Lysophosphatidylcholines are elevated after selective serotonin reuptake inhibitor exposure during neural differentiation and correlate with early neurodevelopmental symptoms

Selective serotonin reuptake inhibitors (SSRIs) are often prescribed during pregnancy. Yet, epidemiological studies link in-utero SSRI exposure with neurodevelopmental disorders, such as autism and ADHD. The potential molecular mechanisms by which SSRIs impact early neurodevelopment are not fully understood. We exposed neuroepithelial stem cells derived from four human induced pluripotent stem cells lines to fluoxetine, citalopram, sertraline, and paroxetine. We then assessed cellular viability, reactive oxygen species (ROS) levels, mitochondrial function using adenosine triphosphate (ATP) assays, and performed high-throughput metabolomics at two timepoints: proliferation and neural differentiation stages. The key metabolic findings were validated in the in-vitro model and in a complementary population-based cohort, the Barwon Infant Study, consisting of 1074 mother-child pairs with analysed cord-blood metabolomes. Sertraline and paroxetine significantly decreased ROS and ATP levels, indicating mitochondrial alteration. Metabolomic profiling revealed consistent elevation of three lysophosphatidylcholines (LPCs 16:0, 18:0, 18:1) across all SSRIs except citalopram. We further observed elevated LPC levels in the cord blood of infants prenatally exposed to SSRIs, with a dose-dependent correlation to autism and ADHD-related symptoms at age two. Furthermore, the three LPCs modulated ROS and ATP levels in the neural cells. These findings provide insights into SSRI-induced molecular changes, highlight candidate metabolites that may warrant further investigation as indicators of SSRI exposure, and emphasise the need for exploring prenatal SSRI exposure effects and neurodevelopmental outcomes.