Investigating the Long-Term Safety of ADHD Medication for Children and Adolescents
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Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms such as inattention, hyperactivity and impulsivity. ADHD diagnoses have increased over the last two decades, and so has the use of one of the main medications for its treatment in children – methylphenidate. This is a stimulant medication that acts on the central nervous system and is thought to help with hyperactivity, impulsiveness and concentration.
Despite its frequent usage, information on the long-term safety of methylphenidate is surprisingly scarce, and the World Health Organization (WHO) has raised concerns “regarding the quality and limitations of the available evidence for both benefit and harm.”
Now, a recent study from the Attention Deficit Hyperactivity Drugs Use Chronic Effects (ADDUCE) project, published in The Lancet, aimed to address these concerns by investigating the safety of methylphenidate in children and adolescents over a 2-year period.
Technology Networks spoke with Dr. Sarah Inglis, trial manager for the ADDUCE study, to learn more about its findings and potential implications.
Sarah Whelan (SW): The WHO rejected the inclusion of methylphenidate on its Essential Medicines List. Why was this the case, and why is inclusion on this list important?
Sarah Inglis (SI): The WHO Essential Medicines list is a list of minimum medicine needs for a basic healthcare system, listing the most efficacious, safe and cost-effective medicines for priority conditions. They are intended to be always available in functioning health systems, in appropriate dosage forms, of assured quality and at prices individuals and health systems can afford. Therefore, the inclusion of methylphenidate on this list would improve the chances of children with ADHD accessing methylphenidate treatment in countries where it is currently unavailable.
In 2021, the 23rd WHO Expert Committee on the Selection and Use of Essential Medicines did not recommend the inclusion of methylphenidate on their list of essential medicines. This was the second time that the Expert Committee has considered methylphenidate, following a recommendation not to include it in 2019 due to uncertainties in the estimates of benefit, and concerns regarding the quality and limitations of the available evidence for benefit and harm.
The most recent Committee considered that the updated evidence still did not support the inclusion of methylphenidate on the Model Lists. The Committee considered that methylphenidate is associated with a relatively large reduction in symptoms in the short term. However, the benefit-to-harm ratio of methylphenidate remained uncertain for long-term use while the medication carries significant risks.
Specifically, the Committee noted that most of the included studies in the network meta-analysis – in both children/adolescents and adults – were judged to be unclear or at a high risk of bias. In addition, there were few included studies that measured outcomes beyond 12 weeks of treatment, which the Committee considered was a major limitation given that ADHD is a longer-term condition and treatment is usually administered for months to years. The evidence also failed to provide adequate information on the frequency and severity of specific adverse effects associated with methylphenidate use. The Committee advised that evidence for the effectiveness and safety of methylphenidate in the treatment of ADHD of at least 52 weeks duration was required.
SW: Can you tell us more about the ADDUCE project – what inspired this study, and what are its main aims?
SI: In 2007, the European Commission requested a referral to the Committee for Medicinal Products for Human Use (CHMP) for all methylphenidate-containing products because of safety concerns.
The main potential safety areas evaluated concerned cardiovascular risks, cerebrovascular risks, psychiatric disorders, carcinogenicity, effect on growth and effects of long-term treatment. The CHMP concluded in January 2009 that the risk–benefit of methylphenidate was favorable but that more data were needed on long-term effects in children and young adults.
The CHMP also concluded that further research was needed on long-term effects, and this should focus on:
- Design of appropriate tools to study developmental effects.
- Study of long-term developmental effects, including growth.
- Study of long-term neurological effects, including cognitive function.
- Study of long-term psychiatric outcomes (including mood disorders, hostility and psychotic disorders).
- Study of long-term effects on sexual development and fertility.
A pan-European group of child and adolescent psychiatrists collaborated to build a project designed to collect these essential data, which became the ADDUCE project. The project was funded by the European Union (EU) and began in 2011.
The work package designed to collect new clinical data, which is reported in our recent paper in The Lancet, was run by the Tayside Clinical Trials Unit at the University of Dundee. The aim was to collect information on growth and development, neurological and psychiatric outcomes and sexual development from children diagnosed with ADHD and taking methylphenidate.
These data were compared with data collected from two control groups; the first, a group of children with ADHD who did not take methylphenidate during the period of the study, and the second a group of similar children who did not have ADHD nor take stimulant medication.
The data were collected from children living in five European countries (the UK, Germany, Italy, Switzerland and Hungary). The design was an observational study and children were assessed at six monthly intervals over a period of six years. The eligibility criteria were designed to be inclusive so that the study cohort accurately reflected the population of children with ADHD in European countries.
SW: What drew you to this research?
SI: I was drawn to this research because it has the potential to be very impactful, particularly for children with ADHD and their families. This was a pragmatic study designed to provide essential data to committees at the WHO and EU to aid their decision-making around recommendations for methylphenidate use in children with ADHD.
Methylphenidate is a controlled drug that is prescribed to thousands of children, often for several years. It is therefore essential that there are adequate data to describe its safety profile, particularly when it is taken by children with ADHD for long durations.
SW: What were the main findings of the study?
SI: The main findings were that long-term treatment with methylphenidate does not impair growth, nor does it have adverse effects on neurological or psychiatric health. We found that blood pressure and pulse rate increased over the 2-year observational period and that this increase, although small, was significantly greater in children taking methylphenidate than in children in the control groups.
Regular measurement of blood pressure and pulse is therefore required for children taking methylphenidate. Overall, we showed that the risk–benefit ratio of methylphenidate when taken by children with ADHD for up to 2 years is favorable.
SW: Were there any major challenges encountered in this project?
SI: The main challenges were consistent with many large international studies and included the different regulations and approvals required in different countries in order to conduct the study. Communication across the 27 sites was critical, particularly for those sites which were unfamiliar with doing research. Recruitment to our control group of children without ADHD was difficult and we introduced a thank-you voucher for all of our participants to compensate them for their time spent at each of the study visits.
SW: Are there any limitations that you wish to highlight?
SI: This was an observational study, so the researchers had no control over the children’s treatment. This was decided by the child’s treating clinician.
The study collected data for two years, as this was the limit enabled by the funding. Many children take methylphenidate for more than two years and further studies would be required to collect data on longer-term impact.
We have reported mean changes in assessment outcomes. While there are no significant changes overall in growth, it is possible that individual children may experience detrimental effects on growth and/or the other parameters measured in our study. Therefore, each individual should be monitored against clinical standards to ensure that any adverse effects are detected.
SW: What are the next steps for this project/research space?
SI: Although we collected data from children for up to two years, many children with ADHD take methylphenidate for longer than this, through their childhood and potentially into adulthood. Therefore, longer-term follow-up studies are needed to establish the safety of methylphenidate for these longer periods.
We focused on methylphenidate treatment for our study. Similar long-term studies are required for children with ADHD taking other stimulant medications.
Dr. Sarah Inglis was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.
