Researchers, using a lab-grown miniature of the developing human brain, found that the selective serotonin reuptake inhibitor (SSRI) paroxetine had numerous neurotoxic effects. They write that their results demonstrate the harmful effects of SSRIs on the developing fetus.
“These results identify paroxetine as a potential human developmental neurotoxicant, and suggest that the contraindication for its use should be evaluated and possibly extended far beyond the first trimester of pregnancy.”
The researchers were led by David Pamies at the Center for Alternatives to Animal Testing (CAAT) at Johns Hopkins and published their results in Frontiers in Cellular Neuroscience.
SSRIs can cross the placental barrier in pregnant women, but their effects on fetal development are still somewhat unknown. Scores of studies have demonstrated harmful effects on the fetus, including increased risk of cardiac problems, birth defects, and an increased prevalence of autism, in children who were exposed to SSRIs in the womb. However, SSRIs are still commonly used by pregnant women.
It is difficult to develop controlled studies on the effects of these drugs in actual developing human brains, making it difficult to find definitive evidence of these harms. Testing the drug on rodents is one method commonly used, but it is expensive, requires killing thousands of animals, and the rodent brain does not always appropriately reflect the complexities of the human brain.
Because of these difficulties, the researchers worked out a new method for testing how drugs might impact the developing human brain. They were able to push human stem cells to develop into miniature brains, which they call “BrainSpheres.” These tiny, almost microscopic clumps of cells organize into structures that closely replicate the developing human brain.
The researchers grew two different batches of BrainSpheres and tested two different levels of paroxetine against them. Both levels of paroxetine (20 ng/mL and 60 ng/mL) were considered normal, “therapeutic” levels of the drug. Although the higher level appeared to cause more damage in one of the batches of BrainSpheres, both levels were consistently associated with neurotoxic effects compared to the control BrainSpheres (which did not receive paroxetine).
Paroxetine did not appear to directly kill neurons. Instead, it damaged a number of elements of neuronal connection. According to the researchers:
“At therapeutic blood concentrations, which lie between 20 and 60 ng/ml, Paroxetine led to an 80% decrease in the expression of synaptic markers, a 60% decrease in neurite outgrowth and a 40–75% decrease in the overall oligodendrocyte cell population, compared to controls.”
The harms observed in this study are consistent with the disruption of the serotonin system in the developing brain and could explain the increased prevalence of autism in children whose mothers took an SSRI. They write that these findings should inform further statements about the dangers of paroxetine in pregnant women.
Zhong, X., Harris, G., Smirnova, L., Zufferey, V. 3, Sá, R., Russo, F. B., . . . & Pamies, D. (2020). Antidepressant paroxetine exerts developmental neurotoxicity in an iPSC-derived 3D human brain model. Front. Cell. Neurosci, 14(25). https://doi.org/10.3389/fncel.2020.00025 (Link)