Attention deficit hyperactivity disorder (ADHD) is characterised by inattention, excessive activity levels and impulsive behaviours. Although it is an early developmental condition and is associated with childhood, in many instances, it is a lifelong condition. ADHD in adulthood is increasingly being recognised. Clinical guidelines and research suggest that the stimulant drug methylphenidate can reduce ADHD symptoms in adults.

However, there is also evidence showing that some adults do not tolerate methylphenidate well and experience harmful side effects. As a result, some adults withdraw from clinical trials of methylphenidate and stop taking the medication. It is unclear whether such dropout rates are higher than for adults receiving placebo. A recent systematic review and meta-analysis of existing literature investigated these issues.

Methods

A range of electronic research databases and the Cochrane clinical trials register were searched for randomised controlled trials (RCTs) comparing use of methylphenidate to a placebo in adults with ADHD.

12 studies (nearly 2,500 patients) met the following inclusion criteria:

• Study was conducted in an outpatient setting
• Study did not include a pre-randomisation phase
• Study reported information on dropout rates

The primary outcome investigated was the number of patients who did not complete the study for any reason, referred to as “all-cause treatment discontinuation” in the study. The secondary outcome was the effectiveness of the drug on reducing ADHD symptoms.

Results

• The rates of patients dropping out of the study were relatively high
• Patients receiving methylphenidate were more likely to drop out of the clinical trials than those receiving placebo (OR=1.44, 95 % CI=1.14–1.82)
  • This effect was only seen after excluding one ‘outlier’ study, which was of the longest follow-up duration
  • The exclusion was done according to criteria defining “outliers” recommended by the Cochrane Collaboration
  • Although several types of methylphenidate were investigated, the higher dropout rate for methylphenidate relative to placebo was particularly clear for one type of medication: osmotic-controlled release oral delivery system, which is the formulation with the longest lasting effects
• The studies were fairly consistent in showing that methylphenidate was more effective at reducing ADHD symptoms than placebo (OR=2.66, 95 % CI=2.12–3.33)

Conclusions

Although methylphenidate does appear to be effective in alleviating ADHD symptoms in adults, its safety is not ideal. More patients receiving this drug than those receiving placebo suffered from adverse side effects which led them to discontinue the treatment and drop out of the clinical trial.

Limitations

• The researchers report that some of the studies may have been biased due to insufficient blinding, which could have meant that the patients and clinicians involved knew who was given which treatment
• Few of the studies reported the number of patients that dropped out of the study because they were unhappy with the ineffectiveness of the treatment. Available results suggest that more adults with placebo dropped out for this reason
• However, the high dropout rate may have biased the results of remission of ADHD symptoms
• Although investigating ADHD symptom remission is important in clinical trials, more information is needed on whether the additional problems (e.g. social difficulties) associated with ADHD also improve

Take-home message

The authors of this review conclude that despite clinical guidelines suggesting using methylphenidate as a routine treatment for adult ADHD, the safety of this practice is not entirely clear.

Link

Castells X, Cunill R, Capellà D. Treatment discontinuation with methylphenidate in adults with attention deficit hyperactivity disorder: a meta-analysis of randomized clinical trials. Eur J Clin Pharmacol. 2013 Mar;69(3):347-56. doi: 10.1007/s00228-012-1390-7. Epub 2012 Sep 16. [PubMed abstract]