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NIHR Signal Methylphenidate remains first-choice drug treatment for children and young people with ADHD

Published on 6 November 2018

doi: 10.3310/signal-000671

The stimulant methylphenidate has the best balance of effectiveness against side effects in children and young people with attention deficit hyperactivity disorder. Amphetamines are more effective, but also more likely to be stopped for a reason other than side effects.

This large, NIHR-funded systematic review compared a range of drugs against each other through a network meta-analysis. Effectiveness and tolerability were assessed at about 12 weeks of treatment. Other second-line drug treatments were also effective and well-tolerated, including modafinil which is currently not licensed for children in the UK.

There were some quality issues due to risk of bias. But this study supports NICE guidance on the range of potential drug options to consider in conjunction with behavioural and support strategies for children and young people with attention deficit hyperactivity disorder.

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Why was this study needed?

Attention deficit hyperactivity disorder (ADHD) is a condition that starts in childhood. Symptoms include inattention, hyperactivity and impulsivity that occur at home and school, interfering with functioning or development. It is thought to affect around 5% of children worldwide and is more common in boys than girls.

Many children improve with behavioural interventions and family support, with drug treatments reserved for more those more severely affected. Drug treatments include stimulants (such as methylphenidate and amphetamines) and non-stimulants (such as atomoxetine). This review aimed to compare the available drugs using a network meta-analysis. This type of analysis can weigh up the effectiveness and side effects of the drugs against one another even if they have not been directly compared in trials, as long as they have been in at least a placebo-controlled trial.

What did this study do?

The child and adolescent parts of this systematic review included 82 trials of 14,346 young people. The network meta-analysis compared amphetamines (including lisdexamfetamine), methylphenidate, atomoxetine, bupropion, clonidine, guanfacine and modafinil. It included unpublished data gathered from study authors and drug manufacturers.

Core symptoms of ADHD were rated by both clinicians and teachers, using a variety of scales. The review only looked at outcomes at about 12 weeks, as few of the trials included longer-term data.

The majority of the trials took place in the US, with only two carried out in the UK. The number of children in the analysis of each drug was not provided and only a quarter of studies were at low risk of bias, which reduces the reliability of the results.

What did it find?

  • All the drugs were better than placebo when rated by clinicians. Amphetamines greatly improved symptoms and were the most effective (standardised mean difference [SMD] -1.02, 95% confidence interval [CI] -1.19 to -0.85). No information was available for teacher ratings.
  • Moderate to large improvements were also seen for methylphenidate by clinicians (SMD -0.78, 95% CI -0.93 to -0.62) and teachers (SMD ‑0.82 ‑1.16 to ‑0.48). Bupropion was also moderate to largely effective when rated by clinicians though there was less confidence in this result (SMD ‑0.96, 95% CI ‑1.69 to ‑0.22) and it was not significantly effective when rated by teachers.
  • Clinicians found moderate improvements for atomoxetine (SMD -0.56, 95% CI -0.66 to ‑0.45), clonidine (SMD ‑0.71, 95% CI ‑1.17 to ‑0.24), guanfacine (SMD ‑0.67, 95% CI ‑0.85 to ‑0.50) and modafanil (SMD ‑0.62, 95% CI ‑0.84 to ‑0.41).
  • There were no differences in tolerability between the drugs, measured as the proportion of participants who left a study because of any side-effects. Acceptability was measured as the proportion of participants who left the study for any reason. Methylphenidate was the only drug that was more acceptable than placebo (odds ratio [OR] 0.66, 95% CI 0.47 to 0.92).
  • Weight loss was common when compared to placebo for young people on amphetamines (SMD -0.71, 95% CI -1.15 to -0.27), methylphenidate (SMD -0.77, 95% -1.09 to -0.45), atomoxetine (SMD ‑0.84, 95% CI ‑1.16 to ‑0.52) and modafinil (SMD ‑0.93, 95% CI ‑1.59 to ‑0.26).

What does current guidance say on this issue?

NICE updated its guidance on the diagnosis and management of ADHD in March 2018. It recommends methylphenidate (either short or long-acting) as the first line drug treatment for children (aged five years and over) and young people with ADHD.  If a six-week trial does not show enough benefit, it recommends switching to once daily lisdexamfetamine.  The shorter acting dexamfetamine can be considered for those whose symptoms respond to lisdexamfetamine but who cannot tolerate the longer effects (and side effects). 

Atomoxetine or guanfacine are second-line options. Clonidine is only used in tertiary services for young people with ADHD and sleep disturbance, rages or tics. Modafinil is only licensed for adults.

What are the implications?

This study supports NICE guidelines for using methylphenidate as the first-choice drug treatment for children over the age of five years and young people with ADHD, and amphetamines as a second choice. There was insufficient evidence to analyse the amphetamines separately, though NICE specifically recommends lisdexamfetamine, having included the convenience of taking it once per day and UK cost information.

Lisdexamfetamine is broken down slowly in the body to dexamfetamine and is only taken once per day. If it works but the effects last too long, standard dexamfetamine can be considered which is taken every few hours.

Longer-term studies would be useful and separate analysis for children and adolescents to determine if age affects outcomes. But overall, each recommended drug is effective and tolerable, thus providing a range of options depending on individual factors and preferences.

Citation and Funding

Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-38.

This project was funded by the National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre (BRC-1215-20005) and Stichting Eunethydis (European Network for Hyperkinetic Disorders).

Bibliography

NHS. Attention deficit hyperactivity disorder (ADHD). London: Department of Health; 2018.

NICE. Attention deficit hyperactivity disorder: diagnosis and management. NG87. London: National Institute for Health and Care Excellence; 2018.

NICE. Attention deficit hyperactivity disorder. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2018.

Why was this study needed?

Attention deficit hyperactivity disorder (ADHD) is a condition that starts in childhood. Symptoms include inattention, hyperactivity and impulsivity that occur at home and school, interfering with functioning or development. It is thought to affect around 5% of children worldwide and is more common in boys than girls.

Many children improve with behavioural interventions and family support, with drug treatments reserved for more those more severely affected. Drug treatments include stimulants (such as methylphenidate and amphetamines) and non-stimulants (such as atomoxetine). This review aimed to compare the available drugs using a network meta-analysis. This type of analysis can weigh up the effectiveness and side effects of the drugs against one another even if they have not been directly compared in trials, as long as they have been in at least a placebo-controlled trial.

What did this study do?

The child and adolescent parts of this systematic review included 82 trials of 14,346 young people. The network meta-analysis compared amphetamines (including lisdexamfetamine), methylphenidate, atomoxetine, bupropion, clonidine, guanfacine and modafinil. It included unpublished data gathered from study authors and drug manufacturers.

Core symptoms of ADHD were rated by both clinicians and teachers, using a variety of scales. The review only looked at outcomes at about 12 weeks, as few of the trials included longer-term data.

The majority of the trials took place in the US, with only two carried out in the UK. The number of children in the analysis of each drug was not provided and only a quarter of studies were at low risk of bias, which reduces the reliability of the results.

What did it find?

  • All the drugs were better than placebo when rated by clinicians. Amphetamines greatly improved symptoms and were the most effective (standardised mean difference [SMD] -1.02, 95% confidence interval [CI] -1.19 to -0.85). No information was available for teacher ratings.
  • Moderate to large improvements were also seen for methylphenidate by clinicians (SMD -0.78, 95% CI -0.93 to -0.62) and teachers (SMD ‑0.82 ‑1.16 to ‑0.48). Bupropion was also moderate to largely effective when rated by clinicians though there was less confidence in this result (SMD ‑0.96, 95% CI ‑1.69 to ‑0.22) and it was not significantly effective when rated by teachers.
  • Clinicians found moderate improvements for atomoxetine (SMD -0.56, 95% CI -0.66 to ‑0.45), clonidine (SMD ‑0.71, 95% CI ‑1.17 to ‑0.24), guanfacine (SMD ‑0.67, 95% CI ‑0.85 to ‑0.50) and modafanil (SMD ‑0.62, 95% CI ‑0.84 to ‑0.41).
  • There were no differences in tolerability between the drugs, measured as the proportion of participants who left a study because of any side-effects. Acceptability was measured as the proportion of participants who left the study for any reason. Methylphenidate was the only drug that was more acceptable than placebo (odds ratio [OR] 0.66, 95% CI 0.47 to 0.92).
  • Weight loss was common when compared to placebo for young people on amphetamines (SMD -0.71, 95% CI -1.15 to -0.27), methylphenidate (SMD -0.77, 95% -1.09 to -0.45), atomoxetine (SMD ‑0.84, 95% CI ‑1.16 to ‑0.52) and modafinil (SMD ‑0.93, 95% CI ‑1.59 to ‑0.26).

What does current guidance say on this issue?

NICE updated its guidance on the diagnosis and management of ADHD in March 2018. It recommends methylphenidate (either short or long-acting) as the first line drug treatment for children (aged five years and over) and young people with ADHD.  If a six-week trial does not show enough benefit, it recommends switching to once daily lisdexamfetamine.  The shorter acting dexamfetamine can be considered for those whose symptoms respond to lisdexamfetamine but who cannot tolerate the longer effects (and side effects). 

Atomoxetine or guanfacine are second-line options. Clonidine is only used in tertiary services for young people with ADHD and sleep disturbance, rages or tics. Modafinil is only licensed for adults.

What are the implications?

This study supports NICE guidelines for using methylphenidate as the first-choice drug treatment for children over the age of five years and young people with ADHD, and amphetamines as a second choice. There was insufficient evidence to analyse the amphetamines separately, though NICE specifically recommends lisdexamfetamine, having included the convenience of taking it once per day and UK cost information.

Lisdexamfetamine is broken down slowly in the body to dexamfetamine and is only taken once per day. If it works but the effects last too long, standard dexamfetamine can be considered which is taken every few hours.

Longer-term studies would be useful and separate analysis for children and adolescents to determine if age affects outcomes. But overall, each recommended drug is effective and tolerable, thus providing a range of options depending on individual factors and preferences.

Citation and Funding

Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-38.

This project was funded by the National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre (BRC-1215-20005) and Stichting Eunethydis (European Network for Hyperkinetic Disorders).

Bibliography

NHS. Attention deficit hyperactivity disorder (ADHD). London: Department of Health; 2018.

NICE. Attention deficit hyperactivity disorder: diagnosis and management. NG87. London: National Institute for Health and Care Excellence; 2018.

NICE. Attention deficit hyperactivity disorder. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2018.

Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis

Published on 12 August 2018

Cortese, S.,Adamo, N.,Del Giovane, C.,Mohr-Jensen, C.,Hayes, A. J.,Carucci, S.,Atkinson, L. Z.,Tessari, L.,Banaschewski, T.,Coghill, D.,Hollis, C.,Simonoff, E.,Zuddas, A.,Barbui, C.,Purgato, M.,Steinhausen, H. C.,Shokraneh, F.,Xia, J.,Cipriani, A.

Lancet Psychiatry Volume 5 , 2018

BACKGROUND: The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. METHODS: We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. FINDINGS: 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1.02, 95% CI -1.19 to -0.85 for amphetamines, -0.78, -0.93 to -0.62 for methylphenidate, -0.56, -0.66 to -0.45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0.82, 95% CI -1.16 to -0.48) and modafinil (-0.76, -1.15 to -0.37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0.79, 95% CI -0.99 to -0.58), methylphenidate (-0.49, -0.64 to -0.35), bupropion (-0.46, -0.85 to -0.07), and atomoxetine (-0.45, -0.58 to -0.32), but not modafinil (0.16, -0.28 to 0.59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2.30, 95% CI 1.36-3.89) and adults (3.26, 1.54-6.92); guanfacine was inferior to placebo in children and adolescents only (2.64, 1.20-5.81); and atomoxetine (2.33, 1.28-4.25), methylphenidate (2.39, 1.40-4.08), and modafinil (4.01, 1.42-11.33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0.46 to -0.24) and adults (-0.94 to -0.29). We did not find sufficient data for the 26-week and 52-week timepoints. INTERPRETATION: Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. FUNDING: Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Inattention is apparent when a child or young person wanders off task, lacks persistence, has difficulty in sustaining focus and is disorganised.

Hyperactivity is manifest by increased motor activity when it is not appropriate, or by excessive fidgeting, tapping, or talkativeness.

Impulsivity refers to hasty actions that occur in the moment without forethought and that have high potential for harm for the individual. Impulsive behaviour may manifest as social intrusiveness and/or making important decisions without considering the long-term consequences.

Expert commentary

This network analysis allows comparisons across all the major drugs for attention deficit hyperactivity disorder.

It confirms some common beliefs among clinicians, such as amphetamines and methylphenidate being generally best across home and school contexts, and that drugs usually used as second-line choices, atomoxetine and guanfacine or clonidine, being less effective.

However what may be new for many is the effectiveness of modafinil for children and adolescents in both settings, whereas it had few effects in adults. We still need more trials with long-term follow-up and more that are not funded by the pharmaceutical industry.

Stephen Scott, Professor of Child Health and Behaviour; Director, National Academy for Parenting Research, Kings’s College London; Head, National Conduct Problems and National Adoption & Fostering Services, Maudsley Hospital, London