{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:19:42Z","timestamp":1790785182099,"version":"4.1.0"},"reference-count":173,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Minister of Science","award":["SKN\/SP\/603081\/2024"],"award-info":[{"award-number":["SKN\/SP\/603081\/2024"]}]},{"name":"Medical College of Rzeszow University (Rzeszow, Poland)","award":["SKN\/SP\/603081\/2024"],"award-info":[{"award-number":["SKN\/SP\/603081\/2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Depressive disorder is the most prevalent mental illness, and increasing evidence suggests its potential bidirectional relationship with metabolic disorders. Given the limited efficacy of conventional antidepressants (including Selective Serotonin Reuptake Inhibitors; SSRIs) and the growing prevalence of treatment-resistant depression, there is a significant need to identify alternative molecular pathways underlying the pathophysiology of depressive disorder, which may represent novel therapeutic targets for other agents. Emerging evidence indicates that metabolic dysfunction and depressive disorder share a common pathophysiological molecular mechanism and increase each other\u2019s risk. Targeting peripheral metabolic pathways and their interactions with the central nervous system may alleviate depressive symptoms. Glucagon-Like Peptide-1 agonists (GLP-1 RAs) and Sodium\u2013Glucose Cotransporter-2 (SGLT2) inhibitors, widely used in the treatment of type 2 diabetes and obesity, exhibit neurotrophic and anti-inflammatory effects, ameliorate oxidative stress, and enhance mitochondrial function, collectively contributing to the antidepressant-like effects observed in preclinical studies. Peroxisome Proliferator-Activated Receptor (PPAR) \u03b1 agonists primarily regulate lipid and glucose metabolism, which may potentially improve neuronal plasticity and mood regulation. Moreover, agents such as Angiotensin Receptor Blockers (ARBs) and Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), used in hypertension treatment, exert central anti-inflammatory and neuroprotective effects via the modulation of the renin\u2013angiotensin\u2013aldosterone system (RAAS), implicated in affective disorders. Nevertheless, long-term, head-to-head trials are required to establish their efficacy, safety, and therapeutic positioning within current treatment paradigms. The aim of this review is to summarize current evidence on metabolic modulators as potential antidepressant strategies, focusing on their molecular mechanisms, preclinical and clinical findings, and prospects for integration into future therapies for depression.<\/jats:p>","DOI":"10.3390\/ijms26178755","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Metabolic Modulators in Depression: Emerging Molecular Mechanisms and Therapeutic Opportunities"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0753-4837","authenticated-orcid":false,"given":"Kinga","family":"Dynda\u0142","sequence":"first","affiliation":[{"name":"Student\u2019s Science Club of Physiology \u201cNEURON\u201d, Faculty of Medicine, Collegium Medicum, University of Rzesz\u00f3w, Kopisto 2a, 35-315 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8760-7494","authenticated-orcid":false,"given":"Patrycja","family":"Pa\u0144czyszyn-Trzewik","sequence":"additional","affiliation":[{"name":"Department of Human Physiology, Faculty of Medicine, Collegium Medicum, University of Rzesz\u00f3w, Al. Tadeusza Rejtana 16C, 35-959 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5956-7229","authenticated-orcid":false,"given":"Magdalena","family":"Sowa-Ku\u0107ma","sequence":"additional","affiliation":[{"name":"Department of Human Physiology, Faculty of Medicine, Collegium Medicum, University of Rzesz\u00f3w, Al. Tadeusza Rejtana 16C, 35-959 Rzesz\u00f3w, Poland"},{"name":"Centre for Innovative Research in Medical and Natural Sciences, Collegium Medicum, University of Rzesz\u00f3w, Warzywna 1a, 35-310 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Luitel, N.P., Lamichhane, B., Pokhrel, P., Upadhyay, R., Taylor Salisbury, T., Akerke, M., Gautam, K., Jordans, M.J.D., Thornicroft, G., and Kohrt, B.A. (2024). 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