Clinicians cannot know for sure whether taking methylphenidate will improve the lives of children and adolescents with attention deficit hyperactivity disorder (ADHD) because of the quality of the available evidence, according to the lead author of a Cochrane Review published on 25 November 2015.
The review considered data from 185 randomised controlled trials (RCTs) that have compared the drug with either a placebo or no drug at all.
“Despite more than 50 years of research in this field, we do not yet know how to identify those patients that may obtain more benefits than harms,” say the researchers, led by Ole Jakob StorebÃ¸, a clinical psychologist at the Psychiatric Research Unit in Region Zealand, Denmark.
Having analysed data from RCTs involving 12,245 children and adolescents with ADHD, the reviewers argue in the Cochrane Database of Systematic Reviews
that better-designed trials are needed to assess the benefits of methylphenidate.
Given the frequency of non-serious adverse events associated with methylphenidate, and the subsequent difficulties for blinding of participants and outcome assessors, the researchers point to the advantage of large, ‘nocebo’-controlled trials. Nocebo trials use a placebo-like substance that causes adverse events in the control arm, like those associated with methylphenidate.
Treatment in the 185 trials ranged from 1 to 425 days, meaning that the long-term effects of methylphenidate could not be assessed.
“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,” says StorebÃ¸.
The reviewers conclude that methylphenidate may improve ADHD symptoms as reported by teachers. Data from 19 trials, involving 1,698 patients, showed a mean difference of -9.6 points (95% confidence interval -13.75 to -6.38) on the ADHD rating scale (range 0 to 72 points, where a change of 6.6 points on the scale is considered clinically relevant).
Analysis of adverse effects showed that children were more likely to experience sleep problems and loss of appetite while taking methylphenidate.
However, these findings came from trials providing very low-quality evidence, they report.
One psychiatrist who published several of the trials reviewed by StorebÃ¸’s team says the reviewers’ conclusions are likely to be controversial. Stephen Faraone, distinguished professor of psychiatry at State University of New York Upstate Medical University, questioned the reviewers’ conclusion that all 185 trials reviewed were at a high risk of bias. “They seem to have defined bias as ‘high’ if it was clearly high or if it was ‘unclear’,” he says. “Because of that, their main conclusion may be misleading.”
Faraone adds that the reviewers did not distinguish between US Food and Drug Administration registration trials and other industry supported trials.
“They imply that the results of the trials might be influenced by bias, yet they present no analyses to support that conclusion,” he says. “Using meta-analysis regression they could determine if each type of bias predicts the effect of medication on outcomes.”
StorebÃ¸’s team concludes that if methylphenidate treatment is considered, clinicians might need to use it for short periods, with careful monitoring of both benefits and harms, and cease its use if no evidence of clear improvement of symptoms is noted, or if harmful effects appear.
“That is exactly what most experts would advise clinicians to do, so I don’t think that the paper will change clinical practice,” says Faraone.