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 associate in-utero SSRI exposure with neurodevelopmental disorders, such as autism and attention-deficit/hyperactivity disorder (ADHD). The potential molecular mechanisms by which SSRIs impact early neurodevelopment are not fully understood. In this study, we examined the effects of four commonly prescribed SSRIs—fluoxetine, citalopram, sertraline, and paroxetine—on neuroepithelial stem cells derived from four different human induced pluripotent stem cells. Following SSRI exposure, we assessed cellular viability, reactive oxygen species (ROS) levels, mitochondrial function through adenosine triphosphate (ATP) assays and performed high throughput metabolomic profiling at two timepoints: proliferation and neural differentiation stages. Sertraline and paroxetine significantly decreased ROS and ATP levels, indicating mitochondrial alteration. Metabolomic analysis identified several affected pathways and pinpointed three lysophosphatidylcholines (LPCs) 16:0, 18:0, and 18:1 as significantly elevated across all SSRI exposures and time points, except for citalopram. In a complementary population-based cohort study, the Barwon Infant Study (BIS), consisting of 1074 mother-child pairs, 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. These findings provide insights into SSRI-induced molecular changes, identify potential biomarkers for SSRI exposure monitoring, and emphasize the need for further clinical investigations into prenatal SSRI exposure and neurodevelopmental outcomes.