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The Capital Region of Denmark - a part of Copenhagen University Hospital

INDICES Work Package 6: The relationship between CES1 genotype and methylphenidate response in children with ADHD

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Methylphenidate (MPH) is first-line drug treatment for Attention Deficit/Hyperactivity Disorder (ADHD) which affects 3-5% of children and adolescents and often persists into adulthood. Adverse reactions and/or non-compliance frequently cause treatment failure. MPH is primarily metabolized by carboxylesterase (CES1) in the liver. Pharmacogenetic studies have shown that variants of CES1 were associated with a change in the response of CES1 metabolized drugs. Few candidate gene association studies have explored the association between CES1 variants identified in DNA from ADHD patients and their MPH response.

The PhD Study (Kristine Kaalund-Brok) investigates the beneficial and adverse reactions over the initial 12-week treatment period with individually titrated dosing of MPH in children aged 7-12 years and recently diagnosed ADHD. The specific objectives are to describe the predictors of MPH treatment outcome and to identify and characterize the variants of CES1 that are associated with the clinical MPH treatment response and to explore the potential for personalized medicine in the treatment of ADHD.

The long-term follow-up (Tine Houmann) is a three-year follow-up of children diagnosed with ADHD and followed with weekly assessments during the first 12 weeks of MPH treatment. We investigate if the early responses to MPH treatment (measured at week 3, and week 12) are associated with improved symptomatic and functional outcome three years later, when adjusting for other predictors. We also explore the association between the severity of ADHD symptoms and the impairments in daily and social functioning at follow-up three years after initiation of treatment.

The study is a longitudinal clinical observational study including a clinical representative sample of 207 MPH naïve children aged 7 to 12 years (mean 9.6 years). The children were diagnosed with ADHD at the Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region Denmark and offered individually titrated MPH treatment until a clinically significant response (normalization or borderline normalization of ADHD symptoms) was achieved, or until adverse reactions prohibited further up-titrations, or the maximum dose was reached. The treatment response of MPH was measured on clinician-rated, parent-rated and teacher-rated ADHD symptoms. Secondary outcomes include global impairments, daily and social functioning, indices of sustained attention, adverse reactions, and end-dose of MPH. The study explores the short- and long-term outcomes and the following predictors of outcome: age, sex, comorbidity, intelligence level, conduct disorder, global impairments, ADHD subtype, and weight, as well as the variants of CES1, and the early response with regard to later clinical response.

Results/discussion/impact (expected):
The results are about to be published (currently in peer review in international scientific journals). Kristine Kaalund-Brok will defend her PhD-thesis on March 3., 2021, with the title: ‘Predictors of methylphenidate treatment outcome – A clinical observational study of the relationship between CES1 genotype and methylphenidate response in children with ADHD’. The 3-year follow-up study is in progress. When the results are published, the next step will be to clarify the potential for improvement of guidelines for treatment of children with ADHD regarding the personalized dosing of MPH.

ID: 61846050