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9 Jun 2019

Wong ICK et al. Lancet Psychiatry 2019; 6: 528-537

There is substantial evidence to support the short-term efficacy and safety of pharmacological treatments for ADHD; however, the long-term effects of these drugs are often unknown, and patients with autism, depression, intellectual disability and substance-use disorders are usually excluded from these clinical trials. In this review, the authors, on behalf of the European ADHD Guidelines Group, made recommendations for improvements across four key areas of research methodology for clinical trials for ADHD.

The use of appropriate trial design

  • The gold standard for the evaluation of drug efficacy is randomised controlled trials (RCTs), which must be carefully designed and interpreted. The authors discouraged use of enrichment methodologies* for examination of short-term efficacy and adverse events, but agreed that they may be helpful when assessing long-term treatment effects.
  • The authors suggested that compared with placebo-controlled trials, high-quality head-to-head RCTs would be more applicable to the clinic, where a wide range of pharmacological treatments are available. The authors emphasised that these trials must still be randomised, and must have an appropriate comparison group and allow for dose optimisation for each treatment group.
  • Long-term placebo-controlled trials that withhold effective treatments from patients for long periods of time may be ethically questionable. The authors supported the European Medicines Agency (EMA) and National Institute for Health and Care Excellence (NICE) guidelines for placebo-controlled withdrawal studies to assess the long-term efficacy of ADHD medications (European Medicines Agency 2010).
  • The authors advocated the development of novel data-collection methodologies that include objective measures and patient-reported outcomes, and would take advantage of new digital technologies, e.g. wearable devices that could track medication-related changes in pulse rate and sleep disturbance (Li et al. 2017).
    • Ecological momentary assessments would facilitate real-time assessments of ADHD symptoms, emotional lability and life quality in the patients’ natural environments (Shiffman et al. 2008).

Measures of effectiveness that move beyond control of core symptoms

  • ADHD has been reported to be associated with an increased risk of addictive behaviours and drug use, antisocial behaviour, driving accidents and violations, low self-esteem, obesity, poor academic performance and reduced social functioning (Shaw et al. 2012). However, when evaluating the efficacy of pharmacological and non-pharmacological therapies, clinical trials often only consider reductions in core ADHD symptoms; the authors acknowledged that this is likely driven by regulatory requirements.
  • The authors strongly suggested that a much broader range of outcome measures should be incorporated into clinical trials, including cognition measures, criminal activity, driving and pedestrian behaviours and violations, family and relationship functioning, functional impairments, grade progression/academic outcomes/employment status, and measures of comorbid psychiatric disorders. Improvements in current measures used to assess functional outcomes and quality of life, as required by the EMA guidelines, are also recommended.
  • ADHD has also been associated with reductions in neurocognitive functioning (Coghill et al. 2014). The authors recommended the use of well-defined and validated tasks with known neuroanatomical and neurophysiological associations to assess the impact of ADHD medications on cognitive abilities, as these may be affected independently of core symptoms.
  • The paucity of long-term studies to evaluate pharmacological treatments for ADHD was highlighted by the authors. The EMA has recommended that pharmaceutical companies report 6 months of efficacy data and 1 year of safety data in order to register all new ADHD medications (European Medicines Agency 2010); however, studies of this length still fail to fully address true long-term effects of these medications.
  • The authors suggested that more sophisticated methodology and robust research is required to evaluate the long-term effectiveness of ADHD medication.

Safety outcome measures

  • Stimulant medication in children and adolescents is well studied; however, further research to address the cardiovascular risk of ADHD medication is required.
  • The safety and tolerability of non-stimulant medications, such as atomoxetine, clonidine and guanfacine, are less well studied, and the authors recommended that further research is required to assess the long-term effects of these drugs.
  • The prescribing prevalence, risk and benefit of polypharmacy should be considered, as children and adults taking ADHD medication may also be taking antipsychotic and antidepressant drugs to control non-core symptoms of ADHD and psychiatric comorbidities.
  • The authors emphasised that adults with ADHD may have a different safety profile to children; however, few reports are available to assess adverse effects in this population. The authors recommended continued monitoring of potential neurological adverse effects in adults taking medication for ADHD.

Use of clinical and research databases to measure real-world outcomes

  • Rare adverse events and long-term safety and tolerability outcomes associated with ADHD medication can most effectively be monitored in real-world settings using observational studies with large databases.
  • Self-controlled case series have been developed to make comparisons between periods on and off medication in the same patient. Compared with traditional cohort and case-control studies, self-controlled case series remove the effects of time-invariant confounders and reduce the problem of confounding by indication.
  • Multinational meta-analyses and mega-analyses were recommended to examine the external validity and generalisability of pharmacoepidemiological studies, as many studies use data from only one country and one database. The authors also called for increased collaborations between research groups and use of a combination of databases for future work, particularly to develop new methodological research approaches.

The authors concluded that in order to advance the research in pharmacological therapy for ADHD, investigators and funding bodies must be prepared to accept the prospect of negative and unexpected results. Furthermore, the authors highlighted the need for regulators to work in combination with pharmaceutical industry stakeholders to ensure the advancement of the field.

Read more about recommendations for pharmacotherapy research on ADHD from the European ADHD Guidelines Group here


*Enrichment methodologies may include, for example, an initial open-label phase to select responders to a treatment, and then only these responders are included in the main RCT phase

Coghill DR, Seth S, Matthews K. A comprehensive assessment of memory, delay aversion, timing, inhibition, decision making and variability in attention deficit hyperactivity disorder: advancing beyond the three-pathway models. Psychol Med 2014; 44: 1989-2001.

European Medicines Agency. Guideline on the clinical investigation of medicinal products for the treatment of attention deficit hyperactivity disorder (ADHD). 2010. Available at: Accessed July 2019.

Li X, Dunn J, Salins D, et al. Digital health: tracking physiomes and activity using wearable biosensors reveals useful health-related information. PLoS Biol 2017; 15: e2001402.

Shaw M, Hodgkins P, Caci H, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med 2012; 10: 99.

Shiffman S, Stone AA, Hufford MR. Ecological momentary assessment. Annu Rev Clin Psychol 2008; 4: 1-32.

Wong ICK, Banaschewski T, Buitelaar J, et al. Emerging challenges in pharmacotherapy research on attention-deficit hyperactivity disorder—outcome measures beyond symptom control and clinical trials. Lancet Psychiatry 2019; 6: 528-537.

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