How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis

Abstract

Background: Numerous small clinical trials have been carried out to study the behaviourally defined efficacy and safety of short-acting methylphenidate compared with placebo for attention-deficit disorder (ADD) in individuals aged 18 years and less. However, no meta-analyses that carefully examined these questions have been done. We reviewed the behavioural evidence from all the randomized controlled trials that compared methylphenidate and placebo, and completed a meta-analysis.

Methods: We searched several electronic sources for articles published between 1981 and 1999: MEDLINE, EMBASE, PsychINFO, ERIC, CINAHL, HEALTHSTAR, Biological Abstracts, Current Contents and Dissertation Abstracts. The Cochrane Library Trials Registry and Current Controlled Trials were also consulted. A study was considered eligible for inclusion if it entailed the following: a placebo-controlled randomized trial that involved short-acting methylphenidate and participants aged 18 years or less at the start of the trial who had received any primary diagnosis of ADD that was made in a systematic and reproducible way.

Results: We included 62 randomized trials that involved a total of 2897 participants with a primary diagnosis of ADD (e.g., with or without hyperactivity). The median age of trial participants was 8.7 years, and the median "percent male" composition of trials was 88.1%. Most studies used a crossover design. Using the scores from 2 separate indices, this collection of trials exhibited low quality. Interventions lasted, on average, 3 weeks, with no trial lasting longer than 28 weeks. Each primary outcome (hyperactivity index) demonstrated a significant effect of methylphenidate (effect size reported by teacher 0.78, 95% confidence interval [CI] 0.64-0.91; effect size reported by parent 0.54, 95% CI 0.40-0.67). However, these apparent beneficial effects are tempered by a strong indication of publication bias and the lack of robustness of the findings, especially those involving core ADD features. Methylphenidate also has an adverse event profile that requires consideration. For example, clinicians only need to treat 4 children to identify an episode of decreased appetite.

Interpretation: Short-acting methylphenidate has a statistically significant clinical effect in the short-term treatment of individuals with a diagnosis of ADD aged 18 years and less. However, the extension of this placebo-controlled effect beyond 4 weeks of treatment has not been demonstrated. Exact knowledge of the extent and definition of the short-term behavioural usefulness of methylphenidate is questioned.

Fig. 1: Effect sizes for the hyperactivity index: teacher ratings (95% confidence interval [CI]). MPH = methylphenidate, ACTRS = Abbreviated Conners Teacher Rating Scale, CTRS = Conners Teacher Rating Scale, SSQ = School Situations Questionnaire. p values for statistical heterogeneity: *p < 0.001, †p = 0.03, ‡p = 0.02, §p = 0.03.

Fig. 2: Effect sizes for the hyperactivity index: parent ratings (95% CI). ACPRS = Abbreviated Conners Parent Rating Scale, CPRS = Conners Parent Rating Scale, HSQ = Home Situations Questionnaire. p values for statistical heterogeneity: *p < 0.001, †p = 0.001, ‡p = 0.008.

Fig. 3: Sensitivity and subgroup analyses of the hyperactivity index: teacher ratings (95% CI). ADHD = attention-deficit hyperactivity disorder (DSM-III-Revised), ADDH = attention-deficit disorder with hyperactivity (DSM-III). p values for statistical heterogeneity: *p = 0.006, †p < 0.001, ‡p = 0.04. §Variance from each trial reduced by 20% to compensate for correlation in crossover phases potentially leading to an underestimate of variance.

Fig. 4: Sensitivity and subgroup analyses of the hyperactivity index: parent ratings (95% CI). *Variance from each trial reduced by 20% to compensate for correlation in crossover phases potentially leading to an underestimate of variance.

Fig. 5: (A) Funnel plot of methylphenidate effect size for the hyperactivity index (T) versus its precision. The trials' symbols are proportional to sample size (median 32, range 11–161). (B) Funnel plot of methylphenidate effect size for the hyperactivity index (P) versus its precision. The trials' symbols are proportional to sample size (median 37, range 11–161).