Horackova Hana, Karahoda Rona, Cerveny Lukas, Vachalova Veronika, Ebner Ronja, Abad Cilia, Staud Frantisek
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Pharmaceutics. 2021 Aug 20;13(8):1306. doi: 10.3390/pharmaceutics13081306.
Depression is a prevalent condition affecting up to 20% of pregnant women. Hence, more than 10% are prescribed antidepressant drugs, mainly serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs). We hypothesize that antidepressants disturb serotonin homeostasis in the fetoplacental unit by inhibiting serotonin transporter (SERT) and organic cation transporter 3 (OCT3) in the maternal- and fetal-facing placental membranes, respectively. Paroxetine, citalopram, fluoxetine, fluvoxamine, sertraline, and venlafaxine were tested in situ (rat term placenta perfusion) and ex vivo (uptake studies in membrane vesicles isolated from healthy human term placenta). All tested antidepressants significantly inhibited SERT- and OCT3-mediated serotonin uptake in a dose-dependent manner. Calculated half-maximal inhibitory concentrations (IC) were in the range of therapeutic plasma concentrations. Using in vitro and in situ models, we further showed that the placental efflux transporters did not compromise mother-to-fetus transport of antidepressants. Collectively, we suggest that antidepressants have the potential to affect serotonin levels in the placenta or fetus when administered at therapeutic doses. Interestingly, the effect of antidepressants on serotonin homeostasis in rat placenta was sex dependent. As accurate fetal programming requires optimal serotonin levels in the fetoplacental unit throughout gestation, inhibition of SERT-/OCT3-mediated serotonin uptake may help explain the poor outcomes of antidepressant use in pregnancy.
抑郁症是一种常见病症，影响着多达20%的孕妇。因此，超过10%的孕妇会被开抗抑郁药，主要是5-羟色胺再摄取抑制剂（SSRIs）和5-羟色胺及去甲肾上腺素再摄取抑制剂（SNRIs）。我们推测，抗抑郁药通过分别抑制母体和胎儿面胎盘膜中的5-羟色胺转运体（SERT）和有机阳离子转运体3（OCT3），扰乱胎儿-胎盘单位中的5-羟色胺稳态。在原位（大鼠足月胎盘灌注）和离体（从健康人类足月胎盘中分离的膜囊泡摄取研究）条件下对帕罗西汀、西酞普兰、氟西汀、氟伏沙明、舍曲林和文拉法辛进行了测试。所有测试的抗抑郁药均以剂量依赖方式显著抑制SERT和OCT3介导的5-羟色胺摄取。计算得出的半数最大抑制浓度（IC）在治疗性血浆浓度范围内。使用体外和原位模型，我们进一步表明胎盘外排转运体不会影响抗抑郁药从母体到胎儿的转运。总体而言，我们认为抗抑郁药在以治疗剂量给药时有可能影响胎盘或胎儿中的5-羟色胺水平。有趣的是，抗抑郁药对大鼠胎盘5-羟色胺稳态的影响存在性别差异。由于准确的胎儿编程需要在整个妊娠期胎儿-胎盘单位中保持最佳的5-羟色胺水平，抑制SERT/OCT3介导的5-羟色胺摄取可能有助于解释孕期使用抗抑郁药的不良后果。
