Abstract
Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat depression during pregnancy. Various concerns have been raised about the possible effects of these drugs on fetal development. Current developmental neurotoxicity (DNT) testing conducted in rodents is expensive, time-consuming, and does not necessarily represent human pathophysiology. A human, in vitro testing battery to cover key events of brain development, could potentially overcome these challenges. In this study, we assess the DNT of paroxetine—a widely used SSRI which has shown contradictory evidence regarding effects on human brain development using a versatile, organotypic human induced pluripotent stem cell (iPSC)-derived brain model (BrainSpheres). 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. These results were consistently shown in two different iPSC lines and indicate that relevant therapeutic concentrations of Paroxetine induce brain cell development abnormalities which could lead to adverse effects.
Highlights
Between 7 and 12% of pregnant women suffer from depression (Bennett et al, 2004)
Paroxetine exposure decreased a post-synaptic marker (PSD95) in both cell lines but to a lesser extent than SYP, as shown by immunohistochemistry (Figure 2D). These results show a consistent decrease in SYP and PSD95 markers after paroxetine exposure which may result in adverse effects on synaptogenesis during neural differentiation
Paroxetine, a Selective serotonin reuptake inhibitors (SSRIs) is contraindicated during the first trimester of pregnancy mainly because of the increased risk of cardiac and other congenital malformations (Cole et al, 2007)
Summary
Between 7 and 12% of pregnant women suffer from depression (Bennett et al, 2004). Selective serotonin reuptake inhibitors (SSRIs) are one of the most commonly used treatments (Andrade et al, 2008; Alwan et al, 2011). Several concerns about the possible developmental neurotoxicity (DNT) effects of different SSRIs have been raised over the years (i.e., antidepressants such as fluoxetine, paroxetine, citalopram, and sertraline). Neurobehavioral studies involving SSRIs have shown adverse effects on neonates (Zeskind and Stephens, 2004; Alwan and Friedman, 2009; Gentile and Galbally, 2011), infants and young children. Paroxetine was shown to cross the placental barrier (Hendrick et al, 2003) and was often the center of attention for possible adverse effects (Nevels et al, 2016), including autism. Croen et al (2011) followed 145,456 full-term infants for a total of 904,035 person-years; they reported increased risk from 1% to 1.87%, with a 95% CI of 1.15–3.04, but several shortcomings of the study were noted (Croen et al, 2011; Nevels et al, 2016). A systematic review in 2016 (Boukhris et al, 2016) reported an odds ratio of 2.13 (95% CI: 1.66–2.73) for developing autism in children prenatally exposed to SSRIs compared to an odds ratio of 1.81 (95% CI: 1.47–2.24) in those unexposed
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