Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China.
Department of Psychiatry, The Fifth Hospital of Tangshan, Tangshan, Hebei, China.
EBioMedicine. 2024 Jun;104:105165. doi: 10.1016/j.ebiom.2024.105165. Epub 2024 May 21.
Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing.
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.
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.
Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach.
National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.
了解 CYP2D6 代谢对广泛使用的抗抑郁药帕罗西汀的影响对于精准剂量至关重要。
我们在中国 921 名患有抑郁或焦虑障碍的汉族患者中进行了一项为期 8 周、多中心、单药、2 周洗脱期前瞻性队列研究（ChiCTR2000038462）。我们进行了 CYP2D6 基因分型（单核苷酸变异和拷贝数变异）以得出 CYP2D6 活性评分，并评估了帕罗西汀治疗的结果，包括稳态浓度、治疗效果和不良反应。CYP2D6 代谢表型被分为弱代谢者（PMs）、中间代谢者（IMs）、广泛代谢者（EMs）和超快代谢者（UMs）。使用多元回归分析和跨种族荟萃分析检查了 CYP2D6 代谢表型对帕罗西汀治疗结果的影响。通过接收者操作特征（ROC）分析估计了帕罗西汀的治疗参考范围。
在调整人口统计学因素后，PMs、IMs 和 UMs 中帕罗西汀的稳态浓度分别为 EMs 的 2.50、1.12 和 0.39 倍，PM 和 UM 的效果具有统计学意义（多元线性回归，P=0.03 和 P=0.04）。性别和种族影响了 IMs 和 EMs 之间的比较。此外，帕罗西汀疗效不佳与 UM 有关，不良反应风险增加与 CYP2D6 活性评分较低有关。最后，跨种族荟萃分析表明，东亚人群中 PMs、IMs、EMs 和 UMs 的剂量调整分别为制造商推荐剂量的 35%、40%、143%和 241%，而非东亚人群中的剂量调整分别为 62%、68%、131%和 159%。
我们的研究结果提倡基于 CYP2D6 代谢表型的精准剂量，其中性别和种族是这种方法的关键考虑因素。
国家自然科学基金；医学科学院研究单位。
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