Effect of Selected Antidepressants on Placental Homeostasis of Serotonin: Maternal and Fetal Perspectives

Abstract

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 (IC50) 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.

Effect of Low and High Doses of Two Selective Serotonin Reuptake Inhibitors on Pregnancy Outcomes and Neonatal Mortality

“…SSRI inhibition of placental SERT prevents the transport of maternal serotonin into the placenta increasing serotonin signaling on the maternal side of the placenta [47]. Interestingly, OCT3 is inhbited by glucocorticoids [51] and exogenous drugs such as SSRI [47,50]. However, fluoxetine, but not sertraline, decreases the capacity of OCT3 to transport serotonin from fetal circulation into the placenta in an in situ model [47].…”

“…Interestingly, rodents exposed to SSRI perinatally have altered cardiac morphology [43,46] and dilated cardiomyopathy [23]. Because both drugs promote comparable neonatal mortality and increase serotonin concentrations in the maternal side of the placenta altering placental homeostasis [18,47] but have distinct placental transfer (70% fluoxetine [23] vs. 25% sertraline [24]), placental insufficiency is likely to be the underlying mechanism of SSRI-related pup mortality rather than a direct toxic effect of SSRI on fetal development. Nevertheless, these results do not exclude a direct role of fluoxetine (highest placental transfer) on fetal organogenesis.…”

“…SERT located on the apical region of syncytiotrophoblast (maternal side of the placenta) transports maternal-derived serotonin into the placenta during early and mid gestation regulating serotonin content (signaling) on the maternal side of the placenta and providing maternal-derived serotonin needed for fetal development [48,49]. However, during late pregnany serotonin is no longer transported from mother to fetus; instead, organic cation transporter 3 (OCT3) located on the fetal side of the placenta transports fetal serotonin into trophoblasts for degradation [47,49,50]. SSRI inhibition of placental SERT prevents the transport of maternal serotonin into the placenta increasing serotonin signaling on the maternal side of the placenta [47].…”

“…However, during late pregnany serotonin is no longer transported from mother to fetus; instead, organic cation transporter 3 (OCT3) located on the fetal side of the placenta transports fetal serotonin into trophoblasts for degradation [47,49,50]. SSRI inhibition of placental SERT prevents the transport of maternal serotonin into the placenta increasing serotonin signaling on the maternal side of the placenta [47]. Interestingly, OCT3 is inhbited by glucocorticoids [51] and exogenous drugs such as SSRI [47,50].…”

Studying the Liver Function in Male Neonates of Rats Born to Sertraline-Treated Mothers

“…Therefore, it seems that the fetus is exposed to this drug through various routes such as placenta and digestion. Also, studies measuring the concentration of Sertraline and its major metabolite, dismethylsertraline, in maternal blood and umbilical cord blood show that the serum concentration of Sertraline in the umbilical cord is almost always lower than the maternal serum concentration (Hostetter et al 2000, Horackova et al 2021. The concentrations of Sertraline and dismethylsertraline in breast milk are highly variable and, on average, are equally concentrated as the maternal blood plasma (Pinheiro et al 2015).…”