Abstract
BackgroundVariation within the CYP2C19 gene has been linked to differential metabolism of selective serotonin reuptake inhibitors (SSRIs). Pharmacogenetic recommendations based on the effect of CYP2C19 variants have been made available and are used increasingly by clinical practitioners. Nonetheless, the underlying assumption linking differential metabolism to efficacy or adverse side effects remains understudied. Here, we aim to fill this gap by studying CYP2C19 polymorphisms and inferred metabolism and patient-reported antidepressant response in a sample of 9531 Australian adults who have taken SSRIs.MethodsMetaboliser status was inferred for participants based on CYP2C19 alleles. Primary analysis consisted of assessing differences in treatment efficacy and tolerability between normal (reference) and: ultrarapid, rapid, intermediate and poor metabolisers.ResultsAcross medications, poor metabolisers reported a higher efficacy, whereas rapid metabolisers reported higher tolerability. When stratified by drug, associations between metaboliser status and efficacy did not survive multiple testing correction. Intermediate metabolisers were at greater odds of reporting any side effect for sertraline and higher number of side effects across medications and for sertraline.ConclusionsThe effects between metaboliser status and treatment efficacy, tolerability and side effects were in the expected direction. Our power analysis suggests we would detect moderate to large effects, at least nominally. Reduced power may also be explained by heterogeneity in antidepressant dosages or concomitant medications, which we did not measure. The fact that we identify slower metabolisers to be at higher risk of side effects even without adjusting for clinical titration, and the nominally significant associations consistent with the expected metabolic effects provide new evidence for the link between CYP2C19 metabolism and SSRI response. Nonetheless, longitudinal and interventional designs such as randomized clinical trials that stratify by metaboliser status are necessary to establish the effects of CYP2C19 metabolism on SSRI treatment efficacy or adverse effects.
Highlights
INTRODUCTION Major DepressiveDisorder (MDD) is one of the leading causes of disability and an important contributor to the burden of disease worldwide [1, 2]
In this study we focus on the selective serotonin reuptake inhibitors (SSRIs): sertraline, escitalopram and citalopram as they are reported to be extensively metabolized by cytochrome P450 2C19 (CYP2C19)
The present study aims to assess the association between CYP2C19 SSRI inferred metaboliser status based on individual CYP2C19 polymorphisms and patient-reported efficacy of sertraline, citalopram and escitalopram in the Australian Genetics of Depression Study (AGDS)
Summary
INTRODUCTION Major DepressiveDisorder (MDD) is one of the leading causes of disability and an important contributor to the burden of disease worldwide [1, 2]. While recent reports support antidepressant efficacy for treating depression [3], a significant proportion of people do not respond optimally or cease treatment due to early adverse effects [4, 5]. Variation within the CYP2C19 gene has been linked to differential metabolism of selective serotonin reuptake inhibitors (SSRIs). The fact that we identify slower metabolisers to be at higher risk of side effects even without adjusting for clinical titration, and the nominally significant associations consistent with the expected metabolic effects provide new evidence for the link between CYP2C19 metabolism and SSRI response. Longitudinal and interventional designs such as randomized clinical trials that stratify by metaboliser status are necessary to establish the effects of CYP2C19 metabolism on SSRI treatment efficacy or adverse effects
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