1. Webinar May 25th METHYLPHENIDATE FOR CHILDREN AND ADOLESCENTS WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)

2. Summary Background: 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. Searches: All relevant databases until March 2015 and 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 We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data.

3. Summary cont. Number of included trials: 38 parallel-group trials and 147 cross-over trials Number of participants: 12245 Age: 3-21 years (mean age 9.7 years) Countries: United States, Canada, United Kingdom, Australia, Brazil, Isreal, Germany, Sweden, New Zealand, Norway, and the Netherlands Primary outcomes: ADHD symptoms and serious adverse events (life threatning) Secondary outcomes: Nonserious adverse events, general behaviour, and quality of life

4. Summary of findings  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).  Serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; nine trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was 0.91 (95% CI 0.02 to 33.2).  Secondary outcomes. Non-serious adverse events: 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).

5.  Sleep problems: RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants); Decreased appetite: RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants).  Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71; five trials, 668 participants; very low-quality evidence).  Parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence

6. The quality of the evidence- Risk of bias Note: We consider all trials as potentially unblinded because methylphenidate is associated with easily recognizable adverse effects

7. GRADE assessments of outcomes  ADHD symptoms (downgraded two levels due to high risk of bias, one level for moderate statistical heterogeneity) Very low quality  Adverse events (downgraded two levels due to high risk of bias and downgraded one level due to imprecision) Very low quality  Non-serious adverse events ( downgraded two levels due to high risk of bias, one level for moderate statistical heterogeneity) Very low quality  General behavior (downgraded two levels due to high risk of bias, downgraded one level due to indirectness) Very low quality  Quality of life (downgraded two levels due to high risk of bias, downgraded one level due to indirectness) Very low quality

8. Conclusion  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 very low quality = Uncertain of the magnitude of the effects.  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, however there was not enough data to assess this.  The median duration of drug treatment was less than 2 months and few trials had a treatment duration greater than 6 months.

9. The evidence base for methylphenidate treatment in children, adolescent and adults is flawed: The Epstein review.  GRADE assessment in the Epstein review: Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults:  Authors' conclusions:  Data from randomized controlled trials suggest that immediate-release methylphenidate is efficacious for treating adults with ADHD with symptoms of hyperactivity, impulsivity, and inattentiveness, and for improving their overall clinical condition.  In May 26 th 2016 this review will be withdrawn, due to subsequent criticism and unsatisfactory responses from the authors.

10. NICE guideline on ADHD in children and adolescents: meta-analysis: methylphenidate versus placebo.

11. Thank you for listening!