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

Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents:Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials

Study question: Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? / Methods: Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour. / Study answer and limitations: The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) −0.77, n=1698), corresponding to a mean difference of −9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD −0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE. / What this study adds: The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events. / Funding, competing interests, data sharing: Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive. Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. OBJECTIVES: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS: In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non‐serious adverse events, general behaviour and quality of life. DATA COLLECTION AND ANALYSIS: Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel‐group trials and first period data from cross‐over trials formed the basis of our primary analyses; separate analyses were undertaken using post‐cross‐over data from cross‐over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias. MAIN RESULTS: The studies. We included 38 parallel‐group trials (5111 participants randomised) and 147 cross‐over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys‐to‐girls ratio of 5:1, and participants' ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high‐income countries. The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials). Risk of Bias. All 185 trials were assessed to be at high risk of bias. Primary outcomes. Methylphenidate may improve teacher‐rated ADHD symptoms (standardised mean difference (SMD) ‐0.77, 95% confidence interval (CI) ‐0.90 to ‐0.64; 19 trials, 1698 participants; very low‐quality evidence). This corresponds to a mean difference (MD) of ‐9.6 points (95% CI ‐13.75 to ‐6.38) on the ADHD Rating Scale (ADHD‐RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD‐RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low‐quality evidence). The Trial Sequential Analysis‐adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2). Secondary outcomes. Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non‐serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non‐serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low‐quality evidence). The Trial Sequential Analysis‐adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non‐serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group. Teacher‐rated general behaviour seemed to improve with methylphenidate (SMD ‐0.87, 95% CI ‐1.04 to ‐0.71; 5 trials, 668 participants; very low‐quality evidence). A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta‐analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent‐reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low‐quality evidence). AUTHORS' CONCLUSIONS: The results of meta‐analyses suggest that methylphenidate may improve teacher‐reported ADHD symptoms, teacher‐reported general behaviour, and parent‐reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow‐up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non‐serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events. Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non‐serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo‐like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent. Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non‐pharmacological treatments

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