Effects of selective serotonin reuptake inhibitors on the placenta†

The rate of depression in pregnant mothers has dramatically risen in the past few decades. One of the well-studied causes of depression is a deficiency of serotonin (5-HT) in the synaptic cleft of neurons in the central nervous system, called the serotonergic theory of depression. The serotonin transporter (SERT/SLC6A4) binds 5-HT such that it can no longer bind and activate its cognate receptors on the post-synaptic neurons. Greater number of pregnant women are prescribed a selective serotonin reuptake inhibitor (SSRI) drug to combat depression. These compounds act to bind to SERT, and thereby prolonging the duration 5-HT remains active within the synaptic cleft. While such treatments might be beneficial for the mother, the placenta and fetal brain can be inadvertently affected. SERT has been proposed to be the primary means by which the placenta internalizes maternal 5-HT and then transfers this neurotransmitter to the emerging brain, where it guides initial brain development. We consider evidence that SSRIs might influence the placenta-brain axis and contribute to gestational disorders, such as preeclampsia, fetal growth restriction, and gestational diabetes. Current data with rodent models, in vitro cell approaches with human trophoblast cell lines, and human epidemiological studies are reviewed. Gaps in our current understanding and future directions are discussed. A better understanding of how SSRIs might affect the placenta is crucial as by obstructing acquisition of maternal 5-HT by the placenta and downstream alterations on fetal brain development, these treatments might impact the lifelong health of sons and daughters.