Real-world effectiveness beyond symptom control and safety of methylphenidate for attention deficit hyperactivity disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 2–7% of children worldwide. However, despite ADHD being a multifactorial disease and many studies have explored it using either self-report in cohorts or medical information in electronic health records (EHRs), very little research has linked these data sources for a more comprehensive understanding of the long-term progression and treatment outcome of ADHD. Methylphenidate is the most commonly prescribed drug for ADHD in many countries including Hong Kong, with the usage rising over the past 20 years. Although methylphenidate has demonstrated acceptable effectiveness and safety in clinical trials, evidence is still lacking on how well it works beyond symptom control to prevent physical abuse and all-cause poisoning, or how safe it is in terms of drug poisoning and fracture risk in real-world settings. Therefore, this thesis presents five objectives to fill the aforementioned research gaps: (1) to investigate the feasibility of linking cohorts with EHRs; (2) to examine the preventive effect of methylphenidate against physical abuse; (3) to assess the association between methylphenidate and all-cause poisoning; (4) to describe ADHD drug poisoning cases and explore its correlation with the prescription trend; and (5) to investigate the fracture risk mediated by methylphenidate. The data used included EHRs, two cohorts – ‘Children of 1997’ birth cohort and the Chinese Early Development Instrument cohort, and poisoning records in Hong Kong. The findings indicated that (1) the use of date of birth and sex is feasible and highly accurate when linking cohorts with EHRs, with some discrepancies found in ADHD between reported symptoms from cohort and clinical information from EHRs; (2) the risk of physical abuse was observed to be higher 90 days before the commencement of methylphenidate, decreased to baseline level 90 days after treatment initiation, and continued to decline throughout the subsequent treatment period, suggesting that such treatment may be associated with a reduced risk of being physically abused; (3) the risk of all-cause poisoning was highest during the period around methylphenidate initiation and decreased in subsequent treatment period, showing that long-term methylphenidate use may be associated with a lower risk of all-cause poisoning; (4) despite there were a few ADHD drug poisoning incidents between 2009 and 2019 in Hong Kong and no significant correlation with the prescribing trend, the management and safe storage of ADHD medications should nevertheless be emphasised; (5) and there was a lower fracture risk associated with methylphenidate treatment compared to non-medicated individuals from the systematic review, and the within-individual comparison showed that the risk was lowered by 32–41% during the treated period versus the pre-treatment period, suggesting that the effectiveness on the protection against traumatic injuries may outweigh the potential fracture risk that may be mediated by methylphenidate. This research provided a feasible linking method and a linked database for future studies and demonstrated that methylphenidate is effective in preventing physical abuse and all-cause poisoning, with fewer safety issues on drug poisoning and fracture, which may provide more evidence for the treatment choices in clinical practice.