Stimulant medication to treat attention-deficit/hyperactivity disorderBMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j2945 (Published 14 July 2017) Cite this as: BMJ 2017;358:j2945
- 1Centre for Interventional Paediatric Psychopharmacology and Rare Diseases, South London and Maudsley NHS Foundation Trust, London, UK
- 2Honorary Reader, Department of child psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
- 3Director, HealthTracker Ltd, Gillingham, UK
- Correspondence to P Santosh
- Accepted 15 June 2017
What you need to know
In children and young people, stimulants should be the first choice in those with severe attention-deficit/hyperactivity disorder (ADHD), or when non-pharmacological approaches have failed
Stimulants are effective in managing ADHD symptoms in adults and should be continued as long as ADHD symptoms have an adverse effect on quality of life
Stimulants can be used in ADHD with most co-existing disorders such as anxiety, oppositional defiant disorder, conduct disorder, tic disorder, and autistic spectrum disorder
A 10 year old boy is restless at school and often disturbs the rest of the class. His mother is concerned that his restlessness interferes with his activities outside school. He is diagnosed with attention deficit/hyperactivity disorder (ADHD) by a paediatrician and starts treatment with methylphenidate. The boy’s mother is worried because the drug is a stimulant and she fears her son might become addicted to it.
People with ADHD display developmentally inappropriate levels of inattentiveness and impulse control, and can have difficulty moderating activity.1 Some 5% of people are thought to be affected by the disorder.2
The core symptoms of ADHD are inattention, hyperactivity, and impulsivity
ADHD can present with one or more co-existing conditions, such as conduct disorder, oppositional defiant disorder, anxiety, and/or depressive disorder36
The cause of ADHD is unknown
o Genetic heritability of ADHD symptoms is about 75%37 in children and adolescents, (meaning that genetic factors can explain 75% of the variance in ADHD symptoms in the general child and adolescent population) and 30% in adults38
o Non-genetic risk factors include smoking during pregnancy and alcohol abuse, prematurity/low birth weight, intrauterine exposure to certain medication, and maternal postnatal depression39
Genes involved in neurite outgrowth37 can lead to subtle changes in the frontal-striatal system40 and the dorsal, ventral, motor, and visual networks of the brain,41 and contribute to the pathophysiology of ADHD. Recent neuroimaging findings indicate that the largest effect is in the amygdala.42 These changes might be associated with reductions in the levels of neurotransmitters such a catecholamines (dopamine and noradrenaline)
What therapeutics are available?
Treatment for ADHD can include drugs, behavioural therapy, or a combination of these (fig 1⇓, fig 2⇓). Stimulant treatments such as methylphenidate and amphetamines are the key drug treatments. They are thought to work by restoring the imbalance in catecholamine levels at the synapse by inhibiting presynaptic dopamine re-uptake, hence increasing the availability of extracellular dopamine.3 Unlike methylphenidate, amphetamine can also reverse dopamine uptake and targets the vesicular monoamine transporter 2 to increase cytoplasmic dopamine levels.4
Stimulant medication is intended to reduce symptoms, boost academic achievement, and improve quality of life, but should be considered as first line treatment in severe cases. Both immediate release and extended release preparations of methylphenidate and amphetamines are available, and each has its practical merits and drawbacks (table 1⇓).
How well do they work?
Treatment responses to stimulants vary according to comorbidity, resulting impairment, and the patient’s age. The patient and their doctor should reach an understanding of what successful treatment would look like to the patient, for example, the ability to remain in class for a lesson.
According to guidelines from the UK National Institute for Health and Care Excellence (NICE), drug treatment in children and young people should be “part of a comprehensive treatment plan that includes psychological, behavioural, and educational advice and intervention.1” In children and young people, stimulants should be considered as a first choice in those with severe ADHD (hyperkinetic disorder).1
Evidence about how well the drugs performed in trials is summarised below.
Early and accurate identification of ADHD in children under 5 is essential given the adverse outcomes of the disorder, and some measures can assist in this regard.5 The response to medication is reduced in preschool children. Meta-analysis of children in this age group who have clinically disruptive behaviour (and are therefore at high risk of ADHD) indicates that there is greater evidence for the effectiveness of interventions that involve parent behaviour training than for treatment with methylphenidate.67
Children and young adolescents
The most relevant study to date is the Multimodal Treatment of ADHD (MTA) study,8 a 14 month randomised clinical trial of intensive behavioural and medication treatment in children aged 7.0–9.9 years with combined ADHD (inattention and hyperactivity/impulsivity) (n=549). The multimodal treatment arms were contrasted with one another and with community intervention (treatment as usual) regarding outcome domains of ADHD symptoms, comorbidities, and core functional impairments. The initial reports from the MTA indicated that drug treatment (mainly methylphenidate) was better than behavioural therapy in managing the symptoms of ADHD, and that the combination of stimulant and behavioural therapy did not produce additional improvement910 for the core ADHD symptoms. However, the combination treatment offered benefit with regard to associated symptoms such as academic achievement, conduct problems, and parental satisfaction.11 A re-analysis of the MTA data using the International Classification of Diseases, 10th edition (ICD-10) classification of hyperkinetic disorder (HKD, severe ADHD, combined subtype) showed that the effect size of stimulants was substantially greater in those with a diagnosis of HKD compared with those who had non-HKD ADHD.12 Longitudinal follow-up data over many years after completion of the trial suggest that there was a diminution in the superiority of medication once the randomly assigned treatment phase turned into naturalistic follow-up.13
Based on effect sizes, meta-analyses of double blind placebo randomised controlled trials in children and adolescents comparing the efficacy of medication in ADHD have found stimulants to be more effective than placebo,14 bupropion, and atomoxetine.15 Recent systematic reviews, however, have questioned the value of these effects in children and adolescents.1617 Their findings have generated an intense debate in the field regarding interpretation of the degree of bias involved in trials sponsored by the pharmaceutical industry.181920212223 To better assess the benefits of treatments, longitudinal clinical effectiveness trials that include patients with co-existing disorders (such as those seen in most clinic settings) are warranted.
Systematic reviews of treatment in adult ADHD conclude that stimulants are effective in managing ADHD symptoms in adults.24 A meta-regression of existing clinical trial data to predict the effect size of lisdexamfetamine for the treatment of ADHD in adults yielded an effect size of 1.070.25 Adult functioning after childhood ADHD is generally worse when symptoms persist into adulthood.26 Better designed randomised controlled trials that minimise bias are warranted to confirm the clinical effectiveness of stimulant use in adults.
The effect size indicates the effectiveness of stimulant treatment. In most studies, the effect size is large, ie, close to or greater than 1.0. Caution should be stressed when extrapolating a large effect size to clinical meaningfulness. The variability of different instruments used across studies could play a substantial role when interpreting the effect size and the subsequent clinical effectiveness of treatments. There are controversies regarding the validity of effect sizes for methylphenidate use in ADHD.161718 However, the clinical effectiveness of treatments and management for ADHD as stated in the NICE guidelines remains appropriate.1
Long term use
The long term use of stimulants has not been rigorously evaluated and remains uncertain. A recent randomised placebo controlled methylphenidate study in boys aged 10-12 and men aged 23-40 measuring changes in cerebral blood flow has suggested age dependent and possibly long lasting effects of methylphenidate on the human dopaminergic system.27 Further long term studies using a larger sample size are warranted. While ADHD clearly responds to stimulants in the short term, evidence for long term effectiveness is currently limited. Current advice is to continue treatment as long as ADHD symptoms have an adverse effect on quality of life, with regular reviews to see whether the patient can manage without medication.
Co-existing disorders associated with ADHD and response to stimulants
Anxiety, oppositional defiant disorder, or conduct disorder, tics, and depression are frequent comorbidities in ADHD.28 In children, the most common co-existing disorders are oppositional defiant disorder (50%), followed by conduct disorder (35%), specific learning disorders, anxiety (33%), and depression (33%).28 More recently, meta-analysis suggests that in children with ADHD, stimulants reduce the risk of anxiety in comparison with placebo29 and that there is no correlation between the frequency and severity of tics and stimulant use in ADHD.30 Stimulants are useful even when ADHD co-exists with autism spectrum disorders, despite the effect size being around 0.5.31 Further work is necessary to evaluate effective treatments in subgroups such as the substance misusing population, those with multiple co-existing disorders, and different ADHD subtypes.
How safe is stimulant use in ADHD?
Common side effects of stimulants include dry mouth, loss of appetite, which is made worse by unpleasant changes in the taste of food and drink, slower growth in height, and sleep problems. Stimulants can reduce height and weight centiles over time. It is advisable not to start stimulants in children who are short or are biologically predisposed to short stature.
Stimulants are contraindicated in schizophrenia, hyperthyroidism, cardiac arrhythmias, angina pectoris, and glaucoma.
Stimulants can induce or worsen psychotic experience and should therefore be avoided in those who have psychotic or quasi-psychotic experiences.
Statistically significant increases in systolic and diastolic blood pressure and heart rate are associated with stimulant treatment in children and adolescents with ADHD. These increases can be clinically significant for a small number of patients. Since increased blood pressure and heart rate in general are considered risk factors for cardiovascular morbidity and mortality during adult life, paediatric patients using ADHD medication should be monitored closely and regularly for heart rate and blood pressure.32 Rare side effects include QTc interval prolongation, epilepsy, and increased risk of suicide related events33 (table 2⇓).
How are stimulants taken and monitored?
Before starting treatment, a full medical history and physical examination should be undertaken, including vital signs, height, and weight, looking for growth retardation. Keep growth charts pre and post 6 month treatment for young people.
Treatment free periods (drug holidays) can be used to minimise adverse side effects. Depending on the symptomatology, drug holidays can last a couple of weeks or months and are monitored carefully by the clinician for the appearance of adverse signs or symptoms. This is particularly important in children to observe growth or to allow growth catch up. Careful attention to new symptoms and to worsening of pre-existing psychiatric disorders such as anxiety, depression, and tic disorder is necessary.
How do stimulants compare with other treatments?
The non-stimulant atomoxetine, α-2 agonists clonidine and guanfacine, and the antidepressant bupropion (in adults) are useful for those who do not respond to stimulant treatment. There is only limited evidence from direct comparative clinical trials of the clinical effectiveness of different pharmacological treatments for ADHD. Meta-analyses have been used to compare the individual double blind placebo controlled trials. However, these are complicated by differences in outcome measures, variability in study design, publication, and cultural bias, and reclassification of diagnostic criteria between classification systems, ie, hyperkinetic disorder (ICD-10) v ADHD (Diagnostic and Statistical Manual of Mental Disorders, 4th edition).
Recent systematic review and meta-analysis of randomised controlled trials of non-pharmacological interventions show a relative lack of efficacy on blinded outcomes in reducing ADHD symptoms.34 The trials focused on training parents of young children using approaches such as the Webster-Stratton Incredible Years and New Forest Parenting Package. The outcomes showed improved oppositional behaviour in children, but did not appear to improve core ADHD symptoms substantially.35
The doctor advised that current evidence suggests it is safe to take methylphenidate and that it does not produce addiction. The primary goal agreed with mother and child was to improve the boy’s school performance; therefore an 8 hour preparation of methylphenidate was prescribed, which substantially improved the boy’s restlessness and concentration on review four weeks later. The boy’s school teachers also noticed a major improvement in his behaviour and concentration at school.
Tips for patients
Different preparations are available (eg, 8 hours v 12 hours) depending on the desired aim of treatment
Side effects occurring with stimulant use are usually minor and include decreased appetite, reduced growth, and decreased sleep
When starting stimulants, regular height, weight, pulse, and blood pressure monitoring is necessary
Treatment can be continued as long as ADHD symptoms adversely affect the patient’s quality of life
How patients were involved in the creation of this article
The manuscript was revised with feedback from a parent, who asked that the language and content of the article were simplified to help with readability for parents.
Education into practice
To what extent are you aware of the monitoring required for children and adults who are taking stimulants for ADHD? How is this provided by your place of work? How might you measure your success?
Does this article give you any new ideas on how you would approach a conversation about the relative benefits and risks, including common side effects, of stimulant medication in children and adults with ADHD?
Does this article give you any new ideas on how to set goals of treatment in children and adults with ADHD? How might you document and monitor whether the treatment is achieving the required result?
Is there anything else that will you do differently as a result of reading this article?
This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Patricia McGettigan, clinical senior lecturer in clinical pharmacology, Queen Mary University, London. To suggest a topic, please email us at email@example.com.
I thank Rachael Bloom Stevenson, a parent of a child with ADHD, for having provided feedback on how to simplify the content of this article and improve its readability for parents and users.
We have read and understood BMJ policy on declaration of interests and declare that we have no competing interests. Dr Paramala Santosh is a member of the European Network for Hyperkinetic Disorders (Eunethydis); and the European ADHD Guidelines Group (EAGG).
Provenance and peer review: not commissioned; externally peer reviewed.