Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis

Abstract

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I² = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Fig. 1. Proportion of metabolic phenotypes in each cohort.

DAST Depression and Sequence of Treatment, GENDEP Genome Based Therapeutic Drugs for Depression, GENPOD GENetic and clinical Predictors Of treatment response in Depression, GODS Geneva Outpatient Depression Study, GSK: Glaxo Smith Kline, GSRD Group for the Study of Resistant Depression, PFZ Pfizer, PGRN Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study, STARD Sequenced Treatment Alternatives to Relieve Depression. PM poor metabolizer, IM intermediate metabolizer, NM normal metabolizer, RM + UM rapid+ultrarapid metabolizer. *Due to undetected variants in genotype, imputation of CYP2D6 metabolic phenotypes was less accurate.

Fig. 2. Association of CYP2C19 metabolizer status with antidepressant outcomes.

a Association of CYP2C19 metabolic phenotypes in all samples. b Association of CYP2C19 metabolic phenotypes stratified by CYP2C19-metabolized antidepressants. PM poor metabolizer, IM intermediate metabolizer, RM + UM rapid+ultrarapid metabolizer, OR odd ratio, SMD standard mean difference, CI confidence interval.