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Meta-Analysis
. 2013 Oct 15;2013(10):CD009582.
doi: 10.1002/14651858.CD009582.pub2.

Atypical antipsychotics for psychosis in adolescents

Ajit Kumar  1 , Soumitra S Datta, Stephen D Wright, Vivek A Furtado, Paul S Russell
Affiliations
Meta-Analysis

Atypical antipsychotics for psychosis in adolescents

Ajit Kumar et al. Cochrane Database Syst Rev. .

Abstract

Background: Schizophrenia often presents in adolescence, but current treatment guidelines are based largely on studies of adults with psychosis. Over the past decade, the number of studies on treatment of adolescent-onset psychosis has increased. The current systematic review collates and critiques evidence obtained on the use of various atypical antipsychotic medications for adolescents with psychosis.

Objectives: To investigate the effects of atypical antipsychotic medications in adolescents with psychosis. We reviewed in separate analyses various comparisons of atypical antipsychotic medications with placebo or a typical antipsychotic medication or another atypical antipsychotic medication or the same atypical antipsychotic medication but at a lower dose.

Search methods: We searched the Cochrane Schizophrenia Group Register (October 2011), which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies and contacted study authors and relevant pharmaceutical companies to ask for more information.

Selection criteria: We included all relevant randomised controlled trials (RCTs) that compared atypical antipsychotic medication with placebo or another pharmacological intervention or with psychosocial interventions, standard psychiatric treatment or no intervention in children and young people aged 13 to 18 years with a diagnosis of schizophrenia, schizoaffective disorder, acute and transient psychoses or unspecified psychosis. We included studies published in English and in other languages that were available in standardised databases.

Data collection and analysis: Review authors AK and SSD selected the studies, rated the quality of the studies and performed data extraction. For dichotomous data, we estimated risk ratios (RRs) with 95% confidence intervals (CIs) using a fixed-effect model. When possible, for binary data presented in the 'Summary of findings' table, we calculated illustrative comparative risks. We summated continuous data using the mean difference (MD). Risk of bias was assessed for included studies.

Main results: We included 13 RCTs, with a total of 1112 participants. We found no data on service utilisation, economic outcomes, behaviour or cognitive response. Trials were classified into the following groups. 1. Atypical antipsychotics versus placebo: Only two studies compared one atypical antipsychotic medication with placebo. In one study, the number of non-responders treated with olanzapine was not different from the number treated with placebo (1 RCT, n = 107, RR 0.84, 95% CI 0.65 to 1.10); however, significantly more (57% vs 32%) people left the study early (1 RCT, n = 107, RR 0.56, 95% CI 0.36 to 0.87) from the placebo group compared with the olanzapine group. With regard to adverse effects, young people treated with aripiprazole had significantly lower serum cholesterol compared with those given placebo (1 RCT, n = 302, RR 3.77, 95% CI 1.88 to 7.58). 2. Atypical antipsychotics versus typical antipsychotics: When the findings of all five trials comparing atypical antipsychotic medications with a typical antipsychotic medication were collated, no difference in the mean end point Brief Psychiatric Rating Scale (BPRS) score was noted between the two arms (5 RCTs, n = 236, MD -1.08, 95% CI -3.08 to 0.93). With regard to adverse effects, the mean end point serum prolactin concentration was much higher than the reference range for treatment with risperidone, olanzapine and molindone in one of the studies. However, fewer adolescents who were receiving atypical antipsychotic medications left the study because of adverse effects (3 RCTs, n = 187, RR 0.65, 95% CI 0.36 to 1.15) or for any reason (3 RCTs, n = 187, RR 0.62, 95% CI 0.39 to 0.97).3. One atypical antipsychotic versus another atypical antipsychotic: The mean end point BPRS score was not significantly different for people who received risperidone compared with those who received olanzapine; however, the above data were highly skewed. Overall no difference was noted in the number of people leaving the studies early because of any adverse effects between each study arm in the three studies comparing olanzapine and risperidone (3 RCTs, n = 130, RR 1.15, 95% CI 0.44 to 3.04). Specific adverse events were not reported uniformly across the six different studies included in this section of the review; therefore it was difficult to do a head-to-head comparison of adverse events for different atypical antipsychotic medications.4. Lower-dose atypical antipsychotic versus standard/higher-dose atypical antipsychotic: Three studies reported comparisons of lower doses of the atypical antipsychotic medication with standard/higher doses of the same medication. One study reported better symptom reduction with a standard dose of risperidone as compared with a low dose (1 RCT, n = 257, RR -8.00, 95% CI -13.75 to -2.25). In another study, no difference was reported in the number of participants not achieving remission between the group receiving 10 mg/d and those who received 30 mg/d of aripiprazole (1 RCT, n = 196, RR 0.84, 95% CI 0.48 to 1.48). Similarly in the other study, authors reported no statistically significant difference in clinical response between the two groups receiving lower-dose (80 mg/d) and higher-dose (160 mg/d) ziprasidone, as reflected by the mean end point BPRS score (1 RCT, n = 17, MD -4.40, 95% CI -19.20 to 10.40).

Authors' conclusions: No convincing evidence suggests that atypical antipsychotic medications are superior to typical medications for the treatment of adolescents with psychosis. However, atypical antipsychotic medications may be more acceptable to young people because fewer symptomatic adverse effects are seen in the short term. Little evidence is available to support the superiority of one atypical antipsychotic medication over another, but side effect profiles are different for different medications. Treatment with olanzapine, risperidone and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidaemia. Adolescents may respond better to standard-dose as opposed to lower-dose risperidone, but for aripiprazole and ziprasidone, lower doses may be equally effective. Future trials should ensure uniform ways of reporting.

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Conflict of interest statement

None known.

Figures

1
1
Review flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Atypical antipsychotics vs placebo (only short term), Outcome 1 Global state: No response (CGI‐S).
1.2
1.2. Analysis
Comparison 1 Atypical antipsychotics vs placebo (only short term), Outcome 2 Mental state: 1. No response.
1.4
1.4. Analysis
Comparison 1 Atypical antipsychotics vs placebo (only short term), Outcome 4 Adverse effects: 1. Different adverse effects (binary measures).
1.5
1.5. Analysis
Comparison 1 Atypical antipsychotics vs placebo (only short term), Outcome 5 Adverse effects: 2. Different adverse effects (continuous measures—mean changes).
1.6
1.6. Analysis
Comparison 1 Atypical antipsychotics vs placebo (only short term), Outcome 6 Leaving study early: 1. Various reasons (olanzapine vs placebo).
1.7
1.7. Analysis
Comparison 1 Atypical antipsychotics vs placebo (only short term), Outcome 7 Leaving study early: 2. Any reason (aripiprazole vs placebo).
2.1
2.1. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 1 Global state: 1. Worse or no improvement.
2.2
2.2. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 2 Global state: 2a. Mean end point score (CGAS, high score = good).
2.3
2.3. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 3 Global state: 2b. Mean end point score (CGI‐I, high score = poor).
2.4
2.4. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 4 Mental state: 1. No improvement (BPRS, high score = poor).
2.5
2.5. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 5 Mental state: 2a. Mean end point scores (various scales, high score = poor).
2.7
2.7. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 7 Adverse effects: 1. Anticholinergic adverse effects (TESS).
2.8
2.8. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 8 Adverse effects: 2a. Extrapyramidal adverse effects (TESS).
2.9
2.9. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 9 Adverse effects: 2b. Extrapyramidal adverse effects (mean end point scores).
2.10
2.10. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 10 Adverse effects: 3a. Other significant adverse effects.
2.11
2.11. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 11 Adverse effects: 3b. Other significant adverse effects (mean end point).
2.12
2.12. Analysis
Comparison 2 Atypical vs typical antipsychotics (only short term), Outcome 12 Leaving study early: various reasons.
3.1
3.1. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 1 Global state: 1. No improvement or no response.
3.2
3.2. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 2 Global state: 2. Mean end point scores (high score = good).
3.3
3.3. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 3 Mental state: 1. No response.
3.4
3.4. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 4 Mental state: mean end point scores (various scales, high score = poor).
3.6
3.6. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 6 Adverse effects: 1a. Different adverse effects (clozapine vs olanzapine).
3.7
3.7. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 7 Adverse effects: 1b. i. Different adverse effects (risperidone vs olanzapine).
3.8
3.8. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 8 Adverse effects: 1b.ii. Different adverse effects—means at end of study (risperidone vs olanzapine, high score = poor).
3.10
3.10. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 10 Adverse effects: 1c. Different adverse effects (risperidone vs quetiapine).
3.11
3.11. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 11 Adverse effects: 2a. Metabolic syndrome measures—means at end of study (clozapine vs olanzapine).
3.12
3.12. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 12 Adverse effects: 2b.i. Metabolic syndrome measures—means at end of study (risperidone vs olanzapine).
3.14
3.14. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 14 Leaving study early: 1a. Clozapine vs olanzapine.
3.15
3.15. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 15 Leaving the study early: 1b. Olanzapine vs quetiapine.
3.16
3.16. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 16 Leaving study early: 1c. Risperidone vs olanzapine.
3.17
3.17. Analysis
Comparison 3 Atypical antipsychotics vs atypical antipsychotics (only short term), Outcome 17 Leaving the study early: 1d. Risperidone vs quetiapine.
4.1
4.1. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 1 Global state: 1. No response—not sustained response at end of 8 weeks.
4.2
4.2. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 2 Global state: 2a. Mean end point score (CGI‐I, high score = poor).
4.3
4.3. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 3 Global state: 2b. Mean scores—at 6 weeks (aripiprazole 30 mg vs 10 mg).
4.4
4.4. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 4 Mental state: 1. No response.
4.5
4.5. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 5 Mental state: 2. Mean end point scores (high score = poor).
4.6
4.6. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 6 Adverse effects: 1. Endrocrine.
4.7
4.7. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 7 Adverse effects: 2. Extrapyramidal.
4.8
4.8. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 8 Adverse effects: 3. Metabolic.
4.9
4.9. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 9 Adverse effects: 4. Others.
4.10
4.10. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 10 Adverse effects: 5. Others (particular to the aripiprazole 30 mg vs 10 mg comparison).
4.12
4.12. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 12 Leaving study early: 1. Various reasons.
4.13
4.13. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 13 Leaving study early: 2. Ziprasidone 160 mg vs 80 mg.
4.14
4.14. Analysis
Comparison 4 Atypical (standard dose) vs atypical (low dose) antipsychotics (only short term), Outcome 14 Leaving study early: 3. Aripiprazole 30 mg vs aripiprazole 10 mg.
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Update of

References

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References to studies excluded from this review

Amminger 2006 {published data only}
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Buchsbaum 2007 {published data only}
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Linszen 2006 {published data only}
    1. Linszen D, Haan L, Dingemans P, Lenior R, Amelsvoort T, Wouters L. The Amsterdam critical period intervention in the early phase of schizophrenia‐like psychoses. Schizophrenia Research 2006;86(Suppl 1):S61.
Lv 2004 {published data only}
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Malik 1980 {published data only}
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Mathai 2004 {published data only}
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McConville 2003 {published data only}
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McGlashan 2003 {published data only}
    1. Hawkins KA, Addington J, Keefe RS, Christensen B, Woods SW, Zipursky RB, et al. Effect of olanzapine vs. placebo on the neuropsychological status of prodromal subjects. 12th Biennial Winter Workshop on Schizophrenia, 2004 February 7‐13, Davos, Switzerland. [PsycINFO]
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McGorry 2007 {published data only}
    1. McGorry PD, Phillips LJ, Nelson B, Leicester S, Baker K, Krstev H, et al. A double blind, placebo‐controlled randomized trial of low‐dose risperidone, cognitive‐behaviour therapy, and befriending in young people with subthreshold symptoms at incipient risk of psychotic disorder: six month outcome data. Schizophrenia Bulletin 2007;33(2):446.
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Newton 2005 {published data only}
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Otsuka 2005 {published data only}
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Schepp 1999 {published data only}
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Sela 2003 {published data only}
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Stain 2006 {published data only}
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Tandon 2005 {published data only}
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Wykes 2007 {published data only}
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Xiu 2004 {published data only}
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Yang 2007 {published data only}
    1. Yang W, Liu X‐Q, Li X‐W. A ramdomized controlled clinical study of aripiprazole in the treatment of childhood schizophrenia [阿立呱唑治疗儿童精神分裂症多中心随机对照研究]. Hunan Medical Journal 2007;24(6):942‐4. [CHINESE: Academic Journals]
Yao 2003 {published data only}
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Yi 2006 {published data only}
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Zhang 2007 {published data only}
    1. Zhang Y, Zhang H, Gu W. A control study of aripiprazole in the treatment of childhood schizophrenia [阿立哌唑治疗儿童精神分裂症对照研究]. Journal of Clinical Psychosomatic Diseases [临床心身疾病杂志] 2007;13(2):122‐4. [CHINESE: Academic Journals]
Zhou 2007 {published data only}
    1. Zhou Z‐H, Yuan G‐Z, Zhu H‐M. Effects of olanzapine treatment on the auditory evoked event‐related potential P300 in childhood and adolescent schizophrenia [奥氮平对儿少期精神分裂症患者听觉事件相关电位P_(300)的影响]. Chinese Journal of Behavioral Medical Science [中国行为医学科学] 2007;16(10):906‐7. [CHINESE: Academic Journals]
杨玲 2004 {published data only}
    1. 杨玲, 杨庆南, 侯永花, 刘涛, 严宏力. [only Chinese Title available] [抗精神病药物对精神分裂症患儿心电图的影响]. Journal of Applied Clinical Pediatrics [实用儿科临床杂志] 2004;19(12):1076‐7.
谭友果 2002 {published data only}
    1. 谭友果, 刘成文, 刘勇, 甘枝勤. [only Chinese Title available] [首发青少年精神分裂症药物疗效的纵向比较]. Chinese Journal of Nervous and Mental Diseases 2002;28(5):365‐7.

References to ongoing studies

Alaghband‐rad 2006 {published data only}
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AstraZeneca 2004 {published data only}
    1. AstraZeneca. A 6‐week, multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled, phase 3b study of the efficacy and safety of quetiapine fumarate (Seroquel™) immediate‐release tablets compared with placebo in adolescents with schizophrenia, 2004. http:www.clinicaltrials.gov.
AstraZeneca 2005 {published data only}
    1. AstraZeneca. A 26‐week, multicenter, open‐label phase 3b study of the safety and tolerability of quetiapine fumarate (Seroquel™) immediate‐release tablets in daily doses of 400 mg to 800 mg in children and adolescents with bipolar I disorder and adolescents with schizophrenia, 2005. http:www.clinicaltrials.gov.
Bechdolf 2007 {published data only}
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Pfizer 2005 {published data only}
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