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A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.ORCID iD: 0000-0002-5795-8100
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.ORCID iD: 0000-0002-9151-4319
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.ORCID iD: 0000-0002-7071-9067
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
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2019 (English)In: Drug development research (Print), ISSN 0272-4391, E-ISSN 1098-2299, p. 1-12Article in journal (Refereed) Epub ahead of print
Abstract [en]

The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population-based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES-D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES-D score, occurrence of a major depressive episode (MDE) during follow-up and regular antidepressant treatment during the 6 months preceding follow-up assessment as outcomes. The GRS was associated with MDE occurrence (p = .02) and ln CES-D score (p = .001). The HTR1A rs878567 variant was associated with ln CES-D after adjustment for demographic and clinical variables [p = .02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six-fold higher likelihood of regular AD therapy at follow-up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p = .03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs.

Place, publisher, year, edition, pages
2019. p. 1-12
Keywords [en]
depression, genetic risk score, pharmacogenetics, random forest, treatment with antidepressants
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-396498DOI: 10.1002/ddr.21609ISI: 000491048200001PubMedID: 31617956OAI: oai:DiVA.org:uu-396498DiVA, id: diva2:1368127
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Swedish Research Council, 2013-2892Available from: 2019-11-06 Created: 2019-11-06 Last updated: 2019-11-06Bibliographically approved

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Kanders, Sofia H.Pisanu, ClaudiaBandstein, MarcusJonsson, JörgenSchiöth, Helgi B.Mwinyi, Jessica
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