Antidepressant aripiprazole induces adverse effects on neural development during cortex organoid generation

A significant number of women experience anxiety and depressive symptoms during pregnancy, leading to the prescription of antidepressants, including aripiprazole. However, although a few animal studies have reported its developmental toxicity, there is a lack of research on the potential risks aripiprazole may pose to the fetus, particularly regarding neural development, as well as an absence of appropriate models to verify these effects. Therefore, this study investigates the impact of aripiprazole on neural development using cortex organoids, which can effectively model human brain development and function while overcoming interspecies differences. Cortex organoids were generated and exposed to aripiprazole at concentrations of 0.3-9 µM over 4 weeks. We assessed morphological changes, cell viability, gene expression, immunofluorescence staining, and electrophysiological function. The results revealed that aripiprazole led to significant reductions in organoid size and increased cell death, particularly at higher concentrations. Immunofluorescence analysis showed abnormalities in the expression patterns of neural stem cells and neuronal markers. Additionally, real-time PCR demonstrated decreased expression of genes related to neural stem cells, neural differentiation and migration, maturation, synaptogenesis, and gliogenesis, along with increased apoptosis-related gene expression. Electrophysiological recordings indicated impaired neural activity, evidenced by reduced mean firing rates. Our study is the first to demonstrate that aripiprazole induces adverse effects on neural development across functional, molecular, and morphological aspects. The findings will aid in a better understanding of the risks associated with antidepressant use during pregnancy in terms of neural development and suggest that cortex organoids are a valuable model for evaluating potential neurodevelopmental toxicants.