Emerging challenges in pharmacotherapy research on attention-deficit hyperactivity disorder—outcome measures beyond symptom control and clinical trials

Summary

Although pharmacological therapies are recommended as a key component in the treatment of attention-deficit hyperactivity disorder, their use continues to prompt intense debate. Despite considerable research efforts, several gaps in the knowledge base and several questions over the quality of evidence exist. Particular issues surrounding pharmacological treatments include uncertainties about long-term effectiveness and safety, safety profiles in adults, and the comparative effectiveness of different medications. In this Review, we focus on four key methodological issues for future research: (1) the use of appropriate trial designs; the need for (2) outcome measures targeting effectiveness beyond symptom control and (3) safety outcome measures; and (4) the application of clinical and administrative research databases to assess real-world outcomes. Potential solutions include increased use of randomised placebo-controlled withdrawal trials and large pharmacoepidemiological studies that use electronic health-care records on the long-term effectiveness and safety of medications. Pragmatic head-to-head randomised trials would also provide direct evidence on comparative effectiveness and safety profiles.

Introduction

Attention-deficit hyperactivity disorder (ADHD), as defined in the DSM, 5th edition,¹ is characterised by age-inappropriate and impairing inattentiveness, hyperactivity–impulsivity, or both of these traits. Hyperkinetic disorder, as per the WHO International Classification of Diseases, 10th edition,² is a more restrictive syndrome, requiring symptoms and impairment in both the inattention and hyperactivity–impulsivity domains. ADHD is one of the most commonly diagnosed neurodevelopmental disorders, with an estimated worldwide prevalence of 5% in children aged 6 to 18 years.³ According to primarily US data, impairing ADHD symptoms persist into adulthood in around 65% of cases, with a pooled prevalence of ADHD estimated at 2.5%.⁴ Emerging evidence also indicates that ADHD might persist into older adulthood (>55 years),⁵ and that when it does, it is frequently accompanied by similar comorbidities such as anxiety and depression, and social impairment as in younger age groups.6, 7

Interventions for ADHD include both pharmacological and non-pharmacological approaches. Licensed medications for ADHD comprise psychostimulants (eg, methylphenidate and amphetamines) and non-psychostimulant drugs (eg, atomoxetine and the α2 adrenoceptor agonists, clonidine and guanfacine). Parent training and behavioural interventions, dietary interventions, and cognitive training and neurofeedback, among others, have been suggested as non-pharmacological options for treating ADHD.⁸ The roles and prioritising of, and balance between non-pharmacological and pharmacological treatments vary between national guidelines, despite all being supposedly evidence-based (table).

Recent meta-analytical studies have not supported the efficacy of psychological therapies for reducing the core symptoms of ADHD (ie, inattention, hyperactivity, and impulsivity) when considering outcomes rated by assessors who were probably masked to treatment;16, 17, 18 however, some non-pharmacological interventions appear effective at improving associated features (eg, parent training for oppositional and conduct problems or cognitive training for working memory deficits). In this Review, we focus on pharmacological treatments for ADHD, for which considerable evidence for short-term efficacy and safety is available;¹⁹ and which are supported by all major evidence-based guidelines (table). However, several unanswered questions remain about the comparative and long-term efficacy and safety of ADHD medications, and their effectiveness in routine clinical practice and for special populations, such as those with intellectual disability, autism, substance use disorder or depression, that are typically excluded from trials. Although in several countries, such as Germany, the prescription of pharmacological treatments for ADHD dropped between 2001 and 2015, many countries (eg, the USA, the UK, Australia, and Hong Kong) also showed a rise in prescriptions for children, adolescents, and adults over this period.²⁰ Because a consensus has not yet been reached on the proportion of people with ADHD whose treatment with medications is clinically justified, this rise in prescriptions continues to prompt intense debate.21, 22, 23, 24 Considerable between-country variation also exists in the number of prescriptions, with data on 150 million individuals in 14 countries showing that in 2010, the prevalence of individuals taking ADHD medications varied between 0·27 and 6·69 per 100 children and adolescents (aged 3–18 years) and between 0·003 and 1·48 per 100 adults (aged >18 years).²⁰ Although future research needs to fill in key gaps in the knowledge base, to do this effectively will require several adjustments in trial methodology and an openness to collaborative interdisciplinary work that combines different designs and approaches. We now discuss the four key methodological issues that we believe are the most important first steps to address in these future research efforts.