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.

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

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

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)