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While the pathophysiology of TRD remains incompletely understood, emerging evidence suggests that sex\u2010based biological differences might influence its onset, progression, and treatment response. Women are disproportionately affected by depression and are more likely to experience residual symptoms and treatment resistance, potentially due to hormonal fluctuations, immune system differences, and variations in brain circuitry and neuroplasticity. This narrative explores the current literature on the mechanisms underlying TRD, with a particular emphasis on sex\u2010specific biological factors. Key focus areas include dysregulation in neurotransmitters and neurotrophic pathways, inflammation, HPA axis alterations, mitochondrial dysfunction, as well as the influence of sex hormones such as estrogen and progesterone. By highlighting these differences, this review underscores the importance of personalized, sex\u2010informed approaches in the prevention and treatment of TRD and calls for further research to elucidate the biological underpinnings that contribute to sex disparities in treatment outcomes.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70215-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70215","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:31:05Z","timestamp":1756963865000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mechanisms Underlying Treatment\u2010Resistant Depression: Exploring Sex\u2010Based Biological Differences"],"prefix":"10.1111","volume":"169","author":[{"given":"Francisco E. 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