
|1.||Remschmidt H, Martin M, Fleischhaker C, Theisen FM, Hennighausen K, Gutenbrunner C, et al. Forty-two-years later: The outcome of childhood-onset schizophrenia. J Neural Transm 2007;114:505-12. |
|2.||Werry JS, McClellan JM, Andrews LK, Ham M. Clinical features and outcome of child and adolescent schizophrenia. Schizophr Bull 1994;20:619-30. |
|3.||Schimmelmann BG, Conus P, Cotton S, McGorry PD, Lambert M. Pre-treatment, baseline, and outcome differences between early-onset and adult-onset psychosis in an epidemiological cohort of 636 first-episode patients. Schizophr Res 2007;95:1-8. |
|4.||Funk RS, Brown JT, Abdel-Rahman SM. Pediatric pharmacokinetics: human development and drug disposition. Pediatr Clin North Am 2012;59:1001-16. |
|5.||Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry 2001;40S:4S-23. |
|6.||NICE. Psychosis and schizophrenia in children and young people: Full guideline [Internet]. Available from: http://www.nice.org.uk/ [Last cited 2013 Feb 7]. |
|7.||Cohen J. The t test for means In Statistical power analysis for the behavioral sciences. pp 567. Hillsdale, NJ, Earlbaum 1988. |
|8.||Hunter JE, Schmidt FL. Fixed effects vs. random effects meta-analysis models: Implications for cumulative research knowledge. Int J Sel Assess 2002;8:275-92. |
|9.||Schmidt FL, Oh IS, Hayes TL. Fixed- versus random-effects models in meta-analysis: Model properties and an empirical comparison of differences in results. Br J Math Stat Psychol 2009;62:97-128. |
|10.||Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods 2006;11:193-206. |
|11.||Varol Tas F, Guvenir T. Amisulpride treatment of adolescent patients with schizophrenia or schizo-affective disorders. Eur Child Adolesc Psychiatry 2009;18:511-3. |
|12.||Bachmann CJ, Lehr D, Theisen FM, Preiss M. Aripiprazole as an adjunct to clozapine therapy in adolescents with early-onset schizophrenia: A retrospective chart review. Pharmacopsychiatry 2009;42:153-7. |
|13.||Blanz B, Schmidt MH. Clozapine for schizophrenia. J Am Acad Child Adolesc Psychiatry 1993;32:223-4. |
|14.||Fleischhaker C, Schulz E, Remschmidt H. Biogenic amines as predictors of response to clozapine treatment in early-onset schizophrenia. J Psychiatr Res 1998;32:325-33. |
|15.||Frazier JA, Gordon CT, McKenna K, Lenane MC, Jih D, Rapoport JL. An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry 1994;33:658-63. |
|16.||Kranzler H, Roofeh D, Gerbino-Rosen G, Dombrowski C, McMeniman M, DeThomas C, et al. Clozapine: Its impact on aggressive behavior among children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 2005;44:55-63. |
|17.||Levkovitch Y, Kaysar N, Kronnenberg Y, Hagai H, Gaoni B. Clozapine for schizophrenia. J Am Acad Child Adolesc Psychiatry 1994;33:431. |
|18.||Sporn AL, Vermani A, Greenstein DK, Bobb AJ, Spencer EP, Clasen LS, et al. Clozapine treatment of childhood-onset schizophrenia: Evaluation of effectiveness, adverse effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry 2007;46:1349-56. |
|19.||Turetz M, Mozes T, Toren P, Chernauzan N, Yoran-Hegesh R, Mester R, et al. An open trial of clozapine in neuroleptic-resistant childhood-onset schizophrenia. Br J Psychiatry 1997;170:507-10. |
|20.||Kumra S, Kranzler H, Gerbino-Rosen G, Kester HM, DeThomas C, Cullen K, et al. Clozapine versus "high-dose" olanzapine in refractory early-onset schizophrenia: An open-label extension study. J Child Adolesc Psychopharmacol 2008;18:307-16. |
|21.||Ercan ES, Kutlu A, Varan A, Cikoðlu S, Coþkunol H, Bayraktar E. Olanzapine treatment of eight adolescent patients with psychosis. Hum Psychopharmacol 2004;19:53-6. |
|22.||Findling RL, McNamara NK, Youngstrom EA, Branicky LA, Demeter CA, Schulz SC. A prospective, open-label trial of olanzapine in adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 2003;42:170-5. |
|23.||Mozes T, Greenberg Y, Spivak B, Tyano S, Weizman A, Mester R. Olanzapine treatment in chronic drug-resistant childhood-onset schizophrenia: An open-label study. J Child Adolesc Psychopharmacol 2003;13:311-7. |
|24.||Ross RG, Novins D, Farley GK, Adler LE. A 1-year open-label trial of olanzapine in school-age children with schizophrenia. J Child Adolesc Psychopharmacol 2003;13:301-9. |
|25.||Sholevar EH, Baron DA, Hardie TL. Treatment of childhood-onset schizophrenia with olanzapine. J Child Adolesc Psychopharmacol 2000;10:69-78. |
|26.||Maagensen M, Aarkrog T. Treatment of adolescent psychoses with olanzapine: A preliminary report. Nord J Psychiatry 1999;53:435-8. |
|27.||Castro-Fornieles J, Parellada M, Soutullo CA, Baeza I, Gonzalez-Pinto A, Graell M, et al. Antipsychotic treatment in child and adolescent first-episode psychosis: A longitudinal naturalistic approach. J Child Adolesc Psychopharmacol 2008;18:327-36. |
|28.||Jensen JB, Kumra S, Leitten W, Oberstar J, Anjum A, White T, et al. A comparative pilot study of second-generation antipsychotics in children and adolescents with schizophrenia-spectrum disorders. J Child Adolesc Psychopharmacol 2008;18:317-26. |
|29.||Mozes T, Ebert T, Michal SE, Spivak B, Weizman A. An open-label randomized comparison of olanzapine versus risperidone in the treatment of childhood-onset schizophrenia. J Child Adolesc Psychopharmacol 2006;16:393-403. |
|30.||Schimmelmann BG, Mehler-Wex C, Lambert M, Schulze-zur-Wiesch C, Koch E, Flechtner HH, et al. A prospective 12-week study of quetiapine in adolescents with schizophrenia spectrum disorders. J Child Adolesc Psychopharmacol 2007;17:768-78. |
|31.||Shaw JA, Lewis JE, Pascal S, Sharma RK, Rodriguez RA, Guillen R, et al. A study of quetiapine: efficacy and tolerability in psychotic adolescents. J Child Adolesc Psychopharmacol 2001;11:415-24. |
|32.||Mandoki M. Risperidone treatment of children and adolescents: Increased risk of extrapyramidal side effects? J Child Adolesc Psychopharmacol 1995;5:49-67. |
|33.||Quintana H, Keshavan M. Case study: Risperidone in children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 1995;34:1292-6. |
|34.||Simeon J, Milin R, Walker S. A retrospective chart review of risperidone use in treatment-resistant children and adolescents with psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:267-75. |
|35.||Armenteros JL, Whitaker AH, Welikson M, Stedge DJ, Gorman J. Risperidone in adolescents with schizophrenia: An open pilot study. J Am Acad Child Adolesc Psychiatry 1997;36:694-700. |
|36.||Pandina G, Kushner S, Karcher K, Haas M. An open-label, multicenter evaluation of the long-term safety and efficacy of risperidone in adolescents with schizophrenia. Child Adolesc Psychiatry Ment Health 2012;6:23. |
|37.||Zalsman G, Carmon E, Martin A, Bensason D, Weizman A, Tyano S. Effectiveness, safety, and tolerability of risperidone in adolescents with schizophrenia: An open-label study. J Child Adolesc Psychopharmacol 2003;13:319-27. |
|38.||Grcevich SJ, Findling RL, Rowane WA, Friedman L, Schulz SC. Risperidone in the treatment of children and adolescents with schizophrenia: A retrospective study. J Child Adolesc Psychopharmacol 1996;6:251-7. |
|39.||Ruan L, Hu S, Huang M, Hu J, Cai W. Efficacy and safety of long-acting risperidone on early onset schizophrenia in adolescent patients. Afr J Pharm Pharmacol 2010;4:184-92. |
|40.||Waizer J, Polizos P, Hoffman SP, Engelhardt DM, Margolis RA. A single-blind evaluation of thiothixene with outpatient schizophrenic children. J Autism Child Schizophr 1972;2:378-86. |
|41.||Stewart M, DelBello MP, Versavel M, Keller D. Psychosocial functioning and health-related quality of life in children and adolescents treated with open-label ziprasidone for bipolar mania, schizophrenia, or schizoaffective disorder. J Child Adolesc Psychopharmacol 2009;19:635-40. |
|42.||Spencer EK, Kafantaris V, Padron-Gayol MV, Rosenberg CR, Campbell M. Haloperidol in schizophrenic children: Early findings from a study in progress. Psychopharmacol Bull 1992;28:183-6. |
|43.||Faretra G, Dooher L, Dowling J. Comparison of haloperidol and fluphenazine in disturbed children. Am J Psychiatry 1970;126:1670-3. |
|44.||Engelhardt DM, Polizos P, Waizer J, Hoffman SP. A double-blind comparison of fluphenazine and haloperidol in outpatient schizophrenic children. J Autism Child Schizophr 1973;3:128-37. |
|45.||Kumra S, Frazier JA, Jacobsen LK, McKenna K, Gordon CT, Lenane MC, et al. Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry 1996;53:1090-7. |
|46.||Sikich L, Hamer RM, Bashford RA, Sheitman BB, Lieberman JA. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: A double-blind, randomized, 8-week trial. Neuropsychopharmacology 2004;29:133-45. |
|47.||Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: Findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008;165:1420-31. |
|48.||Findling RL, Robb A, Nyilas M, Forbes RA, Jin N, Ivanova S, et al. A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Am J Psychiatry 2008;165:1432-41. |
|49.||Kryzhanovskaya L, Schulz SC, McDougle C, Frazier J, Dittmann R, Robertson-Plouch C, et al. Olanzapine versus placebo in adolescents with schizophrenia: A 6-week, randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2009;48:60-70. |
|50.||Singh J, Robb A, Vijapurkar U, Nuamah I, Hough D. A randomized, double-blind study of paliperidone extended-release in treatment of acute schizophrenia in adolescents. Biol Psychiatry 2011;70:1179-87. |
|51.||Findling RL, McKenna K, Earley WR, Stankowski J, Pathak S. Efficacy and safety of quetiapine in adolescents with schizophrenia investigated in a 6-week, double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol 2012;22:327-42. |
|52.||Haas M, Unis AS, Armenteros J, Copenhaver MD, Quiroz JA, Kushner SF. A 6-week, randomized, double-blind, placebo-controlled study of the efficacy and safety of risperidone in adolescents with schizophrenia. J Child Adolesc Psychopharmacol 2009;19:611-21. |
|53.||Shaw P, Sporn A, Gogtay N, Overman GP, Greenstein D, Gochman P, et al. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry 2006;63:721-30. |
|54.||Kumra S, Kranzler H, Gerbino-Rosen G, Kester HM, De Thomas C, Kafantaris V, et al. Clozapine and "high-dose" olanzapine in refractory early-onset schizophrenia: A 12-week randomized and double-blind comparison. Biol Psychiatry 2008;63:524-9. |
|55.||Swadi HS, Craig BJ, Pirwani NZ, Black VC, Buchan JC, Bobier CM. A trial of quetiapine compared with risperidone in the treatment of first onset psychosis among 15- to 18-year-old adolescents. Int Clin Psychopharmacol 2010;25:1-6. |
|56.||Haas M, Delbello MP, Pandina G, Kushner S, Van Hove I, Augustyns I, et al. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: A randomized, double-blind, placebo-controlled study. Bipolar Disord 2009;11:687-700. |
|57.||Pool D, Bloom W, Mielke DH, Roniger JJ Jr, Gallant DM. A controlled evaluation of loxitane in seventy-five adolescent schizophrenic patients. Curr Ther Res Clin Exp 1976;19:99-104. |
|58.||Findling RL, Johnson JL, McClellan J, Frazier JA, Vitiello B, Hamer RM, et al. Double-blind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) study. J Am Acad Child Adolesc Psychiatry 2010;49:583-94. |
|59.||Realmuto GM, Erickson WD, Yellin AM, Hopwood JH, Greenberg LM. Clinical comparison of thiothixene and thioridazine in schizophrenic adolescents. Am J Psychiatry 1984;141:440-2. |
|60.||Arango C, Robles O, Parellada M, Fraguas D, Ruiz-Sancho A, Medina O, et al. Olanzapine compared to quetiapine in adolescents with a first psychotic episode. Eur Child Adolesc Psychiatry 2009;18:418-28. |
|61.||Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: A systematic review and meta-analysis. Lancet 2012;379:2063-71. |
|62.||Leucht S, Arbter D, Engel RR, Kissling W, Davis JM. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 2009;14:429-47. |
|63.||Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antipsychotics versus low-potency conventional antipsychotics: A systematic review and meta-analysis. Lancet 2003;361:1581-9. |
|64.||Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: A meta-analysis. Lancet 2009;373:31-41. |
|65.||Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine′s effectiveness in schizophrenia: A systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999;156:990-9. |
|66.||Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev 2009:CD000059. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]