Depression and post-traumatic stress disorder (PTSD) are treatment-resistant neuropsychiatric conditions closely linked to chronic neuroinflammation. Given the limitations of current pharmacotherapies, selective cyclooxygenase-2 (COX-2) inhibitors have emerged as promising candidates for modulating neuroimmune and oxidative pathways. This systematic review evaluated the efficacy of selective COX-2 inhibitors in improving behavioral and neuroinflammatory outcomes in rodent models of chronic stress or systemic inflammation relevant to depression and PTSD. A comprehensive search was conducted across PubMed, Scopus, Web of Science, and other databases for in vivo rodent studies published between 2010 and 2025. Inclusion criteria required validated chronic stress or inflammation paradigms (≥7 days), selective COX-2 inhibitors, and reporting of quantitative behavioral and neuroinflammatory end points. Thirty-four studies met eligibility criteria and were synthesized both qualitatively and via targeted random-effects meta-analysis for depression-like behaviors. COX-2 inhibitors such as celecoxib, meloxicam, and etoricoxib reduced forced swim test immobility by approximately 40% and increased sucrose preference by 25-30%, effects comparable to or exceeding SSRIs. Reductions in IL-6, TNF-α, and COX-2 expression ranged from 30% to 60%, along with suppression of the NF-κB pathway and markers of glial activation (Iba-1, GFAP). Concurrent activation of antioxidant pathways via Nrf2/HO-1 led to elevated levels of SOD, GSH, and BDNF, which correlated with behavioral improvements. A pooled meta-analysis (n = 15 comparisons) revealed a large standardized effect size (Hedges' g = 3.19; 95% CI: 2.14-4.25; I2 = 92.2%) in favor of COX-2 inhibition. While findings consistently support these agents' antidepressant- and anxiolytic-like efficacy in chronic stress models, their translational potential is limited by male-restricted samples (91% of studies), underreporting of effect sizes, and a scarcity of long-term durability assessments. These results support continued investigation of COX-2 inhibitors as adjunctive treatments in stress-related psychiatric disorders, with an emphasis on sex-stratified analyses and standardized behavioral and molecular reporting.
Keywords: NF-κB signaling; Nrf2 pathway; cyclooxygenase 2 inhibitors; depression; neuroinflammation; oxidative stress; post-traumatic stress disorder; preclinical neuroscience; rodent models; synaptic plasticity.