Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysisResearch in context

• Published in: EBioMedicine Vol. 104; p. 105165
• Main Authors: Yundan Liao, Yutao Sun, Jing Guo, Zhewei Kang, Yaoyao Sun, Yuyanan Zhang, Jiong He, Chengchen Huang, Xin Sun, Jian-min Zhang, Jun Wang, Hua-ning Wang, Zhi-yu Chen, Kai Wang, Jiyang Pan, Ai-hua Ni, Saizheng Weng, Anzhen Wang, Changbin Cao, Lidong Sun, Yong Zhang, Li Kuang, Yunshu Zhang, Zhongchun Liu, Weihua Yue, Hanping Bai, Maolin Hu, Bing Li, Jingshan Han, Jiaojiao Xiang, Ruhong Jiang, Jian Zhang, Yuxiang He, Huailiang Yang, Guifang Liu, Lili Peng, Hui Yu, Xialong Cheng, Wenmei Fang, Rongyan Zheng, Ruiqian Lin, Xiao-yan Zhai, Rui Tang, Fangyi Deng, Chunyan Zhu, Ting Zhang, Yan Yang, Ji-ting Geng, Di Wu, Yi-huan Chen, Yifan Sun, Yong-can Zhou, Wei-xin Wang
• Format: Journal Article
• Language: English
• Published: Elsevier 01.06.2024
• Subjects: Copy number variant; CYP2D6; Dose adjustment; Metabolizer status; Paroxetine; Precision medicine

Background: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. Methods: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. Findings: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. Interpretation: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. Funding: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.