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. 2021 Nov 3;12(11):1758.
doi: 10.3390/genes12111758.

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

Isabelle Austin-Zimmerman  1   2 , Marta Wronska  1 , Baihan Wang  1 , Haritz Irizar  1   3 , Johan H Thygesen  1   4 , Anjali Bhat  1 , Spiros Denaxas  5 , Ghazaleh Fatemifar  5 , Chris Finan  6   7   8 , Jasmine Harju-Seppänen  1 , Olga Giannakopoulou  1   9 , Karoline Kuchenbaecker  1   9 , Eirini Zartaloudi  1 , Andrew McQuillin  1 , Elvira Bramon  1
Affiliations

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

Isabelle Austin-Zimmerman et al. Genes (Basel). .

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.

Keywords: CYP2C19; CYP2D6; HbA1c; UK Biobank; diabetes; personalized medicine; pharmacogenetics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Frequency table of identified antipsychotics (blue bars) and antidepressants (red bars) in UK Biobank.
Figure 2
Figure 2
Violin plots showing the relationship between CYP2D6 metabolic status and HbA1c levels (mmol/mol) among subjects taking (from left to right) paroxetine, fluoxetine, venlafaxine, and all antipsychotics.
See this image and copyright information in PMC

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