Endothelial damage in major depression patients is modulated by SSRI treatment, as demonstrated by circulating biomarkers and an in vitro cell model

Abstract

There is a link between depression, cardiovascular events and inflammation. We have explored this connection through endothelial dysfunction, using in vivo and in vitro approaches. We evaluated circulating biomarkers of endothelial dysfunction in patients with major depression at their diagnosis (MD-0) and during antidepressant treatment with the selective serotonin reuptake inhibitor escitalopram, for 8 and 24 weeks (MD-8 and MD-24). Results were always compared with matched healthy controls (CON). We measured in vivo circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in blood samples, and assessed plasma levels of soluble von Willebrand factor (VWF) and vascular cell adhesion molecule-1 (VCAM-1). CEC counts, soluble VWF and VCAM-1 were statistically elevated in MD-0 (P<0.01 versus CON) and gradually decreased during treatment. Conversely, EPC levels were lower in MD-0, tending to increase throughout treatment. In vitro studies were performed in human endothelial cells cultured in the presence of sera from each study group. Elevated expression of the inflammation marker intercellular adhesion molecule-1 and oxidative stress, with lower presence of endothelial nitric oxide synthase and higher reactive oxygen species production, were found in cells exposed to MD-0 sera (P<0.05 versus CON). These results were normalized in cells exposed to MD-24 sera. Thrombogenicity of extracellular matrices generated by these cells, measured as expression of VWF, tissue factor and platelet reactivity, showed non-significant differences. We provide a model of cultured endothelial cells reproducing endothelial dysfunction in naive patients with major depression, demonstrating endothelial damage and inflammation at diagnosis, and recovering with selective serotonin reuptake inhibitor treatment for 24 weeks.

Model Placental Barrier Phenotypic Response to Fluoxetine and Sertraline: A Comparative Study

“…Interestingly, there was no significant dose‐response to either drug for trophoblast cells, while ECs appeared to have a dose‐response, where low drug doses caused higher than baseline TGFβ secretions while higher dosages reduced these secretions to a baseline level over time. This time and dose‐dependent response is intriguing as others have previously shown that SSRI treatment changes cell physiology, both in vivo in depressed patients and in vitro following exposure to serum from depressed patients, where SSRI treatment leads to a return to baseline levels over time . Given that TGFβ is important for survival, homeostasis and barrier function of ECs, as well as angiogenesis, it is interesting that these drugs can elicit a time and dose‐dependent effect .…”

“…As previously mentioned, SSRIs have been shown to influence cell‐level phenotype, having been shown to modulate CAM expression mediated by a pro‐inflammatory response and in depressed patients . Given that CAMs are intercellular molecules, secretions of these proteins into solution indicates delocalization of the CAMs from cell–cell junctions to the surrounding solution, and thus damage to cell–cell junctions . A study by Lopez‐Vilchez et al showed that, over time, SSRIs reduced both cell surface ICAM expression and soluble VCAM expression in depressed patients back toward a healthy control, where both of these markers were significantly elevated over the healthy control with no treatment .…”

“…As previously mentioned, SSRIs have been shown to influence cell‐level phenotype, having been shown to modulate CAM expression mediated by a pro‐inflammatory response and in depressed patients . Given that CAMs are intercellular molecules, secretions of these proteins into solution indicates delocalization of the CAMs from cell–cell junctions to the surrounding solution, and thus damage to cell–cell junctions .…”

“…Given that CAMs are intercellular molecules, secretions of these proteins into solution indicates delocalization of the CAMs from cell–cell junctions to the surrounding solution, and thus damage to cell–cell junctions . A study by Lopez‐Vilchez et al showed that, over time, SSRIs reduced both cell surface ICAM expression and soluble VCAM expression in depressed patients back toward a healthy control, where both of these markers were significantly elevated over the healthy control with no treatment . Both fluoxetine and sertraline exhibited a dose‐dependent effect in causing ICAM secretions, though the two drugs were not significantly different in their extent to impact either ICAM or VCAM secretions from the whole BPB model.…”

“…Elucidating these interactions, particularly if they can induce adverse drug–drug interactions during pregnancy, is critically important. Additionally, SSRIs have been shown to alter cell phenotype in depressed patients, such as modulating cell adhesion molecule (CAM) expression and causing changes in transforming growth factor beta (TGFβ) expression . Given these observations, and that TGFβ has been implicated in damaging tight junctions and compromising the BPB, studies to understand cell‐level changes from SSRI exposure are needed.…”