Placental Transport and Metabolism: Implications for the Developmental Effects of Selective Serotonin Reuptake Inhibitors (SSRI) Antidepressants

Velasquez, Juan C.; Bonnin, Alexandre

doi:10.1007/978-1-4939-3014-2_12

Cited by 4 publications

(7 citation statements)

References 74 publications

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“…Previous rodent studies have also shown that fluoxetine and sertraline exposure during the perinatal period increase neonatal mortality [23,40,42]. Fetal developmental malformations (primarily cardiac, respiratory, and neurodevelopmental disorders) have been reported as possible causes of neonatal mortality associated with perinatal SSRI exposure [3,23,[43][44][45]. However, neonatal mortality may be due to placental insufficiency caused by SSRI disruption of uterine/placental vascular perfusion and structure [3,10,13,18] rather than a direct effect of SSRI on fetal development.…”

Section: Discussionmentioning

confidence: 99%

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

Domingues

Fricke

Sheftel

et al. 2022

Toxics

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Selective serotonin reuptake inhibitors (SSRI) are the most common antidepressant used by pregnant women; however, they have been associated with adverse pregnancy outcomes and perinatal morbidity in pregnant women and animal models. We investigated the effects of two SSRI, fluoxetine and sertraline, on pregnancy and neonatal outcomes in mice. Wild-type mice were treated daily with low and high doses of fluoxetine (2 and 20 mg/kg) and sertraline (10 and 20 mg/kg) from the day of detection of a vaginal plug until the end of lactation (21 days postpartum). Pregnancy rate was decreased only in the high dose of fluoxetine group. Maternal weight gain was reduced in the groups receiving the high dose of each drug. Number of pups born was decreased in the high dose of fluoxetine and low and high doses of sertraline while the number of pups weaned was decreased in all SSRI-treated groups corresponding to increased neonatal mortality in all SSRI-treated groups. In conclusion, there was a dose-dependent effect of SSRI on pregnancy and neonatal outcomes in a non-depressed mouse model. However, the distinct placental transfer of each drug suggests that the effects of SSRI on pup mortality may be mediated by SSRI-induced placental insufficiency rather than a direct toxic effect on neonatal development and mortality.

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Section: Discussionmentioning

confidence: 99%

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

Domingues

Fricke

Sheftel

et al. 2022

Toxics

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“…A liquid−liquid extraction was used to prepare samples for analysis as previously described. 78 Samples were thawed on ice and extracted with ice-cold extraction buffer (0.2 M perchloric acid + 500 mM D-mannitol +100 μM EDTA) with isoproterenol as internal standard. Extraction buffer was added to fetal serum and microsomal incubations (1:1 v/v) and to maternal serum samples (1:3 v/v).…”

Section: ■ Methodsmentioning

confidence: 99%

“…The eluate was collected on both the maternal and fetal sides at 10 min intervals for 120 min and stored at −80 °C until analysis. The ex vivo placental perfusion system and protocol are detailed in refs − .…”

Section: Methodsmentioning

confidence: 99%

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Maternal Pharmacokinetics and Fetal Disposition of (±)-Citalopram during Mouse Pregnancy

Velasquez¹,

Goeden²,

Herod

et al. 2016

ACS Chem. Neurosci.

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While selective-serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed in the treatment of depression, their use during pregnancy leads to fetal drug exposures. According to recent reports, such exposures could affect fetal development and long-term offspring health. A central question is how pregnancy-induced physical and physiological changes in mothers, fetuses, and the placenta influence fetal SSRI exposures during gestation. In this study, we examined the effects of gestational stage on the maternal pharmacokinetics and fetal disposition of the SSRI (±)-citalopram (CIT) in a mouse model. We determined the maternal and fetal CIT serum concentration–time profiles following acute maternal administration on gestational days (GD)14 and GD18, as well as the fetal brain drug disposition. The results show that pregnancy affects the pharmacokinetics of CIT and that maternal drug clearance increases as gestation progresses. The data further show that CIT and its primary metabolite desmethylcitalopram (DCIT) readily cross the placenta into the fetal compartment, and fetal exposure to CIT exceeds that of the mother during gestation 2 h after maternal administration. Enzymatic activity assays revealed that fetal drug metabolic capacity develops in late gestation, resulting in elevated circulating and brain concentrations of DCIT at embryonic day (E)18. Fetal exposure to the SSRI CIT in murine pregnancy is therefore influenced by both maternal gestational stage and embryonic development, suggesting potential time-dependent effects on fetal brain development.

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“…Despite the relative consistency in findings of these studies exposing offspring to SSRIs postnatally, translation of the results must be taken with caution. In the clinical scenario, SSRIs are transferred via the mother in utero or through breast milk, which has been shown to influence the pharmacokinetics of SSRIs (Heikkinen et al, 2002;Velasquez and Bonnin, 2016). Therefore, directly exposing offspring to SSRIs postnatally could have an exaggerated influence on their behaviour and neurobiology.…”

Section: Considerations For Human Studiesmentioning

confidence: 99%

The effects of maternal antidepressant use on offspring behaviour and brain development: Implications for risk of neurodevelopmental disorders

Millard

Weston–Green

Newell

2017

Neuroscience & Biobehavioral Reviews

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Approximately 10% of pregnant women are prescribed antidepressant drugs (ADDs), with selective serotonin reuptake inhibitors (SSRIs) the most widely prescribed. SSRIs bind to the serotonin transporter (SERT), blocking the reabsorption of serotonin by the presynaptic neuron and increasing serotonin levels in the synaptic cleft. The serotonergic system regulates a range of brain development processes including neuronal proliferation, migration, differentiation and synaptogenesis. Given the presence of SERT in early brain development, coupled with the ability of SSRIs to cross the placenta and also enter breast milk, concerns have been raised regarding the effects of SSRI exposure on the developing foetus and newborns. In this review, we evaluate preclinical and clinical studies that have examined the effects of maternal SSRI exposure and the risk for altered neurodevelopment and associated behaviours in offspring. While the current body of evidence suggests that maternal SSRI treatment may cause perturbations to the neurobiology, behaviour and ultimately risk for neurodevelopmental disorders in exposed offspring, conflicting findings do exist and the evidence is not conclusive. However, given the increasing incidence of depression and number of women prescribed ADDs during pregnancy, further investigation into this area is warranted.

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Placental Transport and Metabolism: Implications for the Developmental Effects of Selective Serotonin Reuptake Inhibitors (SSRI) Antidepressants

Cited by 4 publications

References 74 publications

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

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

Maternal Pharmacokinetics and Fetal Disposition of (±)-Citalopram during Mouse Pregnancy

The effects of maternal antidepressant use on offspring behaviour and brain development: Implications for risk of neurodevelopmental disorders

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