{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:00:22Z","timestamp":1791644422026,"version":"4.3.4"},"reference-count":94,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Minister of Science under the program \u2018Student Scientific Societies Create Innovation\u2019","award":["SKN\/SP\/603081\/2024"],"award-info":[{"award-number":["SKN\/SP\/603081\/2024"]}]},{"name":"Medical College of Rzeszow University","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>Gepirone, a selective 5-hydroxytryptamine (serotonin) 1A (5-HT1A) receptor agonist, offers a promising strategy for treating mood and anxiety disorders. The therapeutic importance of 5-HT1A modulation is well established, as these receptors regulate serotonergic neurotransmission both presynaptically, in the somatodendritic regions of raphe neurons, and postsynaptically, in structures including the hippocampus, neocortex, septum, amygdala, and hypothalamus. Gepirone exhibits a distinctive pharmacological profile, acting as a full agonist at presynaptic autoreceptors and a partial agonist at postsynaptic receptors, with high affinity for 5-HT1A and much lower affinity for 5-HT2A receptors. Its effects on serotonergic signaling are time-dependent. Acute administration suppresses serotonergic firing through autoreceptor activation, while chronic treatment induces autoreceptor desensitization, leading to enhanced 5-HT release in projection areas. This process is complemented by partial agonism at postsynaptic 5-HT1A receptors, which further supports long-term neuromodulation. This article provides an integrated overview of gepirone\u2019s mechanism of action, bridging receptor pharmacology, neurophysiological adaptations, and therapeutic implications. Particular emphasis is placed on the compound\u2019s unique dual role in regulating serotonergic tone over time, a feature that differentiates it from other 5-HT1A-targeting agents. By linking molecular mechanisms to clinical outcomes, we highlight gepirone\u2019s potential advantages in efficacy, safety, and tolerability compared with conventional antidepressants. This comprehensive perspective underscores gepirone as a paradigmatic example of selective 5-HT1A modulation and offers novel insights into the development of targeted treatments for depression and anxiety.<\/jats:p>","DOI":"10.3390\/ijms26199805","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T09:41:02Z","timestamp":1760002862000},"page":"9805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Gepirone for Major Depressive Disorder: From Pharmacokinetics to Clinical Evidence: A Narrative Review"],"prefix":"10.3390","volume":"26","author":[{"given":"Natalia","family":"Ga\u0142ka","sequence":"first","affiliation":[{"name":"Department of Human Physiology, Faculty of Medicine, University of Rzesz\u00f3w, Al. Tadeusza Rejtana 16C, 35-959 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Tomaka","sequence":"additional","affiliation":[{"name":"Student\u2019s Science Club of Physiology \u201cNEURON\u201d, Faculty of Medicine, University of Rzesz\u00f3w, Al. Tadeusza Rejtana 16C, 35-959 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Tomaszewska","sequence":"additional","affiliation":[{"name":"Student\u2019s Science Club of Physiology \u201cNEURON\u201d, Faculty of Medicine, University of Rzesz\u00f3w, Al. Tadeusza Rejtana 16C, 35-959 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, 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, 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":[[2025,10,8]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022). World Mental Health Report: Transforming Mental Health for All, WHO. 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