Systematic evidence synthesis of treatments for ADHD in children and adolescents: indirect treatment comparisons of lisdexamfetamine with methylphenidate and atomoxetine

Objective: Systematically review and synthesize the clinical evidence of treatments for attention deficit hyperactivity disorder (ADHD) by indirectly comparing established treatments in the UK with a drug recently approved in Europe (lisdexamfetamine [LDX]).

Population: children and adolescents.

Setting: Europe. Comparators: methylphenidate (MPH), atomoxetine (ATX), and dexamphetamine (DEX). Electronic databases and relevant conference proceedings were searched for randomized, controlled clinical trials evaluating efficacy and safety of at least one of the comparators and LDX. Quality assessments for each included trial were performed using criteria recommended by the Centre for Reviews and Dissemination. Network meta-analysis methods for dichotomous outcomes were employed to evaluate treatment efficacy.

Main outcome measures: Response, as defined by either a reduction from baseline of at least 25% in the ADHD Rating Scale [ADHD-RS] total score or, separately, as assessed on the Clinical Global Impression-Improvement [CGI-I] scale, and safety (all-cause withdrawals and withdrawal due to adverse events).

Results: The systematic review found 32 trials for the meta-analysis, including data on LDX, ATX, and different formulations of MPH. No trials for DEX meeting the inclusion criteria were found. Sufficient data were identified for each outcome: ADHD-RS, 16 trials; CGI-I, 20 trials; all-cause withdrawals, 28 trials; and withdrawals due to adverse events, 27 trials. The relative probability of treatment response for CGI-I (95% confidence intervals [CI]) for ATX versus LDX was 0.65 (0.53-0.78); for long-acting MPH versus LDX, 0.82 (0.69-0.97); for intermediate release MPH versus LDX, 0.51 (0.40-0.65); and for short-acting MPH versus LDX, 0.62 (0.51-0.76). The relative probabilities of ADHD-RS treatment response also favored LDX.

Conclusions: For the treatment of ADHD, the synthesis of efficacy data showed statistically significant better probabilities of response with LDX than for formulations of MPH or ATX. The analysis of safety data proved inconclusive due to low event rates. These results may be limited by the studies included, which only investigated the short-term efficacy of medications in patients without comorbid disorders.