TITLE: Antipsychotics for Pediatric Patients: A Review of ... · A summary of the characteristics...

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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 second-generation) 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?

Antipsychotics for Pediatrics 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, 2016. 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


Critical Appraisal of Individual Studies

The included SRs and evidence-based guidelines were critically appraised, using the Assessment of Multiple Systematic Reviews (AMSTAR) tool12 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 SRs2-4,7,9,14-17 provided information on the clinical effectiveness and safety of using antipsychotics in pediatric patients. One SR2 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 2012. Study Design Four SRs3,7,15,17 included RCTs. One SR16 included RCTs and open-label studies. Two SRs2,4 included RCTs and controlled before-and-after studies. One SR

14 included RCTs and non-

randomized controlled studies. One SR9 included RCTs, non-randomized controlled and uncontrolled studies, and case series and reports. One SR2 was part of an HTA, and seven SRs2-4,9,15-17 conducted MAs on subsets of included studies. Country of Origin Three SRs2,3,15 were conducted in the United Kingdom (UK), one3 of which was by the Cochrane Collaboration. One SR14 was conducted in the United States (US), by the Agency for Healthcare Research and Quality (AHRQ). Two SRs7,16 were conducted in Canada. One SR4 was


conducted in China. One SR9 was conducted in collaboration between Canada and the US. One SR17 was conducted in collaboration between Canada, China, and the UK. Patient Population Nine SRs2-4,7,9,14-17 included children and adolescents, aged 18 years old or younger. Two SRs2,4 concerned tic disorders, including Tourette syndrome and chronic tic disorder (CTD). Two SRs7,14 concerned disruptive behaviour disorders, excluding14 or including7 attention deficit hyperactivity disorder (ADHD)-related behaviours. Two SRs3,15 concerned psychosis, pertaining to schizophrenia and related disorders. One SR16 concerned autism spectrum disorders, including Asperger’s disorder and high functioning autism. Two SRs9,17 concerned multiple conditions, including psychiatric, developmental, and behavioural disorders9 or any indications for atypical antipsychotics.17 Interventions and Comparators Three SRs2,14,15 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

ziprasidone2,14) to placebo or other antipsychotics. Three SRs3,16,17 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 ziprasidone3) 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 SRs4,7,9 included studies comparing a single antipsychotic (i.e., aripiprazole,4 olanzapine,9 or risperidone7) to placebo,4,7,9 other antipsychotics (i.e., clozapine,9 haloperidol,4,9 risperidone,4,9 and tiapride4), or no control.9 Outcomes Two SRs2,4 included tic severity measures and personal and social impairment measures. Two SRs7,16 included disruptive7 or aberrant16 behavior measures. Two SRs3,15 included psychotic symptom15 or mental state3 measures (i.e., reflecting the severity of an abnormal mental state). Three SRs2,3,16 included overall global state measures (i.e., reflecting illness severity and clinical improvement). Seven SRs2-4,9,14,15,17 included adverse effect measures. All nine SRs2-4,7,9,14-17 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 guidelines18-20 provided recommendations regarding the use antipsychotics in pediatric patients. Study Design One guideline19 was developed in 2015; one guideline,20 in 2013; and one guideline,18 in 2012.


Country of Origin One guideline20 was developed in the US, by the American Academy of Child and Adolescent Psychiatry Committee on Quality Issues (AACAP CQI). Two guidelines18,19 were developed in Canada; one of them19 was endorsed by the Canadian Paediatric Society and the Canadian Academy of Child and Adolescent Psychiatry. Patient Population Three guidelines18-20 included children and adolescents, aged 18 years old or younger. One guideline18 concerned tic disorders. One guideline19 concerned disruptive behavioural disorders, including ADHD. One guideline20 concerned schizophrenia. Interventions and Comparators Three guidelines18-20 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 guidelines18-20 provided recommendations on specific populations,18 doses,18 and strategies (for example, first- versus second-line treatment or preferred medications),18-20 related to the use of antipsychotics. All three guidelines18-20 rated the quality of evidence, using the GRADE tool18,19 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 SRs2-4,7,9,14-17 were of moderate-to-high quality. Five SRs2,3,14,15,17 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 SRs2-4,7,14-17 used validated tools to assess the quality of evidence; and six SRs3,7,14-17 explicitly used the quality of the included studies in formulating conclusions. However, five SRs3,4,7,9,14 did not use an “a priori” design; one SR7 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 SR9 did not specify what models (for example, fixed- or random-effects) were used in their MAs; seven SRs2-4,7,9,14,15 did not assess2,7,9,14,15 or discuss3,4 the likelihood of publication bias; and three SRs2,7,17 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 guidelines18-20 were of high quality. All three guidelines18-20 explicitly stated their scope and purpose, involved all relevant stakeholders, and sought input from target


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 guideline20 may not have been externally reviewed prior to publication; none of the three guidelines18-20 described a procedure for updating their recommendations; one guideline18 did not consider applicability, such as facilitators and barriers for implementation and resource implications; and all three guidelines18-20 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 SR2 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 SR4 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 SR2 on Tourette syndrome and CTD reported on adverse effects associated with ziprasidone and risperidone, compared to placebo, including weight gain and sedation. The SR2 also reported that aripiprazole, haloperidol, and risperidone, compared to pimozide, were associated with weight gain, EPSs, or cardiac risks. One SR4 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 SR7 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 SR14 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 SR14 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 SR15 on psychosis or schizophrenia reported that various antipsychotics (i.e., aripiprazole, olanzapine, paliperidone, and quetiapine), compared to placebo, showed reductions in


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 SR3 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 SR3 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 SRs3,15 on schizophrenia reported that, some antipsychotics (i.e., olanzapine,3 paliperidone,15 and quetiapine15) but not others (i.e., aripiprazole3), 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 SR16 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 SR16 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 SR9 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 SR17 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.


What are the Guidelines Regarding the Use of Antipsychotics in Pediatric Patients? Tic Disorders One evidence-based guideline18 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 guideline18 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 non-antipsychotics [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 guideline20 recommended most antipsychotics, with the exception of clozapine, as a primary treatment option for schizophrenia. The guideline20 also recommended that a trial of clozapine be considered with treatment-resistant schizophrenia spectrum disorders. Limitations

Although nine SRs2-4,7,9,14-17 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 SR2 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 SRs2,4,15 and guidelines18,19 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 I2 ranging from 62% to 87%.4 One SR3 also reported variability in the instruments used to measure outcomes. Several SRs2,4,16 and guideline18 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.


CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

This report, which is a follow-up to two previous CADTH reports10,11 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 2012.11 This report includes: two SRs2,4 and one evidence-based guideline18 on tic disorders; two SRs7,14 and one evidence-based guideline19 on disruptive behavior disorders; two SRs3,15 and one evidence-based guideline20 on schizophrenia and related disorders; one SR16 on autism spectrum disorders; and two SRs9,17 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 SRs2,4,7,17 and guidelines18-20 proposed first using aripiprazole,2,4,18 clonidine,2 or risperidone2,7,18,19 or avoiding olanzapine17—especially in those who are overweight18—and clozapine.20 However, these proposals should be considered with caution, since, while several SRs2,4,15 and guidelines18,19 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: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


REFERENCES

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3. Kumar A, Datta SS, Wright SD, Furtado VA, Russell PS. Atypical antipsychotics for psychosis in adolescents. Cochrane Database Syst Rev. 2013;10:CD009582.

4. 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]. 2015 [cited 2016 Mar 1];15:179. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518630/

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6. Pringsheim T, Lam D, Patten SB. The pharmacoepidemiology of antipsychotic medications for Canadian children and adolescents: 2005-2009. J Child Adolesc Psychopharmacol. 2011 Dec;21(6):537-43.

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8. 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. 2011 Apr;26(3):144-58.

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13. 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]. 2010 Dec [cited 2016 Mar 23];182(18):E839-E842. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001530/

14. 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: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0079669/

15. 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]. 2015 [cited 2016 Mar 1];10(2):e0117166. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324833/

16. Sochocky N, Milin R. Second generation antipsychotics in Asperger's Disorder and high functioning autism: a systematic review of the literature and effectiveness of meta-analysis. Curr Clin Pharmacol. 2013 Nov;8(4):370-9.

17. 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. 2013 Apr;15(2):139-50.

18. 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. 2012 Mar;57(3):133-43.

19. 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]. 2015 Feb [cited 2016 Mar 10];60(2):62-76. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344948

20. McClellan J, Stock S, American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI). Practice parameter for the assessment and

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treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry [Internet]. 2013 Sep;52(9):976-90. Available from: http://www.sciencedirect.com/science/article/pii/S0890856713001123

http://www.sciencedirect.com/science/article/pii/S0890856713001123


APPENDIX 1: Selection of Included Studies

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

164 citations identified from electronic literature search

and screened


APPENDIX 2: Characteristics of Included Publications

Table A1: Characteristics of Included SRs

First Author, Publication

Year, Country,

Sources of Funding

Types and Numbers of Primary Studies

Included

Population Characteristics

Intervention Comparator(s) Clinical Outcomes, Length of Follow-Up

Tic Disorders

Hollis2

2016

UK Funded by the

National Institute for Health Research HTA

programme

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

Children and adolescents (i.e,. aged




Year, Country, Sources of

Funding


Included



Disruptive Behaviour Disorders

Epstein14

2015 US

Funded by the Agency for Healthcare

Research and Quality

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

Children and

adolescents (i.e,. aged





Funding


Included



and assessment of

quality of evidence using the GRADE approach

Kumar3

2013 UK

Conducted by the Cochrane Collaboration,

with no external funding

SR of 13 RCTs,

published between 1996 and 2010

MAs of study subsets using random-effects models and

assessment of risk of bias using the Cochrane approach

Children and

adolescents (i.e,. aged 13-18 years old) with schizophrenia or related

disorders

Atypical antipsychotics

(i.e., aripiprazole, clozapine, olanzapine, paliperidone,

quetiapine, risperidone, ziprasidone)

Placebo, typical

antipsychotics (i.e., chlorpromazine, haloperidol, molindone,

perphenazine), or other atypical antipsychotics (see the Interventions

column)

Outcomes:

mental state (measured by BPRS), overall global state (measured by

PANSS), adverse effects Follow-up length:

up to 26 weeks

Autism Spectrum Disorders

Sochocky16

2013 Canada

Sources of funding not reported

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

Children and

adolescents (i.e., aged 2-18 years old) with Asperger’s disorder or

high functioning autism

Atypical antipsychotics

(i.e., aripiprazole, olanzapine, risperidone, and

quetiapine)

Placebo, combination

treatment (i.e., risperidone with parent training), or none

Outcomes:

aberrant behavior (measured by ABC), overall global state

(measured by GCI), adverse effects

Follow-up length: 8 weeks to 6 months





Funding


Included



Multiple Conditions

Flank9

2014 Canada and US

No external funding

SR of 2 RCTs, 15

prospective open-label 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

Children and

adolescents (i.e,. aged 0.6-18 years old) with psychiatric,

developmental, or behavioural disorders

Olanzapine Placebo, other

antipsychotics (i.e., clozapine, haloperidol, risperidone), or none

Outcomes:

adverse effects Follow-up length:

up to 1 year

Almandil17

2013

Canada, China, UK

No external funding

SR of 21 RCTs, published between

2000 and 2009 MAs using random-

effects model and assessment of evidence using the

Jadad scale

Children and adolescents (i.e,. aged


Table A2: Characteristics of Included Evidence-Based Guidelines

Objectives Methodology

Intended Users,

Target Population,

Development

Country, Sources of

Funding

Intervention and Practice

Considered

Major Outcomes

Considered

Evidence Collection,

Selection, and Synthesis

Evidence Quality and Strength

Recommendations Development and

Evaluation

Guideline Validation

Tic Disorders

Pringsheim 201218

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

Pharmacotherapy

for tic disorders in children

Appropriate

populations for, doses of, and strategies for

medications, including antipsychotics,

for tic disorders

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 low-

quality evidence; and benefits that clearly outweigh

risks

Weak recommendation: high-, moderate-,

low-, or very low-quality evidence; and closely-

balanced or uncertain benefits and risks

Category X: insufficient evidence to make

a formal recommendation

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.

The guideline was

published in a peer-reviewed journal.




Intended Users,

Target Population,

Development

Country, Sources of

Funding


Considered

Major Outcomes

Considered





Evaluation



Gorman 201519

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

Appropriate

strategies for medications, including

antipsychotics, for behavioural problems

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

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.

External

stakeholders reviewed the guideline. Their

feedback was considered and incorporated into the

final guideline.




Intended Users,

Target Population,

Development

Country, Sources of

Funding


Considered

Major Outcomes

Considered





Evaluation


Schizophrenia and Related Disorders

McClellan 201320

- 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

Appropriate

strategies for medications, including

antipsychotics, for schizophrenia

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

were developed by a committee, consisting of a panel of experts.

The guideline was

internally peer-reviewed.




Intended Users,

Target Population,

Development

Country, Sources of

Funding


Considered

Major Outcomes

Considered





Evaluation


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


APPENDIX 3: Critical Appraisal of Included Publications

Table A3: Strengths and Limitations of Included SRs

Using AMSTAR12 link to AMSTAR checklist Strengths Limitations

Tic Disorders

Hollis 20162

An “a priori” design was used.

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 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, using the GRADE approach.

The methods used to combine the study findings were appropriate.

There was no duplicate study selection and no duplicate data extraction.

The quality of the included studies was not explicitly used in formulating conclusions.

Although the likelihood of publication bias was assessed as part of the quality assessment, using GRADE, the results of the assessment was not explicitly reported.

One of the authors disclosed having received financial support from pharmaceutical companies.

Yang 20154

There was duplicate study selection and data extraction.

A flow diagram for the search results was provided.

A list of the included studies was provided.


The risk of bias of the included studies was assessed and documented, and the included studies were rated, using the Cochrane risk of bias tool.


No conflict of interest was declared.

It is unclear whether an “a priori” design was used.

Although a literature search was performed, using several databases, many of the databases were Chinese, it is unclear if grey literature was included, and a detailed search strategy was not provided. Therefore, it is unclear whether a comprehensive literature search was performed.

A list of the excluded studies was not provided.


Although the likelihood of publication bias was assessed, the results of the assessment were not explicitly discussed.


Epstein 201514


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




http://amstar.ca/Amstar_Checklist.php




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 likelihood of publication bias was not assessed.

Pringsheim 20127


A detailed search strategy was 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.


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.


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.


One of the authors disclosed having received financial support from a pharmaceutical company.


Stafford 201515

An “a priori” design was provided.



A list of the included and excluded studies was






provided.


The risk of bias in the included studies and confidence in the results were assessed and documented, and the included studies were rated, using the Cochrane risk of bias tool and the GRADE approach.




Kumar 20133


A list of the included and excluded studies was provided.


The risk of bias of the included studies was assessed and documented, and the included studies were rated, using the Cochrane risk of bias tool.





Although the authors conducted some partial validation through sampling, there was no full duplicate study selection and data extraction.



Sochocky 201316

An “a priori” design was provided.

A detailed search strategy and a flow diagram for the search results were provided.



The quality of the included studies was assessed and documented, and the included studies were rated, using the GRADE approach.

The quality of the included studies was used

There was no duplicate study selection or data extraction.

Although the authors conducted a literature search for published articles, no grey literature was included. Therefore, a comprehensive literature search was not performed.






appropriately in formulating conclusions.

The methods used to combine the findings of studies were appropriate.

The likelihood of publication bias was assessed to be low.

No conflict of interest was declared. Multiple Conditions

Flank 20149


A detailed search strategy and a flow diagram for the search results were provided.

A list of the included was provided.




Although a literature search was performed, using several databases, no grey literature was included.


Although the risk of bias of the included studies was assessed and documented, it is unclear if the tool used, with modification, was a generally-accepted one.

Although the methods used to combine the study findings were appropriate, it is unclear what models (e.g., fixed- or random-effects) were used in MAs.



Almandil 201317

An “a priori” design was provided. There was duplicate study selection and data

extraction.




The quality of the included studies was assessed and documented, and the included studies were rated, using the Jadad scale.


The methods used to combine the findings of


Some of the authors disclosed having received financial support from pharmaceutical companies





studies were appropriate.

The likelihood of publication bias was assessed to be low.

AMSTAR = Assessment of Multiple Systematic Review s; GRADE = Grading of Recommendation, Assessment, Development and

Evaluation; MA = meta-analysis; RCT = randomized controlled trial; RTI = Research Triangle Institute; SR = systematic review; USPSTF = United States Preventive Services Task Force

Table A4: Strengths and Limitations of Included Evidence-Based Guidelines

Using AGREE II13 link to checklist Strengths Limitations

Tic Disorders

Pringsheim 201218

Scope and Purpose

Objectives were described. Health questions were described.

Target populations were described. Stakeholder Involvement

The guideline was developed by individuals from all relevant professional groups.

Target population input was sought.

Targets users were described. Rigour of Development

Systematic search methods were used.

Evidence selection criteria were described.

Appraisals on the quality of included evidence were provided.

Methods for formulating recommendations were described.

Recommendations considered benefits, harms, costs, and quality of evidence, and their links to supporting evidence tables were explicit.

The guideline was externally reviewed by experts prior to its publication.

Clarity of Presentation Recommendations were unambiguous,

specific for different types of conditions or issues, and easily identifiable.

Applicability

The guideline provided monitoring and/or auditing criteria.

Editorial Independence Funding sources were disclosed.

Rigour of Development

A procedure for updating the guideline was not described.

Applicability

Facilitators and barriers to implementing the guideline were not described.

The guideline did not provide links to tools and resources including a summary document.

The guideline did not consider resource implications.

Editorial Independence

The authors reported several conflicts of interest, which may have had an impact on the report.

http://amstar.ca/Amstar_Checklist.phphttp://www.agreetrust.org/wp-content/uploads/2013/06/AGREE_II_Users_Manual_and_23-item_Instrument_ENGLISH.pdf





Gorman 201519

Scope and Purpose

Objectives were described.

Health questions were described.

Target populations were described. Stakeholder Involvement The guideline was developed by individuals

from all relevant professional groups.


Targets users were described. Rigour of Development


Evidence selection criteria were described. Appraisals on the quality of included evidence

were provided.


Recommendations considered benefits, harms, costs, and quality of evidence, and their links to supporting evidence tables were explicit.

The guideline was externally reviewed by experts prior to its publication.

Clarity of Presentation

Recommendations were unambiguous, specific for different types of conditions or issues, and easily identifiable.

Applicability Facilitators and barriers to implementing the

guideline were described.

The guideline provided links to tools and resources including a summary document.

The guideline considered resource implications.



Funding sources were disclosed.


A procedure for updating the guideline was not described.




McClellan 201320

Scope and Purpose

Objectives were described. Health questions were described.

Target populations were described.


It is unclear if the guideline was externally reviewed by experts prior to its publication.

A procedure for updating the guideline was not

http://www.agreetrust.org/wp-content/uploads/2013/06/AGREE_II_Users_Manual_and_23-item_Instrument_ENGLISH.pdf




Stakeholder Involvement

The guideline was developed by individuals from all relevant professional groups.


Targets users were described. Applicability

Facilitators and barriers to implementing the guideline were described.

The guideline provided links to tools and resources including a summary document.

The guideline considered resource implications.




Evidence selection criteria were described.

Appraisals on the quality of included evidence were provided.


Recommendations considered benefits, harms, costs, and quality of evidence, and there were links to supporting evidence tables.

Clarity of Presentation

Recommendations were unambiguous, specific for different types of conditions or issues, and easily identifiable.


Funding sources were disclosed.

described. Editorial Independence


AGREE = Appraisal of Guidelines for Research and Evaluation

http://www.agreetrust.org/wp-content/uploads/2013/06/AGREE_II_Users_Manual_and_23-item_Instrument_ENGLISH.pdf


APPENDIX 4: Main Study Findings and Author’s Conclusions

Table A5: Summary of Findings of Included SRs Main Study Findings Author’s Conclusions

Tic Disorders

Hollis 20162 Tic Severity

According to MAs, for children and adolescents with Tourette syndrome or CTD, antipsychotics (i.e., antihaloperidol, pimozide, risperidone, and ziprasidone), compared to placebo, showed reductions in tic severity, as measured by the YGTSS total tic scale (SMD = -0.74, 95% CI = -1.08 to -0.41), with no evidence of differences among the different antipsychotics.

Personal and Social Impairment

According to MAs, for children and adolescents with Tourette syndrome or CTD, antipsychotics (i.e., haloperidol, pimozide, and ziprasidone), compared to placebo, showed reductions in impairment, as measured by the TS global scale (SMD = -0.51, 95% CI = -0.86 to -0.15), with no evidence of differences among the different antipsychotics.

Overall Global State

According to MAs, for children and adolescents with Tourette syndrome or CTD, antipsychotics (i.e., haloperidol, pimozide, and ziprasidone), compared to placebo, showed reductions in the overall global state, as measured by the CGI-TS scores (SMD = -1.01, 95% CI = -1.49 to -0.53), with little evidence of differences among the different antipsychotics.

Adverse Effects

One study reported that, compared to placebo, ziprasidone was associated with adverse effects, including akathisia, drowsiness, and sedation, and risperidone was associated with weight gain. Single studies reported no differences in adverse effects with haloperidol or pimozide, compared to placebo.

Single studies reported that, compared to pimozide: o Aripiprazole was associated with lower

reductions in blood pressure and lower increases in ECG-QT;

Antipsychotics are effective in the short term in reducing tics and tic-related impairments in children and adolescents with Tourette syndrome. There are few clear differences between antipsychotics in effectiveness.

Side effect profiles differ between antipsychotics, with weight gain, sedation, EPSs, and cardiac risks being particular concerns.

The balance of benefits and harms favours the most commonly-used medications, such as risperidone, clonidine, and aripiprazole.


Table A5: Summary of Findings of Included SRs

Main Study Findings Author’s Conclusions

o Haloperidol was associated with greater rates of treatment-limiting adverse effects, including EPSs; and

o Risperidone was associated with weight gain.

One study reported that olanzapine, compared to haloperidol, was associated with lower adverse effect scores, as measured by the STESS (SMD = -0.57, 95% CI = -1.12 to -0.03).

Quality of Included Studies

The number and quality of clinical trials were low, downgrading the strength of the evidence and conclusions.

Yang 20154

Tic Severity According to MAs, for children and

adolescents with tic disorders, there was no significant difference in reductions in tic severity between aripiprazole and other antipychotics (i.e., haloperidol, risperidone, and tiapride), as measured by the YGTSS total tic scale.

Personal and Social Impairment

According to MAs, for children and adolescents with tic disorders, there was no significant difference in reductions in impairment between aripiprazole and tiapride, as measured by the YGTSS impairment scale.

Adverse Effects Across the included studies, the most

common adverse effects associated with aripiprazole, haloperidol, risperidone, and tiapride included drowsiness, increased appetite, nausea, and headache.


The quality of the included studies was generally poor, and there was large heterogeneity in the MAs, as measured by I2.

Aripiprazole appears to be a promising therapy for children with tic disorders.


Epstein 201514

Adverse Effects

Across the included studies, for children and adolescents with disruptive behaviour disorders, risperidone, compared to placebo, was associated with adverse effects that were

Adverse events were generally considered mild across studies.




generally considered mild, with weight gain, sedation, and drowsiness frequently reported.

Single studies 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.


The quality of evidence across the included studies ranged from fair to good.

Pringsheim 20127 Disruptive Behaviour

According to a general, qualitative concluding statement, for children and adolescents with disruptive behaviour disorders and sub-average IQs, risperidone, compared to placebo, generally showed improvement in disruptive behaviors, as measured by the ABC, NCBRF, or OAS.


The quality of evidence across the included studies ranged from fair to good.

There is good evidence to support the short-term efficacy of risperidone for the treatment of disruptive behavior disorders in children with sub-average IQs.


Stafford 201515 Psychotic Symptoms

According to MAs, for children and adolescents with psychosis or schizophrenia, antipsychotics (i.e., aripiprazole, olanzapine, paliperidone, and quetiapine), compared to placebo, showed reductions in psychotic symptoms, as measured by the PANSS total symptoms scale (SMD = -0.42, 95% CI = -0.58 to -0.26). Reductions were identified at both low doses (SMD = -0.34, 95% CI = -0.55 to -0.14) and high doses (SMD = -0.53, 95% CI = -0.78 to -0.29).

According to MAs, for children and adolescents with psychosis or schizophrenia, there was no significant difference in reductions in psychotic symptoms between haloperidol and risperidone, as measured by the PANSS total symptoms scale.

Adverse Effects

According to MAs, for children and adolescents with psychosis or schizophrenia, antipsychotics (i.e., paliperidone and quetiapine), compared to placebo, showed

Low-quality evidence suggests small effects for antipsychotics on psychotic symptoms but medium effects on weight gain.

For children and adolescents, the balance of risk and benefit of antipsychotics appears less favourable than in adults.

In the absence of high-quality evidence for the effectiveness of antipsychotics in children and adolescents, their routine use in the treatment of psychosis and schizophrenia should be undertaken cautiously.




weight gain, as measured by the number of participants gaining >7% of their baseline body weight (RR = 3.62, 95% CI = 1.29 to 10.17). There was no significant difference in weight gain between low and high doses.

Quality of Included Studies The quality of evidence across the included

studies was poor.

Kumar 20133 Psychotic Symptoms

According to MAs, for children and adolescents with schizophrenia or related disorders, 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), as measured by the BPRS.

According to MAs, for children and adolescents with schizophrenia or related disorders, there was no significant difference in the mean end-point in mental states at high (or standard) or low doses of atypical antipsychotics (i.e., aripiprazole [high= 30 mg per day, low = 10 mg per day] and risperidone [high = 1.5-6.0 mg per day, low = 0.15-0.5 mg per day]), as measured by the PANSS.


According to MAs, for children and adolescents with schizophrenia or related disorders, there was no significant difference in improvement in the overall global state between two atypical antipsychotics (i.e., olanzapine and risperidone), as measured by the CGI scale.

According to MAs, for children and adolescents with schizophrenia or related disorders, atypical antipsychotics (i.e., aripiprazole [high= 30 mg per day, low = 10 mg per day], risperidone [high = 1.5-6.0 mg per day, low = 0.15-0.5 mg per day], and ziprasidone [high= 160 mg per day, low = 80 mg per day) at high (or standard) doses, compared to low doses, showed greater improvement in the overall global state, as measured by the CGI-I scale (MD = -0.34,

No convincing evidence suggests that atypical antipsychotics are superior to typical antipsychotics for the treatment of children and adolescents with psychosis. However, atypical antipsychotics 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 over another. However, side effect profiles are different for different medications. Treatment with olanzapine, risperidone, and clozapine is often associated with weight gain whereas aripiprazole is not.

Children and adolescents may respond better to standard-dose as opposed to lower-dose risperidone.




95% CI = -0.55 to -0.13). Adverse Effects

Single studies reported that, for children and adolescents with schizophrenia or related disorders, compared to placebo: o Olanzapine showed weight gain, as

measured by the number of participants gaining >7% of their baseline body weight (RR = 3.56, 95% CI = 1.14 to 11.11).

o Aripiprazole showed no significant difference in weight gain >5%.

Single studies reported that, for children and adolescents with schizophrenia or related disorders: o There was no significant difference in

EPSs, such as tremours or restlessness, between an atypical antipsychotic (i.e., risperidone) and typical antipsychotics (i.e., chlorpromazine and perphenazine).

o Compared to haloperidol, clozapine was associated with greater drowsiness (RR = 3.30, 95% CI = 1.23 to 8.85).

o Compared to molindone, olanzapine was associated with higher mean serum cholesterol concentration (MD = 25.60, 95% CI 5.84 to 45.36).

Singe studies that compared two different atypical antipsychotics reported that, for children and adolescents with schizophrenia or related disorders: o Compared to risperidone, olanzapine was

associated with greater gain in body weight (mean = 6.1 + 3.6 kg versus 3.6 + 4 kg, statistical results not reported).

o There was no significant difference in the number of participants who gained >7% of baseline body weight between clozapine and olanzapine.

o There was no significant difference in the number of participants reporting akathisia (i.e., motor restlessness) or muscle stiffness between olanzapine and risperidone, administered alone or with quetiapine, or between quetiapine and risperidone, as measured by the BAS, SAAS, and AIMS.

Singe studies that compared different doses




of atypical antipsychotics reported that, for children and adolescents with schizophrenia or related disorders: o Low doses of risperidone, compared to

high (or standard) ones (i.e, 0.15-0.6 versus 1.5-6.0 mg per day), were associated with significantly less-frequent EPSs (RR = 3.31, 95% CI 1.86 to 5.87) and dystonia (i.e., continuous spasms and muscle contractions) (RR = 3.04, 95% CI 1.41 to 6.53).


The quality of evidence in many of the included studies was high.


Sochocky 201316 Aberrant Behaviour

According to MAs, for children and adolescents with Asperger’s disorder or high functioning autism, atypical antipsychotics (i.e., aripiprazole, olanzapine, and risperidone), compared to controls (i.e., placebo or combination treatment), showed improvement in aberrant behaviour, as measured by the ABC (SMD = 1.423, 95% CI = 0.467 to 2.380).


According to MAs, for children and adolescents with Asperger’s disorder or high functioning autism, atypical antipsychotics (i.e., aripiprazole, olanzapine, quetiapine, and risperidone), compared to controls (i.e., placebo or combination treatment), showed improvement in the overall global state, as measured by the CGI scale (SMD = 1.910, 95% CI = 1.166 to 2.654).

Adverse Effects

Single studies reported that olanzapine and risperidone, compared to placebo, were associated with significant weight gain.

Single studies also reported as adverse effects increased appetite, pulse rates, systolic blood pressure; however, the changes were not always deemed clinically relevant.


The quality of evidence in many of the included studies was low.

The results of the MAs indicated significant benefits of atypical antipsychotics on aberrant behaviours in children and adolescents with Asperger’s disorder or high functioning autism. However, those results were tempered with a low number of included studies, small sample sizes, and open-label designs.

There is a lack of robustly-conducted trials on the use of atypical antipsychotics in the management of Asperger’s disorder and high functioning autism.



Main Study Findings Author’s Conclusions Multiple Conditions

Flank 20149 Adverse Effects

According to MAs, for children and adolescents with psychiatric, developmental, or behavioural disorders, the following adverse effects were reported from RCTs and prospective studies: o Weight gain (RR = 0.78, 95% CI 0.63 to

0.95) o Sedation (RR = 0.48, 95% CI 0.35 to 0.67) o Electrocardiogram abnormalities (RR =

0.14, 95% CI 0.07 to 0.26) o EPS (RR = 0.09, 95% CI 0.04 to 0.21) o Liver function test abnormalities (RR =

0.07, 95% CI 0.02 to 0.20) o Blood glucose abnormalities (RR = 0.04,

95% CI 0.01 to 0.17) o Others, including akathisia; anxiety; cold

or flu-like symptoms; constipation; dry eyes, nose, or mouth; gastrointestinal problems; headaches; hypersalivation; and urinary adverse effects

Case series or reports also reported weight gain, sedation, catatonia, and neuroleptic malignant syndrome as adverse effects and olanzapine poisoning in cases of overdose.


The quality of evidence across the included studies ranged from low to high.

Most adverse effects associated with olanzapine use in children and adolescents are weight gain and sedation and of minor clinical significance.

Patients with weight gain received olanzapine for at least six weeks, suggesting a temporal relationship between the use of olanzapine and weight gain, with the risk increasing with the duration of treatment.

Almandil 201317

Adverse Effects

According to MAs, for children and adolescents with any indication for atypical antipsychotic, the following adverse effects were reported: o Aripiprazole, compared to placebo, was

associated with weight gain (mean = 0.94 kg, 95% CI 0.65 to 1.24), with no evidence of heterogeneity across studies.

o Olanzapine, compared to placebo, was associated with weight gain (mean = 3.45 kg, 95% CI 2.93 to 3.98), with no evidence of heterogeneity across studies.

o Risperidone, compared to placebo, was associated with weight gain (mean = 1.77 kg, 95% CI 1.35 to 2.20), with

There is published evidence to indicate that treatment of young people with atypical antipsychotics (i.e., aripiprazole, olanzapine, and risperidone), compared to placebo, is associated with weight gain. The effect appears to be greatest with olanzapine.




considerable heterogeneity across studies.

Single studies reported: o Significant decreases in prolactin with

aripiprazole; o Significant increases in glucose, total

cholesterol, and prolactin with olanzapine; and

o Significant increases in prolactin with risperidone.


The quality of evidence in the included studies was high.

ABC = aberrant behavior checklist; AIMS = abnormal involuntary movement scale; BAS = Barnes akathisia scale; BPRS = brief psychiatric rating scale; CGI = clinical global impression; CGI-I = clinical global impression improvement; CGI-TS = clinical global

impression tic severity; CI = confidence interval; CTD = chronic tic disorder; ECG-QT = electrocardiogram on Q and T w aves; EPS = extrapyramidal symptom; IQ = intelligence quotient; MA = meta-analysis; MD = mean difference; NCBRF = Nisonger child behavior rating form; OAS = overt aggression scale; PANSS = positive and negative syndrome scale; RCT = randomized controlled trial; RR = risk ratio; SAAS = Simpson Angus akathisia scale; SMD = standardized mean difference; SR = systematic review; STESS =

subjective treatment emergent symptom scale; TS = Tourette syndrome; YGTSS = Yale Global Tic Severity Score


Table A6: Summary of Recommendations of Included Evidence-Based Guidelines

Tic Disorders

Pringsheim 201218

Recommendations for antipsychotics for the treatment of tics include the following: o Aripiprazole, 2-15 mg per day (weak recommendation, low-quality evidence) o Fluphenazine, 0.25-3 mg per day (weak recommendation, low-quality evidence) o Haloperidol, 0.5-3 mg per day (weak recommendation, high-quality evidence) o Olanzapine, 2.5-10 mg per day (weak recommendation, low-quality evidence) o Pimozide, 1-4 mg per day (weak recommendation, high-quality evidence) o Quetiapine, 25-400 mg per day (weak recommendation, very low-quality evidence) o Risperidone, 0.25-3 mg per day (weak recommendation, high-quality evidence) o Ziprasidone, 20-40 mg per day (weak recommendation, low-quality evidence)

Behavioural therapy and non-antipsychotics (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. Four antipsychotics (i.e., fluphenazine, haloperidol, pimozide, and ziprasidone) should be third-line therapies.

Children and adults who are overweight, as measured by the BMI or waist circumference, should avoid olanzapine, quetiapine, and risperidone because of the risk of further weight gain associated with the antipsychotics.


Gorman 201519

Recommendations for antipsychotics for the treatment of disruptive and aggressive behaviour include the following: o Clonidine (very low quality of evidence, small benefit, moderate side effect burden, strength of

recommendation: very low) o Haloperidol (very low quality of evidence, some benefit, major side effect burden, strength of

recommendation: strong, against) o Quetiapine (very low quality of evidence, large benefit, major side effect burden, strength of

recommendation: conditional, against) o Risperidone (moderate quality of evidence, moderate magnitude of benefit, major side effect

burden, strength of recommendation: conditional, in favour)

Risperidone is the most effective medication to treat disruptive and aggressive behaviours in the absence of ADHD.


McClellan 201320

Antipsychotics are a primary treatment option for schizophrenia spectrum disorders in children and adolescents. Most atypical and typical antipsychotics, with the exception of clozapine, can be used as a primary treatment option for early-onset schizophrenia.

A trial of clozapine should be considered for youth with treatment-resistant schizophrenia spectrum disorders.

ADHD = attention deficit hyperactivity disorder; BMI = body mass index


APPENDIX 5: Additional References of Potential Interest Reviews Following reviews were deemed not fully systematic and were excluded from this report:

Reviews that did not include a clear description of search methods or selection criteria: o Datta SS, Kumar A, Wright SD, Furtado VA, Russell PS. Evidence base for using

atypical antipsychotics for psychosis in adolescents. Schizophr Bull. 2014 Mar;40(2):252-4.

Reviews that did not assess the quality, or risk of bias, of included studies: o Liu Y, Ni H, Wang C, Li L, Cheng Z, Weng Z. Effectiveness and Tolerability of

Aripiprazole in Children and Adolescents with Tourette's Disorder: A Meta-Analysis. J Child Adolesc Psychopharmacol. 2016 Feb 25.

o Galling B, Correll CU. Do antipsychotics increase diabetes risk in children and adolescents? Expert Opin Drug Saf. 2015 Feb;14(2):219-41.

o Tourian L, LeBoeuf A, Breton JJ, Cohen D, Gignac M, Labelle R, et al. Treatment Options for the Cardinal Symptoms of Disruptive Mood Dysregulation Disorder. J Can Acad Child Adolesc Psychiatry. 2015;24(1):41-54.

o Politte LC, McDougle CJ. Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl). 2014 Mar;231(6):1023-36.

o Schneider C, Corrigall R, Hayes D, Kyriakopoulos M, Frangou S. Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia. Eur Psychiatry. 2014 Jan;29(1):1-10.

o Balestrieri M, Oriani MG, Simoncini A, Bellantuono C. Psychotropic drug treatment in anorexia nervosa. Search for differences in efficacy/tolerability between adolescent and mixed-age population. Eur Eat Disord Rev. 2013 Sep;21(5):361-73.

o Linton D, Barr AM, Honer WG, Procyshyn RM. Antipsychotic and psychostimulant drug combination therapy in attention deficit/hyperactivity and disruptive behavior disorders: a systematic review of efficacy and tolerability. Curr Psychiatry Rep. 2013 May;15(5):355.

o Martinez-Ortega JM, Funes-Godoy S, Diaz-Atienza F, Gutierrez-Rojas L, Perez-Costillas L, Gurpegui M. Weight gain and increase of body mass index among children and adolescents treated with antipsychotics: a critical review. Eur Child Adolesc Psychiatry. 2013 Aug;22(8):457-79.

o Rizzo R, Gulisano M, Cali PV, Curatolo P. Tourette Syndrome and comorbid ADHD: current pharmacological treatment options. Eur J Paediatr Neurol. 2013 Sep;17(5):421-8.

o Sarkar S, Grover S. Antipsychotics in children and adolescents with schizophrenia: a systematic review and meta-analysis. Indian J Pharmacol. 2013 Sep;45(5):439-46.

o Teixeira EH, Jacintho A, Celeri HV, Dalgalarrondo P. Atypical antipsychotics in the treatment of pathological aggression in children and adolescents: literature review and clinical recommendations. Trends Psychiatry Psychother. 2013;35(3):151-9.

o Doey T. Aripiprazole in pediatric psychosis and bipolar disorder: a clinical review. J Affect Disord. 2012;138 Suppl:S15-S21.

o Ghanizadeh A. Systemic review of aripiprazole for the treatment of children and adolescents with tic disorders. Neurosciences (Riyadh). 2012 Jul;17(3):200-4.


Guidelines Following guidelines were evidenced-based and provided recommendations on assessment and monitoring of the use of antipsychotics in pediatric patients.

National Collaborating Centre for Mental Health. Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care [Internet]. London (GB): National Institute for Health and Care Excellence; 2014 Sep [cited 2016 Mar 23]. 58 p. (NICE clinical guideline 185). Available from: https://www.nice.org.uk/guidance/cg185/resources/bipolar-disorder-assessment-and-management-35109814379461 Guideline summary available from: http://www.guideline.gov/content.aspx?id=48565

o Recommendations for starting antipsychotics: Before beginning antipsychotic medication to treat bipolar disor

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