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

Ferrán Catalá-López, Brian Hutton, Amparo Núñez-Beltrán, Matthew J Page, Manuel Ridao, Diego Macías Saint-Gerons, Miguel A Catalá, Rafael Tabarés-Seisdedos, David Moher, Ferrán Catalá-López, Brian Hutton, Amparo Núñez-Beltrán, Matthew J Page, Manuel Ridao, Diego Macías Saint-Gerons, Miguel A Catalá, Rafael Tabarés-Seisdedos, David Moher

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 Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016).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.

Conflict of interest statement

Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: BH has previously received funds from Amgen Canada, Eisai Canada and Cornerstone Research Group for the provision of methodologic advice related to systematic reviews and meta-analysis. None of the advice is related to the content of this manuscript. AN-B received salary from Centro de Atención Integral a Drogodependientes (CAID) Norte, Madrid Regional Health Council and Dionisia Plaza Rehabilitation Center during the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Figures

Fig 1. Evidence network diagram for primary…
Fig 1. Evidence network diagram for primary outcome of efficacy among therapeutic classes.
Solid lines represent direct comparisons within randomised trials. Nodes in blue represent controls. Nodes in green represent psychological interventions. Nodes in grey represent pharmacological interventions. Nodes in purple represent complementary and alternative medicine interventions. Nodes in red represent combined interventions. Size of node is proportional to number of randomised trials, and thickness of line connecting nodes is proportional to number of randomised trials directly comparing the two treatments. PUFA = polyunsaturated fatty acids.
Fig 2. Evidence network diagram for primary…
Fig 2. Evidence network diagram for primary outcome of efficacy among individual therapies.
Solid lines represent direct comparisons within randomised trials. Nodes in blue represent controls. Nodes in green represent psychological interventions. Nodes in grey represent pharmacological interventions. Nodes in purple represent complementary and alternative medicine interventions. Nodes in red represent combined interventions. Size of node is proportional to number of randomised trials, and thickness of line connecting nodes is proportional to number of randomised trials directly comparing the two treatments. AMPH = amphetamine. ATX = atomoxetine. CLON = clonidine. GUAN = guanfacine. MODAF = modafinil. CARBA = carbamazepine. BUP = bupropion. DESIP = desipramine. REBOX = reboxetine. VENLAF = venlafaxine. RISP = risperidone. THIO = thioridazine. L-CARN = L-carnitine. HYP = hypericum. C, P, T training = child, parent and/or teacher training. P training = parent training. C training = child training. T training = teacher training. WM training = working memory training.
Fig 3. Evidence network diagram for primary…
Fig 3. Evidence network diagram for primary outcome of acceptability among therapeutic classes.
Solid lines represent direct comparisons within randomised trials. Nodes in blue represent controls. Nodes in green represent psychological interventions. Nodes in grey represent pharmacological interventions. Nodes in purple represent complementary and alternative medicine interventions. Nodes in red represent combined interventions. Size of node is proportional to number of randomised trials, and thickness of line connecting nodes is proportional to number of randomised trials directly comparing the two treatments. PUFA = polyunsaturated fatty acids.
Fig 4. Evidence network diagram for primary…
Fig 4. Evidence network diagram for primary outcome of acceptability among individual therapies.
Solid lines represent direct comparisons within randomised trials. Nodes in blue represent controls. Nodes in green represent psychological interventions. Nodes in grey represent pharmacological interventions. Nodes in purple represent complementary and alternative medicine interventions. Nodes in red represent combined interventions. Size of node is proportional to number of randomised trials, and thickness of line connecting nodes is proportional to number of randomised trials directly comparing the two treatments. AMPH = amphetamine. ARIP = aripiprazole. ATX = atomoxetine. CLON = clonidine. GUAN = guanfacine. MODAF = modafinil. CARBA = carbamazepine. BUP = bupropion. DESIP = desipramine. REBOX = reboxetine. VENLAF = venlafaxine. RISP = risperidone. THIO = thioridazine. L-CARN = L-carnitine. HYP = hypericum. HOMEO = homeopathy. C, P, T training = child, parent and/or teacher training. P training = parent training. C training = child training. T training = teacher training. WM training = working memory training.
Fig 5. Network meta-analyses for efficacy and…
Fig 5. Network meta-analyses for efficacy and acceptability of classes of pharmacological and psychological interventions.
Data in blue represents efficacy (treatment response). Data in red represents acceptability (all-cause discontinuation). Results are the ORs in the column-defining treatment compared with the ORs in the row-defining treatment. For efficacy (acceptability), ORs higher than 1 favour the row-defining treatment. For acceptability, ORs lower than 1 favour the row-defining treatment. Significant results are in bold and underscored. PBO = placebo. CONT = control. WL = waiting list. BEHAV = behavioural therapy. COGN = cognitive training. NF = neurofeedback. STI = stimulants. N-STI = non-stimulants. AD = antidepressants. A-PSY = antipsychotics. O-DRU = other unlicensed drugs. STI+BEHAV = stimulants+behavioural therapy. N-STI+BEHAV = non-stimulants+behavioural therapy. STI+N-STI = stimulants+non-stimulants. OR = Odds ratio. CI = credibility interval.
Fig 6. Network meta-analyses for efficacy and…
Fig 6. Network meta-analyses for efficacy and acceptability of commonly prescribed medications for ADHD.
Data in blue represents efficacy (treatment response). Data in red represents acceptability (all-cause discontinuation). Results are the ORs in the column-defining treatment compared with the ORs in the row-defining treatment. For efficacy (acceptability), ORs higher than 1 favour the row-defining treatment. For acceptability, ORs lower than 1 favour the row-defining treatment. Significant results are in bold and underscored. PBO = placebo. MPH = methylphenidate. AMPH = amphetamine. ATX = atomoxetine. CLON = clonidine. GUAN = guanfacine. MODAF = modafinil. BUP = bupropion. OR = Odds ratio. CI = credibility interval.

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