Abstract

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressants, yet their long-term effects on periodontal and bone homeostasis remain unclear. This study investigated the impact of prolonged escitalopram administration on alveolar bone loss and immunoinflammatory responses. Escitalopram toxicity was first evaluated in Galleria mellonella, where doses ranging from 10 to 1000 mg/kg produced no mortality or alterations in health index over 72 h. Moreover, rats received daily intraperitoneal escitalopram for 91 days, and experimental periodontitis was induced by ligature placement on day 70. Alveolar bone loss was quantified by methylene blue staining and micro-computed tomography, while gingival inflammatory mediators were assessed at gene and protein levels. In vitro, RAW 264.7 macrophages were exposed to escitalopram and stimulated with lipopolysaccharide to measure TNF-alpha and CXCL2 release. Cervical lymph nodes were analyzed to determine T-cell-related transcriptional responses. In rats, periodontitis induced significant bone loss, and escitalopram modified this outcome in a dose-dependent manner: 1 mg/kg did not differ statistically from periodontitis alone, whereas 5 and 10 mg/kg significantly increased horizontal bone loss and worsened micro-CT parameters, including reduced bone volume fraction, increased porosity, and decreased trabecular number (P < 0.05). Periodontitis upregulated gingival RANK, RANKL, and pro-inflammatory cytokines. Although escitalopram reduced their gene expression at all doses, only 1 mg/kg significantly lowered TNF-alpha, IL-1 beta, IL-6, and IL-17 protein levels; higher doses restored or amplified these mediators. Escitalopram did not suppress Th17-related markers in cervical lymph nodes and reduced TGF beta 1 and FOXP3. In vitro, escitalopram was non-cytotoxic and dose-dependently inhibited LPS-induced TNF-alpha and CXCL2. Collectively, long-term escitalopram exposure exerts a dual, dose-dependent effect on periodontal inflammation and bone loss.