Citalopram and sertraline exposure compromises embryonic bone development

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.

The effects of fluoxetine on the human adipose‐derived stem cell proliferation and differentiation

“…These drugs reduced bone mineralization and decreased osteoblast markers during embryogenesis. In differentiation process of human mesenchymal stem cells, decreasing the activity of osteoblasts and reducing the expression of RUNX2 and ALP genes were observed . In the study of Fraher, the cells types were similar to those of our study, but they evaluated other drugs of SSRI class that their results were in consistent with the results of our study.…”

“…They showed that citalopram increases the expression of OCN and ALP in osteogenesis and causes cranio-facial defects by modifying the bone property of mouse calvarial pre-osteoblast cells [36]. Our results were paralleled with the study of Bradaschia et al which was conducted on osteogenic In differentiation process of human mesenchymal stem cells, decreasing the activity of osteoblasts and reducing the expression of RUNX2 and ALP genes were observed [37]. In the study of Fraher, the cells types were similar to those of our study, but they evaluated other drugs of SSRI class that their results were in consistent with the results of our study.…”

Cluster analysis profiling of behaviors in zebrafish larvae treated with antidepressants and pesticides

“…We thus included concentrations that are similar to the doses used in animal model systems and doses prescribed for human use, as well as lower concentrations. For a comparison of concentrations in other species we refer to (Fraher et al, 2016; GlaxoSmithKline, 2017; Lilly, 2009; Lu et al, 2008; Lu et al, 2006; Pfizer, 2002; Vermoesen et al, 2011). On days larvae were not treated, all groups were housed in egg water.…”

Sertraline Induces Toxicity and Behavioral Alterations in Planarians

“…Although sertraline is considered a safe drug, several reports have associated it with toxic effects on the liver [14–16] and hepatic cells [2, 13, 17]. Recently, cardiac toxicity has been related to sertraline, even in therapeutic doses [18, 19], and its use during pregnancy was associated with an increased risk of major malformations [20] and compromise of embryonic bone development [21]. …”