Department of Mental Health Neurosciences, Division of Psychiatry, University College London, London W1T 7BN, UK.
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
Genes (Basel). 2021 Nov 3;12(11):1758. doi: 10.3390/genes12111758.
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 and 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; < 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; < 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; = 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.
CYP2D6 和 CYP2C19 酶在抗抑郁药和抗精神病药的代谢中至关重要。这些基因的遗传变异可能会增加药物不良反应的风险。抗抑郁药和抗精神病药以前与糖尿病风险相关。我们研究了个体在 CYP2D6 和 CYP2C19 中的遗传差异是否会导致这些影响。我们在英国生物银行中确定了 31579 名服用抗抑郁药和 2699 名服用抗精神病药的个体。参与者被分类为 CYP2D6 的差代谢者、中间代谢者或正常代谢者，以及 CYP2C19 的差代谢者、中间代谢者、正常代谢者、快速代谢者或超快代谢者。通过 HbA1c 水平来检查糖尿病的风险，并与代谢表型相关。服用帕罗西汀的 CYP2D6 差代谢者的 Hb1Ac 高于正常代谢者（平均差异：2.29mmol/mol； < 0.001）。在服用文拉法辛的糖尿病患者中，CYP2D6 差代谢者的 HbA1c 水平高于正常代谢者（平均差异：10.15mmol/mol； < 0.001）。在服用氟西汀的糖尿病患者中，CYP2D6 中间代谢者的 HbA1c 水平低于正常代谢者（平均差异：-7.74mmol/mol； = 0.017）。我们没有观察到 CYP2D6 或 CYP2C19 代谢状态与服用抗精神病药物的参与者的 HbA1c 水平之间存在任何关系。我们的结果表明，CYP2D6 遗传变异的影响取决于糖尿病的状态。尽管我们的发现支持现有的临床指南，但进一步的研究对于告知服用抗抑郁药和抗精神病药的人群进行药物遗传学检测至关重要。
