Wong Win Lee Edwin, Fabbri Chiara, Laplace Benjamin, Li Danyang, van Westrhenen Roos, Lewis Cathryn M, Dawe Gavin Stewart, Young Allan H
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
Pharmaceuticals (Basel). 2023 Sep 11;16(9):1277. doi: 10.3390/ph16091277.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used psychopharmaceutical treatment for major depressive disorder (MDD), but individual responses to SSRIs vary greatly. CYP2C19 is a key enzyme involved in the metabolism of several drugs, including SSRIs. Variations in the CYP2C19 gene are associated with differential metabolic activity, and thus differential SSRI exposure; accordingly, the CYP2C19 genotype may affect the therapeutic response and clinical outcomes, though existing evidence of this link is not entirely consistent. Therefore, we analysed data from the UK Biobank, a large, deeply phenotyped prospective study, to investigate the effects of CYP2C19 metaboliser phenotypes on several clinical outcomes derived from primary care records, including multiple measures of antidepressant switching, discontinuation, duration, and side effects. In this dataset, 24,729 individuals were prescribed citalopram, 3012 individuals were prescribed escitalopram, and 12,544 individuals were prescribed sertraline. Consistent with pharmacological expectations, CYP2C19 poor metabolisers on escitalopram were more likely to switch antidepressants, have side effects following first prescription, and be on escitalopram for a shorter duration compared to normal metabolisers. CYP2C19 poor and intermediate metabolisers on citalopram also exhibited increased odds of discontinuation and shorter durations relative to normal metabolisers. Generally, no associations were found between metabolic phenotypes and proxies of response to sertraline. Sensitivity analyses in a depression subgroup and metabolic activity scores corroborated results from the primary analysis. In summary, our findings suggest that CYP2C19 genotypes, and thus metabolic phenotypes, may have utility in determining clinical responses to SSRIs, particularly escitalopram and citalopram, though further investigation of such a relationship is warranted.
选择性5-羟色胺再摄取抑制剂（SSRIs）是治疗重度抑郁症（MDD）最常用的精神药物，但个体对SSRIs的反应差异很大。CYP2C19是参与包括SSRIs在内的多种药物代谢的关键酶。CYP2C19基因的变异与代谢活性差异相关，进而导致SSRIs暴露量不同；因此，CYP2C19基因型可能会影响治疗反应和临床结果，尽管现有关于这种联系的证据并不完全一致。因此，我们分析了英国生物银行的数据，这是一项大型的、具有深度表型的前瞻性研究，以调查CYP2C19代谢表型对从初级保健记录中得出的几种临床结果的影响，包括抗抑郁药换药、停药、用药时长和副作用的多项指标。在这个数据集中，24729人被开具了西酞普兰，3012人被开具了艾司西酞普兰，12544人被开具了舍曲林。与药理学预期一致，与正常代谢者相比，使用艾司西酞普兰的CYP2C19慢代谢者更有可能更换抗抑郁药，首次用药后出现副作用，且使用艾司西酞普兰的时间更短。与正常代谢者相比，使用西酞普兰的CYP2C19慢代谢者和中代谢者停药的几率也增加，用药时长更短。一般来说，未发现代谢表型与舍曲林反应指标之间存在关联。在抑郁症亚组中的敏感性分析和代谢活性评分证实了初步分析的结果。总之，我们的研究结果表明，CYP2C19基因型以及由此产生的代谢表型，可能有助于确定对SSRIs，特别是艾司西酞普兰和西酞普兰的临床反应，不过这种关系还有待进一步研究。
