ERIC Proquest

Searched up to 2014.

(SU.EXACT.EXPLODE("Pervasive Developmental Disorders") OR autis* OR Asperger* OR kanner* OR "pervasive development* disorder*" OR "childhood schizophrenia" OR pervasive NEAR/3 child* OR pdd OR pdds OR asd OR asds OR pdd‐nos)) AND (Attenta* OR Biphentin* OR Centedrin* OR Concerta* OR Daytrana* OR dexmethylphenidat* OR Equasym* OR Focalin* OR Medikinet* OR Metadate* OR Methylphenidat* OR Methylin* OR Penid* OR Phenidyl* OR Ritalin* OR Rubifen OR tranquilyn* OR Tsentedrin*)

ERIC EBSCOhost

Searched after 2014.

S1DE "Developmental Disabilities"
S2DE "Pervasive Developmental Disorders" OR DE "Asperger Syndrome" OR DE "Autism"
S3(pervasive development* disorder* or PDD or PDDs)
S4(autis* or ASD or ASDs)
S5Asperger*
S6Rett*
S7Kanner*
S8childhood schizophren*
S9S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8
S10methylphenidat*
S11(Attenta* or Biphentin* or Centedrin* or Concerta* or Daytrana* or dexmethylphenidat* or Equasym*)
S12(Focalin* or Medikinet* or Metadate* or Methylin* or Penid* or Phenidyl* or Ritalin* or Rubifen or tranquilyn* or Tsentedrin*)
S13S10 OR S11 OR S12
S14S9 AND S13

Cluster‐randomised trials

In cluster‐randomised trials, groups rather than individuals are randomised, which requires an adjustment to be made to account for the clustering effect. If trials used cluster randomisation, we would have expected cluster effects to have been appropriately controlled for (robust standard errors or hierarchical linear models). If it was unclear whether appropriate controls for clustering were applied, we planned to contact the investigators for further details. If appropriate controlling was not used, we planned to request and reanalyse individual participant data using appropriate multilevel models. Following this, we planned to analyse effect sizes and standard errors in Review Manager 5 (RevMan 5) (Review Manager 2014) using the generic inverse method (Deeks 2017). If there was insufficient information to control for clustering, we planned to enter outcome data using individuals as the units of analysis, and then conduct a sensitivity analysis to assess the impact of inadequately controlled cluster‐randomised trials on the effect estimate.

The method for adjustment for clustering suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c) is based on reducing the size of effect of each clustered trial to its 'effective sample size', which is the original sample size of the cluster‐randomised trial divided by the 'design effect' (i.e. 1 + (M – 1) *ICC, where M is the average cluster size and ICC is the intracluster correlation coefficient) (Higgins 2011c). We planned to estimate the ICC based upon similar studies (in similar populations, but including other treatments). This would have enabled us to pool non‐clustered and clustered trials to obtain an overall estimate of effect.

Trials with repeated measurements

In trials with repeated measurements for the same patient (for example, measurements at different time points), we planned to attempt to reduce the impact of multiple analysis by analysing the most frequently reported or the most clinically relevant time points (usually the longest duration of follow‐up, which is likely to be the best indication of a clinically sustainable effect), or both (Higgins 2011c).

Trials with multiple treatment arms

We planned to attempt to combine arms to create a single pair‐wise comparison where appropriate (for example, slow‐ or controlled‐release and immediate‐release methylphenidate formulations). If this was not possible, we planned to use all treatment groups but split the comparison (placebo) group evenly across the intervention groups (Higgins 2011c). Criteria for assessing the relevance of the treatment arms for each comparison would have included clinical relevance (is the expected clinical effect likely to be different or not?) and clinical availability or use of the treatment in question (for example, transdermal formulations of methylphenidate are not commonly used. Therefore, if a trial has two active treatment arms with one of them a transdermal patch, we might have chosen to consider only the oral formulation).

Abdominal discomfort

Two studies, Handen 2000 and Pearson 2013, included abdominal discomfort in their adverse effects checklist rated by teachers. However, abdominal discomfort was reported for only one child in the treatment group in Pearson 2013, which corresponds to a non‐significant RR of 3.00 (95% CI 0.13 to 70.16). We were not able to pool the results of both studies because abdominal discomfort was not reported in Handen 2000 (Analysis 1.4).

Two studies, Pearson 2013 and RUPP 2005, included abdominal discomfort in their adverse effects checklist rated by parents. The pooled difference in rates between treatment and placebo was not statistically significant (RR 4.30, 95% CI 0.91 to 20.34; 74 participants; Analysis 5.3). There was no clear heterogeneity given the I² of 0%.

Reduced appetite

Two studies, Handen 2000 and Pearson 2013, both included reduced appetite in their adverse effects checklist rated by teachers. The pooled difference between treatment and placebo was not statistically significant (RR 1.33, 95% CI 0.43 to 4.12; 34 participants; Analysis 1.4).

Only one study, Pearson 2013, reported on weight and found no significant difference in average weight at any dose of methylphenidate. There was no clear heterogeneity given the I² of 19%. We applied a random‐effects model and this did not change the results.

Two studies, Pearson 2013 and RUPP 2005, both included reduced appetite in their adverse effects checklist rated by parents. The pooled difference between treatment and placebo was statistically significant (RR 8.28, 95% CI 2.57 to 26.73; 74 participants; Analysis 5.3); the risk for reduced appetite was almost eight times higher in the treatment group compared to placebo. This RR is equivalent to a risk difference (RD) of 0.24 (95% CI 0.13 to 0.35), with a number needed to treat for one additional harmful outcome of 4.17 (95% CI 7.69 to 2.86). An I² of 0% did not indicate heterogeneity.

Other

Other recorded gastrointestinal effects included diarrhoea (RUPP 2005), dry mouth and nausea (Pearson 2013). The difference between treatment and placebo was not statistically significant for any of these symptoms.

Dizziness

Two studies, Handen 2000 and Pearson 2013, included symptoms of dizziness in their adverse effects checklist rated by teachers. However, we were not able to pool the results of both studies because dizziness was not reported in the Pearson 2013 study (Analysis 1.4).

Dizziness was not included in any of the studies' adverse effects checklists rated by parents.

Drowsiness

Two studies, Handen 2000 and Pearson 2013, included symptoms of drowsiness in their adverse effects checklist rated by the teachers. The pooled difference between treatment and placebo was not statistically significant (RR 2.00, 95% CI 0.47 to 8.55; 34 participants; Analysis 1.4). An I² of 10% did not indicate any clear heterogeneity.

Drowsiness was not included in the adverse effects checklists rated by parents in any of the studies.

Headache

Two studies, Handen 2000 and Pearson 2013, included headache in their adverse effects checklists rated by teachers. However, were not able to pool the results of both studies because headache was not reported in the Handen 2000 study (Analysis 1.4).

Two studies, Pearson 2013 and RUPP 2005, included headache in their adverse effects checklists rated by parents. The pooled difference between treatment and placebo was not statistically significant (RR 1.87, 95% CI 0.10 to 33.86; 74 participants; Analysis 5.3). An I² of 58% indicated moderate heterogeneity. There is no evident clinical explanation for this heterogeneity, although Pearson 2013 used an extended‐release preparation and is likely to have studied less unwell children who may have been more able to communicate the presence of headache.

Sleep disturbance

Sleep disturbance was not included in the adverse effects checklists rated by teachers in any of the studies.

Two studies, Pearson 2013 and RUPP 2005, included sleep disturbance in their adverse effects checklists rated by parents. The pooled difference between treatment and placebo was not statistically significant (RR 3.51, 95% CI 0.59 to 20.82; 74 participants Analysis 5.3). An I² of 62% indicated moderate heterogeneity. There is no evident clinical explanation for this heterogeneity, although Pearson 2013 used an extended‐release preparation in the morning (and an immediate‐release preparation in the afternoon).

Increased activity

Hyperactivity was one of our primary outcomes and was rated using psychometric scales in all four studies. Results for this outcome are reported above (see Analysis 1.2 for teachers and Analysis 5.2 for parents).

Two studies, Handen 2000 and RUPP 2005, also included increased activity in their adverse effects checklists rated by teachers. Neither reported a significant difference between treatment and placebo. We were unable to pool this data because the effect was rated by teachers in Handen 2000 and by parents in RUPP 2005.

Other

Two studies recorded other general physical effects related to fever and skin rash (Pearson 2013), and fatigue (RUPP 2005). The difference between treatment and placebo was not statistically significant for any of these effects.

Two studies reported blood pressure and pulse (Pearson 2013; RUPP 2005). RUPP 2005 did not report any results and Pearson 2013 reported no significant differences at any dose of methylphenidate as measured by clinicians. Pearson 2013 also included racing heart in their adverse effects checklist rated by parents, and reported no significant difference, while RUPP 2005 included bradycardia in their adverse effects checklist, and reported no significant difference between treatment and placebo (RUPP 2005).

Anxiety

Two studies, Handen 2000 and Pearson 2013, included anxiety in their adverse effects checklist rated by teachers. The pooled difference between treatment and placebo was not statistically significant (RR 1.02, 95% CI 0.47 to 2.18; 34 participants; Analysis 1.4). There was no clear heterogeneity given the I² of 0%. We applied a random‐effects model and this did not change the results.

Two studies, Pearson 2013 and RUPP 2005, included anxiety in their adverse effects checklist rated by parents. The pooled difference between treatment and placebo was not statistically significant (RR 1.13, 95% CI 0.22 to 5.79; 74 participants; Analysis 5.3). An I² of 50% indicated moderate heterogeneity. There is no evident clinical explanation for this heterogeneity, although Pearson 2013 used an extended‐release preparation and is likely to have studied less unwell children who may have been more able to communicate adverse psychological effects.

Depressed mood

Two studies, Handen 2000 and Pearson 2013, included depressed mood in their adverse effects checklists rated by teachers. The pooled difference between treatment and placebo was not statistically significant (RR 1.19, 95% CI 0.37 to 3.79; 34 participants; Analysis 1.4). An I² of 55% indicated moderate heterogeneity. Pearson 2013 used an extended‐release preparation and is likely to have studied less unwell children who may have been more able to communicate adverse psychological effects.

Two studies, Pearson 2013 and RUPP 2005, included symptoms of depressed mood in their adverse effects checklist rated by parents. The pooled difference between treatment and placebo was not statistically significant (RR 1.75, 95% CI 0.05 to 62.33; 74 participants; Analysis 5.3). An I² of 74% indicated considerable heterogeneity. Pearson 2013 used an extended‐release preparation and is likely to have studied less unwell children who may have been more able to communicate adverse psychological effects.

Irritability

Two studies, Handen 2000 and Pearson 2013, recorded symptoms of irritability rated by teachers. The pooled difference between treatment and placebo was not statistically significant (RR 0.81, 95% CI 0.29 to 2.27; 34 participants; Analysis 1.4). An I² of 46% indicated moderate heterogeneity. Pearson 2013 used an extended‐release preparation and is likely to have studied less unwell children who may have been more able to communicate adverse psychological, cognitive and/or affective states.

Two studies, Pearson 2013 and RUPP 2005, both included symptoms of irritability in their adverse effects checklists rated by parents. The pooled difference between treatment and placebo was not statistically significant (RR 1.25, 95% CI 0.25 to 6.36; 74 participants; Analysis 5.3). An I² of 71% indicated considerable heterogeneity. Pearson 2013 used an extended‐release preparation and is likely to have studied less unwell children who may have been more able to communicate adverse psychological, cognitive and/or affective states.

Social withdrawal

Social withdrawal is one aspect of impaired social interaction and it was one of our primary outcomes. Two studies, Handen 2000 and RUPP 2005, included social withdrawal in their adverse effects checklists. Neither reported a significant difference between methylphenidate and placebo. We were unable to pool this data because the effect was rated by teachers in Handen 2000 and by parents in RUPP 2005.

Impaired social interaction was rated using psychometric scales in three studies (Handen 2000; Pearson 2013; RUPP 2005). Combined results for this outcome are reported above (see Analysis 1.3 for teachers and Analysis 5.2 for parents).

Other psychological effects

Two studies recorded other psychological effects including emotional outbursts and self‐injury in RUPP 2005 and euphoria in Pearson 2013. The difference between treatment and placebo was not statistically significant for self‐injury or euphoria, but RUPP 2005 reported a significant increase in emotional outbursts at medium‐dose methylphenidate.

General repetitive behaviours

Repetitive behaviours were not recorded for teachers.

Two studies, Pearson 2013 and RUPP 2005, included repetitive behaviours in the adverse events checklist rated by parents. The pooled difference between treatment and placebo was not statistically significant (RR 0.87, 95% CI 0.43 to 1.75; 74 participants; Analysis 5.3). An I² of 8% indicated no clear heterogeneity.

Repetitive movements or tics

Two studies, Handen 2000 and Pearson 2013, included repetitive movements and tics in their adverse events checklists rated by teachers. The pooled difference between treatment and placebo was not statistically significant (RR 0.57, 95% CI 0.21 to 1.57; 34 participants; Analysis 1.4). One study, Quintana 1995, also measured abnormal involuntary movements rated by the paediatrician on a psychometric scale and reported no significant difference between treatment and placebo. An I² of 0% indicated no heterogeneity.

Repetitive movements were not recorded for parents.

Other repetitive behaviours

One study, Pearson 2013, reported other repetitive behaviours included in their adverse events checklist, namely hair or skin pulling, unusual blinking, and repetitive language. The difference between treatment and placebo was not statistically significant for any of these effects.