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NIHR Signal Amphetamines probably the best first-choice treatment for adults with ADHD

Published on 30 October 2018

doi: 10.3310/signal-000668

There is further evidence to support the amphetamines as the most effective group of drugs for treating adults with attention deficit hyperactivity disorder in the short-term. Two of these drugs were shown to provide the most improvement in core symptoms of attention deficit hyperactivity disorder, are tolerated as well as any other drug treatment and are less likely to be stopped.  

The review did not identify data to determine whether amphetamines should continue to be used for longer than 12 weeks.

This large, comprehensive NIHR-funded systematic review included published and unpublished randomised controlled trials of different drug treatments. The quality of the included trials was mixed, with only a quarter of the studies having low risk of bias. The network meta-analysis allowed the authors to compare different drugs with each other as well as with placebos (dummy pills).

It strengthens the evidence behind NICE guidelines which recommend a trial of either the amphetamine lisdexamfetamine or another stimulant, methylphenidate, as first-line treatments. 

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Why was this study needed?

Attention deficit hyperactivity disorder (ADHD) is a persistent pattern of inattention, hyperactivity and impulsivity that interferes with functioning or learning.  ADHD affects 3-4% of adults in the UK, who may develop far-reaching, long-lasting negative effects. Treatment can involve drugs and psychological interventions such as cognitive behavioural therapy.

Drug treatments include stimulants (e.g. methylphenidate and amphetamines) and non-stimulants (e.g. atomoxetine). It is not clear which drugs are most effective, as they are usually tested against placebos, rather than against each other. Network meta-analyses allow comparisons of drugs, even if they have not been directly tested against each other in trials. Previous network meta-analyses in ADHD have looked just at specific age groups, or a small number of drugs, or safety. This review aimed to be more comprehensive, looking at all ages, and the effectiveness and tolerability of a wide range of drugs. 

What did this study do?

Part of this systematic review focused on adults and included 10,296 participants from 52 randomised controlled trials. The network analysis compared a range of drugs used to treat ADHD either with each other or with placebo. Due to the small number of trials the amphetamines, (including lisdexamfetamine and dexamfetamine) were grouped together. The review included unpublished data gathered from study authors, regulatory agencies and drug manufacturers.  The majority of trials took place in the US.

Core symptoms of ADHD were rated by clinicians, using a variety of scales at 12 weeks.

All trials were double-blind, so neither the clinician nor the person with ADHD knew which drug they were taking which increases the reliability of the results. The number of studies for each comparison was not provided in the study report.

What did it find?

  • Amphetamines greatly improved symptoms (standardised mean difference [SMD] ‑0.79, 95% confidence interval [CI] -0.99 to -0.58). Moderate improvements were seen for methylphenidate (SMD -0.49, 95% CI -0.64 to -0.35) and atomoxetine (SMD -0.45, 95% CI -0.58 to -0.32).
  • There was less certainty of a moderate improvement with bupropion (SMD ‑0.46, 95% CI ‑0.85 to ‑0.07), and modafinil was no better than placebo (SMD 0.16, ‑0.28 to 0.59).
  • There were no differences between the drugs in terms of tolerability when measured as the proportion of participants who left a study because of side-effects.
  • Amphetamines were the only drugs that were more acceptable than placebo, measured as the proportion of participants who left the study for any reason (odds ratio [OR] 0.68, 95% CI 0.49 to 0.95).
  • People lost weight taking amphetamines (SMD -0.60, 95% CI -1.03 to -0.18) and methylphenidate (SMD -0.74, 95% -1.20 to -0.28).

What does current guidance say on this issue?

NICE updated its guidance on the diagnosis and management of ADHD in March 2018. It recommends lisdexamfetamine or methylphenidate as first-line drug treatment for adults. It suggests switching to the other of these two drugs if a six-week trial of one hasn’t shown enough benefit.

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

Atomoxetine should be offered to adults if they cannot tolerate lisdexamfetamine or methylphenidate, or their symptoms have not responded to either of these drugs.

What are the implications?

This study supports amphetamines as the first-choice drug treatment for adults with ADHD. As the largest network meta-analysis to date, it strengthens the evidence behind the NICE guideline. The review doesn’t distinguish between lisdexamfetamine and other amphetamines, as the authors felt that there wasn’t enough evidence to do this.  NICE recommends lisdexamfetamine specifically, having included UK cost information.

The authors found very little evidence on the effectiveness of any drugs in the longer term, so future research should focus on effectiveness, tolerability and acceptability at six and twelve months after starting treatment.

As it is difficult to predict individual responses and to determine the role of additional psychological therapies, the full treatment pathway for this long-term condition will need looking at further.

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 persistent pattern of inattention, hyperactivity and impulsivity that interferes with functioning or learning.  ADHD affects 3-4% of adults in the UK, who may develop far-reaching, long-lasting negative effects. Treatment can involve drugs and psychological interventions such as cognitive behavioural therapy.

Drug treatments include stimulants (e.g. methylphenidate and amphetamines) and non-stimulants (e.g. atomoxetine). It is not clear which drugs are most effective, as they are usually tested against placebos, rather than against each other. Network meta-analyses allow comparisons of drugs, even if they have not been directly tested against each other in trials. Previous network meta-analyses in ADHD have looked just at specific age groups, or a small number of drugs, or safety. This review aimed to be more comprehensive, looking at all ages, and the effectiveness and tolerability of a wide range of drugs. 

What did this study do?

Part of this systematic review focused on adults and included 10,296 participants from 52 randomised controlled trials. The network analysis compared a range of drugs used to treat ADHD either with each other or with placebo. Due to the small number of trials the amphetamines, (including lisdexamfetamine and dexamfetamine) were grouped together. The review included unpublished data gathered from study authors, regulatory agencies and drug manufacturers.  The majority of trials took place in the US.

Core symptoms of ADHD were rated by clinicians, using a variety of scales at 12 weeks.

All trials were double-blind, so neither the clinician nor the person with ADHD knew which drug they were taking which increases the reliability of the results. The number of studies for each comparison was not provided in the study report.

What did it find?

  • Amphetamines greatly improved symptoms (standardised mean difference [SMD] ‑0.79, 95% confidence interval [CI] -0.99 to -0.58). Moderate improvements were seen for methylphenidate (SMD -0.49, 95% CI -0.64 to -0.35) and atomoxetine (SMD -0.45, 95% CI -0.58 to -0.32).
  • There was less certainty of a moderate improvement with bupropion (SMD ‑0.46, 95% CI ‑0.85 to ‑0.07), and modafinil was no better than placebo (SMD 0.16, ‑0.28 to 0.59).
  • There were no differences between the drugs in terms of tolerability when measured as the proportion of participants who left a study because of side-effects.
  • Amphetamines were the only drugs that were more acceptable than placebo, measured as the proportion of participants who left the study for any reason (odds ratio [OR] 0.68, 95% CI 0.49 to 0.95).
  • People lost weight taking amphetamines (SMD -0.60, 95% CI -1.03 to -0.18) and methylphenidate (SMD -0.74, 95% -1.20 to -0.28).

What does current guidance say on this issue?

NICE updated its guidance on the diagnosis and management of ADHD in March 2018. It recommends lisdexamfetamine or methylphenidate as first-line drug treatment for adults. It suggests switching to the other of these two drugs if a six-week trial of one hasn’t shown enough benefit.

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

Atomoxetine should be offered to adults if they cannot tolerate lisdexamfetamine or methylphenidate, or their symptoms have not responded to either of these drugs.

What are the implications?

This study supports amphetamines as the first-choice drug treatment for adults with ADHD. As the largest network meta-analysis to date, it strengthens the evidence behind the NICE guideline. The review doesn’t distinguish between lisdexamfetamine and other amphetamines, as the authors felt that there wasn’t enough evidence to do this.  NICE recommends lisdexamfetamine specifically, having included UK cost information.

The authors found very little evidence on the effectiveness of any drugs in the longer term, so future research should focus on effectiveness, tolerability and acceptability at six and twelve months after starting treatment.

As it is difficult to predict individual responses and to determine the role of additional psychological therapies, the full treatment pathway for this long-term condition will need looking at further.

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 7 August 2018

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

The Lancet Psychiatry , 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 someone wanders off task, lacks persistence, has difficulty in sustaining focus and is disorganised.

Hyperactivity in an adult is manifest by extreme restlessness or wearing others out with their activity.

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

Recent years have seen recognition of the need for growth in attention deficit hyperactivity disorder services, particularly for older adolescents and adults. However, guidelines on medication have often been based on data from younger cohorts or less clear on any differences between age groups. 

This study, the most comprehensive of its kind, meta-analysed the available data and demonstrated that there are variations in what is most effective at varying life-stages.

This information is important for those who take and those who prescribe these medications in helping maximise effectiveness and minimise unnecessary harms. It reinforces the need for study of longer-term outcomes.

Dr Derek Tracy, Consultant Psychiatrist & Clinical Director, Oxleas NHS Foundation Trust, London; Senior Lecturer, King's College London