The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics.

Isabelle Austin-Zimmerman,Haritz Irizar,Ghazaleh Fatemifar,Johan H Thygesen,Karoline Kuchenbaecker,Elvira Bramon,Anjali Bhat,Olga Giannakopoulou,Chris Finan,Baihan Wang,Eirini Zartaloudi,Jasmine Harju-Seppänen,Andrew Mcquillin,Marta Wronska,Spiros Denaxas

doi:10.3390/genes12111758

Abstract

CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels compared to normal metabolizers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, CYP2D6 intermediate metabolizers and decreased HbA1c, compared to normal metabolizers (mean difference −7.74 mmol/mol; p = 0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Our results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics.

Highlights

The use of both antidepressant and antipsychotic medications has increased steadily in recent years
For several of the antidepressants investigated, we consistently found that the interaction of diabetes status and CYP2D6 and CYP2C19 metabolic phenotype is statistically significant (Supplementary Figure S2)
In participants taking venlafaxine (SNRI), we found that, amongst people with diabetes, for CYP2D6 had higher HbA1c than normal metabolizers (mean difference: 10.15mmol/mol; 95% CI (2.63,17.67); p = 0.008)

Summary

Introduction

The use of both antidepressant and antipsychotic medications has increased steadily in recent years. A similar trend is seen in the prescription of antipsychotics, with an increase from eight to 12 million prescriptions between 2008 and 2018 [2]. Both antidepressant and antipsychotic medication provide essential and often lifesaving treatment for many patients. They are associated with a range of common and sometimes serious adverse drug reactions including sedation, weight gain, movement disorders, and an increased risk of developing diabetes mellitus [4,5]

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