Abstract
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 We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data.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.
Plain language summary
Benefits and harms of methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)
Review question
We reviewed the evidence of the effects of methylphenidate on the behaviour of children and adolescents with ADHD.
Background
ADHD is one of the most commonly diagnosed and treated childhood psychiatric disorders. Children diagnosed with ADHD find it hard to concentrate. They are often hyperactive (fidgety, unable to sit still for long periods) and impulsive (doing things without stopping to think). ADHD can make it difficult for children to do well at school, because they find it hard to follow instructions and to concentrate. Their behavioural problems can interfere with their ability to get on well with family and friends, and they often get into more trouble than other children. Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD.
Study characteristics
We found 185 randomised controlled trials (RCTs; studies in which participants are randomly assigned to one of two or more treatment groups), involving 12,245 children or adolescents with a diagnosis of ADHD. Most of the trials compared methylphenidate to a placebo – something designed to look and taste the same as methylphenidate but with no active ingredient. Most trials were small and of low quality. Treatment generally lasted an average of 75 days (range 1 to 425 days), making it impossible to assess the long-term effects of methylphenidate. Seventy-two of the 185 included trials (40%) were funded by industry.
The evidence is current to February 2015.
Key results
Findings suggest that methylphenidate might improve some of the core symptoms of ADHD – reducing hyperactivity and impulsivity, and helping children to concentrate. Methylphenidate might also help to improve the general behaviour and quality of life of children with ADHD. However, we cannot be confident that the results accurately reflect the size of the benefit of methylphenidate.
The evidence in this review of RCTs suggests that methylphenidate does not increase the risk of serious (life threatening) harms when used for periods of up to six months. However, taking methylphenidate is associated with an increased risk of non-serious harms such as sleeping problems and decreased appetite.
Quality of the evidence
The quality of the evidence was very low for all outcomes. It was possible for people in the trials to know which treatment the children were taking, the reporting of the results was not complete in many trials and for some outcomes the results varied across trials. These considerations limit our confidence in the overall results of the review.
Conclusions
At the moment, the quality of the available evidence means that we cannot say for sure whether taking methylphenidate will improve the lives of children and adolescents with ADHD. Methylphenidiate is associated with a number of non-serious adverse events such as problems with sleeping and decreased appetite. Although we did not find evidence that there is an increased risk of serious adverse events, we need trials with longer follow-up to better assess the risk of serious adverse events in people who take methylphenidate over a long period of time.
Given that methylphenidate is associated with adverse events, designing high quality trials is challenging. It can be easy for clinicians, researchers and participants to work out whether a child is in the experimental group (receiving methylphenidate) or in the control group (receiving the placebo). This is a serious risk of bias that can make us less confident in the results of a trial. One way to avoid this is to design trials that compare methylphenidate with a placebo that can produce similar adverse events, but which has no other active ingredient. These trials are known as ‘nocebo trials’. For ethical reasons, nocebo trials should first be undertaken with adults. Only if the results suggest that methylphenidate is effective for adults, should researchers consider recruiting children to trials with this design.
