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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Cambridge University Press
2022-06-01
|
| Series: | European Psychiatry |
| Subjects: | |
| Online Access: | https://www.cambridge.org/core/product/identifier/S0924933822005880/type/journal_article |
| _version_ | 1797616155622375424 |
|---|---|
| author | K. Ishtiak-Ahmed C. Lunenburg J. Thirstrup L. Clausen P. Thomsen C. Gasse |
| author_facet | K. Ishtiak-Ahmed C. Lunenburg J. Thirstrup L. Clausen P. Thomsen C. Gasse |
| author_sort | K. Ishtiak-Ahmed |
| collection | DOAJ |
| description |
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.
|
| first_indexed | 2024-03-11T07:37:22Z |
| format | Article |
| id | doaj.art-bec622e072fd4545bc2f80f098d04609 |
| institution | Directory Open Access Journal |
| issn | 0924-9338 1778-3585 |
| language | English |
| last_indexed | 2024-03-11T07:37:22Z |
| publishDate | 2022-06-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | European Psychiatry |
| spelling | doaj.art-bec622e072fd4545bc2f80f098d046092023-11-17T05:09:19ZengCambridge University PressEuropean Psychiatry0924-93381778-35852022-06-0165S227S22710.1192/j.eurpsy.2022.588Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatmentK. Ishtiak-Ahmed0C. Lunenburg1J. Thirstrup2L. Clausen3P. Thomsen4C. Gasse5Aarhus University Hospital Psychiatry, Department Of Affective Disorders, Aarhus N, DenmarkAarhus University Hospital Psychiatry, Department Of Affective Disorders, Aarhus N, DenmarkAarhus University, Department Of Clinical Medicine, Aarhus N, DenmarkAarhus University Hospital Psychiatry, Department Of Child & Adolescent Psychiatry, Aarhus N, DenmarkAarhus University Hospital Psychiatry, Department Of Child & Adolescent Psychiatry, Aarhus N, DenmarkAarhus University Hospital Psychiatry, Department Of Affective Disorders, Aarhus N, Denmark 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. https://www.cambridge.org/core/product/identifier/S0924933822005880/type/journal_articletreatment switchingCYP2D6 inhibitorsadhdsleeping problem |
| spellingShingle | K. Ishtiak-Ahmed C. Lunenburg J. Thirstrup L. Clausen P. Thomsen C. Gasse Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment European Psychiatry treatment switching CYP2D6 inhibitors adhd sleeping problem |
| title | Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment |
| title_full | Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment |
| title_fullStr | Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment |
| title_full_unstemmed | Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment |
| title_short | Pharmacogenetic CYP2D6 variability, phenoconversion and treatment outcomes: A Danish population-based cohort study in 6,798 individuals initiating atomoxetine treatment |
| title_sort | pharmacogenetic cyp2d6 variability phenoconversion and treatment outcomes a danish population based cohort study in 6 798 individuals initiating atomoxetine treatment |
| topic | treatment switching CYP2D6 inhibitors adhd sleeping problem |
| url | https://www.cambridge.org/core/product/identifier/S0924933822005880/type/journal_article |
| work_keys_str_mv | AT kishtiakahmed pharmacogeneticcyp2d6variabilityphenoconversionandtreatmentoutcomesadanishpopulationbasedcohortstudyin6798individualsinitiatingatomoxetinetreatment AT clunenburg pharmacogeneticcyp2d6variabilityphenoconversionandtreatmentoutcomesadanishpopulationbasedcohortstudyin6798individualsinitiatingatomoxetinetreatment AT jthirstrup pharmacogeneticcyp2d6variabilityphenoconversionandtreatmentoutcomesadanishpopulationbasedcohortstudyin6798individualsinitiatingatomoxetinetreatment AT lclausen pharmacogeneticcyp2d6variabilityphenoconversionandtreatmentoutcomesadanishpopulationbasedcohortstudyin6798individualsinitiatingatomoxetinetreatment AT pthomsen pharmacogeneticcyp2d6variabilityphenoconversionandtreatmentoutcomesadanishpopulationbasedcohortstudyin6798individualsinitiatingatomoxetinetreatment AT cgasse pharmacogeneticcyp2d6variabilityphenoconversionandtreatmentoutcomesadanishpopulationbasedcohortstudyin6798individualsinitiatingatomoxetinetreatment |