Abstract
RationaleCytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive.ObjectivesWe explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (n = 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline.MethodsPatients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation.ResultsP450 genotype did not predict total side effect burden (nortriptyline: n = 251, p = 0.5638, β = −0.133, standard error (SE) = 0.229; escitalopram: n = 340, p = 0.9627, β = −0.004, SE = 0.085), study discontinuation (nortriptyline n = 284, hazard ratio (HR) = 1.300, p = 0.174; escitalopram n = 376, HR = 0.870, p = 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea.ConclusionsIn this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-015-3898-x) contains supplementary material, which is available to authorized users.
Highlights
Cytochrome P450 enzymes play a key role in the metabolism of antidepressant drugs into less active compounds
In Genome-Based Therapeutic Drugs for Depression (GENDEP; a European pharmacogenetic study where patients received either nortriptyline or escitalopram), we found no evidence for a relationship between treatment response and P450 genotype (Hodgson et al 2014)
We examined CYP2C19 as the relevant P450 genotype in the escitalopram-specific analyses, with CYP2D6 genotype included as a fixed effect covariate given the smaller reported role of the CYP2D6 enzyme (Olesen and Linnet 1999)
Summary
We explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (n=868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline
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