Selective Serotonin Reuptake Inhibitors Aggravate Depression-Associated Dry Eye Via Activating the NF-κB Pathway

Abstract

PURPOSE. Our study aimed to evaluate the side effects of selective serotonin reuptake inhibitors (SSRIs) on the ocular surface. METHODS. Twenty patients with depression and dry eye disease (DED) were randomly picked to receive SSRI treatment, whereas another 20 patients received placebo treatment. The serotonin, inflammatory cytokine, and proapoptotic protein levels were determined by using protein chip, qRT-PCR, and ELISA analyses. A rat depression model was established, and SSRIs were applied for 3 or 6 weeks. Tear production and corneal epithelial barrier function were evaluated. The serotonin and inflammatory cytokine levels were analyzed by qRT-PCR, immunohistochemical staining, and ELISA. Human corneal epithelial cells were subjected to serotonin, a HTR antagonist, and/or an NF-jB signaling inhibitor. The inflammatory cytokine and proapoptotic protein levels were determined by qRT-PCR, Western blot analysis, and ELISA. The cell apoptosis rate was assessed by using flow cytometry. RESULTS. The SSRI group had higher tear serotonin levels and more serious inflammation and cell apoptosis on the ocular surface. In the rat depression model, depression decreased tear secretion and increased IL-1b and TNF-a production, whereas the serotonin, TLR2, and TLR4 levels were not increased. SSRI aggravated DED, disrupted the corneal epithelial barrier, and promoted an inflammatory response on the ocular surface by increasing the tear serotonin levels. In addition, serotonin induced an inflammatory response and cell apoptosis in corneal epithelial cells by activating NF-jB signaling. CONCLUSIONS. SSRIs aggravate depression-associated DED via activating the NF-jB pathway. The antagonist of HTRs or the inhibitor of NF-jB signaling presents a potential therapeutic strategy for depression-associated DED. (Trial registration number, ChiCTR1800015592).

Early effects of selective serotonin reuptake inhibitors (SSRIs) on cornea and lens density in patients with depression

“…If refractive surgery is planned, it should be ensured that a patient's refractive status remains stable. A previous study reported that serotonin induces cell inflammation and apoptosis in corneal epithelial cells [27]. Since this effect may lead to changes in CD, the present research performed CD measurements by Pentacam HR, finding that SSRIs made no significant changes in anterior chamber parameters, LD or CD at the three-month follow-ups.…”

Sudden cessation of fluoxetine before alcohol drinking reinstatement alters microglial morphology and TLR4/inflammatory neuroadaptation in the rat brain

“…Experimental studies reflecting the incongruence of clinical outcomes hypothesize that an interplay between SSRIs and the quality of the environmental Fig. 8 Schematic representation that summarize the main effects of fluoxetine treatment cessation and ethanol drinking reinstatement on microglial morphology and its association with reactive phenotype (inflammatory response) in each brain region analyzed conditions (Alboni et al 2016(Alboni et al ,2017) may support the divergent effects of SSRI treatment on the inflammatory response (Tynan et al 2012;Horowitz et al 2014;Lu et al 2017;Zhang et al 2019). Regarding our findings on microglial morphology, fluoxetine treatment cessation induced subtle changes in main morphometric parameters that indicate higher spatial complexity (fractal dimension) and lower heterogeneity (lacunarity), as well as increases in process thickening and shortening (density and roughness), effects that are also more prominent in the striatum and hippocampal CA1.…”

“…However, conventional SSRI antidepressants fail to respond to immunotherapies involving depressive disorder, demonstrating no, anti- or even pro-inflammatory effects (Hannestad et al 2011 ; Kim et al 2013 ; Chen et al 2018 ; Tomaz et al 2020 ; Yoshimura et al 2013 ). Experimental studies reflecting the incongruence of clinical outcomes hypothesize that an interplay between SSRIs and the quality of the environmental conditions (Alboni et al 2016 , 2017 ) may support the divergent effects of SSRI treatment on the inflammatory response (Tynan et al 2012 ; Horowitz et al 2014 ; Lu et al 2017 ; Zhang et al 2019 ). Regarding our findings on microglial morphology, fluoxetine treatment cessation induced subtle changes in main morphometric parameters that indicate higher spatial complexity (fractal dimension) and lower heterogeneity (lacunarity), as well as increases in process thickening and shortening (density and roughness), effects that are also more prominent in the striatum and hippocampal CA1.…”

Sudden Cessation of Fluoxetine Before Alcohol Drinking Reinstatement Alters Microglial Morphology and TLR4/inflammatory Neuroadaptation in the Rat Brain

“…However, conventional SSRI antidepressants fail to respond to immunotherapies involving depressive disorder, demonstrating no, anti-or even pro-in ammatory effects [39][40][41]68,70]. Experimental studies re ecting the incongruence of clinical outcomes hypothesize that an interplay between SSRIs and the quality of the environmental conditions [35,71] may support the divergent effects of SSRI treatment on the in ammatory response [42,[72][73][74]. Regarding our ndings on microglial morphology, uoxetine treatment cessation induced subtle changes in main morphometric parameters that indicate higher spatial complexity (fractal dimension) and lower heterogeneity (lacunarity), as well as increases in process thickening and shortening (density and roughness), effects that are also more prominent in the striatum and hippocampal CA1.…”