Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder:A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

OBJECTIVES:To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review. METHODS AND FINDINGS:We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were summarised as risk ratios (RR) with 95% confidence intervals (CI) using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA) was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse events. All trials were at high risk of bias. In parallel group trials, methylphenidate decreased appetite (RR 3.66, 95% CI 2.56 to 5.23) and weight (RR 3.89, 95% CI 1.43 to 10.59). In cross-over trials, methylphenidate increased abdominal pain (RR 1.61, 95% CI 1.27 to 2.04). We found no significant differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. CONCLUSION:Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found

Parallel group trials: Risk of decreased weight.

<p>IV: inverse variance, Random: random-effect model. CI: confidence interval. The risk of bias items was rated as low (plus), unclear (question mark) or high risk of bias (minus): A: Random sequence generation (selection bias). B: Allocation concealment (selection bias). C: Blinding of participants and personnel (performance bias). D: Blinding of outcome assessment (detection bias). E: Incomplete outcome data (attrition bias). F: Selective reporting (reporting bias). G: Vested interest.</p

Trial Sequential Analysis, parallel group trials, decreased appetite, nausea, vomiting, and abdominal pain.

<p>DARIS: diversity adjusted required information size; Pc: Event proportion in the control group; RRR: relative risk reduction in the intervention group; a: type I error; b: type II error; DIVERSITY: diversity (D-square). A) Decreased appetite: The required information size was 14,286 participants. The cumulative Z-score (dark line) crosses the trial sequential monitoring boundaries for harm (lighter inward sloping line) after the twelfth trial, and stayed below the boundary, thus the risk of random error in the finding can be excluded. Therefore, there may be no need for conducting further trials based on the assumed intervention effect of RRR of 20%, an alpha of 5%, and a beta of 20% regarding this outcome. B) Nausea: The cumulative Z-scores (dark lines) crossed into the areas of futility (in between the two lighter lines). Therefore, there may be no need for conducting further trials based on the assumed intervention effect of RRR of 10%, an alpha of 5%, and a beta of 20%. C) Vomiting: The cumulative Z-scores (dark lines) crossed into the areas of futility (in between the two lighter lines). Therefore, there may be no need for conducting further trials based on the assumed intervention effect of RRR of 10%, an alpha of 5%, and a beta of 20%. D) Abdominal pain: The required information size was 4,830 participants. The cumulative Z curve did not cross the conventional or trial sequential monitoring boundaries for benefit, harm, or futility. Therefore, based on the assumed intervention effect of RRR of 10%, an alpha of 5%, and a beta of 20% we may still need more evidence on this adverse event.</p

Description of the included trials on methylphenidate for children and adolescents with attention deficit hyperactivity disorder.

<p>Description of the included trials on methylphenidate for children and adolescents with attention deficit hyperactivity disorder.</p

Parallel group trials and cross-over trials: Risk of decreased appetite.

<p>IV: inverse variance. Random: random-effect model. CI: confidence interval. The risk of bias items was rated as low (plus), unclear (question mark) or high risk of bias (minus): A: Random sequence generation (selection bias). B: Allocation concealment (selection bias). C: Blinding of participants and personnel (performance bias). D: Blinding of outcome assessment (detection bias). E: Incomplete outcome data (attrition bias). F: Selective reporting (reporting bias). G: Vested interest.</p

Parallel group trials and cross-over trials: Risk of abdominal pain.

<p>IV: inverse variance, Random: random-effects model. CI: confidence interval. The risk of bias items was rated as low (plus), unclear (question mark) or high risk of bias (minus): A: Random sequence generation (selection bias). B: Allocation concealment (selection bias). C: Blinding of participants and personnel (performance bias). D: Blinding of outcome assessment (detection bias). E: Incomplete outcome data (attrition bias). F: Selective reporting (reporting bias). G: Vested interest.</p