Among the neurodevelopmental disorders, one of the most frequent and with most treatment options available is attention deficit and hyperactivity disorder (ADHD). Historically, it was considered only a disease present in children and adolescents, while it is increasingly being diagnosed in adults as well. Now ADHD has an estimated prevalence rate ranging from 5.9% to 7.1% (Willcutt 2012).

Symptoms include difficulty in staying focused and paying attention, difficulty in controlling behaviour, and hyperactivity. ADHD can affect learning, behaviour, self-esteem, social skills and family function (Posner et al., 2020).

Academia and the pharmaceutical industry in the last 30 years have set in motion major resources for clinical research to understand its pathophysiology and seek therapeutic targets. Several compounds have been found to be effective in the treatment of ADHD and several pharmacological and non-pharmacological therapies are now available to clinicians. Treatment for people with ADHD can be pharmacologic, non-pharmacologic, or both. Medications are considered when symptoms persist after an initial attempt to modify the environment (NICE 2018).

This review article by Prof Samuele Cortsese, published last year in the New England Journal of Medicine, aimed to “summarise recent evidence regarding medications for ADHD that have been approved by regulatory agencies”. Importantly it does “not address the advisability or inadvisability of using these medications”.

Methods

This was a high-quality, narrative and evidence-based review on the pharmacological treatment of ADHD, based on different types of studies, including systematic reviews, randomised trials and large observational studies.

Results

Access to ADHD assessment and medication

Access to ADHD assessment and medication is unequal. There is a great geographic variation in the prevalence of medication use for ADHD, both among children and adolescents and among adults and there has been a high yearly increase in medication use since 2001. The geographic variations could be related to changes in access to diagnostic facilities, number of specialists in each country/region, diagnostic culture, socioeconomic status and resources designated to healthcare (Fulton et al., 2009). The prevalence of medications used in ADHD ranges from 0.39% to 5.56% among children and adolescents and from 0.01% to 2.11% among adults (Raman et al., 2018).

However, the prevalence of ADHD medication use is still substantially lower than the estimated prevalence of ADHD and most individuals remain undiagnosed or sub-optimally treated (Cortese 2020).

Also, there is a high rate of discontinuation and the average duration of treatment is low (136 days for stimulants in children and 230 days for stimulants in adults). The high rate of discontinuation is due to numerous reasons, including side effects, perceived lack of effectiveness, dislike of taking medications, stigma, and issues with the transition from child to adult services (Gajria et al., 2014).

Short term efficacy

Cortese (2020) considered a good range of effective medications used to treat ADHD both for the short and for the long-term.

In the short-term, medications approved by regulatory agencies were superior to placebo, and the most effective were amphetamines, followed by methylphenidate. In terms of comparative effectiveness between active compounds, amphetamines were found superior to a range of ADHD medications, including methylphenidate, atomoxetine and guanfacine. Effectiveness was proved on clinical outcomes, such as clinician rated severity of inattention, hyperactivity, and impulsivity. Also, ADHD medications were found to have an effect on other important outcomes, as they decreased unintentional physical injuries, motor vehicle accidents, substance use, and criminal acts.

Overall, ADHD medications seem helpful in the short term in increasing academic performances.

Long term efficacy

In the long-term, the evidence for effectiveness is less strong. Long-term RCTs are rare and not very feasible. Observational studies and open label trials are a good way to evaluate the safety of a medication, but equally are more prone to bias and confounding for the evaluation of efficacy. A placebo controlled RCT of methylphenidate with 4.5 years of follow up, showed ongoing benefit of methylphenidate, with smaller effect size compared to short-term RCTs (Matthijssen et al., 2019).

Side effects

Medication side effects often include decreased appetite, deficits in height and weight gain, increased blood pressure or heart rate, sleep disturbance, tics, seizures, psychotic symptoms.

Non-medical use of stimulants

Interestingly, Cortese 2020 reported a high usage of non-medical use of stimulants. Faraone et al. found up to 58.7% of University college students in the United States used stimulants non-medically, and 2.1% of adults reported at least one episode of use in the previous year. Reasons for non-medical use of stimulants include enhancement of academic or work performance, followed by recreational drug use.

Conclusions

This excellent review by one of the world’s leading scholars on ADHD, has brilliantly brought to light strengths and weaknesses of pharmacological treatments of ADHD, which benefit so many patients every day.

In summary, pharmacological treatments are effective for the short-term treatment of ADHD. More evidence is needed to establish the long-term effectiveness and it is important to correctly manage adverse events during treatment. It is also important to reduce stimulants use for work and academic enhancement and for recreational reasons in order to reduce the stigma related to these medications.

Strengths and limitations

This was a high-quality, narrative and evidence-based review on the pharmacological treatment of ADHD, which was found effective and safe.

As a limitation, it would have been interesting to present more evidence on the effects on neuropsychological tests of ADHD medications. For example, a deficit in behavioural inhibition could be considered core to the ADHD diagnosis and it would have been interesting to see the results of the impact of medications on this important domain (Barkley 1997).

Also, ADHD is a highly comorbid condition and it is very difficult to tailor treatment to individuals with a comorbid condition. For example, individuals with a cardiovascular condition, where amphetamines might be not indicated, or individuals with a psychiatric condition such as autism spectrum disorder or bipolar disorder.

In addition, it would be helpful to have had a hint of what is in the pipeline of the main biotech/pharmaceuticals interested in ADHD. It is mentioned the study of genes that are the target of medication might lead to the development of compounds with a novel mechanism of action, but it was not clear whether any interesting compound is currently being tested in phase 2 or 3 trials. This maybe of interest for patients who are finding current treatments sub-optimal.

Implications for practice

This review summarises all the essential concepts needed for clinical practice.

ADHD is a prevalent neurodevelopmental disorder and there are effective pharmacological agents to treat it, including amphetamines and methylphenidate. Different adverse events should be monitored closely, depending on the medication prescribed. More research is needed on the long-term effectiveness of medications for ADHD.

In future, the use of predictive models based on individual patient data from randomised studies or large and high-quality patient registries can help better tailoring the treatments to individual patient characteristics. The use of various sources of data, including phenotypic, genetic, neuroimaging and laboratory data could further boost the discriminative capabilities of such predictive models and realise the dream of personalised care in ADHD.

Statement of interests

None

Links

Primary paper

Cortese S. (2020) Pharmacologic Treatment of Attention Deficit-Hyperactivity Disorder. N Engl J Med. 2020 Sep 10;383(11):1050-1056. doi: 10.1056/NEJMra1917069. PMID: 32905677.

Other references

Barkley RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull. 1997 Jan;121(1):65-94. doi: 10.1037/0033-2909.121.1.65. PMID: 9000892.

Faraone SV, Rostain AL, Montano CB, Mason O, Antshel KM, Newcorn JH. Systematic review: nonmedical use of prescription stimulants: risk factors, outcomes, and risk reduction strategies. J Am Acad Child Adolesc Psychiatry 2020;59:100-12.

Fulton BD, Scheffler RM, Hinshaw SP, Levine P, Stone S, Brown TT, et al. National variation of ADHD diagnostic prevalence and medication use: health care providers and education policies. Psychiatr Serv. 2009;60(8):1075–1083.

Gajria K, Lu M, Sikirica V, et al. Adherence, persistence, and medication discontinuation in patients with attention- deficit/hyperactivity disorder — a systematic literature review. Neuropsychiatr Dis Treat 2014;10:1543-69.

Matthijssen A-FM, Dietrich A, Bierens M, et al. Continued benefits of methylphenidate in ADHD after 2 years in clinical practice: a randomized placebo-controlled discontinuation study. Am J Psychiatry 2019;176:754-62.

National Institute for Health and Care Excellence (NICE). Attention deficit hyperactivity disorder: diagnosis and management. NICE guideline NG87.

Posner J, Polanczyk GV, Sonuga-Barke E. Attention-deficit hyperactivity disorder. Lancet. 2020 Feb 8;395(10222):450-462. doi: 10.1016/S0140-6736(19)33004-1. Epub 2020 Jan 23. PMID: 31982036; PMCID: PMC7880081.

Raman SR, Man KKC, Bahmanyar S, et al. Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases. Lancet Psychiatry 2018;5:824-35.

Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics 2012;9:490–99.

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