TITLE: Antipsychotics for Pediatric Patients: A Review of the Clinical Effectiveness, Safety, and Guidelines

Transcription

1 TITLE: Antipsychotics for Pediatric Patients: A Review of the Clinical Effectiveness, Safety, and Guidelines DATE: 24 March 2016 CONTEXT AND POLICY ISSUES Antipsychotics are widely used to treat various psychiatric disorders. They are commonly divided into two types: typical (or first-generation) antipsychotics and atypical (or secondgeneration) antipsychotics. 1 Typical antipsychotics include chlorpromazine, haloperidol, molindone, perphenazine, and pimozide. 2,3 Atypical antipsychotics include aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, tiapride, and ziprasidone. 2-4 Antipsychotics may alleviate psychotic symptoms but are associated with various adverse effects, including weight gain, sedation, and neurological symptoms (for example, extrapyramidal symptoms [EPSs], which are drug-induced movement disorders). 2 EPSs include akathisia (i.e., motor restlessness) and dystonia (i.e., continuous spasms and muscle contractions). Nevertheless, the use of antipsychotics to treat pediatric patients with mental disorders has increased significantly during the past 20 years. 1,5 In Canada, antipsychotics recommendations by specialists for children increased by 114% from 2005 to 2009; the majority of the recommendations were for atypical antipsychotics. 6 While antipsychotics approved for pediatric patients may be restricted mainly for schizophrenia and bipolar disease, 1,7 they are increasingly used for off-label indications, raising concerns and controversies. 8,9 The purpose of this report is to provide evidence on the clinical benefits and harms of using antipsychotics in pediatric patients and to summarize evidence-based guidelines on the use of antipsychotics in these patients. This report is an update of two previous reports on this topic, 10,11 produced by the Canadian Agency for Drugs and Technologies in Health (CADTH). RESEARCH QUESTIONS 1. What are the clinical benefits and harms of using antipsychotics in pediatric patients? 2. What are the guidelines regarding the use of antipsychotics in pediatric patients? Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that the Canadian Agency for Drugs and Technologies in Health (CADTH) could identify using all reasonable efforts within the time allow ed. Rapid responses should be considered along w ith other ty pes of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in w hich a third party ow ns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a w eb site, redistributed by or stored on an electronic system w ithout the prior w ritten permission of CADTH or applicable copyright ow ner. Links: This report may contain links to other information available on the w ebsites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the ow ners ow n terms and conditions.

2 KEY FINDINGS Overall, treatment with antipsychotics, whether typical or atypical, results in improvement in tic disorders, disruptive and aggressive behaviors, schizophrenia, and autism in pediatric patients but is associated with adverse effects. While the effectiveness of various antipsychotics appears comparable, side effect profiles appear to differ significantly among antipsychotics. Considering the balance between benefits and harms associated with various antipsychotics, some proposed the use of aripiprazole, clonidine, or risperidone over olanzapine and clozapine; however, these proposals were not necessarily based on high-quality evidence and should be considered with caution. METHODS Literature Search Methods A limited literature search was conducted on key resources, including PubMed, the Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, and Canadian and major international health technology agencies. A focused Internet search was also conducted. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies containing safety data, and guidelines. Where possible, retrieval was limited to the human population. The search was also limited to English language documents, published between January 1, 2012 and February 26, Selection Criteria and Methods Two reviewers screened non-overlapping sets of citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially-relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Table 1: Selection Criteria Population Pediatric patients (i.e., aged <18 years old) Intervention Antipsychotics (any type or any generation) Comparator Any or no control, if literature is limited to HTAs, SRs, and MAs Any control, including before-and-after, if literature includes primary studies Outcomes Efficacy, safety, and guidelines Study Designs HTAs, SRs, MAs, and evidence-based guidelines; and RCTs and nonrandomized studies, if few HTAs, SRs, or MAs are found Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, if they had been included in the previous CADTH reports on this topic, 10,11 or if they were duplicate publications. Studies on mixed populations (i.e., pediatric and adult) that did not report data separately for pediatric patients were excluded. Antipsychotics for Pediatrics 2

3 Critical Appraisal of Individual Studies The included SRs and evidence-based guidelines were critically appraised, using the Assessment of Multiple Systematic Reviews (AMSTAR) tool 12 and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, 13 respectively. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included study were described. SUMMARY OF EVIDENCE Quantity of Research Available A total of 905 citations were identified in the literature search. Due to the large volume of literature available, a decision was made to restrict the final selection of articles to HTAs, SRs, MAs, and evidence-based guidelines; individual RCTs or non-randomized studies were not considered. Therefore, a total of 164 citations from the literature search were considered. Following screening of the 164 titles and abstracts, 112 citations were excluded, and 52 potentially relevant reports from the electronic search were retrieved for full-text review. Seven potentially relevant reports were also retrieved from the grey literature search. Of these 59 potentially relevant reports, 47 publications were excluded for various reasons, while 12 publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Additional references of potential interest are provided in Appendix 5. Summary of Study Characteristics A summary of the characteristics of the included SRs and evidence-based guidelines is presented in Appendix 2. Clinical Benefits and Harms of Using Antipsychotics in Pediatric Patients A total of nine SRs 2-4,7,9,14-17 provided information on the clinical effectiveness and safety of using antipsychotics in pediatric patients. One SR 2 was published in 2016; three SRs, 4,14,15 in 2015; one SR, 9 in 2014; three SR, 3,16,17 in 2013; and one SR, 7 in Study Design Four SRs 3,7,15,17 included RCTs. One SR 16 included RCTs and open-label studies. Two SRs 2,4 included RCTs and controlled before-and-after studies. One SR 14 included RCTs and nonrandomized controlled studies. One SR 9 included RCTs, non-randomized controlled and uncontrolled studies, and case series and reports. One SR 2 was part of an HTA, and seven SRs 2-4,9,15-17 conducted MAs on subsets of included studies. Country of Origin Three SRs 2,3,15 were conducted in the United Kingdom (UK), one 3 of which was by the Cochrane Collaboration. One SR 14 was conducted in the United States (US), by the Agency for Healthcare Research and Quality (AHRQ). Two SRs 7,16 were conducted in Canada. One SR 4 was Antipsychotics for Pediatrics 3

4 conducted in China. One SR 9 was conducted in collaboration between Canada and the US. One SR 17 was conducted in collaboration between Canada, China, and the UK. Patient Population Nine SRs 2-4,7,9,14-17 included children and adolescents, aged 18 years old or younger. Two SRs 2,4 concerned tic disorders, including Tourette syndrome and chronic tic disorder (CTD). Two SRs 7,14 concerned disruptive behaviour disorders, excluding 14 or including 7 attention deficit hyperactivity disorder (ADHD)-related behaviours. Two SRs 3,15 concerned psychosis, pertaining to schizophrenia and related disorders. One SR 16 concerned autism spectrum disorders, including Asperger s disorder and high functioning autism. Two SRs 9,17 concerned multiple conditions, including psychiatric, developmental, and behavioural disorders 9 or any indications for atypical antipsychotics. 17 Interventions and Comparators Three SRs 2,14,15 included studies comparing various antipsychotics (i.e., aripiprazole, 2,14,15 haloperidol, 2,15 olanzapine, 2,15 pimozide, 2 paliperidone, 15 quetiapine, 14,15 risperidone, 2,14,15 and ziprasidone 2,14 ) to placebo or other antipsychotics. Three SRs 3,16,17 included studies comparing atypical antipsychotics (i.e., aripiprazole, 3,16,17 clozapine, 3 olanzapine, 3,16,17 paliperidone, 3 quetiapine, 3,16 risperidone, 3,16,17 and ziprasidone 3 ) to placebo, 3,16,17 typical antipsychotics (i.e., chlorpromazine, haloperidol, molindone, and perphenazine), 3 other atypical antipsychotics, 3 combination treatment (i.e., risperidone with parent training), 16 or no control. 16 Three SRs 4,7,9 included studies comparing a single antipsychotic (i.e., aripiprazole, 4 olanzapine, 9 or risperidone 7 ) to placebo, 4,7,9 other antipsychotics (i.e., clozapine, 9 haloperidol, 4,9 risperidone, 4,9 and tiapride 4 ), or no control. 9 Outcomes Two SRs 2,4 included tic severity measures and personal and social impairment measures. Two SRs 7,16 included disruptive 7 or aberrant 16 behavior measures. Two SRs 3,15 included psychotic symptom 15 or mental state 3 measures (i.e., reflecting the severity of an abnormal mental state). Three SRs 2,3,16 included overall global state measures (i.e., reflecting illness severity and clinical improvement). Seven SRs 2-4,9,14,15,17 included adverse effect measures. All nine SRs 2-4,7,9,14-17 rated the quality of evidence, using various tools including: the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool; 2,15,16 the Cochrane risk of bias tool; 3,4,14,15 the Research Triangle Institute (RTI) Item Bank tool; 14 the United States Preventive Services Task Force (USPSTF) tool; 7 a modified tool initially developed for prognostic studies; 9 and the Jadad scale. 17 Guidelines Regarding the Use of Antipsychotics in Pediatric Patients A total of three evidence-based guidelines provided recommendations regarding the use antipsychotics in pediatric patients. Study Design One guideline 19 was developed in 2015; one guideline, 20 in 2013; and one guideline, 18 in Antipsychotics for Pediatrics 4

5 Country of Origin One guideline 20 was developed in the US, by the American Academy of Child and Adolescent Psychiatry Committee on Quality Issues (AACAP CQI). Two guidelines 18,19 were developed in Canada; one of them 19 was endorsed by the Canadian Paediatric Society and the Canadian Academy of Child and Adolescent Psychiatry. Patient Population Three guidelines included children and adolescents, aged 18 years old or younger. One guideline 18 concerned tic disorders. One guideline 19 concerned disruptive behavioural disorders, including ADHD. One guideline 20 concerned schizophrenia. Interventions and Comparators Three guidelines provided recommendations on the use of various treatments, including antipsychotics, for different disorders; the recommendations related to the use of antipsychotics in children and adolescents are included in this report. Outcomes Three guidelines provided recommendations on specific populations, 18 doses, 18 and strategies (for example, first- versus second-line treatment or preferred medications), related to the use of antipsychotics. All three guidelines rated the quality of evidence, using the GRADE tool 18,19 or a four-level rating system, categorizing clinical standard, clinical guideline, clinical option, and no endorsement. 20 Summary of Critical Appraisal A summary of the critical appraisal of the included SRs and evidence-based guidelines is presented in Appendix 3. Clinical Benefits and Harms of Using Antipsychotics in Pediatric Patients The nine SRs 2-4,7,9,14-17 were of moderate-to-high quality. Five SRs 2,3,14,15,17 performed a comprehensive literature search, including multiple databases and grey literature; seven SRs 4,7,9,14-17 had duplicate study selection and data extraction; six SRs 2,3,7,15-17 provided a list of the excluded studies; eight SRs 2-4,7,14-17 used validated tools to assess the quality of evidence; and six SRs 3,7,14-17 explicitly used the quality of the included studies in formulating conclusions. However, five SRs 3,4,7,9,14 did not use an a priori design; one SR 7 provided no synthesis of the study findings, other than a detailed summary of each of the included studies and their outcomes reported and general, qualitative concluding statements; one SR 9 did not specify what models (for example, fixed- or random-effects) were used in their MAs; seven SRs 2-4,7,9,14,15 did not assess 2,7,9,14,15 or discuss 3,4 the likelihood of publication bias; and three SRs 2,7,17 had one or more authors who disclosed having received financial support from pharmaceutical companies. Guidelines Regarding the Use of Antipsychotics in Pediatric Patients The three evidence-based guidelines were of high quality. All three guidelines explicitly stated their scope and purpose, involved all relevant stakeholders, and sought input from target Antipsychotics for Pediatrics 5

6 populations; used systematic search strategies and well-defined selection criteria to identify all relevant articles from notable databases and rated the strength of their recommendations; and developed recommendations that were explicit and supported with evidence and described the methods for formulating them. However, one guideline 20 may not have been externally reviewed prior to publication; none of the three guidelines described a procedure for updating their recommendations; one guideline 18 did not consider applicability, such as facilitators and barriers for implementation and resource implications; and all three guidelines had authors declare several conflicts of interest. Summary of Findings A summary of the findings of the included SRs and evidence-based guidelines is presented in Appendix 4. What are the Clinical Benefits and Harms of Using Antipsychotics in Pediatric Patients? Tic Disorders One SR 2 on Tourette syndrome and CTD reported that various antipsychotics (i.e., aripiprazole, haloperidol, olanzapine, pimozide, risperidone, and ziprasidone), compared to placebo, showed reductions in tic severity and personal and social impairment and better overall global states, with little to no evidence of differences among the different antipsychotics. One SR 4 on tic disorders also reported that there was no significant difference in reductions in tic severity or personal and social impairment between aripiprazole and other antipsychotics (i.e., haloperidol, risperidone, and tiapride). One SR 2 on Tourette syndrome and CTD reported on adverse effects associated with ziprasidone and risperidone, compared to placebo, including weight gain and sedation. The SR 2 also reported that aripiprazole, haloperidol, and risperidone, compared to pimozide, were associated with weight gain, EPSs, or cardiac risks. One SR 4 on tic disorders reported that the most common adverse effects associated with aripiprazole, haloperidol, risperidone, and tiapride included drowsiness, increased appetite, nausea, and headaches. Disruptive Behaviour Disorders One SR 7 on disruptive behavior disorders reported that, for children with sub-average intelligence quotients (IQs), risperidone, compared to placebo, generally showed improvement in disruptive behaviors. One SR 14 on disruptive behaviour disorders reported on adverse effects associated with risperidone, compared to placebo, including weight gain, sedation, and drowsiness. However, some studies included in the SR 14 reported that adverse effects were more frequent with placebo, compared to quetiapine, and that sedation was frequently reported in both arms of a study comparing aripiprazole and ziprasidone. 14 Schizophrenia and Related Disorders One SR 15 on psychosis or schizophrenia reported that various antipsychotics (i.e., aripiprazole, olanzapine, paliperidone, and quetiapine), compared to placebo, showed reductions in Antipsychotics for Pediatrics 6

7 psychotic symptoms. Reductions were identified at both low and high doses, and there was no significant difference in reductions between haloperidol and risperidone. 15 One SR 3 on schizophrenia and related disorders also reported that there was no significant difference in the mean end-point in mental states between atypical antipsychotics (i.e., clozapine, olanzapine, paliperidone, and risperidone) and typical antipsychotics (i.e., chlorpromazine, haloperidol, molindone, and perphenazine) or between different doses of atypical antipsychotics (i.e., aripiprazole and risperidone). One SR 3 on schizophrenia and related disorders reported that there was no significant difference in improvement in overall global states between two atypical antipsychotics (i.e., olanzapine and risperidone). However, atypical antipsychotics (i.e., aripiprazole, risperidone, and ziprasidone) at high doses, compared to low doses, showed significantly greater improvement in overall global states. 3 Two SRs 3,15 on schizophrenia reported that, some antipsychotics (i.e., olanzapine, 3 paliperidone, 15 and quetiapine 15 ) but not others (i.e., aripiprazole 3 ), compared to placebo, showed weight gain. One SR 3 reported that there was no significant difference in EPSs between an atypical antipsychotic (i.e., risperidone) and typical antipsychotics (i.e., chlorpromazine and perphenazine); however, some antipsychotics, compared to others, were associated with greater gain in body weight (i.e., olanzapine versus risperidone), greater drowsiness (i.e., clozapine versus haloperidol), or higher mean serum cholesterol concentration (i.e., olanzapine versus molindone). No significant difference was reported from other comparisons in body weight (i.e., clozapine versus olanzapine) or muscle stiffness or akathisia (i.e., olanzapine versus risperidone). 3 There was no significant difference in weight gain between low and high doses of paliperidone and quetiapine. 15 However, low doses of risperidone, compared to high doses, were associated with significantly less-frequent EPSs and dystonia. 3 Autism Spectrum Disorders One SR 16 on Asperger s disorder and high functioning autism reported that, atypical antipsychotics (i.e., aripiprazole, olanzapine, and risperidone), compared to controls (i.e., placebo or combination treatment), showed improvement in aberrant behaviors and overall global states. However, the SR 16 reported that olanzapine and risperidone were associated with significant weight gain and that other adverse effects included increased appetite, pulse rates, systolic blood pressure; not all of the adverse effects were deemed clinically relevant. Multiple Conditions One SR 9 on psychiatric, developmental, and behavioural disorders reported that olanzapine, compared to placebo or other antipsychotics (i.e., clozapine, haloperidol, and risperidone), showed increases in weight gain, sedation, electrocardiogram abnormalities, EPSs, liver function test abnormalities, and blood glucose abnormalities. Other adverse effects identified included the following: akathisia; anxiety; cold or flu-like symptoms; constipation; dry eyes, nose, or mouth; gastrointestinal problems; headaches; hypersalivation; urinary adverse effects; and olanzapine poisoning, in cases of overdose. 9 One SR 17 on any indication for atypical antipsychotics reported that atypical antipsychotics (i.e., aripiprazole, olanzapine, and risperidone), compared to placebo, was associated with weight gain; the effect appeared to be greatest with olanzapine. Antipsychotics for Pediatrics 7

8 What are the Guidelines Regarding the Use of Antipsychotics in Pediatric Patients? Tic Disorders One evidence-based guideline 18 recommended that children and adults who are overweight, as measured by the body mass index (BMI) or waist circumference, should avoid olanzapine, quetiapine, and risperidone, because of the risk of further weight gain associated with the antipsychotics. One evidence-based guideline 18 recommended specific doses for various antipsychotics (i.e., aripiprazole, fluphenazine, haloperidol, olanzapine, pimozide, quetiapine, risperidone, and ziprasidone) and also recommended specific strategies (i.e., behavioural therapies and nonantipsychotics [i.e., clonidine and guanfacine] should be considered first-line therapies for tics; two antipsychotics [i.e., aripiprazole and risperidone] should be second-line therapies; and four antipsychotics [i.e., fluphenazine, haloperidol, pimozide, and ziprasidone] should be third-line therapies). Disruptive Behaviour Disorders One evidence-based guideline 19 recommended the use of clonidine, haloperidol, quetiapine, and risperidone to treat disruptive and aggressive behaviours, with risperidone as the most effective medication to treat those behaviours in the absence of ADHD. Schizophrenia and Related Disorders One evidence-based guideline 20 recommended most antipsychotics, with the exception of clozapine, as a primary treatment option for schizophrenia. The guideline 20 also recommended that a trial of clozapine be considered with treatment-resistant schizophrenia spectrum disorders. Limitations Although nine SRs 2-4,7,9,14-17 were identified and included in this report, the number of studies for each antipsychotic for each disorder for each outcome identified by each SR was limited, ranging from one to seven. For example, one SR 2 reported many of its findings from single studies. In this report, the findings of the nine SRs that had been synthesized, either quantitatively (for example, through MAs) or qualitatively (for example, general concluding statements, summarizing the included studies), in regards to the clinical effectiveness of using antipsychotics in pediatric patients were reported. In terms of safety, all findings of the nine SRs, including those from single studies, were reported. Since no primary studies were included in this report, some findings may have been missed. While the included SRs and guidelines were of moderate-to-high quality, several SRs 2,4,15 and guidelines 18,19 rated the quality of the studies included in their review as low, due to limited sample sizes, ranging from 19 to 335 participants, 18,19 or large heterogeneity observed in MA results, with I 2 ranging from 62% to 87%. 4 One SR 3 also reported variability in the instruments used to measure outcomes. Several SRs 2,4,16 and guideline 18 suggested that, in addition to more studies, higher-quality trials are needed. Lack of long-term effects was also noted by five SRs. 2-4,14,16 Therefore, caution is warranted when considering their conclusions. Antipsychotics for Pediatrics 8

9 CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING This report, which is a follow-up to two previous CADTH reports 10,11 on the clinical benefits, harms, and guidelines on using antipsychotics in pediatric patients, contains information that became available since the publication of the last report in This report includes: two SRs 2,4 and one evidence-based guideline 18 on tic disorders; two SRs 7,14 and one evidencebased guideline 19 on disruptive behavior disorders; two SRs 3,15 and one evidence-based guideline 20 on schizophrenia and related disorders; one SR 16 on autism spectrum disorders; and two SRs 9,17 on multiple conditions, including any indications for antipsychotics and psychiatric, developmental, and behavioural disorders. Overall, treatment with antipsychotics, whether typical or atypical, results in improvement in various disorders in pediatric patients but is associated with adverse effects, including weight gain, sedation, and neurological symptoms. Most of the evidence was collected from short-term studies, and long-term studies are lacking. These findings are consistent with the last CADTH report on this topic. 11 The effectiveness of various antipsychotics, whether typical or atypical or used at either low or high doses, appears comparable, with no or minor differences at best in psychotic symptoms, personal and social impairment, and overall global states among different antipsychotics. Nevertheless, side effect profiles appear to differ significantly among antipsychotics. Considering the balance between benefits and harms associated with various antipsychotics, some SRs 2,4,7,17 and guidelines proposed first using aripiprazole, 2,4,18 clonidine, 2 or risperidone 2,7,18,19 or avoiding olanzapine 17 especially in those who are overweight 18 and clozapine. 20 However, these proposals should be considered with caution, since, while several SRs 2,4,15 and guidelines 18,19 rated the quality of the studies included in their review as low, they did not necessarily incorporate the quality of the included studies in formulating their conclusions. These findings are additions to the last CADTH report on this topic. 11 PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Antipsychotics for Pediatrics 9

10 REFERENCES 1. First- and second-generation antipsychotics for children and young adults [Internet]. Rockville (MD): Agency for Healthcare Research and Quality; 2012 Feb. [cited 2012 Dec 13]. (Comparative effectiveness review number 39). Available from: 2. Hollis C, Pennant M, Cuenca J, Glazebrook C, Kendall T, Whittington C, et al. Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis. Health Technol Assess [Internet] Jan [cited 2016 Mar 1];20(4): Available from: data/assets/pdf_file/0010/159832/fullreporthta20040.pdf 3. Kumar A, Datta SS, Wright SD, Furtado VA, Russell PS. Atypical antipsychotics for psychosis in adolescents. Cochrane Database Syst Rev. 2013;10:CD Yang CS, Huang H, Zhang LL, Zhu CR, Guo Q. Aripiprazole for the treatment of tic disorders in children: a systematic review and meta-analysis. BMC Psychiatry [Internet] [cited 2016 Mar 1];15:179. Available from: 5. Pringsheim T, Lam D, Ching H, Patten S. Metabolic and neurological complications of second-generation antipsychotic use in children: a systematic review and meta-analysis of randomized controlled trials. Drug Saf Aug 1;34(8): Pringsheim T, Lam D, Patten SB. The pharmacoepidemiology of antipsychotic medications for Canadian children and adolescents: J Child Adolesc Psychopharmacol Dec;21(6): Pringsheim T, Gorman D. Second-generation antipsychotics for the treatment of disruptive behaviour disorders in children: a systematic review. Can J Psychiatry Dec;57(12): De Hert M, Dobbelaere M, Sheridan EM, Cohen D, Correll CU. Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: A systematic review of randomized, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry Apr;26(3): Flank J, Sung L, Dvorak CC, Spettigue W, Dupuis LL. The safety of olanzapine in young children: a systematic review and meta-analysis. Drug Saf Oct;37(10): Anti-psychotics in pediatric patients: a review of the clinical effectiveness, safety, and guidelines [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; [cited 2012 Nov 19]. Available from: ents%20final.pdf Antipsychotics for Pediatrics 10

11 11. Antipsychotics for pediatric patients: A review of the clinical effectiveness, safety, and guidelines [Internet]. Ottawa: CADTH; 2012 Dec 17. [cited 2016 Mar 9]. (Rapid response report: summary with critical appraisal). Available from: /RC0414%20Antipsychotics%20Ped%20Final.pdf 12. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] [cited 2016 Mar 23];7:10. Available from: Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in healthcare. CMAJ [Internet] Dec [cited 2016 Mar 23];182(18):E839-E842. Available from: Epstein R, Fonnesbeck C, Williamson E, Kuhn T, Lindegren ML, Rizzone K, et al. Psychosocial and pharmacologic interventions for disruptive behavior in children and adolescents [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2015 Oct. [cited 2016 Mar 11]. (Comparative effectiveness reviews; no. 154). Available from: Stafford MR, Mayo-Wilson E, Loucas CE, James A, Hollis C, Birchwood M, et al. Efficacy and safety of pharmacological and psychological interventions for the treatment of psychosis and schizophrenia in children, adolescents and young adults: a systematic review and meta-analysis. PLoS ONE [Internet] [cited 2016 Mar 1];10(2):e Available from: Sochocky N, Milin R. Second generation antipsychotics in Asperger's Disorder and high functioning autism: a systematic review of the literature and effectiveness of metaanalysis. Curr Clin Pharmacol Nov;8(4): Almandil NB, Liu Y, Murray ML, Besag FM, Aitchison KJ, Wong IC. Weight gain and other metabolic adverse effects associated with atypical antipsychotic treatment of children and adolescents: a systematic review and meta-analysis. Paediatr Drugs Apr;15(2): Pringsheim T, Doja A, Gorman D, McKinlay D, Day L, Billinghurst L, et al. Canadian guidelines for the evidence-based treatment of tic disorders: pharmacotherapy. Can J Psychiatry Mar;57(3): Gorman DA, Gardner DM, Murphy AL, Feldman M, Belanger SA, Steele MM, et al. Canadian guidelines on pharmacotherapy for disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, or conduct disorder. Can J Psychiatry [Internet] Feb [cited 2016 Mar 10];60(2): Available from: McClellan J, Stock S, American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI). Practice parameter for the assessment and Antipsychotics for Pediatrics 11

12 treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry [Internet] Sep;52(9): Available from: Antipsychotics for Pediatrics 12

13 APPENDIX 1: Selection of Included Studies 164 citations identified from electronic literature search and screened 112 citations excluded 52 potentially-relevant articles retrieved for scrutiny (full text, if available) 7 potentially-relevant reports retrieved from other sources (i.e., grey literature or hand search) 59 potentially-relevant reports 47 reports excluded due to: irrelevant population (7) irrelevant intervention (3) irrelevant outcomes (4) already included in previous CADTH reports on this topic (5) duplicate citation (1) irrelevant study design (e.g., narrative reviews, guidelines that are not evidence-based, or editorials) (27) 12 reports included in review Antipsychotics for Pediatrics 13

14 APPENDIX 2: Characteristics of Included Publications First Author, Publication Year, Country, Sources of Funding Tic Disorders Hollis UK Funded by the National Institute for Health Research HTA programme Yang China Funded by the Natural Science Foundation of China Types and Numbers of Primary Studies Included SR/HTA of 5 RCTs and 3 controlled before-and-after studies, published between 1997 and 2011 MAs of study subsets using random-effects models and assessment of quality of evidence using the GRADE approach SR of 12 RCTs and controlled before-andafter studies, published between 2010 and 2013 MAs of study subsets using random- or fixed-effects models and assessment of risk of bias using the Cochrane approach Table A1: Characteristics of Included SRs Population Intervention Comparator(s) Clinical Outcomes, Characteristics Length of Follow-Up Children and adolescents (i.e,. aged <18 years old) with Tourette syndrome or CTD Children and adolescents (i.e,. aged <18 years old) with a tic disorder Pharmacological interventions, including antipsychotics (i.e., aripiprazole, haloperidol, olanzapine, pimozide, risperidone, ziprasidone) Aripiprazole Placebo or other antipsychotics (see the Interventions column) Placebo or other antipsychotics (i.e., haloperidol, risperidone, tiapride) Outcomes: tic severity (measured by YGTSS), personal and social impairment (measured by TS global scale), overall global state (measured by CGI-TS), adverse effects Follow-up length: 4 weeks to 24 months Outcomes: tic severity (measured by YGTSS), personal and social impairment (measured by YGTSS), adverse effects Follow-up length: 8-12 weeks Antipsychotics for Pediatrics 14

15 First Author, Publication Year, Country, Sources of Funding Types and Numbers of Primary Studies Included Disruptive Behaviour Disorders Epstein US Funded by the Agency for Healthcare Research and Quality Pringsheim Canada Funded by the Canadian Psychiatric Association SR of 5 RCTs and 2 non-randomized controlled studies, published between 2000 and 2009 Assessment of risk of bias using the Cochrane (for RCTs) and RTI Item Bank (for non-randomized controlled studies) approaches SR of 4 RCTs, published between 2001 and 2002 Assessment of risk of bias using the USPSTF approach Schizophrenia and Related Disorders Stafford 15 SR of 19 RCTs, 2015 published between UK 1976 and 2012 Funded by the National Collaborating Centre for Mental Health MAs of study subsets using random-effects models and assessment of risk of bias using Cochrane Table A1: Characteristics of Included SRs Population Intervention Comparator(s) Clinical Outcomes, Characteristics Length of Follow-Up Children and adolescents (i.e,. aged <18 years old) with disruptive behaviour disorders, excluding ADHD-related behaviours Children and adolescents (i.e,. aged 5-18 years old) with disruptive behaviour disorders and subaverage IQs (i.e., within range or with mean) Children and adolescents (i.e,. aged <18 years old) with psychosis or schizophrenia Pharmacological interventions, including antipsychotics (i.e., aripiprazole, quetiapine, risperidone, ziprasidone) Placebo or other antipsychotics (see the Interventions column) Outcomes: adverse effects Follow-up length: up to 6 months Risperidone Placebo Outcomes: disruptive behaviour (measured by ABC, NCBRF, or OAS) Antipsychotics (i.e., aripiprazole, haloperidol, olanzapine, paliperidone, risperidone, quetiapine) Placebo or other antipsychotics (see the Interventions column) Follow-up length: up to 10 weeks Outcomes: psychotic symptoms (measured by PANSS), adverse effects Follow-up length: 4-52 weeks Antipsychotics for Pediatrics 15

16 First Author, Publication Year, Country, Sources of Funding Kumar UK Conducted by the Cochrane Collaboration, with no external funding Types and Numbers of Primary Studies Included and assessment of quality of evidence using the GRADE approach SR of 13 RCTs, published between 1996 and 2010 Autism Spectrum Disorders Sochocky Canada Sources of funding not reported MAs of study subsets using random-effects models and assessment of risk of bias using the Cochrane approach SR of 5 RCTs and 6 open-label studies, published between 2002 and 2012 MAs on study subsets using random-effects models and assessment of evidence using the GRADE approach Table A1: Characteristics of Included SRs Population Intervention Comparator(s) Clinical Outcomes, Characteristics Length of Follow-Up Children and adolescents (i.e,. aged years old) with schizophrenia or related disorders Children and adolescents (i.e., aged 2-18 years old) with Asperger s disorder or high functioning autism Atypical antipsychotics (i.e., aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone) Atypical antipsychotics (i.e., aripiprazole, olanzapine, risperidone, and quetiapine) Placebo, typical antipsychotics (i.e., chlorpromazine, haloperidol, molindone, perphenazine), or other atypical antipsychotics (see the Interventions column) Placebo, combination treatment (i.e., risperidone with parent training), or none Outcomes: mental state (measured by BPRS), overall global state (measured by PANSS), adverse effects Follow-up length: up to 26 weeks Outcomes: aberrant behavior (measured by ABC), overall global state (measured by GCI), adverse effects Follow-up length: 8 weeks to 6 months Antipsychotics for Pediatrics 16

17 First Author, Publication Year, Country, Sources of Funding Multiple Conditions Flank Canada and US No external funding Almandil Canada, China, UK No external funding Types and Numbers of Primary Studies Included SR of 2 RCTs, 15 prospective openlabel studies, 2 retrospective reviews, and 28 case series or reports, published between 1997 and 2013 MAs of study subsets using unspecified models and assessment of risk of bias using a modified tool initially developed for prognostic studies SR of 21 RCTs, published between 2000 and 2009 MAs using randomeffects model and assessment of evidence using the Jadad scale Table A1: Characteristics of Included SRs Population Intervention Comparator(s) Clinical Outcomes, Characteristics Length of Follow-Up Children and adolescents (i.e,. aged years old) with psychiatric, developmental, or behavioural disorders Children and adolescents (i.e,. aged <18 years old) with any indication for atypical antipsychotics Olanzapine Atypical antipsychotics (i.e., aripiprazole, olanzapine, risperidone) Placebo, other antipsychotics (i.e., clozapine, haloperidol, risperidone), or none Placebo Outcomes: adverse effects Follow-up length: up to 1 year Outcomes: adverse effects Follow-up length: 3 to 26 weeks ABC = aberrant behavior checklist; ADHD = attention deficit hyperactivity disorder; BPRS = brief psychiatric rating scale; CGI = clinical global impression; CGI-TS = Clinical Global Impressions Scale for Tic Severity; CTD = chronic tic disorder; GRADE = Grading of Recommendations Assessment, Development and Evaluation; HTA = health technology assessment; IQ = intelligence quotient; MA = meta-analysis; NCBRF = Nisonger child behavior rating form; OAS = overt aggression scale; PANSS = positive and negative syndrome scale; RCT = randomized controlled trial; RTI = Research Triangle Institute; SR = systematic review; TS = Tourette syndrome; UK = United Kingdom; US = United States; USPSTF = United States Preventive Services Task Force; YGTSS = Yale Global Tic Severity Score Antipsychotics for Pediatrics 17

18 Intended Users, Target Population, Development Country, Sources of Funding Tic Disorders Pringsheim Intended Users: clinicians Target Population: children with tic disorders Development Country: Canada Sources of Funding: the Canadian Institute of Health Research and the Tourette Syndrome Foundation of Canada Objectives Intervention and Practice Considered Pharmacotherapy for tic disorders in children Table A2: Characteristics of Included Evidence-Based Guidelines Methodology Major Evidence Quality Outcomes and Strength Considered Appropriate populations for, doses of, and strategies for medications, including antipsychotics, for tic disorders Evidence Collection, Selection, and Synthesis Systematic search of peer-reviewed literature published up to 2010 Selection of studies based on inclusion/ exclusion criteria Grading of included recommendations, using the GRADE approach Quality of evidence was rated, using GRADE: Strong recommendation: high-, moderate-, low-, or very lowquality evidence; and benefits that clearly outweigh risks Weak recommendation: high-, moderate-, low-, or very lowquality evidence; and closelybalanced or uncertain benefits and risks Category X: insufficient evidence to make a formal recommendation Recommendations Development and Evaluation Recommendations were developed by a multi-institutional group of 14 experts in different fields of study. Evidence was presented and discussed. Nominal group techniques were used to arrive at consensus on recommendations. Guideline Validation The guideline was published in a peerreviewed journal. Antipsychotics for Pediatrics 18

19 Intended Users, Target Population, Development Country, Sources of Funding Objectives Intervention and Practice Considered Disruptive Behaviour Disorders Gorman Intended Users: clinicians Target Population: children and adolescents with behavioural problems Development Country: Canada Sources of Funding: a grant from the Royal Bank of Canada Knowledge Translation Fund and the Sickkids Foundation Pharmacotherapy for disruptive and aggressive behaviors in children and adolescents with ADHD, CD, or ODD Table A2: Characteristics of Included Evidence-Based Guidelines Methodology Major Evidence Quality Outcomes and Strength Considered Appropriate strategies for medications, including antipsychotics, for behavioural problems Evidence Collection, Selection, and Synthesis Systematic search of peer-reviewed and grey literature published up to 2013 Selection of studies based on inclusion/ exclusion criteria Grading of included recommendations, using the GRADE criteria Quality of evidence was rated, using GRADE: Strong recommendation in favour of an intervention Conditional recommendation in favour of an intervention Conditional recommendation against an intervention Strong recommendation against an intervention Recommendations Development and Evaluation Recommendations were developed by a multidisciplinary team 12 members in different fields of study. The team members anonymously participated in an online survey to review each medication. Guideline Validation External stakeholders reviewed the guideline. Their feedback was considered and incorporated into the final guideline. Antipsychotics for Pediatrics 19

20 Intended Users, Target Population, Development Country, Sources of Funding Objectives Intervention and Practice Considered Schizophrenia and Related Disorders McClellan AACAP CQI Intended Users: clinicians Target Population: children and adolescents with schizophrenia Development Country: US Sources of Funding: AACAP CQI Treatment of schizophrenia in children and adolescents Table A2: Characteristics of Included Evidence-Based Guidelines Methodology Major Evidence Quality Outcomes and Strength Considered Appropriate strategies for medications, including antipsychotics, for schizophrenia Evidence Collection, Selection, and Synthesis Systematic search of peer-reviewed literature published up to 2010 Selection of studies based on inclusion/ exclusion criteria Grading of included recommendations, using categorization Quality of evidence was rated, using the following categorization: Clinical standard: recommendations that are based on rigorous empirical evidence and/ or vast clinical consensus Clinical guideline: recommendations that are based on strong empirical evidence and/ or clinical consensus Clinical option: recommendations that are based on emerging empirical evidence or clinical opinion No endorsement: practices that are Recommendations Development and Evaluation Recommendations were developed by a committee, consisting of a panel of experts. Guideline Validation The guideline was internally peerreviewed. Antipsychotics for Pediatrics 20

21 Intended Users, Target Population, Development Country, Sources of Funding Objectives Intervention and Practice Considered Table A2: Characteristics of Included Evidence-Based Guidelines Methodology Major Evidence Quality Outcomes and Strength Considered Evidence Collection, Selection, and Synthesis Recommendations Development and Evaluation Guideline Validation known to be ineffective or contraindicated AACAP CQI = American Academy of Child and Adolescent Psychiatry Committee on Quality Issues, ADHD = attention deficit hyperactivity disorder; CD = conduct disorder; GRADE = Grading of Recommendations Assessment, Development and Evaluation; ODD = oppositional defiant disorder; US = United States Antipsychotics for Pediatrics 21

22 APPENDIX 3: Critical Appraisal of Included Publications Table A3: Strengths and Limitations of Included SRs Using AMSTAR 12 link to AMSTAR checklist Strengths Limitations Tic Disorders Hollis An a priori design was used. There was no duplicate study selection and no A comprehensive literature search was duplicate data extraction. performed, including multiple databases and grey literature. A detailed search strategy and The quality of the included studies was not explicitly used in formulating conclusions. a flow diagram for the search results were provided. Although the likelihood of publication bias was assessed as part of the quality assessment, A list of the included and excluded studies was provided. using GRADE, the results of the assessment was not explicitly reported. The characteristics of the included studies were provided. One of the authors disclosed having received financial support from pharmaceutical The quality of the included studies was assessed and documented, and the included studies were rated, using the GRADE approach. companies. The methods used to combine the study findings were appropriate. Yang There was duplicate study selection and data extraction. It is unclear whether an a priori design was used. A flow diagram for the search results was provided. Although a literature search was performed, using several databases, many of the A list of the included studies was provided. databases were Chinese, it is unclear if grey The characteristics of the included studies were provided. literature was included, and a detailed search strategy was not provided. Therefore, it is The risk of bias of the included studies was unclear whether a comprehensive literature assessed and documented, and the included search was performed. studies were rated, using the Cochrane risk of bias tool. A list of the excluded studies was not provided. The methods used to combine the study findings were appropriate. The quality of the included studies was not explicitly used in formulating conclusions. No conflict of interest was declared. Although the likelihood of publication bias was assessed, the results of the assessment were not explicitly discussed. Disruptive Behaviour Disorders Epstein There was duplicate study selection and data extraction. It is unclear whether an a priori design was used. A comprehensive literature search was performed, including multiple databases and A list of the excluded studies was not provided. grey literature. A detailed search strategy and a flow diagram for the search results were The quality of the included studies was not explicitly used in formulating conclusions. Antipsychotics for Pediatrics 22

23 Table A3: Strengths and Limitations of Included SRs Using AMSTAR 12 link to AMSTAR checklist Strengths Limitations provided. The likelihood of publication bias was not A list of the included studies was provided. assessed. The characteristics of the included studies were provided. The risk of bias of the included studies was assessed and documented, and the included studies were rated, using Cochrane (for RCTs) and RTI Item Bank (for non-randomized controlled studies). The methods used to combine the study findings were appropriate. No conflict of interest was declared. Pringsheim There was duplicate study selection and data extraction. A detailed search strategy was provided. A list of the included studies was provided. The characteristics of the included studies were provided. The quality of the included studies was assessed and documented, and the included studies were rated on their quality, using the USPSTF criteria. The quality of the included studies was used appropriately in formulating conclusions. Schizophrenia and Related Disorders Stafford An a priori design was provided. There was duplicate study selection and data extraction. A comprehensive literature search was performed, including multiple databases and grey literature. A detailed search strategy and a flow diagram for the search results were provided. A list of the included and excluded studies was It is unclear whether an a priori design was used. Although the authors conducted a literature search for published articles, no grey literature was included. Therefore, a comprehensive literature search was not performed. A flow diagram for the search results was not provided. A list of the excluded studies was not provided. Other than a detailed summary of each of the included studies and general, qualitative concluding statements, no synthesis of the study findings were provided. Therefore, the methods used to combine the study findings were not appropriate. The likelihood of publication bias was not assessed. One of the authors disclosed having received financial support from a pharmaceutical company. The likelihood of publication bias was not assessed. Antipsychotics for Pediatrics 23