Li Danyang, Pain Oliver, Fabbri Chiara, Wong Win Lee Edwin, Lo Chris Wai Hang, Ripke Stephan, Cattaneo Annamaria, Souery Daniel, Dernovsek Mojca Z, Henigsberg Neven, Hauser Joanna, Lewis Glyn, Mors Ole, Perroud Nader, Rietschel Marcella, Uher Rudolf, Maier Wolfgang, Baune Bernhard T, Biernacka Joanna M, Bondolfi Guido, Domschke Katharina, Kato Masaki, Liu Yu-Li, Serretti Alessandro, Tsai Shih-Jen, Weinshilboum Richard, McIntosh Andrew M, Lewis Cathryn M
Social, Genetic and Developmental Psychiatry Centre, King's College London, London, GB.
Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, GB.
medRxiv. 2023 Dec 11:2023.06.26.23291890. doi: 10.1101/2023.06.26.23291890.
Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. The association of CYP2C19 and CYP2D6 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR=1.46, 95% CI [1.03, 2.06], p=0.033, heterogeneity I=0%, subgroup difference p=0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19 and CYP2D6, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.
包括CYP2C19和CYP2D6在内的细胞色素P450酶对于抗抑郁药的代谢很重要，并且已确定这些基因的多态性可预测代谢物水平。尽管如此，仍需要更多证据来了解基因变异对抗抑郁反应的影响。在本研究中，收集了来自欧洲和东亚血统人群的13项研究的个体临床和基因数据。抗抑郁反应通过临床缓解和改善百分比进行评估。使用推算基因型将基因多态性转化为CYP2C19和CYP2D6的代谢表型（慢代谢、中间代谢、正常代谢和快代谢+超快代谢）。以正常代谢者作为对照，研究了CYP2C19和CYP2D6代谢表型与治疗反应之间的关联。在5843例抑郁症患者中，CYP2C19慢代谢者的缓解率高于正常代谢者，具有名义上的显著性，但在多重检验校正后未存活（OR=1.46，95%CI[1.03,2.06]，p=0.033，异质性I=0%，亚组差异p=0.72）。没有代谢表型与基线改善百分比相关。在按主要由CYP2C19和CYP2D6代谢的抗抑郁药进行分层后，未发现代谢表型与抗抑郁反应之间存在关联。代谢表型在欧洲和东亚血统研究之间频率存在差异，但效应无差异。总之，使用基因型从基因变异推算出的代谢表型与抗抑郁反应无关。CYP2C19慢代谢者可能对抗抑郁疗效有潜在贡献，但还需要更多证据。无法从基因型数据推算出CYP
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