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23 Aug 2018

Cortese S et al. Lancet Psychiatry 2018; 5: 727-738

Over the past few decades, the use of pharmacological treatments for ADHD has increased significantly. Despite this, the benefits and safety of ADHD medications remain controversial, and current guidelines lack consensus on which medications are preferred across different age groups. To address this issue, this systematic review and meta-analysis estimated the compared efficacy and tolerability of oral medications for ADHD in children, adolescents and adults.

First, a literature search for published and unpublished double-blind, randomised controlled trials was performed, comparing amfetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate and modafinil with each other or placebo.* Data were extracted by at least two independent investigators, and the risk of bias in individual studies was assessed using the Cochrane risk of bias tool. Primary outcomes included efficacy (defined as a change in severity of ADHD core symptoms based on teachers’ and clinicians’ ratings) and tolerability (defined as the proportion of patients who dropped out of studies because of side effect). Outcomes were assessed at time points closest to 12 weeks, 26 weeks and 52 weeks. Summary odds ratios (ORs) and standardised mean differences (SMDs) were estimated using pairwise and network meta-analyses with random effects. All analyses were performed separately for studies in children and adolescents and for studies in adults. The certainty of estimates was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach for network meta-analyses.

The literature search, study selection and data extraction were performed between 11 January 2014 and 9 September 2017. Data analysis was performed from 10 September 2017 to 24 February 2018. Of the 9948 records that were screened, 133 studies were selected for inclusion in the network meta-analysis (81 studies in children and adolescents, 51 studies in adults, and 1 study in children, adolescents and adults). In children and adolescents, the risk of bias was rated overall low, unclear and high in 23.5%, 65.4% and 11.1% of studies, respectively. In adults, the corresponding values were 27.5%, 56.8% and 15.7%, respectively.

Results for the primary outcomes were as follows:

  • Efficacy: According to clinicians’ ratings of ADHD core symptoms in children and adolescents, all drugs were more efficacious than placebo (e.g. amfetamines: SMD –1.02, 95% confidence interval [CI] –1.19 to –0.85; methylphenidate: SMD –0.78, 95% CI –0.93 to –0.63; atomoxetine: SMD –0.56, 95% CI –0.66 to –0.45). When comparisons were based on teachers’ ratings, only methylphenidate (SMD –0.82, 95% CI –1.16 to –0.48) and modafinil (SMD –0.76, 95% CI –1.15 to –0.37) were superior to placebo. In adults, amfetamines (SMD –0.79, 95% CI –0.99 to –0.58), methylphenidate (SMD –0.49, 95% CI –0.64 to –0.35), bupropion (SMD –0.46, 95% CI –0.85 to –0.07) and atomoxetine (SMD –0.45, 95% CI –0.58 to –0.32), but not modafinil (SMD 0.16, 95% CI –0.28 to 0.59), were superior to placebo. In head-to-head comparisons, amfetamines were superior to modafinil, atomoxetine and methylphenidate in both children and adolescents (SMDs –0.46 to –0.24) and adults (SMDs –0.94 to –0.29).
  • Tolerability: Amfetamines were inferior to placebo in both children and adolescents (OR 2.30, 95% CI 1.36–3.89) and adults (OR 3.26, 95% CI 1.54–6.92). Guanfacine was less well tolerated than placebo in children and adolescents only (OR 2.64, 95% CI 1.20–5.81), whilst modafinil (OR 4.01, 95% CI 1.42–11.33), methylphenidate (OR 2.39, 95% CI 1.40–4.08) and atomoxetine (OR 2.33, 95% CI 1.28–4.25) were less well tolerated than placebo in adults only. No differences were observed in head-to-head comparisons between active drugs in children, adolescents and adults.

The limitations of this study were largely related to a paucity of existing longitudinal and active comparator studies. Due to a lack of longer-term data, planned analyses at 26 weeks and 52 weeks were not possible. As a result, the findings from this study can only inform the choice of short-term treatment for ADHD. Furthermore, the lack of head-to-head studies meant that comparative efficacy between interventions was often based on indirect comparisons, which resulted in very low confidence estimates. As confidence estimates were low or very low for multiple comparisons, the certainty of the findings is unclear.

Taking into account both safety and efficacy, the authors concluded that evidence from this network meta-analysis supports methylphenidate in children and adolescents, and amfetamines in adults, as the preferred first-line medications for short-term pharmacological treatment of ADHD. The authors suggested that these findings should inform future guidelines and daily clinical decision-making on the choice of medications for ADHD.

Find out more about the network meta-analysis here


*Inclusion criteria included double-blind, randomised controlled trials (parallel-group, crossover or cluster), of at least 1 week in duration, that enrolled children (aged ≥5 years and <12 years), adolescents (aged  ≥12 years and <18 years) or adults (≥18 years) with a primary diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III, DSM-III-R, DSM-IV-TR, DSM-5TM, or the International Statistical Classification of Diseases and Related Health Problems (ICD)-9 or ICD-10. The search was not restricted by ADHD subtype or presentation, gender, IQ, socioeconomic status or comorbidities (except for those who needed concomitant pharmacotherapy)
In total, 14,346 children and 10,296 adults were included in the network meta-analysis. For 83% of studies, additional data and information not reported in the full-text paper were used

Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry 2018; 5: 727-738.

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