Vilazodone exposure during pregnancy: Effects on embryo-fetal development, pregnancy outcomes and fetal neurotoxicity by BDNF/Bax-Bcl2/5-HT mediated mechanisms

Abstract

The high prevalence of major depressive disorder (MDD) among women of childbearing age necessitates careful consideration of antidepressant use during pregnancy. Although newer antidepressants, such as Vilazodone (VLZ), are preferred for their enhanced therapeutic profiles; however, their safety during pregnancy and long-term effects on offspring brains remain inadequately addressed. Therefore, this study aimed to investigate the reproductive and developmental neurotoxicity of VLZ given at equivalent therapeutic doses during gestation in a rat model. Pregnant Wistar dams were orally administered either with 1 mg/day or 2 mg/day of VLZ from gestation day (GD) 6–21. The dams were sacrificed at GD 21, and the placentas and fetuses were collected. Fetal brains were then subjected to neurohistopathological, neurochemical, and biochemical analysis. Prenatal exposure to VLZ at 2 mg/day resulted in significant maternal, reproductive, and embryo-fetal toxicity, characterized by reduced food intake, diminished weight gain in pregnant dams, and smaller litter sizes, along with decreased fetal and placental weights. These effects were associated with developmental neurotoxicity, which manifested as decreased fetal brain size and weight, a substantial reduction in neocortical layer thickness, brain-derived neurotrophic factor (BDNF) expression, serotonin, dopamine, and norepinephrine neurotransmitter levels (5-HT, DA, and NE), and increased apoptotic activity (Bax and Bcl-2 ratio) and acetylcholinesterase levels in the developing brain. Our findings indicate that prenatal VLZ exposure interfere with crucial brain development processes involving the BDNF/Bax-Bcl2/5-HT signalling pathways, leading to long-lasting neurodevelopmental impairments. This study is the first to document the adverse effects of VLZ on fetal brain development, highlighting the need for further research to assess the safety of VLZ use during pregnancy.