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An international research team led by Professor Ian Wong Chi-kei, Head of the Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, the University of Hong Kong (HKUMed) and Professor David Coghill, Department of Paediatrics, University of Melbourne found that long-term methylphenidate treatment does not increase the risk of growth impairments, psychiatric or neurological adverse events in a naturalistic, prospective, controlled, longitudinal study.

In a separate study, the team found that levels of ADHD medication consumption in high income countries such as United States and United Kingdom were ten-fold or even 100 times higher than in middle-income countries such as Philippines and India. In the middle-income countries, the rates of ADHD medication consumption were much lower than the prevalence of ADHD, suggesting potential disparities of ADHD medication access by country-income levels. The findings have been published in The Lancet Psychiatry [link to publication] and eClinicalMedicine [link to publication].

Background
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, with a global prevalence of around 7% in children and 2% in adults.¹,² When untreated, individuals with ADHD are prone to adverse outcomes such as emotional problems, self-harm, substance misuse, educational underachievement and exclusion from school, difficulties with employment and relationships, and criminality.³ Therefore, timely recognition and appropriate treatment of ADHD is essential to enhance the long-term well-being of individuals with the condition. However, the global patterns and trends of ADHD medication use, particularly in middle-income countries and for more recently licensed medications remained unclear, the research team thus investigated the trends of ADHD medication consumption for 64 countries from 2015 to 2019.

Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. HKUMed estimates that about 2% of children and adolescents in Hong Kong received methylphenidate treatment from the Hospital Authority in 2020. Although short-term efficacy, tolerability, and safety are supported by many randomised controlled trials, data on long-term safety and tolerability of methylphenidate are scarce. As a result, methylphenidate, was rejected by the World Health Organization (WHO) for inclusion in their Essential Medicines List due to ‘concerns regarding the quality and limitations of the available evidence for both benefit and harm’.⁴ To address these concerns around long-term safety, the European Union funded the Attention Deficit Hyperactivity-Disorder Drugs Use Chronic Effects (ADDUCE) project, a two-year naturalistic study that assessed the adverse effects of methylphenidate on growth and development, psychiatric, neurological, and cardiovascular health outcomes.

Research findings
To better understand prescribing patterns, the research team used pharmaceutical sales data of ADHD medication from 64 countries. It showed that multinational ADHD medication consumption increased by +9.72% (95%CI, +6.25%, +13.31%) per year, from 1.19 defined daily dose per 1,000 inhabitants (aged 5-19) per day (DDD/TID) in 2015 to 1.43 DDD/TID in 2019. However, when the analysis by country income level was stratified, these increases in ADHD medication consumption were only observed in high-income countries but not middle-income countries. The pooled consumption rate of ADHD medication was also much higher in high-income countries (6.39 DDD/TID; 95%CI, 4.63, 8.84) than that in middle-income countries (0.14 DDD/TID; 95%CI, 0.08,0.23). 

The ADDUCE study recruited a cohort of 1,410 children and adolescents with ADHD from 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary over a two-year period. ADDUCE is unique in that it is the first study to directly compare children and adolescents with ADHD who were and were not taking methylphenidate. After controlling for differences in ADHD symptom severity and other participant characteristics, the team found that long-term methylphenidate use was not associated with slow-down in growth (24 months height velocity SD score difference –0·07 (95% CI –0.18 to 0.04; p=0.20)), psychiatric or neurological symptoms but was associated with, albeit modest, average increases in systolic and diastolic blood pressure and pulse rate when comparing methylphenidate group with the no-methylphenidate group. However, such increases are not considered to be serious or detrimental to health. In studies Professor Ian Wong Chi-kei and Professor David Coghill have demonstrated the safety of methylphenidate did not increase risks of suicide attempts, all-cause poisoning,⁵ and could lower the risk of being a victim of physical abuse.⁶

Research significance
Professor Ian Wong Chi-kei, Lo Shiu Kwan Kan Po Ling Professor in Pharmacy, Head of Department of Pharmacology and Pharmacy, HKUMed, commented, ‘Our findings show that long-term treatment with methylphenidate for two years is safe and well tolerated. We also found no evidence to support that long-term methylphenidate treatment leads to a reduction in growth.’

Professor Wong further commented, ‘Together with other studies,⁷ which demonstrated the effectiveness of methylphenidate and other ADHD medication, these data strengthen the argument for the WHO to reconsider their decision to include methylphenidate in the Essential Medicines List. This will help address the observed inequity in ADHD medication consumption in middle-income countries. The WHO Essential Medicines List guides medication procurement and availability in many middle-income countries. As none of the ADHD medications is listed on Essential Medicines List, access will be challenging for millions of people around the world, leading to inequity by country-income levels and unmet treatment needs, especially for those with moderate-to-severe ADHD. This disproportionately affects children who are at economic and educational disadvantages as they are often at the highest risk of adverse effects from ADHD.’

About the research team
The research was jointly led by Professor Ian Wong Chi-kei, Lo Shiu Kwan Kan Po Ling Professor in Pharmacy, Head of Department of Pharmacology and Pharmacy, HKUMed; and Professor David Coghill, Financial Markets Foundation Chair of Developmental Mental Health, Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne. Dr Kenneth Man Keng-cheung, Honorary Assistant Professor at Department of Pharmacology and Pharmacy, HKUMed and Lecturer at School of Pharmacy, University College London; Adrienne Chan Yu-ling, Research Assistant at Department of Pharmacology and Pharmacy, HKUMed and PhD candidate at the University of Groningen, were the first authors. Other co-authors include experts in child psychiatry and epidemiology from the ADDUCE Consortium (Alexander Häge, Tobias Banaschewski, Sarah K Inglis, Jan Buitelaar, Sara Carucci, Marina Danckaerts, Ralf W Dittmann, Bruno Falissard, Peter Garas, Chris Hollis, Kerstin Konrad, Hanna Kovshoff, Elizabeth Liddle, Suzanne McCarthy, Antje Neubert, Peter Nagy, Eric Rosenthal, Edmund J S Sonuga-Barke and Alessandro Zuddas), and Dr Tian-Tian Ma, Postdoctoral Fellow, and Dr Wallis CY Lau, Honorary Research Associate, Department of Pharmacology and Pharmacy, HKUMed; Dr Patrick Ip, Clinical Associate Professor of Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, HKUMed; Le Gao, Dr Yogini H Jani, Dr Yingfen Hsia, Professor Li Wei, Professor Katja Taxis, Professor Emily Simonoff, Professor David Taylor and Professor Terry Y Lum, Henry G Leong Professor in Social Work and Social Administration and Professor, Department of Social Work and Social Administration, HKU.

Acknowledgements
This research was supported by the EU Seventh Framework Programme and the Hong Kong Research Grants Council - Collaborative Research Fund (C7009-19G).

Media enquiries
Please contact LKS Faculty of Medicine of The University of Hong Kong by email (medmedia@hku.hk).

¹ Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics. 2015;135(4):e994-1001.
² Song P, Zha M, Yang Q, Zhang Y, Li X, Rudan I. The prevalence of adult attention-deficit hyperactivity disorder: A global systematic review and meta-analysis. J Glob Health. 2021;11:04009.
³ 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.
⁴ Pereira Ribeiro J, Lunde C, Gluud C, Simonsen E, Storebo OJ. Methylphenidate denied access to the WHO List of Essential Medicines for the second time. BMJ Evid Based Med. 2022.
⁵ All-cause poisoning refers to poisoning (all-cause, by drugs and chemicals, intentional or accidental). Both core symptoms (inattention, hyperactivity, impulsivity) and comorbidities (e.g. anxiety, depression, substance misuse) of ADHD contribute to higher risks of all-cause poisoning in patients. Specifically, children and young people with ADHD are at a four-fold higher risk of poisoning compared with those without ADHD.
⁶ Children with ADHD are at higher risk than their peers of being victims of physical abuse. Multiple factors may contribute to this increased risk. (1) As ADHD is highly heritable and has shared genes with other psychiatric disorders, many parents of children with ADHD also suffer from ADHD and psychiatric disorders including depression, parents may not be able to control their impulses and perpetrate abuse. (2) Harsh parenting may also lead to oppositional symptoms in the child. (3) Many parents may find parenting a child with ADHD challenging, particularly when ADHD is untreated. Children with untreated ADHD may push boundaries laid down by adults, and such behaviours may be viewed as disobedient and wilful, further increasing parental stress and creating a cycle of escalating negative parent and child behaviours.
⁷ Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-738.