Daniela Lopez

Background: Perinatal depression is a mood disorder that affects about 7-20% of women during pregnancy.¹ To be diagnosed, a woman must experience a major depressive episode during pregnancy according to the DSM-5.² Currently, first line treatment consists of Selective Serotonin Reuptake Inhibitors (SSRI), but other treatment options include Serotonin and Norepinephrine Reuptake Inhibitors (SNRI) or Tricyclic Antidepressants (TCA) alongside cognitive behavioral therapy.^2,3 SSRIs cross into the CNS and work to increase the amount of serotonin (5-HT) in the synaptic cleft by inhibiting presynaptic 5-HT reuptake and allowing 5-HT to accumulate. This regulates mood as well as personality and wakefulness.⁴ Exposure to SSRIs during pregnancy is correlated with differences in neurodevelopment indicating that 5-HT signaling and regulation is crucial during embryonic development. Some of these differences include lower cerebral gray and white matter volume in children up until age 15, increased hippocampal volume, right frontal asymmetry, and a larger amygdala.⁵

Objective: This review explored different mechanisms by which altering 5-HT signaling during fetal development may impact brain development.

Methods: A PubMed database online search from 2019 to 2024 was conducted using the following keywords: “perinatal depression”, “fetal neurodevelopment”, “SSRI”, “fetus”.

Results: Studies indicate the serotonin transporter (SERT) in the syncytiotrophoblasts is the main entry point for 5-HT from the mother to the fetus.⁶ SSRIs may inhibit the accumulation of exogenous 5-HT in the syncytiotrophoblasts all the way up to the villus core as the SERT receptor is blocked by the SSRI. Therefore, 5-HT is not able to cross into the fetus properly⁶. SERT knockout mice also exhibited GLUN1 and PSD95 downregulation which signifies a downregulation of components involved in glutamatergic synapses in the prefrontal cortex.⁷ Fetal mice brains exposed to maternal inflammation and SSRI exhibited significant elevation in genes involved in cytokine signaling, protein synthesis, and serotonin signaling.⁸ Additionally, the maternal fetal interface (MFI) responds to inflammation by significantly increasing IL-6 and IL-17 levels and a 2-fold increase in 5-HT which may lead to an immune driven harm to the developing fetus.⁸ However, when an SSRI was added, 5-HT levels were nearly undetectable and cytokine levels returned to baseline, demonstrating how SSRIs may transform the MFI and the immune landscape.⁸ Brain imaging of children exposed to SSRI and/or maternal depression during pregnancy exhibited decreased white matter volumes and presented with child attention problems at age 10.⁹

Conclusion: Maternal 5-HT crosses the placenta and is directly involved in fetal brain development as dysregulation of maternal 5-HT levels shows implications for fetal programing and pregnancy outcomes. The potential mechanisms that alter fetal neurodevelopment regarding 5-HT levels may be due to various pathways including SSRI and maternal depressive symptom exposure. Medications that alter SERT may impact the MFI and downregulate glutamatergic signaling allowing for sensitivity to stress-related disorders. Physicians should consider the effects of antidepressant use and uncontrolled maternal depression when treating patients. More in vivo human studies should continue to explore the long-term impact of this complex topic.

Works Cited:

1. Rotem-Kohavi N, Williams LJ, Oberlander TF. Advanced neuroimaging: A window into the neural correlates of fetal programming related to prenatal exposure to maternal depression and SSRIs. Semin Perinatol. 2020;44(3):151223. doi:10.1016/j.semperi.2020.151223
2. Dagher RK, Bruckheim HE, Colpe LJ, Edwards E, White DB. Perinatal Depression: Challenges and Opportunities. J Womens Health (Larchmt). 2021;30(2):154-159. doi:10.1089/jwh.2020.8862
3. Lautarescu A, Craig MC, Glover V. Prenatal stress: Effects on fetal and child brain development. Int Rev Neurobiol. 2020;150:17-40. doi:10.1016/bs.irn.2019.11.002
4. Lebin LG, Novick AM. Selective Serotonin Reuptake Inhibitors (SSRIs) in Pregnancy: An Updated Review on Risks to Mother, Fetus, and Child. Curr Psychiatry Rep. 2022;24(11):687-695. doi:10.1007/s11920-022-01372-x
5. Koc D, Tiemeier H, Stricker BH, Muetzel RL, Hillegers M, El Marroun H. Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory. JAMA Psychiatry. 2023;80(12):1208-1217. doi:10.1001/jamapsychiatry.2023.3161
6. Kliman HJ, Quaratella SB, Setaro AC, et al. Pathway of Maternal Serotonin to the Human Embryo and Fetus. Endocrinology. 2018;159(4):1609-1629. doi:10.1210/en.2017-03025
7. Brivio P, Homberg JR, Riva MA, Calabrese F. Alterations of Glutamatergic Markers in the Prefrontal Cortex of Serotonin Transporter Knockout Rats: A Developmental Timeline. Cell Mol Neurobiol. 2019;39(5):715-720. doi:10.1007/s10571-019-00673-9
8. Zengeler KE, Shapiro DA, Bruch KR, Lammert CR, Ennerfelt H, Lukens JR. SSRI treatment modifies the effects of maternal inflammation on in utero physiology and offspring neurobiology. Brain Behav Immun. 2023;108:80-97. doi:10.1016/j.bbi.2022.10.024
9. Koc D, El Marroun H, Stricker BH, Muetzel RL, Tiemeier H. Intrauterine Exposure to Antidepressants or Maternal Depressive Symptoms and Offspring Brain White Matter Trajectories From Late Childhood to Adolescence. Biol Psychiatry Cogn Neurosci Neuroimaging. 2024;9(2):217-226. doi:10.1016/j.bpsc.2023.10.00