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.
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 It included unpublished data gathered from study authors and drug manufacturers.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).
NHS. Attention deficit hyperactivity disorder (ADHD). London: Department of Health and Social Care; 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.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre