Placental serotonin: implications for the developmental effects of SSRIs and maternal depression

Abstract

In addition to its role in the pathophysiology of numerous psychiatric disorders, increasing evidence points to serotonin (5-HT) as a crucial molecule for the modulation of neurodevelopmental processes. Recent evidence indicates that the placenta is involved in the synthesis of 5-HT from maternally derived tryptophan (TRP). This gives rise to the possibility that genetic and environmental perturbations directly affecting placental TRP metabolism may lead to abnormal brain circuit wiring in the developing embryo, and therefore contribute to the developmental origin of psychiatric disorders. In this review, we discuss how perturbations of the placental TRP metabolic pathway may lead to abnormal brain development and function throughout life. Of particular interest is prenatal exposure to maternal depression and antidepressants, both known to alter fetal development. We review existing evidence on how antidepressants can alter placental physiology in its key function of maintaining fetal homeostasis and have long-term effects on fetal forebrain development.

Keywords: SSRI; depression; fetal brain; fetal programming; placenta; serotonin; serotonin transporter; tryptophan.

Figure 1

(A) Treatment of maternal depression with SSRIs is associated with varying pregnancy outcomes. While every gestational stage of SSRI exposure has been implicated in increased risks for cognitive, physiological, or developmental teratogenicity, the period of exposure is an important factor that appears to influence clinical outcomes in the offspring. We limited this list to outcomes that have been the focus of several epidemiological studies in recent years and for which differential exposure data during pregnancy was available. (B) Untreated maternal depression and stress have been associated with several risks that affect cognitive and developmental outcomes. While associations are not generally correlated to specific trimesters, exposure to untreated maternal depression or stress during pregnancy pose adverse risks to fetal health and development. Study Selection and Data Extraction Studies were selected if they had clearly identified maternal SSRI exposure for specific trimesters of pregnancy and assessed neonatal outcomes. Epidemiological studies that included medium-to-large number samples exposed to different SSRI drugs were selected. Direct comparison of absolute odds ratio values across these studies is not possible due to varying specific study designs, adjustments for level of maternal depression and various sociodemographic and lifestyle factors, drug dosages, length of exposure, and SSRI treatment options. ^*PPHN, Persistent pulmonary hypertension of the newborn.

Figure 2

The effects of SSRIs on fetal brain development may be through direct (A) or indirect pathways that affect placental (B), maternal (C), or both maternal and placental physiology (D), ultimately resulting in downstream effects on the fetus. Direct effects (A) suggest that SSRIs readily cross the placenta and enter the fetal circulation, where they would directly target the developing brain's serotonergic system. Alternatively, physiological changes in the placenta (B), or delivery of maternal factors essential for the developing fetal brain (C) may be affected through indirect pathways. The combination of both direct and indirect pathways inducing adverse effects on the fetal brain may also be possible (D). Under the influence of varying s maternal, fetal and placental (maternal-fetal combination) genetic susceptibilities (DNA double helix), the effects of SSRI exposure at different pregnancy stages may lead to diverse developmental outcomes.