Gestational vortioxetine exposure impairs pregnancy outcomes and fetal brain development via modulation of BDNF/Bax-Bcl2/5-HT pathways in rats

Pregnancy presents a critical period during which the use of antidepressants requires cautious evaluation, especially due to the high incidence of depression in women of reproductive age. Vortioxetine hydrobromide (VOX), a newer multimodal antidepressant, is increasingly favored for its improved efficacy and tolerability. However, its safety profile during gestation and its potential long-term impact on fetal brain development remain insufficiently explored. This study aimed to assess the reproductive and developmental neurotoxicity of VOX administered at clinically relevant doses during pregnancy using a Wistar rat model. Pregnant dams received daily oral doses of either 1 mg/kg or 2 mg/kg of VOX from gestation day (GD) 6 to 21. On GD 21, the dams were euthanized, and fetuses along with placental tissues were collected for further analysis. Fetal brains underwent morphological, neurochemical, and histopathological evaluations. Exposure to VOX at the higher dose led to significant maternal and fetal toxicity, marked by reduced maternal weight gain, smaller litter sizes, and decreased fetal and placental weights. Notably, adverse neurodevelopmental outcomes were observed, including reduced fetal brain dimensions, cortical and hippocampal thinning, altered levels of brain-derived neurotrophic factor (BDNF), disrupted monoaminergic neurotransmitter levels (serotonin, dopamine, and norepinephrine), elevated apoptotic markers (Bax/Bcl-2 ratio), and increased acetylcholinesterase activity. These findings suggest that prenatal VOX exposure disrupts essential neurodevelopmental pathways, particularly those involving BDNF and monoaminergic signaling, potentially leading to persistent alterations in brain development. This is the first study to systematically demonstrate the developmental neurotoxicity of VOX, emphasizing the urgent need for further investigation into its safety during pregnancy.