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

Abstract

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]).

Research design and methods:

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.

Keywords::

• Adolescent
• Atomoxetine
• Attention deficit hyperactivity disorder
• Child
• Lisdexamfetamine dimesylate
• Meta-analysis
• Methylphenidate

Transparency

Declaration of funding

This study was funded by Shire. Shire develops and markets psychiatric drugs including treatments for ADHD.

Author contributions: N.R. planned, performed and interpreted the meta-analyses. E.Z., P.H., and J.S. designed the research question and contributed to the content and review of all aspects of the systematic review, meta-analyses, and reporting. All authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors, are fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development.

Declaration of financial or other relationships

RTI Health Solutions (RTI-HS) was paid as a consultant to Shire for this study. N.R. and E.Z. have disclosed that at the time of this research and analysis they were employees of RTI-HS. N.R. has disclosed that he is now an employee of BresMed Health Solutions. J.S. is an employee of Shire and holds stock/or stock options. P.H. was a full-time employee of Shire and held stock/or stock options when this work was conducted. He is now an employee of Vertex Pharmaceuticals.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank Miny Samuel, RTI Health Solutions, for her contributions regarding the design and conduct of the literature searches and systematic review. Haim Erder from Shire and Moshe Fridman from AMF Consultancy also reviewed and edited the manuscript for scientific accuracy.