The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials

PLoS One. 2017 Jul 12;12(7):e0180355. doi: 10.1371/journal.pone.0180355. eCollection 2017.

Abstract

Background: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents.

Methods and findings: We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution.

Conclusions: Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adolescent
  • Attention Deficit Disorder with Hyperactivity / diet therapy
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / therapy
  • Behavior Therapy
  • Central Nervous System Depressants / adverse effects
  • Central Nervous System Depressants / therapeutic use
  • Central Nervous System Stimulants / adverse effects
  • Central Nervous System Stimulants / therapeutic use
  • Child
  • Complementary Therapies / adverse effects
  • Female
  • Humans
  • Male
  • Randomized Controlled Trials as Topic

Substances

  • Central Nervous System Depressants
  • Central Nervous System Stimulants

Grant support

Specific funding from the Alicia Koplowitz Foundation was received for this work. FCL and RTS are partially supported by the Generalitat Valenciana (PROMETEOII/2015/021) and CIBERSAM/Institute of Health Carlos III. BH is supported by a New Investigator Award from the Canadian Institutes of Health Research and the Drug Safety and Effectiveness Network. BH is also supported by a grant from the National Center for Complementary and Alternative Medicine (NCCAM) of the US National Institutes of Health. MJP is supported by an Australian National Health and Medical Research Council Early Career Fellowship (1088535). DM is supported by a University of Ottawa Research Chair. FCL and RTS did not receive additional external funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. FCL is the study guarantor.