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Acute experimental manipulations of serotonin have provided compelling evidence for its role in reinforcement learning. However, it remains unknown how more chronic manipulation of serotonin, which holds greater clinical relevance, affects reinforcement learning and the underlying neural mechanisms. Consequently, we aimed to investigate the effect of a three-week administration of the SSRI, escitalopram, on a reinforcement learning paradigm during functional magnetic resonance imaging. The study used a double-blind, placebo-controlled design with 64 healthy volunteers. Participants were semi-randomised, ensuring matched groups for age, sex and intelligence quotient (IQ), to receive either 20\u2009mg of escitalopram (<jats:italic>n<\/jats:italic>\u2009=\u200932) or placebo (<jats:italic>n<\/jats:italic>\u2009=\u200932) for at least 21 days. We analysed group differences in reinforcement learning using both analysis of covariance as well as innovative hierarchical Bayesian modelling of the reinforcement learning task. Escitalopram reduced learning from punishment during punishment trials. A key novel finding was that there was decreased activation of the intraparietal sulcus in the escitalopram group when compared to the placebo group during reward trials. The involvement of the intraparietal sulcus suggests that escitalopram affects the encoding of value outcome, which may lead to reduced reinforcement sensitivity, and thereby impacting adaptive learning from feedback. Understanding these mechanisms may help to optimize SSRI treatment to mitigate clinical symptoms and improve quality of life for neuropsychiatric patients, by elucidating serotonin\u2019s effects on affect, cognition, and behaviour.<\/jats:p>","DOI":"10.1038\/s41398-025-03392-6","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T09:16:14Z","timestamp":1747818974000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Computational modelling and neural correlates of reinforcement learning following three-week escitalopram: a double-blind, placebo-controlled semi-randomised study"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5061-2820","authenticated-orcid":false,"given":"Christelle","family":"Langley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8296-1742","authenticated-orcid":false,"given":"Graham K.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6368-3329","authenticated-orcid":false,"given":"Sophia","family":"Armand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Knolle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8751-5167","authenticated-orcid":false,"given":"Rudolf N.","family":"Cardinal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0264-2368","authenticated-orcid":false,"given":"Annette","family":"Johansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dea S.","family":"Stenb\u00e6k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1508-6866","authenticated-orcid":false,"given":"Gitte M.","family":"Knudsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8115-0611","authenticated-orcid":false,"given":"Patrick M.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7352-1745","authenticated-orcid":false,"given":"Barbara J.","family":"Sahakian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"3392_CR1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.tics.2007.10.011","volume":"12","author":"R Cools","year":"2008","unstructured":"Cools R, Roberts AC, Robbins TW. 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GMK served as a speaker for Angelini, Abbvie, Cybin, and H. Lundbeck, as an advisor for Sanos, Onsero, Pangea Botanica, Gilgamesh, Pure Technologies, and her lab is a research site for Reunion and Delix Therapeutics. RNC receives royalties from Routledge, Cambridge University Press, and Cambridge Enterprise, and has consulted for Campden Instruments. BJS consults for Cambridge Cognition.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"175"}}