Immune Cell-Placenta-Serotonin Axis in Peripartum Depression and SSRI Therapy

SUMMARY. Peripartum depression (PPD) is widely prevalent, affecting about 1 in 4 birthing women worldwide, and includes the antenatal onset of depression (AND). PPD is associated with adverse clinical outcomes in both the child and mother; suicide is now a leading cause of death in the first year postpartum. Selective serotonin reuptake inhibitors (SSRI) are the preferred first-line pharmacotherapy for PPD and are effective at alleviating depressive symptoms. Despite this, the safety of SSRI use during pregnancy for both mother and fetus remains under debate, as its full spectrum of mechanisms of action remain elusive. The maternal immune system and placenta, whose regulation are both critical for successful pregnancies, are known to express serotonin signaling systems and may be affected by serotonin dysregulation in AND or by SSRIs. The immense knowledge gap of the effects of AND and SSRIs in these systems prevents informed outcome assessment for untreated and SSRI- treated AND. There is, therefore, a critical need to advance our understanding of AND and SSRI therapy effects in the immune system and placenta to improve clinical management of pregnancies affected by AND. The overall goal of this proposal is to comprehensively test the effects of AND and SSRI treatment in the maternal-placental serotonin-immune systems during pregnancy. Our central hypothesis is that pregnancy-induced flux of serotonin levels changes immune function and may unmask AND in patients at risk, which subsequently drives dysfunction of the immune system and placenta, contributing to adverse clinical outcomes. The anti-inflammatory and serotonin-enhancing properties of SSRI therapy, in contrast, restores the function of these systems. We will test our hypothesis with two aims: In Aim 1, we will determine the contribution of circulating CD4 T cells to modulating depressive symptoms during AND and antenatal SSRI therapy, analyzing longitudinally collected peripheral blood from pregnant women with untreated, or sertraline-treated AND, and at-risk controls via single-cell mass cytometry. We will build a predictive model of third trimester AND severity from first trimester profiles and validate these profiles in a demographically distinct test cohort. A preclinical non-invasive, translationally relevant model of sertraline administration will then link immune and behavioral outcomes. In Aim 2, we will determine the extent to which AND and SSRI induce molecular and functional changes in the placenta, performing whole genome and RNA sequencing as well as single-cell spatial imaging (mass cytometry) on placental tissue matched with the cohort in the first aim. Finally, we will correlate molecular alterations in placental tissue with clinical histopathologic features, maternal health parameters, and fetal outcomes. The expected outcome is a further understanding of how the immune and placental serotonergic systems are altered by AND and antenatal SSRI therapy. The positive translational impact of this project is improved outcome prediction for untreated versus SSRI-treated PPD. It will provide a framework for risk-benefit analysis of antenatal SSRI use in future clinical trials that will ultimately improve public health by reducing hesitancy toward antidepressant use in pregnancy. Project Number: 1R01HD120567-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Kathleen Fisch | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $663,493 | Activity Code: R01 | Study Section: Advancing Therapeutics - B Study Section[ATB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366567