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Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment

INTRODUCTION: Atomoxetine, a first-line treatment option for ADHD, is affected by pharmacogenetic (PGx) variation of the drug-metabolizing enzyme CYP2D6. Despite the recommendation of CYP2D6 testing, the use of PGx-guided dosing remains low in Denmark. OBJECTIVES: We investigated wide-ranging clinic...

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Detalles Bibliográficos
Autores principales: Ishtiak-Ahmed, K., Lunenburg, C., Thirstrup, J., Clausen, L., Thomsen, P., Gasse, C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cambridge University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9567364/
http://dx.doi.org/10.1192/j.eurpsy.2022.588
Descripción
Sumario:INTRODUCTION: Atomoxetine, a first-line treatment option for ADHD, is affected by pharmacogenetic (PGx) variation of the drug-metabolizing enzyme CYP2D6. Despite the recommendation of CYP2D6 testing, the use of PGx-guided dosing remains low in Denmark. OBJECTIVES: We investigated wide-ranging clinical outcomes in atomoxetine users in association with PGx variability. METHODS: We analyzed 6,798 individuals (55% children) with a first prescription for atomoxetine identified from the Danish population-based iPSYCH case-cohort study linking biobank information with Danish registers. Individuals were categorized based on their single-nucleotide-polymorphism-based CYP2D6 genotype into normal (NM), intermediate (IM), and poor metabolizer (PM). Clinical outcomes included treatment switching, discontinuation, psychiatric inpatient-, outpatient-, and emergency contact, suicide attempt/self-harm, sleep problem, and depression. Individuals’ CYP2D6-status could change due to drug-drug-interactions of weak, intermediate, or strong-CYP2D6 inhibitors (phenoconversion), which we accounted for by time-varying phenotype assessment. Incidence rate ratios (IRR) were estimated using Poisson regression analyses and adjusted for a wide range of potential confounders and covariates. RESULTS: Over two-thirds of the individuals had a hospital diagnosis of ADHD at the first atomoxetine prescription. The distribution of CYP2D6 phenotypes was similar in children and adults. IM/PM children had a significantly higher risk of a sleeping problem compared with NM children (IRR 1.25, 95% CI 1.01-1.54). Compared with NM adults, those with IM/PM had a higher risk of switching (1.15, 95% CI 0.98-1.35). CONCLUSIONS: This is the first study showing the potential impact of PGx variability on clinical outcomes of atomoxetine users in a population-based setting, highlighting the utility of PGx testing. DISCLOSURE: No significant relationships.