The influence of CYP2D6 and CYP2C19 genetic variation on diabetes mellitus risk in people taking antidepressants and antipsychotics.

Background: 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. Methods: We identified 31,579 individuals taking antidepressants and 2,699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate or normal metabolisers of CYP2D6, and as poor, intermediate, normal, rapid and ultra-rapid metabolisers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. We analysed drugs either individually (where sample size permitted) or grouped by class. Results: CYP2D6 poor metabolisers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolisers had higher HbA1c levels compared to normal metabolisers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, we observe that CYP2D6 intermediate metabolisers and decreased HbA1c, compared to normal metabolisers (mean difference -7.74mmol/mol; p=0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Conclusion: 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.