Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials

Abstract

Study question: Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents?

Methods: Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour.

Study answer and limitations: The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) -0.77, n=1698), corresponding to a mean difference of -9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD -0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE.

What this study adds: The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events.

Funding, competing interests, data sharing: Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure for at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: CRMM receives financial research support from the government agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); has served as speaker to Novartis, developed educational material for Novartis; received travel awards from the Health Technology Assessment Institute (IATS), Universidade Federal do Rio Grande do Sul (UFRGS), and travel and registration support to the 4th World Congress on ADHD from the World Federation of ADHD; MZ sits on the Paediatric Medicines Expert Advisory Group at the Medicines and Healthcare Regulatory Agency, which considers applications regarding the licensing of paediatric medicines. Payment for MZ’s attendance at this meeting goes to his NHS organization. RK is currently employed by South Asian Cochrane Centre, funded by Indian Council for Medical Research, India and Effective Healthcare Research Consortium (DFID), UK. CG received funds from the Lundbeck Foundation to finance part of her Ph.D in the paediatric field on Tourette Syndrome. CG confirms that none of these funds were used to work on this review.

© Storebø et al 2015.

Figures

Fig 1 Flow of studies through review

Fig 2 Teacher rated symptoms of attention-deficit/hyperactivity disorder in parallel group trials.

Fig 3 Serious adverse events in parallel group trials. Green=low risk of bias; yellow=uncertain risk of bias; red=high risk of bias. See Cochrane review for details of references

Fig 4 Trial sequential analysis on total number of serious adverse events. DARIS=diversity adjusted required information size; RRR=relative risk reduction

Fig 5 Non-serious adverse events in parallel group trials. Green=low risk of bias; yellow=uncertain risk of bias; red=high risk of bias. See Cochrane review for details of references

Fig 6 Trial sequential analysis on total number of non-serious adverse events. DARIS=diversity adjusted required information size; RRR=relative risk reduction

Fig 7 Teacher rated general behaviour in parallel group trials. Green=low risk of bias; yellow=uncertain risk of bias; red=high risk of bias. See Cochrane review for details of references

Fig 8 Quality of life in parallel group trials. Green=low risk of bias; yellow=uncertain risk of bias; red=high risk of bias. See Cochrane review for details of references