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Antipsicóticos atípicos para los trastornos de conducta desestabilizantes en niños y jóvenes

Appendices

Appendix 1. Rating scales

Scales for aggression (observer rated)

  1. Children’s Aggression Scale – Parent’s version (CAS‐P) (Halperin 2002).

  2. Children’s Aggression Scale – Teacher’s version (CAS‐T) (Halperin 2003).

  3. Overt Aggression Scale (OAS) (Yudofsky 1986).

  4. Modified Overt Aggression scale (MOAS) (Sorgi 1991).

  5. Overt Aggression Scale Modified (OAS‐M) (Coccaro 1991).

  6. Proactive and Reactive Aggression Scale (PRA) (Dodge 1987).

  7. Revised Teacher Rating Scale for Reactive and Proactive Aggression (R‐TRPA) (Brown 1996).

  8. Vitiello Aggression Questionnaire (VAQ) (Vitiello 1997).

  9. Children's Social Behaviour Scale (CSBS) (Crick 1995).

  10. General Behavior Inventory (Parent Version) (P‐GBI) (Youngstrom 2001).

  11. Life History of Aggression (LHA) (Coccaro 1997).

Scale for aggression (self‐report)

  1. Buss‐Durkee Hostility Inventory (BDHI) (Buss 1957).

  2. Aberrant Behaviour Checklist (ABC) – Irritability subscale (Aman 1985a).

  3. Child Behaviour Checklist (CBCL) – Aggression subscale (Achenbach 1991).

  4. Barratt Aggressive Acts Questionnaire (AAQ) (Barratt 1999).

  5. Spielberger Anger and Expression of Anger Inventory (STAXI) (Fuqua 1991).

  6. Anger, Irritability, and Aggression Questionnaire (AAIQ) (Coccaro 1991).

  7. Buss‐Perry Aggression Questionnaire (B‐PAQ) (Buss 1992).

  8. Aggression Questionnaire (AQ) (Vitiello 1990; Malone 1998).

Scales for disruptive behaviour disorders or conduct disorder

  1. Nisonger Child Behaviour Rating Form (NCBRF) – Conduct Problem subscale (Aman 1996).

  2. Connors' Parent Rating Scale – Revised (CPRS‐R) (Conners 1997a).

  3. Conners' Teacher Rating Scale – Revised (CTRS‐R) (Conners 1997a).

  4. Swanson, Nolan and Pelham scale, Fourth Edition (SNAP‐IV) (Swanson 1992).

  5. Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS) (Wolraich 2003).

  6. Vanderbilt ADHD Diagnostic Teacher Rating Scale (VADTRS) (Wolraich 1998).

  7. Achenbach Child Behavior Checklist (CBCL) (Achenbach 1991).

  8. Eyberg Child Behaviour Inventory (ECBI) (Eyberg 1999).

  9. New York Teacher Rating Scale for Disruptive and Antisocial Behaviour (NYTRS) (Miller 1995).

  10. Home and School Questionnaire (HSQ/SSQ) (Barkley 1997).

  11. Antisocial Process Screening Device (APSD) (Frick 2001).

  12. Sutter‐Eyberg Student Behavior Inventory Revised (SESBI‐R) (Eyberg 1999).

  13. Youth Self Report (YSR) (Achenbach 1991).

  14. Conners/Wells' Adolescent Self Report of Symptoms (CASS) – conduct problem and anger control problem subscales (Conners 1997b).

  15. Parent Daily report (PDA) (Kazdin 1986).

  16. Interview for Antisocial Behaviour (IAB) (Chamberlain 1991).

Appendix 2. Search strategies up to 2011

Cochrane Central Register of Controlled Studies (CENTRAL) in the Cochrane Library, which includes the Cochrane Developmental, Psychosocial and Learning Problems Specialised Register

#1 MeSH descriptor Child Behavior Disorders, this term only
#2 MeSH descriptor Attention Deficit and Disruptive Behavior Disorders, this term only
#3 MeSH descriptor Attention Deficit Disorder with Hyperactivity, this term only
#4 MeSH descriptor Conduct Disorder, this term only
#5 conduct NEAR/5 (disorder* or disturb*)
#6 oppositional*
#7 MeSH descriptor Antisocial Personality Disorder, this term only
#8 (antisocial or anti NEXT social) NEAR/5 (behav* or histor* or conduct*)
#9 attention NEAR/5 deficit*
#10 ad/hd
#11 adhd or "ad/hd" or adhkd or addh or adhs
#12 hyperactiv*
#13 MeSH descriptor Hyperkinesis, this term only
#14 hyperkine*
#15 MeSH descriptor Aggression, this term only
#16 aggress*
#17 MeSH descriptor Agonistic Behavior, this term only
#18 agonistic*
#19 MeSH descriptor Anger, this term only
#20 MeSH descriptor Rage, this term only
#21 anger or angry
#22 malic*
#23hostil*
#24 deceit*
#25 cruel*
#26 MeSH descriptor Juvenile Delinquency, this term only
#27 threaten*
#28 (dangerous* or disrupt* ) NEAR/5 (behav* or histor* or conduct*)
#29 MeSH descriptor Impulsive Behavior, this term only
#30 impulse* or impulsiv*
#31 MeSH descriptor Crime explode all trees
#32 criminal* or violen* or unlawful* or delinquen*
#33 MeSH descriptor Violence, this term only
#34 offend* or offence* or offense*
#35 correctional* or penal*
#36 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35)
#37 MeSH descriptor Clozapine, this term only
#38 MeSH descriptor Risperidone, this term only
#39 risperidon*
#40 clozapin*
#41 amisulprid*
#42 amisulpirid*
#43 aripiprazol*
#44 olanzapin*
#45 quetiapin*
#46 sertindol*
#47 ziprasidon*
#48 zotepin*
#49 atypical NEAR/3 (anti next psychotic* or antipsychotic*)
#50(#37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49)
#51 MeSH descriptor Infant, this term only
#52 MeSH descriptor Child explode all trees
#53 MeSH descriptor Adolescent, this term only
#54 MeSH descriptor Minors, this term only
#55 (child* or boy* or girl* or baby or babies or toddler* or infant* or teen* or adolescen* or juvenile* or preschool* or pre next school* or schoolchild*)
#56 youth* or young* people
#57 young* people
#58 (#51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57)
#59 (#36 AND #50 AND #58)

OVID MEDLINE(R)

1 Child Behavior Disorders/
2 Attention Deficit Disorder with Hyperactivity/
3 "Attention Deficit and Disruptive Behavior Disorders"/
4 Conduct Disorder/
5 (conduct adj5 (disorder$ or disturb$)).mp.
6 oppositional$.mp.
7 ((antisocial$ or anti‐social$) adj5 (behav$ or histor$ or conduct)).mp.
8 Antisocial Personality Disorder/
9 (attention adj5 deficit$).mp.
10 (adhd or "ad/hd" or adhkd or addh or adhs).tw.
11 hyperactiv$.mp.
12 Hyperkinesis/
13 hyperkine$.mp.
14 Aggression/
15 Agonistic behavior/
16 aggress$.mp.
17 agonistic$.mp.
18 Anger/
19 Rage/
20 (anger or angry).mp.
21 malic$.mp.
22 hostil$.mp.
23 ((dangerous$ or disrupt$ or defiant$) adj3 (behav$ or histor$ or conduct$)).mp.
24 deceit$.mp.
25 cruel$.mp.
26 juvenile delinquency/
27 delinquen$.mp.
28 threaten$.mp.
29 Impulsive Behavior/
30 impulsiv$.mp.
31 impulse$.mp.
32 unlawful$.mp.
33 Violence/
34 violen$.mp.
35 exp Crime/
36 criminal$.mp.
37 penal$.mp.
38 (offend$ or offenc$ or offens$).mp.
39 correctional.mp.
40 or/1‐39
41 amisulprid$.mp.
42 amisulpirid$.mp.
43 aripiprazol$.mp.
44 Clozapine/
45 clozapin$.mp.
46 olanzapin$.mp.
47 quetiapin$.mp.
48 Risperidone/
49 risperidon$.mp.
50 sertindol$.mp.
51 ziprasidon$.mp.
52 zotepin$.mp.
53 (atypical$ adj3 (antipsychotic$ or anti‐psychotic)).mp.
54 or/41‐53
55 (child$ or boy$ or girl$ or baby or babies or toddler$ or infant$ or teen$ or adolescen$ or juvenile$ or preschool$ or pre‐school$ or schoolchild$).mp.
56 (youth$ or young$ people).mp.
57 Child/ or Child, preschool/
58 Infant/
59 Adolescent/
60 Minors/
61 or/55‐60
62 40 and 54 and 61

The search terms "iloperidone" "asenapine", "lurasidone" and "paliperidone" were included in the searches from 2015 onwards to reflect the availablity of new drugs.

Embase Ovid

1 behavior disorder/ or attention deficit disorder/ or disruptive behavior/ or impulse control disorder/ or oppositional defiant disorder/
2 (conduct adj5 (disorder$ or disturb$)).mp.
3 oppositional$.mp.
4 antisocial behavior/
5 ((antisocial$ or anti‐social$) adj5 (behav$ or histor$ or conduct)).mp.
6 ((antisocial$ or anti‐social$) adj personality adj disorder$).mp.
7 (attention adj5 deficit$).mp.
8 (adhd or "ad/hd" or adhkd or addh or adhs).tw.
9 hyperactiv$.mp.
10 hyperkinesia/
11 hyperkine$.mp.
12 exp aggression/
13 aggress$.mp.
14 agonistic$.mp.
15 (anger or angry).mp.
16 malic$.mp.
17 hostil$.mp.
18 ((dangerous$ or disrupt$) adj3 (behav$ or histor$ or conduct$)).mp.
19 deceit$.mp.
20 cruel$.mp.
21 delinquen$.mp.
22 threaten$.mp.
23 impulsiveness/
24 impulse control disorder/
25 (impulsiv$ or impulse$).mp.
26 unlawful$.mp.
27 exp violence/
28 violen$.mp.
29 exp crime/
30 criminal$.mp.
31 penal$.mp.
32 (offend$ or offenc$ or offens$).mp.
33 correctional.mp.
34 or/1‐33
35 exp atypical antipsychotic agent/
36 amisulprid$.mp.
37 amisulpirid$.mp.
38 aripiprazol$.mp.
39 clozapin$.mp.
40 olanzapin$.mp.
41 quetiapin$.mp.
42 risperidon$.mp.
43 sertindol$.mp.
44 ziprasidon$.mp.
45 zotepin$.mp.
46 (atypical$ adj3 (antipsychotic$ or anti‐psychotic$)).mp.
47 or/35‐46
48 (baby or babies or infant$ or toddler$ or child$ or boy$ or girl$ or preschool$ or pre school$ or teen$ or adolescen$ or juvenile$ or minor$ or youth$ or young people).tw.
49 infant/
50 child/
51 school child/
52 preschool child/
53 adolescent/
54 or/49‐53
55 34 and 47 and 54

PsycINFO strategies

During the preparation of the 2012 review the supplier for PsycINFO changed from EBSCOhost to Ovid . The search stategy was therefore adapted in 2011 for the Ovid platform.

PsycINFO EBSCOhost: 2010 search

S52 S47 and S48 and S51
S51 S49 or S50
S50 baby or babies or infant* or toddler* or child* or boy* or girl* or preschool* or pre school* or schoolchild* or juvenile* or minor* or teen* or adolescen* or youth* or young* people
S49 (ZG "adolescence (13‐17 yrs)") or (ZG "childhood (birth‐12 yrs)") or (ZG "infancy (2‐23 mo)") or (ZG "preschool age (2‐5 yrs)") or (ZG "schoolage (6‐12 yrs)")
S48 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33
S47 S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41 or S42 or S43 or S44 or S45 or S46
S46 atypical* N3 anti psychotic*
S45 atypical* N3 antipsychotic*
S44 zotepin*
S43 ziprasidon*
S42 sertindol*
S41 risperidon*
S40 quetiapin*
S39 olanzapin*
S38 clozapin*
S37 aripiprazol*
S36 amisulpirid*
S35 amisulprid*
S34 DE "Aripiprazole" or DE "Clozapine" or DE "Olanzapine" or DE "Quetiapine" or DE "Risperidone"
S33 impulsiv* or impulse*
S32 DE "Impulsiveness"
S31 (DE "Violent Crime") or (DE "Violence")
S30 DE "Crime"
S29 DE "Criminal Behavior" OR DE "Juvenile Delinquency"
S28 offend* or offenc* or offens*
S27 violen* or criminal* or penal* or correctional*
S26 unlawful*
S25 threaten*
S24 delinquen*
S23 (disrupt* N3 behav* ) or (disrupt* N3 histor*) or (disrupt* N3 conduct*)
S22 (dangerous* N3 behav* ) or (dangerous* N3 histor*) or (dangerous* N3 conduct*)
S21 cruel*
S20 deceit*
S19 hostil*
S18 malic*
S17 anger or angry or rage*
S16 aggress* or agonistic*
S15 hyperkine*
S14 hyperactiv*
S13 adhd or "ad/hd" or adhkd or addh or adhs
S12 attention N5 deficit*
S11 (anti social* N5 behav*) or (anti social* N5 histor*) or (anti social* N5 conduct*)
S10 (antisocial* N5 behav*) or (antisocial* N5 histor*) or (antisocial* N5 conduct*)
S9 oppositional*
S8 (conduct N5 disturb*)
S7 (conduct N5 disorder*)
S6 DE "Anger" OR DE "Hostility"
S5 (DE "Attention Deficit Disorder with Hyperactivity" or DE "Attention Deficit Disorder" or DE "Hyperkinesis" or DE "Impulsiveness" or DE "Oppositional Defiant Disorder")
S4 DE "Aggressive Behavior" or DE "Aggressiveness"
S3 DE "Conduct Disorder"
S2 DE "Behavior Disorders"
S1 (DE "Antisocial Personality Disorder")

PsycINFO Ovid: 2011 search

1 antisocial behavior/
2 Antisocial Personality Disorder/
3 Behavior Disorders/
4 Conduct Disorder/
5 Aggressive Behavior/
6 Aggressiveness/
7 Impulsiveness/
8 Oppositional Defiant Disorder/
9 exp attention deficit disorder/
10 Hyperkinesis/
11 Anger/
12 Hostility/
13 (conduct adj5 (disorder$ or disturb$)).mp.
14 oppositional$.mp.
15 ((antisocial$ or anti‐social$) adj5 (behav$ or histor$ or conduct)).mp.
16 (attention adj5 deficit$).mp.
17 (adhd or "ad/hd" or adhkd or addh or adhs).tw.
18 hyperactiv$.mp.
19 hyperkine$.mp.
20 aggress$.mp.
21 agonistic$.mp.
22 (anger or angry).mp.
23 malic$.mp.
24 hostil$.mp.
25 ((dangerous$ or disrupt$ or defiant$) adj3 (behav$ or histor$ or conduct$)).mp.
26 deceit$.mp.
27 cruel$.mp.
28 Juvenile Delinquency/
29 delinquen$.mp.
30 threaten$.mp.
31 impulsiv$.mp.
32 impulse$.mp.
33 unlawful$.mp.
34 Violence/
35 violen$.mp.
36 exp Crime/
37 criminal$.mp.
38 penal$.mp.
39 (offend$ or offenc$ or offens$).mp.
40 correctional.mp.
41 or/1‐40
42 Clozapine/
43 clozapin$.mp.
44 exp Olanzapine/
45 olanzapin$.mp.
46 Quetiapine/
47 quetiapin$.mp.
48 Risperidone/
49 risperidon$.mp.
50 sertindol$.mp.
51 ziprasidon$.mp.
52 zotepin$.mp.
53 amisulprid$.mp.
54 amisulpirid$.mp.
55 aripiprazole/
56 aripiprazol$.mp.
57 (atypical$ adj3 (antipsychotic$ or anti‐psychotic$)).mp.
58 or/42‐57
59 (child$ or boy$ or girl$ or baby or babies or toddler$ or infant$ or teen$ or adolescen$ or juvenile$ or preschool$ or pre‐school$ or schoolchild$).mp.
60 (youth$ or young$ people).mp.
61 ("100" or "120" or "140" or "160" or "180" or "200" or "320").ag.
62 59 or 60 or 61
63 41 and 58 and 62

CINAHL EBSCOhost (Cumulative Index to Nursing and Allied Health Literature)

S53 S33 and S47 and S52
S52 (S48 or S49 or S50 or S51)
S51 AG preschool
S50 AG adolescent
S49 AG child
S48 baby or babies or infant* or toddler* or child* or boy* or girl* or preschool* or pre school* or schoolchild* or juvenile* or minor* or teen* or adolescen* or youth* or young* people
S47 S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41 or S42 or S43 or S44 or S45 or S46
S46 atypical* N3 anti psychotic*
S45 atypical* N3 antipsychotic*
S44 zotepin*
S43 ziprasidon*
S42 sertindol*
S41 risperidon*
S40 quetiapin*
S39 olanzapin*
S38 clozapin*
S37 aripiprazol*
S36 amisulpirid*
S35 amisulprid*
S34 (MH "Aripiprazole") or (MH "Clozapine") or (MH "Olanzapine") or (MH "Quetiapine") or (MH "Risperidone")
S33 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32
S32 impulse* or impulsiv*
S31 (MH "Impulse Control Disorders")
S30 (MH "Violence") or (MH "School Violence") or (MH "Sibling Violence")
S29 (MH "Juvenile Delinquency") or (MH "Juvenile Offenders+")
S28 (MH "Crime")
S27 (MH "Public Offenders")
S26 offend* or offenc* or offens*
S25 violen* or criminal* or penal* or correctional* or unlawful* or threaten*
S24 delinquen*
S23 (disrupt* N3 behav* ) or (disrupt* N3 histor*) or (disrupt* N3 conduct*)
S22 (dangerous* N3 behav* ) or (dangerous* N3 histor*) or (dangerous* N3 conduct*)
S21 cruel*
S20 deceit*
S19 hostil*
S18 malic*
S17 anger or angry or rage*
S16 aggress* or agonistic*
S15 hyperkine*
S14 hyperactiv*
S13 adhd or "ad/hd" or adhkd or addh or adhs
S12 attention N5 deficit*
S11 (anti social* N5 behav*) or (anti social* N5 histor*) or (anti social* N5 conduct*)
S10 (antisocial* N5 behav*) or (antisocial* N5 histor*) or (antisocial* N5 conduct*)
S9 oppositional*
S8 (conduct N5 disorder*) OR (conduct N5 disturb*)
S7 (MH "Anger")
S6 (MH "Aggression")
S5 (MH "Hyperkinesis")
S4 (MH "Disruptive Behavior")
S3 (MH "Antisocial Personality Disorder")
S2 (MH "Attention Deficit Hyperactivity Disorder")
S1 (MH "Child Behavior Disorders")

ClinicalTrials.gov

(clinicaltrials.gov)

adhd OR dispruptive OR oppositional OR conduct OR impulsive OR anger OR rage OR antisocial | aripiprazole OR olanzapine OR quetiapine OR sertindole OR ziprasidone OR zotepine OR clozapine OR risperidone OR amisulpride OR amisulpirid | Child, Adult |

CenterWatch

(www.centerwatch.com)

Advanced search: (amisulpride or amisulpiride or aripiprazole or clozapine or olanzapine or quetiapine or risperidone or sertindole or ziprasidone or zotepine ) AND (adhd or disruptive or oppositional or "conduct disorder" or impulsive or anger or rage or antisocial

WHO ICTRP

(apps.who.int/trialsearch)

Intervention| aripiprazole OR olanzapine OR quetiapine OR sertindole OR ziprasidone OR zotepine OR clozapine OR risperidone OR amisulpride OR amisulpiride

metaRegister of Controlled Trials

antipsychotic* AND child* AND behav*

UK Clinical Research Network (UKCRN)

atypical antipsychotics

Appendix 3. Search strategies from 2011 onwards

CENTRAL, in the Cochrane Library, which includes the Cochrane Developmental, Psychosocial and Learning Problems Specialised Register

#1MeSH descriptor: [Child Behavior Disorders] this term only
#2MeSH descriptor: [Attention Deficit and Disruptive Behavior Disorders] this term only
#3MeSH descriptor: [Attention Deficit Disorder with Hyperactivity] this term only
#4MeSH descriptor: [Conduct Disorder] this term only
#5(conduct near/5 (disorder* or disturb*))
#6oppositional*
#7MeSH descriptor: [Antisocial Personality Disorder] this term only
#8((antisocial or anti next social) near/5 (behav* or histor* or conduct*))
#9(attention near/5 deficit*)
#10(adhd or "ad/hd" or adhkd or addh or adhs)
#11hyperactiv* or hyper next activ*
#12hyperkine* or hyper next kin*
#13aggress*
#14agonistic*
#15MeSH descriptor: [Anger] this term only
#16MeSH descriptor: [Rage] this term only
#17(anger or angry)
#18anger or angry
#19malic*
#20hostil*
#21deceit*
#22cruel*
#23(dangerous* or disrupt*) near/5 (behav* or histor* or conduct*)
#24MeSH descriptor: [Impulsive Behavior] this term only
#25impulse* or impulsiv*
#26MeSH descriptor: [Crime] explode all trees
#27criminal* or violen* or unlawful* or delinquen*
#28MeSH descriptor: [Violence] this term only
#29offend* or offence* or offense*
#30correctional* or penal*
#31(offend* or offenc* or offens*)
#32{or #1‐#31}
#33MeSH descriptor: [Risperidone] this term only
#34MeSH descriptor: [Clozapine] this term only
#35amisulpirid*
#36amisulprid*
#37aripiprazol*
#38asenapin*
#39clozapin*
#40iloperidon*
#41lurasidon*
#42olanzapin*
#43paliperid*
#44quetiapin*
#45risperidon*
#46sertindol*
#47ziprasidon*
#48zotepin*
#49atypical near/3 (anti next psychotic* or antipsychotic*)
#50{or #33‐#49}
#51MeSH descriptor: [Infant] this term only
#52MeSH descriptor: [Child] explode all trees
#53MeSH descriptor: [Adolescent] this term only
#54MeSH descriptor: [Minors] this term only
#55(child* or boy* or girl* or baby or babies or toddler* or infant* or teen* or adolescen* or juvenile* or preschool* or pre next school* or schoolchild*)
#56youth* or young* people
#57{or #51‐#56}
#58#32 and #50 and #57

Ovid MEDLINE(R)

1 Child Behavior Disorders/
2 Attention Deficit Disorder with Hyperactivity/
3 "Attention Deficit and Disruptive Behavior Disorders"/
4 Conduct Disorder/
5 (conduct adj5 (disorder$ or disturb$)).mp.
6 oppositional$.mp.
7 ((antisocial$ or anti‐social$) adj5 (behav$ or histor$ or conduct)).mp.
8 Antisocial Personality Disorder/
9 (attention adj5 deficit$).mp.
10 (adhd or "ad/hd" or adhkd or addh or adhs).tw.
11 hyperactiv$.mp.
12 Hyperkinesis/
13 hyperkine$.mp.
14 Aggression/
15 Agonistic behavior/
16 aggress$.mp.
17 agonistic$.mp.
18 Anger/
19 Rage/
20 (anger or angry).mp.
21 malic$.mp.
22 hostil$.mp.
23 ((dangerous$ or disrupt$ or defiant$) adj3 (behav$ or histor$ or conduct$)).mp.
24 deceit$.mp.
25 cruel$.mp.
26 delinquen$.mp.
27 threaten$.mp.
28 Impulsive Behavior/
29 impulsiv$.mp.
30 impulse$.mp.
31 unlawful$.mp.
32 Violence/
33 violen$.mp.
34 Crime/
35 criminal$.mp.
36 penal$.mp.
37 (offend$ or offenc$ or offens$).mp.
38 correctional.mp.
39 or/1‐38
40 amisulprid$.mp.
41 amisulpirid$.mp.
42 aripiprazol$.mp.
43 asenapin$.mp.
44 Clozapine/
45 clozapin$.mp.
46 iloperidon$.mp.
47 lurasidon$.mp.
48 olanzapin$.mp.
49 paliperidon$.mp.
50 quetiapin$.mp.
51 Risperidone/
52 risperidon$.mp.
53 sertindol$.mp.
54 ziprasidon$.mp.
55 zotepin$.mp.
56 (atypical$ adj3 (antipsychotic$ or anti‐psychotic)).mp.
57 or/40‐56
58 (child$ or boy$ or girl$ or baby or babies or toddler$ or infant$ or teen$ or adolescen$ or juvenile$ or preschool$ or pre‐school$ or schoolchild$).mp.
59 (youth$ or young$ people).mp.
60 Child/ or Child, preschool/
61 Infant/
62 Adolescent/
63 Minors/
64 or/58‐63
65 39 and 57 and 64

Ovid MEDLINE(R) In‐Process & Other Non‐Indexed Citations

1 (conduct adj5 (disorder$ or disturb$)).mp.
2 oppositional$.mp.
3 ((antisocial$ or anti‐social$) adj5 (behav$ or histor$ or conduct)).mp.
4 (attention adj5 deficit$).mp.
5 (adhd or "ad/hd" or adhkd or addh or adhs).mp.
6 hyperactiv$.mp.
7 hyperkine$.mp.
8 aggress$.mp.
9 agonistic$.mp.
10 (anger or angry).mp.
11 malic$.mp.
12 hostil$.mp.
13 ((dangerous$ or disrupt$ or defiant$) adj3 (behav$ or histor$ or conduct$)).mp.
14 deceit$.mp.
15 cruel$.mp.
16 delinquen$.mp.
17 threaten$.mp.
18 impulsiv$.mp.
19 impulse$.mp.
20 unlawful$.mp.
21 violen$.mp.
22 criminal$.mp.
23 penal$.mp.
24 (offend$ or offenc$ or offens$).mp.
25 correctional.mp.
26 amisulprid$.mp.
27 amisulpirid$.mp.
28 aripiprazol$.mp.
29 asenapin$.mp.
30 clozapin$.mp.
31 iloperidon$.mp.
32 lurasidone.mp.
33 olanzapin$.mp.
34 paliperid$.mp.
35 quetiapin$.mp.
36 risperidon$.mp.
37 sertindol$.mp.
38 ziprasidon$.mp.
39 zotepin$.mp.
40 (atypical$ adj3 (antipsychotic$ or anti‐psychotic)).mp.
41 (child$ or boy$ or girl$ or baby or babies or toddler$ or infant$ or teen$ or adolescen$ or juvenile$ or preschool$ or pre‐school$ or schoolchild$).mp.
42 (youth$ or young$ people).mp.
43 or/1‐25
44 or/26‐40
45 or/41‐42
46 43 and 44 and 45

Embase Ovid

1 behavior disorder/ or attention deficit disorder/ or disruptive behavior/ or impulse control disorder/ or oppositional defiant disorder/
2 (conduct adj5 (disorder$ or disturb$)).mp.
3 oppositional$.mp.
4 antisocial behavior/
5 ((antisocial$ or anti‐social$) adj5 (behav$ or histor$ or conduct)).mp.
6 ((antisocial$ or anti‐social$) adj personality adj disorder$).mp.
7 (attention adj5 deficit$).mp.
8 (adhd or "ad/hd" or adhkd or addh or adhs).tw.
9 hyperactiv$.mp.
10 hyperkinesia/
11 hyperkine$.mp.
12 exp aggression/
13 aggress$.mp.
14 agonistic$.mp.
15 (anger or angry).mp.
16 malic$.mp.
17 hostil$.mp.
18 ((dangerous$ or disrupt$) adj3 (behav$ or histor$ or conduct$)).mp.
19 deceit$.mp.
20 cruel$.mp.
21 delinquen$.mp.
22 threaten$.mp.
23 impulsiveness/
24 impulse control disorder/
25 (impulsiv$ or impulse$).mp.
26 unlawful$.mp.
27 exp violence/
28 violen$.mp.
29 exp crime/
30 criminal$.mp.
31 penal$.mp.
32 (offend$ or offenc$ or offens$).mp.
33 correctional.mp.
34 or/1‐33
35 exp atypical antipsychotic agent/
36 amisulprid$.mp.
37 amisulpirid$.mp.
38 aripiprazol$.mp.
39 asenapin$.mp.
40 clozapin$.mp.
41 iloperidon$.mp.
42 lurasidone.mp.
43 olanzapin$.mp.
44 paliperid$.mp.
45 quetiapin$.mp.
46 risperidon$.mp.
47 sertindol$.mp.
48 ziprasidon$.mp.
49 zotepin$.mp.
50 (atypical$ adj3 (antipsychotic$ or anti‐psychotic$)).mp.
51 or/35‐50
52 (baby or babies or infant$ or toddler$ or child$ or boy$ or girl$ or preschool$ or pre school$ or teen$ or adolescen$ or juvenile$ or minor$ or youth$ or young people).tw.
53 infant/
54 child/
55 school child/
56 preschool child/
57 adolescent/
58 or/53‐57
59 34 and 51 and 58

PsycINFO Ovid

1 antisocial behavior/
2 Antisocial Personality Disorder/
3 Behavior Disorders/
4 Conduct Disorder/
5 Aggressive Behavior/
6 Aggressiveness/
7 Impulsiveness/
8 Oppositional Defiant Disorder/
9 exp attention deficit disorder/
10 Hyperkinesis/
11 Anger/
12 Hostility/
13 (conduct adj5 (disorder$ or disturb$)).mp.
14 oppositional$.mp.
15 ((antisocial$ or anti‐social$) adj5 (behav$ or histor$ or conduct)).mp.
16 (attention adj5 deficit$).mp.
17 (adhd or "ad/hd" or adhkd or addh or adhs).tw.
18 hyperactiv$.mp.
19 hyperkine$.mp.
20 aggress$.mp.
21 agonistic$.mp.
22 (anger or angry).mp.
23 malic$.mp.
24 hostil$.mp.
25 ((dangerous$ or disrupt$ or defiant$) adj3 (behav$ or histor$ or conduct$)).mp.
26 deceit$.mp.
27 cruel$.mp.
28 Juvenile Delinquency/
29 delinquen$.mp.
30 threaten$.mp.
31 impulsiv$.mp.
32 impulse$.mp.
33 unlawful$.mp.
34 Violence/
35 violen$.mp.
36 exp Crime/
37 criminal$.mp.
38 penal$.mp.
39 (offend$ or offenc$ or offens$).mp.
40 correctional.mp.
41 or/1‐40
42 Clozapine/
43 clozapin$.mp.
44 exp Olanzapine/
45 olanzapin$.mp.
46 Quetiapine/
47 quetiapin$.mp.
48 Risperidone/
49 risperidon$.mp.
50 sertindol$.mp.
51 ziprasidon$.mp.
52 zotepin$.mp.
53 amisulprid$.mp.
54 amisulpirid$.mp.
55 aripiprazole/
56 aripiprazol$.mp.
57 asenapin$.mp.
58 iloperidon$.mp.
59 lurasidone.mp.
60 paliperid$.mp.
61 (atypical$ adj3 (antipsychotic$ or anti‐psychotic)).mp.
62 or/42‐61
63 (child$ or boy$ or girl$ or baby or babies or toddler$ or infant$ or teen$ or adolescen$ or juvenile$ or preschool$ or pre‐school$ or schoolchild$).mp. (829362)
64 (youth$ or young$ people).mp. (94048)
65 ("100" or "120" or "140" or "160" or "180" or "200" or "320").ag.
66 63 or 64 or 65 )
67 41 and 62 and 66

CINAHL Plus EBSCOhost (Cumulative Index to Nursing and Allied Health Literature)

S1 (MH "Child Behavior Disorders")
S2 (MH "Attention Deficit Hyperactivity Disorder")
S3 (MH "Antisocial Personality Disorder")
S4 (MH "Disruptive Behavior")
S5 (MH "Hyperkinesis")
S6 (MH "Aggression")
S7 (MH "Anger")
S8 (conduct N5 disorder*) OR (conduct N5 disturb*)
S9 oppositional*
S10 (antisocial* N5 behav*) or (antisocial* N5 histor*) or (antisocial* N5 conduct*)
S11 (anti social* N5 behav*) or (anti social* N5 histor*) or (anti social* N5 conduct*)
S12 attention N5 deficit*
S13 adhd or "ad/hd" or adhkd or addh or adhs
S14 hyperactiv*
S15 hyperkine*
S16 aggress* or agonistic*
S17 anger or angry or rage*
S18 malic* or hostil*
S19 deceit*
S20 cruel*
S21 (dangerous* N3 behav* ) or (dangerous* N3 histor*) or (dangerous* N3 conduct*)
S22 (disrupt* N3 behav* ) or (disrupt* N3 histor*) or (disrupt* conduct*)
S23 delinquen*
S24 violen* or criminal* or penal* or correctional* or unlawful* or threaten*
S25 offend* or offenc* or offens*
S26 (MH "Public Offenders")
S27 (MH "Crime")
S28 (MH "Juvenile Delinquency") or (MH "Juvenile Offenders+")
S29 (MH "Violence") or (MH "School Violence") or (MH "Sibling Violence")
S30 (MH "Impulse Control Disorders")
S31 impulse* or impulsiv*
S32 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31
S33 (MH "Aripiprazole") or (MH "Clozapine") or (MH "Olanzapine") or (MH "Quetiapine") or (MH "Risperidone")
S34 (MH "Asenapine")
S35 (MH "Iloperidone")
S36 (MH "Paliperidone")
S37 amisulpirid*
S38 amisulprid*
S39 aripiprazol*
S40 asenapin*
S41 clozapin*
S42 iloperidon*
S43 lurasidon*
S44 olanzapin*
S45 paliperid*
S46 quetiapin*
S47 risperidon*
S48 sertindol*
S49 ziprasidon*
S50 zotepin*
S51 (atypical n3 (antipsychotic* or anti‐psychotic*))
S52S33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 OR S47 OR S48 OR S49 OR S50 OR S51
S53 S32 AND S52
S54 baby or babies or infant* or toddler* or child* or boy* or girl* or preschool* or pre school* or schoolchild* or juvenile* or minor* or teen* or adolescen* or youth* or young* people
S55 AG child
S56 AG adolescent
S57 AG preschool
S58 S54 OR S55 OR S56 OR S57
S59 S53 AND S58

Cochrane Database of Systematic Reviews (CDSR) in the Cochrane Library

#1 MeSH descriptor: [Child Behavior Disorders] this term only
#2 MeSH descriptor: [Attention Deficit and Disruptive Behavior Disorders] this term only
#3 MeSH descriptor: [Attention Deficit Disorder with Hyperactivity] this term only
#4 MeSH descriptor: [Conduct Disorder] this term only
#5 (conduct near/5 (disorder* or disturb*)):ti,ab,kw
#6 (oppositional*):ti,ab,kw
#7 MeSH descriptor: [Antisocial Personality Disorder] this term only
#8 ((antisocial or anti next social) near/5 (behav* or histor* or conduct*)):ti,ab,kw
#9 (attention near/5 deficit*):ti,ab,kw
#10 (adhd or "ad/hd" or adhkd or addh or adhs):ti,ab,kw
#11 hyperactiv*:ti,ab,kw
#12 hyperkine*:ti,ab,kw
#13 aggress*:ti,ab,kw
#14 agonistic*:ti,ab,kw
#15 MeSH descriptor: [Anger] this term only
#16 MeSH descriptor: [Rage] this term only
#17(anger or angry):ti,ab,kw
#18 malic*:ti,ab,kw
#19 hostil*:ti,ab,kw
#20 deceit*:ti,ab,kw
#21 cruel*:ti,ab,kw
#22 ((dangerous* or disrupt*) near/5 (behav* or histor* or conduct*)):ti,ab,kw
#23 MeSH descriptor: [Impulsive Behavior] this term only
#24 (impulse* or impulsiv*):ti,ab,kw
#25 MeSH descriptor: [Crime] explode all trees
#26 (criminal* or violen* or unlawful* or delinquen*):ti,ab,kw
#27 MeSH descriptor: [Violence] this term only
#28 (offend* or offence* or offens*):ti,ab,kw
#29 (correctional* or penal*):ti,ab,kw
#30 {or #1‐#29}
#31 MeSH descriptor: [Risperidone] this term only
#32 MeSH descriptor: [Clozapine] this term only
#33 amisulpirid*:ti,ab,kw
#34 amisulprid*:ti,ab,kw
#35 aripiprazol*:ti,ab,kw
#36 asenapin*:ti,ab,kw
#37 clozapin*:ti,ab,kw
#38 iloperidon*:ti,ab,kw
#39 lurasidon*:ti,ab,kw
#40 olanzapin*:ti,ab,kw
#41 paliperid*:ti,ab,kw
#42 quetiapin*:ti,ab,kw
#43 risperidon*:ti,ab,kw
#44 sertindol*:ti,ab,kw
#45 ziprasidon*:ti,ab,kw
#46 zotepin*:ti,ab,kw
#47 (atypical near/3 (anti next psychotic* or antipsychotic*)):ti,ab,kw
#48 {or #31‐#47}
#49 MeSH descriptor: [Infant] this term only
#50 MeSH descriptor: [Child] explode all trees
#51 MeSH descriptor: [Adolescent] this term only
#52 MeSH descriptor: [Minors] this term only
#53 (child* or boy* or girl* or baby or babies or toddler* or infant* or teen* or adolescen* or juvenile* or preschool* or pre next school* or schoolchild*):ti,ab,kw
#54 (youth* or young* next people):ti,ab,kw
#55 {or #49‐#54}
#56#48 and #55 and #30

Database of Abstracts of Reviews of Effects (DARE) in the Cochrane Library

#1 MeSH descriptor: [Child Behavior Disorders] this term only
#2 MeSH descriptor: [Attention Deficit and Disruptive Behavior Disorders] this term only
#3 MeSH descriptor: [Attention Deficit Disorder with Hyperactivity] this term only
#4 MeSH descriptor: [Conduct Disorder] this term only
#5 (conduct near/5 (disorder* or disturb*)):ti,ab,kw
#6 (oppositional*):ti,ab,kw
#7 MeSH descriptor: [Antisocial Personality Disorder] this term only
#8 ((antisocial or anti next social) near/5 (behav* or histor* or conduct*)):ti,ab,kw
#9 (attention near/5 deficit*):ti,ab,kw
#10 (adhd or "ad/hd" or adhkd or addh or adhs):ti,ab,kw
#11 hyperactiv*:ti,ab,kw
#12 hyperkine*:ti,ab,kw
#13 aggress*:ti,ab,kw
#14 agonistic*:ti,ab,kw
#15 MeSH descriptor: [Anger] this term only
#16 MeSH descriptor: [Rage] this term only
#17(anger or angry):ti,ab,kw
#18 malic*:ti,ab,kw
#19 hostil*:ti,ab,kw
#20 deceit*:ti,ab,kw
#21 cruel*:ti,ab,kw
#22 ((dangerous* or disrupt*) near/5 (behav* or histor* or conduct*)):ti,ab,kw
#23 MeSH descriptor: [Impulsive Behavior] this term only
#24 (impulse* or impulsiv*):ti,ab,kw
#25 MeSH descriptor: [Crime] explode all trees
#26 (criminal* or violen* or unlawful* or delinquen*):ti,ab,kw
#27 MeSH descriptor: [Violence] this term only
#28 (offend* or offence* or offens*):ti,ab,kw
#29 (correctional* or penal*):ti,ab,kw
#30 {or #1‐#29}
#31 MeSH descriptor: [Risperidone] this term only
#32 MeSH descriptor: [Clozapine] this term only
#33 amisulpirid*:ti,ab,kw
#34 amisulprid*:ti,ab,kw
#35 aripiprazol*:ti,ab,kw
#36 asenapin*:ti,ab,kw
#37 clozapin*:ti,ab,kw
#38 iloperidon*:ti,ab,kw
#39 lurasidon*:ti,ab,kw
#40 olanzapin*:ti,ab,kw
#41 paliperid*:ti,ab,kw
#42 quetiapin*:ti,ab,kw
#43 risperidon*:ti,ab,kw
#44 sertindol*:ti,ab,kw
#45 ziprasidon*:ti,ab,kw
#46 zotepin*:ti,ab,kw
#47 (atypical near/3 (anti next psychotic* or antipsychotic*)):ti,ab,kw
#48 {or #31‐#47}
#49 MeSH descriptor: [Infant] this term only
#50 MeSH descriptor: [Child] explode all trees
#51 MeSH descriptor: [Adolescent] this term only
#52 MeSH descriptor: [Minors] this term only
#53 (child* or boy* or girl* or baby or babies or toddler* or infant* or teen* or adolescen* or juvenile* or preschool* or pre next school* or schoolchild*):ti,ab,kw
#54 (youth* or young* next people):ti,ab,kw
#55 {or #49‐#54}
#56#48 and #55 and #30

ClinicalTrials.gov

(clinicaltrials.gov)

Interventional Studies | antisocial OR disruptive OR conduct OR oppositional OR attention deficit OR adhd | aripiprazole OR olanzapine OR quetiapine OR sertindole OR ziprasidone OR zotepine OR clozapine OR risperidone OR amisulpride OR amisulpirid OR asenapine OR iloperidone OR lurasidone OR paliperidone OR atypical | Child |

WHO ICTRP

(apps.who.int/trialsearch)

Condition: antisocial OR disruptive OR conduct OR oppositional OR attention OR adhd AND Intervention: aripiprazole OR olanzapine OR quetiapine OR sertindole OR ziprasidone OR zotepine OR clozapine OR risperidone OR amisulpride OR amisulpirid OR asenapine OR iloperidone OR lurasidone OR paliperidone OR atypical AND Clinical Trials in children= selected AND Recruitment status =all

Appendix 4. Search summary 2011 onwards

Database

Search date

Database date range or issue

Number of records

Limits applied

Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library and which includes the Cochrane Developmental, Psychosocial and Learning Problems Specialised Register

26 January 2015

2014, Issue 12 (December)

42

Limited to 2011‐2015 and new drugs for all years

17 February 2016

2016, Issue 1

12

Limited to 2015‐2016

19 January 2017

2016, Issue 11

19

Limited to 2015‐2017 and de‐duped with previous records

Ovid MEDLINE

23 January 2015

1946 to January Week 3 2015

158

ED=20110801‐20150123 and new drugs for all years

17 February 2016

1946 to February Week 1 2016

47

ED=20150101‐20160204

19 January 2017

1946 to December Week 1 2016

52

ED=20150101‐20161114 and de‐duped with previous records

Ovid MEDLINE(R) In‐Process & Other Non‐Indexed Citations

23 January 2015

22 January 2015

56

No limits

17 February 2016

16 February 2016

70

No limits

19 January 2017

18 January 2017

53

De‐dupedlicated with previous records

Embase Ovid

28 January 2015

1980 to 2015 Week 03

721

2011 to current and new drugs for all years

17 February 2016

1980 to 2016 Week 07

311

2015 to current

19 January 2017

1980 to 2017 Week 03

240

2015 to current. De‐duped with previous records

PsycINFO Ovid

23 January 2015

1806 to January Week 3 2015

245

UP=20110801‐20150115 and new drugs for all years

17 February 2016

1806 to February Week 1 2016

67

UP=20150115‐20160201

19 January 2017

1806 to January Week 2 2017

60

UP=20150115‐20170109 de‐duped with previous records

CINAHL Plus EBSCO (Cumulative Index to Nursing and Allied Health Literature)

27 January 2015

1937 to current

73

EM = 2011801 onwards plus new drugs for all years

17 February 2016

1937 to current

29

EM = 20150101 onwards

19 January 2017

1937 to current

17

EM 20150101onwards . De‐duped with previous records

Cochrane Database of Systematic Reviews (CDSR), part of the Cochrane Library

26 January 2015

1 of 12 2015

5

No date limits. Not searched in 2011

17 February 2016

2016 Issue 2 (February)

0

2015‐2016

19 January 2017

2017, Issue 1 (January)

1

2016‐2017

Database of Abstracts of Reviews of Effect (DARE), part of the Cochrane Library

26 January 2015

2014 Issue 4 (October)

5

No date limits; not searched previously

17 February 2016

2015 Issue 2 (April)

0

2014‐2015. Not searched in later years because there is no new content after 2015 Issue 2

ClinicalTrials.gov (clinicaltrials.gov)

26 January 2015

All available years

6

Limited to trials registered since 1 August 2011

18 February 2016

All available years

42

No limits

20 January 2017

All available years

12

Limited to trials received from 18 February 2016 to 20 January 2017

World Health Organisation International Clinical Trials Registry Platform (WHO ICTRP;apps.who.int/trialsearch)

27 January 2015

All available years

8

Limited to trials registered since 1 August 2011

18 February 2016

All available years

32

No limits

20 January 2017

All available years

7

Limited to trials registered since 18 February 2017

Total records

2390

study flow diagram
Figures and Tables -
Figure 1

study flow diagram

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Risperidone versus placebo, Outcome 1 Aggression: ABC irritability (mean change scores).
Figures and Tables -
Analysis 1.1

Comparison 1 Risperidone versus placebo, Outcome 1 Aggression: ABC irritability (mean change scores).

Comparison 1 Risperidone versus placebo, Outcome 2 Aggression: OAS‐M, ABS Reactive subscale (final scores).
Figures and Tables -
Analysis 1.2

Comparison 1 Risperidone versus placebo, Outcome 2 Aggression: OAS‐M, ABS Reactive subscale (final scores).

Comparison 1 Risperidone versus placebo, Outcome 3 Aggression: OAS‐M, ABS Proactive subscale (final scores).
Figures and Tables -
Analysis 1.3

Comparison 1 Risperidone versus placebo, Outcome 3 Aggression: OAS‐M, ABS Proactive subscale (final scores).

Comparison 1 Risperidone versus placebo, Outcome 4 Conduct: NCBR‐CP (mean change scores).
Figures and Tables -
Analysis 1.4

Comparison 1 Risperidone versus placebo, Outcome 4 Conduct: NCBR‐CP (mean change scores).

Comparison 1 Risperidone versus placebo, Outcome 5 Weight gain (antipsychotic only): Kg (mean change scores).
Figures and Tables -
Analysis 1.5

Comparison 1 Risperidone versus placebo, Outcome 5 Weight gain (antipsychotic only): Kg (mean change scores).

Comparison 1 Risperidone versus placebo, Outcome 6 Weight gain (antipsychotic and stimulant): Kg (mean change scores).
Figures and Tables -
Analysis 1.6

Comparison 1 Risperidone versus placebo, Outcome 6 Weight gain (antipsychotic and stimulant): Kg (mean change scores).

Summary of findings for the main comparison. Risperidone compared to placebo for disruptive behaviours in children and youths

Risperidone compared to placebo for disruptive behaviours in children and youths

Patient or population: Disruptive behaviours in children and youths
Setting: Mostly outpatient clinics
Intervention: Risperidone
Comparison: Placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo

Risk with risperidone

Aggression
Assessed with: Aberrant Behaviour Checklist ‒ Irritability (ABC‐I) subscale
Scale from: 0 to 45
Follow‐up: range 4 weeks to 6 weeks

The mean aggression ABC‐I score ranged across control groups from −4.40 to 0.10

The mean aggression ABC‐I score in the intervention groups was, on average, 6.49 lower (8.79 lower to 4.19 lower)

238
(3 RCTs)

⊕⊕⊝⊝
Low1

Included studies: Aman 2002; Snyder 2002; Van Bellinghen 2001

Aggression
Assessed with: OAS‐M and ABS Proactive subscales
Follow‐up: mean 6 weeks

The mean aggression OAS‐M and ABS Proactive score ranged across control groups from 8.10 to 15.10

The mean aggression OAS‐M and ABS Proactive score in the intervention groups was, on average, 1.12 lower (2.30 lower to 0.06 higher)

190
(2 RCTs)

⊕⊕⊕⊝
Moderate2

Included studies: Buitelaar 2001; TOSCA study

Conduct
Assessed with: Nisonger Child Behaviour Rating ‒ Conduct Problems subscale
Scale from: 0 to 48
Follow‐up: mean 6 weeks

The mean conduct score ranged across control groups from −6.20 to 25.80

The mean conduct score in the intervention groups was, on average, 8.61 lower (11.49 lower to 5.74 lower)

225
(2 RCTs)

⊕⊕⊕⊝
Moderate3

Included studies: Aman 2002; Snyder 2002

Weight gain (treatment with antipsychotic only)
Assessed with: mean change scores measured in kilograms

The mean weight gain (treatment with antipsychotic only) score in the control groups ranged from 0.74 to 0.90

The mean weight gain score in the intervention groups was, on average, 2.37 higher (0.26 higher to 4.49 higher)

138
(2 RCTs)

⊕⊕⊕⊝
Moderate4

Included studies: Aman 2002; Findling 2000

Weight gain (treatment with antipsychotic and stimulant)
Assessed with: mean change scores measured in kilograms

The mean weight gain (treatment with antipsychotic and stimulant) score in the control groups ranged from −1.20 to 0.90

The mean weight gain score in the intervention groups was, on average, 2.14 higher (1.04 higher to 3.23 higher)

305
(3 RCTs)

⊕⊕⊝⊝
Low 5

Included studies: Aman 2002; Findling 2000; TOSCA study

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio

ABS: Antisocial Behavior Scale;CI: Confidence interval; MD: Mean difference;OAS: Overt Aggression Scale;OAS‐M: Overt Aggression Scale ‒ Modified; RCT: Randomised controlled trial; SMD: Standardized mean difference

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

1 Downgraded 2 levels because of unclear risk of bias due to lack of information on selection bias and detection bias in 2 studies, and unclear risk of bias due to lack of information and poor reporting standards in 1 study. 2 trials assessed outpatients, 1 trial assessed patients in residential care.

2 Unclear allocation concealment and unclear blinding of outcome assessment for 1 study and potential reporting bias in both studies.

3 Downgraded 1 level because of unclear allocation concealment and unclear blinding of outcome assessment for both studies and unclear attrition and potential reporting bias.

4 Downgraded 1 level because of unclear blinding of outcome assessment and potential reporting bias. Heterogeneity: Tau² = 2.22; Chi² = 20.77, df = 1 (P < 0.00001); I² = 95%.

5 Downgraded 2 levels because of unclear blinding of outcome assessment in 2 studies, potential reporting bias in 3 studies, and potential attrition bias in 2 studies. Heterogeneity: Tau² = 0.85; Chi² = 23.32, df = 2 (P < 0.00001); I² = 91%.

Figures and Tables -
Summary of findings for the main comparison. Risperidone compared to placebo for disruptive behaviours in children and youths
Table 1. Methods specified in protocol and not used in this review

Analysis

Method

Measures of treatment effect

For dichotomous data, we planned to analyse data on the intention‐to‐treat principle with dropouts included in the analysis. Out of the 10 studies, 1 used dichotomous outcomes (Armenteros 2007), therefore we were not able to perform further analyses.

Unit of analysis issues

For cross‐over trials, we planned to do paired analysis if data were presented. Otherwise, we planned to take all measurements from intervention periods and all measurements from control periods and analyse these as if the trial was a parallel‐group trial, acknowledging that there might be unit of analysis errors that could underestimate the precision of the estimate of the treatment effect (Deeks 2011). However, no cross‐over trials were identified. Also, there were no cluster‐randomised controlled trials, so we did not have to take this into account in our analyses.

Dealing with missing data ‒ missing participants

We intended to calculate the best‐ and worst‐case scenarios for the clinical response outcome, if possible. For example, the best‐case scenario assumed that dropouts in the intervention group had positive outcomes and those in the control group had negative outcomes. In the worst‐case scenario, dropouts in the intervention group had negative outcomes and those in the control group had positive outcomes.

Assessment of heterogeneity

Chapter 9 in the Cochrane Handbook recommends using a range for I² and a guide to interpretation (Deeks 2011). Had we found either moderate heterogeneity (I² in the range of 30% to 60%) or substantial heterogeneity (I² in the range of 50% to 90%), as specified in our protocol (Loy 2010), we planned to examine it using specified subgroup and sensitivity analyses (see Subgroup analysis and investigation of heterogeneity and Sensitivity analysis).

Assessment of reporting bias

We intended to draw funnel plots (effect size versus standard error) to assess publication bias if sufficient studies were found. Asymmetry of the plots may indicate publication bias, although they may also represent a true relationship between trial size and effect size. If such a relationship were identified, we planned to examine the clinical diversity of the studies as a possible explanation (Egger 1997). There were insufficient studies in our meta‐analysis to perform a funnel plot.

Subgroup analysis and investigation of heterogeneity

 It was our intention to conduct separate analyses on the following subgroups, where possible.

  1. Each separate drug.

  2. Diversity in doses of the same drug.

  3. Presence or absence of comorbid ADHD.

  4. Duration of treatment: 6 weeks or less compared to more than 6 weeks.

  5. Participants with intellectual disability versus participants without intellectual disability.

There were too few studies in any of the analyses for us to carry out any subgroup analyses.

Sensitivity analysis

We intended to perform sensitivity analyses to explore whether the results of the review were robust in relation to certain study characteristics. We intended to exclude trials with 'no' or 'unclear' ratings for allocation concealment and use the fixed‐effect model for our primary outcome. We identified a limited number of trials and we did not exclude any of them based on the ratings of allocation concealment. We were not able to carry out a sensitivity analysis due to the small number of trials.

ADHD: attention deficit hyperactivity disorder

Figures and Tables -
Table 1. Methods specified in protocol and not used in this review
Table 2. Rating scales used in included trials to assess aggression

Name of rating scale

Description

Construction

Study

Source of Information used in the study

Aberrant Behaviour Checklist (ABC) (Aman 1985a; Aman 1985b

Symptom checklist for assessing problem behaviours of children and adults with mental retardation. It is also used for classifying problem behaviours of children and adolescents with mental retardation.

58 items, 5 scales.

  1. Irritability and agitation.

  2. Lethargy and social withdrawal.

  3. Stereotypic behaviour.

  4. Hyperactivity and non‐compliance.

  5. Inappropriate speech.

Van Bellinghen 2001

Aman 2002

Snyder 2002

 Parent/caregiver

Child Behaviour Checklist (CBCL) (Achenbach 1991

 

Checklist for evaluating maladaptive behavioural and emotional problems.

113 items, 8 subscales.

  1. Withdrawn.

  2. Somatic complaints.

  3. Anxious/depressed.

  4. Social problems.

  5. Thought problems.

  6. Attention problems.

  7. Delinquent problems.

  8. Aggressive behaviour.

Findling 2000

Parent

Overt Aggression Scale (OAS) (Yudofsky 1986)

Assesses the severity and frequency of overt aggression.

25 items, 4 subscales.

  1. Verbal aggression.

  2. Physical aggression against self.

  3. Physical aggression against objects.

  4. Physical aggression towards other people.

Within each category, aggressive behaviour is rated according to its severity.

Connor 2008

Parent

Overt Aggression Scale ‒ Modified (OAS‐M) (Kay 1988)

Assesses the severity and frequency of overt aggression.

20 items, 4 subscales.

  1. Verbal aggression.

  2. Destruction of property.

  3. Aggression to self.

  4. Physical violence.

5‐point interval scale that represents increasing level of aggression. The total aggression score is obtained by multiplying the 4 individual scales by weights of 1, 2, 3 or 4 and then summing the 4 weighted scores.

Buitelaar 2001

Nurse or teacher

Rating of aggression against people and/or property scale (RAAP) (Kemph 1993)

Global rating scale, 1 item.

Scored from 1 (no aggression reported) to 5 (intolerable behaviour).

Findling 2000

Clinician

Children's Aggression Scale ‒ Parent (CAS‐P; Halperin 2002) and Teacher (CAS‐T; Halperin 2003)

Retrospectively measures the frequency and severity of 4 categories of aggression: verbal aggression; aggression against objects and animals; provoked physical aggression; and initiated physical aggression

Respondents (parents/guardians and teachers) complete a Likert scale to evaluate the frequency of an act. The frequency of aggressive events is multiplied by its designated severity weight factor and then summed to yield a total score.

Armenteros 2007

Parent and teacher

Antisocial Behavior Scale (ABS) Proactive and Reactive Subscales (Brown 1996)

Instrument used to differentiate reactive/affective from proactive subtypes of aggression

28 items.

Proactive Aggression subscale: 5 proactive items and 5 covert antisocial items.

Reactive Aggression subscale: 6 items.

TOSCA study

Parent

Figures and Tables -
Table 2. Rating scales used in included trials to assess aggression
Table 3. Rating scales used in the reviewed trials to assess conduct problems

Name of rating scale

Description

Construction

Study

Source of information used in the study

Conners' Parent Rating Scale (CPRS) (Conners 1989)

Checklist for assessing behavioural and emotional difficulties.

48 items, 6 subscales.

  1. Conduct problem.

  2. Learning problem.

  3. Psychosomatic.

  4. Impulsive‐hyperactive.

  5. Anxiety.

  6. Hyperactivity index.

Findling 2000

Connor 2008

Parent

Nisonger Child Behaviour Rating Form (NCBRF) (Aman 1996; Tassé 1996)

Assesses behaviour of children and adolescents with intellectual disability or autism spectrum disorders, or both.

76 items, 8 subscales.

  1. Compliant/calm.

  2. Adaptive/social.

  3. Conduct problem.

  4. Insecure/anxious.

  5. Hyperactive.

  6. Self‐injury/stereotypic.

  7. Self‐isolated/ritualistic.

  8. Overly sensitive.

Findling 2000

Aman 2002

Snyder 2002

Reyes 2006a

Parent

Nisonger Child Behavior Rating Form ‒ Typical IQ D‐Total (includes conduct problems and oppositional subscales)

Typical IQ version: assesses behaviour of children and adolescents with normal IQ.

10 items, 1 prosocial subscale.

  1. positive/social

54 items, 6 problem behaviour subscales.

  1. Conduct problems.

  2. Oppositional behaviour.

  3. Hyperactive.

  4. Inattentive.

  5. Overly sensitive.

  6. Withdrawn/dysphoric.

TOSCA study

Parent

IQ: intelligence quotient.

Figures and Tables -
Table 3. Rating scales used in the reviewed trials to assess conduct problems
Table 4. Other adverse events

Study ID

General

Neurological

Gastrointestinal

Respiratory

Cardiovascular/Metabolic

Serious adverse event

(unspecified)

Other

Armenteros 2007

(risperidone = 12, placebo = 13)

  1. Sedation (risperidone = 1, placebo = 2)

  1. Agitation (risperidone = 1, placebo = 0)

  1. Abdominal pain (risperidone = 3, placebo = 1)

  2. Vomiting (risperidone = 2, placebo = 3)

  3. Increased appetite (risperidone = 1, placebo = 0)

Not reported

Buitelaar 2001

(risperidone = 19, placebo = 19)

  1. Sedation (risperidone = 2, placebo = 0)

  2. Headache (risperidone = 4, placebo = 2)

  3. Dizziness (risperidone = 2, placebo = 1)

  4. Decreased energy/fatigue (risperidone = 2, placebo = 0)

  5. Tiredness (risperidone = 2, placebo = 5)

  1. Akathisia/restless leg syndrome (risperidone = 3, placebo = 5)

  2. Tremor (risperidone = 4, placebo = 2)

  3. Muscle stiffness (risperidone = 3, placebo = 2)

  4. Difficulty swallowing (risperidone = 4, placebo = 0)

  5. Tardive dyskinesia (risperidone = 0, placebo = 1)

  1. Nausea (risperidone = 3, placebo = 0)

  2. Sialorrhoea (risperidone = 4, placebo = 0)

  1. Rhinitis/rhinorrhoea (risperidone = 11, placebo = 1)

Not reported

Connor 2008

(quetiapine = 9, placebo = 10)

  1. Sedation (quetiapine = 6, placebo = 9)

  2. Decreased energy/fatigue (quetiapine = 3, placebo = 5)

  1. Akathisia/restless leg syndrome (quetiapine = 1, placebo = 0)

  2. Agitation (quetiapine = 6, placebo = 9

  3. Muscle stiffness (quetiapine = 1, placebo = 2)

  4. Decreased facial expression (quetiapine = 1, placebo = 6)

No differences across groups found on ECG QRS or QTc intervals.

Findling 2000

(risperidone = 10, placebo = 10)

  1. Sedation (risperidone = 3, placebo = 2)

  2. Headache (risperidone = 3, placebo = 2)

  1. Nausea (risperidone = 1, placebo = 1)

  2. Increased appetite (risperidone = 3, placebo = 0)

No clinically significant changes in ECG.

  1. Enuresis/urinary incontinence (risperidone = 0, placebo = 1)

  2. Restlessness (risperidone = 0, placebo = 1)

  3. Irritability (risperidone = 0, placebo = 1)

  4. Sleeping problems (risperidone = 0, placebo = 1)

Van Bellinghen 2001

(risperidone = 6, placebo = 7)

No side effects reported in any category.

Aman 2002

(risperidone = 55, placebo = 63)

  1. Sedation (risperidone = 28, placebo = 6)

  2. Headache (risperidone = 16, placebo = 9)

  1. Hyperprolactinaemia (risperidone = 7, placebo = 1)

  2. EPSE (unspecified; risperidone = 2, placebo = 0)

  1. Abdominal pain/dyspepsia (risperidone = 3, placebo = 1)

  2. Vomiting (risperidone = 2, placebo = 3)

  3. Increased appetite (risperidone = 1, placebo = 0)

  1. Rhinitis/rhinorrhoea (risperidone = 6, placebo = 3

  1. No QTc abnormalities.

Reyes 2006a

(risperidone = 172, placebo = 163)

  1. Sedation (risperidone = 3, placebo = 2)

  2. Headache (risperidone = 8, placebo = 11)

  3. Decreased energy/fatigue (risperidone = 3, placebo = 0)

  1. Hyperprolactinaemia (risperidone = 5, placebo = 0)

  2. EPSE (unspecified; risperidone = 3, placebo = 1)

  1. Abdominal pain/dyspepsia (risperidone = 6, placebo = 3)

  2. Increased appetite (risperidone = 4, placebo = 0)

  1. Pharyngitis (risperidone = 10, placebo = 4

  2. URTI (risperidone = 13, placebo = 9)

  1. No significant changes in QTc intervals.

  1. Serious adverse event (unspecified; risperidone = 6, placebo = 5)

Snyder 2002

(risperidone = 53, placebo = 57)

  1. Sedation (risperidone = 22, placebo = 8)

  2. Headache (risperidone = 9, placebo = 4)

  3. Decreased energy/fatigue (risperidone = 4, placebo = 0)

  1. Hyperprolactinaemia (risperidone = 4, placebo = 0)

  2. EPSE (unspecified; risperidone = 7, placebo = 3)

  3. Tardive dyskinesia (risperidone = 0, placebo = 1)

  1. Abdominal pain/dyspepsia (risperidone = 8, placebo = 4)

  2. Vomiting (risperidone = 6, placebo = 4)

  3. Increased appetite (risperidone = 8, placebo = 2)

  4. Anorexia (risperidone = 4, placebo = 2)

  5. Sialorrhoea (risperidone = 6, placebo = 1)

  1. Pharyngitis (risperidone = 5, placebo = 3)

  2. Nose bleeds (risperidone = 5, placebo = 0)

  3. Rhinitis/rhinorrhoea (risperidone = 7, placebo = 5)

  1. No abnormal QTc intervals.

  1. Adverse events (unspecified; risperidone = 5, placebo = 10)

  1. Rash (risperidone = 4, placebo = 1)

  2. Abnormal crying (risperidone = 4, placebo = 0)

  3. Enuresis/urinary incontinence (risperidone = 7, placebo = 3)

TOSCA study

(risperidone = 73, placebo = 80)

  1. Sedation (risperidone = 16, placebo = 20)

  2. Headache (risperidone = 16, placebo =17)

  1. Hyperprolactinaemia (risperidone = 2, placebo = 0)

  1. Abdominal pain/dyspepsia (risperidone = 12, placebo = 4)

  2. Vomiting (risperidone = 10, placebo = 6)

  3. Increased appetite (risperidone = 10, placebo = 7)

  4. Anorexia (risperidone = 9, placebo = 19)

  5. Diarrhoea (risperidone = 5, placebo = 9)

  1. Cough (risperidone = 14, placebo = 20)

  2. Rhinitis/rhinorrhoea (risperidone = 11, placebo = 14)

  1. Hyperlipidaemia (risperidone = 2, placebo = 0)

  2. Elevated fasting glucose and insulin (risperidone = 0, placebo = 2)

  1. Sleeping problems (risperidone = 14, placebo = 29)

Fleischhaker 2011

(ziprasidone = 25,

placebo = 25)

  1. Headache (ziprasidone = 8, placebo = 10)

  2. Decreased energy/fatigue (ziprasidone = 12, placebo = 7)

  1. Hyperprolactineamia (ziprasidone = 3, placebo = 1)

  2. Hypopolactinaemia (ziprasidone = 1, placebo = 3)

  3. Akathisa/restless leg syndrome (ziprasidone = 5, placebo = 2)

  4. EPSE (unspecified; ziprasidone = 3, placebo = 1)

  5. Tremor (ziprasidone = 11, placebo = 8)

  6. Muscle stiffness (ziprasidone = 5, placebo = 1)

  1. Dyspepsia/abdominal pain (ziprasidone = 5, placebo = 4)

  2. Vomiting (ziprasidone = 7, placebo = 2)

  3. Nausea (ziprasidone = 1, placebo = 4)

  4. Increased appetite (ziprasidone = 3, placebo = 1)

  5. Anorexia (ziprasidone = 3, placebo = 2)

  6. Diarrhoea (ziprasidone = 5, placebo = 3)

  1. Pharyngitis (ziprasidone = 12, placebo = 10)

  2. Cough (ziprasidone = 9, placebo = 11)

  3. Rhinitis/rhinorrhoea (ziprasidone = 3, placebo = 0)

  1. No increases in QTc levels were observed in either group.

  1. Adverse events (unspecified; ziprasidone = 3, placebo = 2)

  1. Fever (ziprasidone = 5, placebo = 3)

  2. Oropharyngeal pain (ziprasidone = 3, placebo = 0)

  3. Excessive blinking (ziprasidone = 2, placebo = 3)

  4. Aggression (ziprasidone = 3, placebo = 7)

Bpm: beats per minute; ECG: electrocardiogram; URTI: upper respiratory tract infection; EPSE: Extrapyramidal side effects; QRS: the name for the 3 waves (Q wave, R wave and S wave) on an electrocardiogram; QTc: correct QT (start of Q wave to end of T wave) interval

Figures and Tables -
Table 4. Other adverse events
Comparison 1. Risperidone versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Aggression: ABC irritability (mean change scores) Show forest plot

3

238

Mean Difference (IV, Random, 95% CI)

‐6.49 [‐8.79, ‐4.19]

2 Aggression: OAS‐M, ABS Reactive subscale (final scores) Show forest plot

2

190

Mean Difference (IV, Random, 95% CI)

‐1.30 [‐2.21, ‐0.40]

3 Aggression: OAS‐M, ABS Proactive subscale (final scores) Show forest plot

2

190

Mean Difference (IV, Random, 95% CI)

‐1.12 [‐2.30, 0.06]

4 Conduct: NCBR‐CP (mean change scores) Show forest plot

2

225

Mean Difference (IV, Random, 95% CI)

‐8.61 [‐11.49, ‐5.74]

5 Weight gain (antipsychotic only): Kg (mean change scores) Show forest plot

2

138

Mean Difference (IV, Random, 95% CI)

2.37 [0.26, 4.49]

6 Weight gain (antipsychotic and stimulant): Kg (mean change scores) Show forest plot

3

305

Mean Difference (IV, Random, 95% CI)

2.14 [1.04, 3.23]

Figures and Tables -
Comparison 1. Risperidone versus placebo