{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:39:30Z","timestamp":1788068370722,"version":"build-2784847793"},"reference-count":28,"publisher":"Royal College of Psychiatrists","issue":"3","license":[{"start":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T00:00:00Z","timestamp":1722988800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000627","name":"Guarantors of Brain","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000627","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["216430\/Z\/19\/Z"],"award-info":[{"award-number":["216430\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Br J Psychiatry"],"published-print":{"date-parts":[[2024,9]]},"abstract":"\n Background<\/jats:title>\n \n The serotonin 4 receptor (5-HT\n 4<\/jats:sub>\n R) is a promising target for the treatment of depression. Highly selective 5-HT\n 4<\/jats:sub>\n R agonists, such as prucalopride, have antidepressant-like and procognitive effects in preclinical models, but their clinical effects are not yet established.\n <\/jats:p>\n <\/jats:sec>\n \n Aims<\/jats:title>\n \n To determine whether prucalopride (a 5-HT\n 4<\/jats:sub>\n R agonist and licensed treatment for constipation) is associated with reduced incidence of depression in individuals with no past history of mental illness, compared with anti-constipation agents with no effect on the central nervous system.\n <\/jats:p>\n <\/jats:sec>\n \n Method<\/jats:title>\n Using anonymised routinely collected data from a large-scale USA electronic health records network, we conducted an emulated target trial comparing depression incidence over 1 year in individuals without prior diagnoses of major mental illness, who initiated treatment with prucalopride versus two alternative anti-constipation agents that act by different mechanisms (linaclotide and lubiprostone). Cohorts were matched for 121 covariates capturing sociodemographic factors, and historical and\/or concurrent comorbidities and medications. The primary outcome was a first diagnosis of major depressive disorder (ICD-10 code F32) within 1 year of the index date. Robustness of the results to changes in model and population specification was tested. Secondary outcomes included a first diagnosis of six other neuropsychiatric disorders.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Treatment with prucalopride was associated with significantly lower incidence of depression in the following year compared with linaclotide (hazard ratio 0.87, 95% CI 0.76\u20130.99;\n P<\/jats:italic>\n = 0.038;\n n<\/jats:italic>\n = 8572 in each matched cohort) and lubiprostone (hazard ratio 0.79, 95% CI 0.69\u20130.91;\n P<\/jats:italic>\n < 0.001;\n n<\/jats:italic>\n = 8281). Significantly lower risks of all mood disorders and psychosis were also observed. Results were similar across robustness analyses.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These findings support preclinical data and suggest a role for 5-HT\n 4<\/jats:sub>\n R agonists as novel agents in the prevention of major depression. These findings should stimulate randomised controlled trials to confirm if these agents can serve as a novel class of antidepressant within a clinical setting.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1192\/bjp.2024.97","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T08:20:07Z","timestamp":1723018807000},"page":"371-378","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":16,"title":["Association between a selective 5-HT\n 4<\/sub>\n receptor agonist and incidence of major depressive disorder: emulated target trial"],"prefix":"10.1192","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7848-1295","authenticated-orcid":false,"given":"Angharad N.","family":"de Cates","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine J.","family":"Harmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6719-1126","authenticated-orcid":false,"given":"Paul J.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Cowen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Emmanuel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Travis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susannah E.","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8987-952X","authenticated-orcid":false,"given":"Maxime","family":"Taquet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"170","published-online":{"date-parts":[[2024,8,7]]},"reference":[{"key":"S0007125024000977_ref7","first-page":"120","article-title":"A high-resolution in vivo atlas of the human brain's serotonin system","volume":"37","author":"Beliveau","year":"2017","journal-title":"J Neurosci"},{"key":"S0007125024000977_ref11","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2022.4539"},{"key":"S0007125024000977_ref13","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.21383"},{"key":"S0007125024000977_ref15","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(20)30462-4"},{"key":"S0007125024000977_ref17","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.03.214"},{"key":"S0007125024000977_ref19","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01615-6"},{"key":"S0007125024000977_ref12","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01568-4"},{"key":"S0007125024000977_ref22","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac256"},{"key":"S0007125024000977_ref24","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2023.2067"},{"key":"S0007125024000977_ref16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1003773"},{"key":"S0007125024000977_ref18","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00973"},{"key":"S0007125024000977_ref20","doi-asserted-by":"publisher","DOI":"10.7326\/M16-2607"},{"key":"S0007125024000977_ref9","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2013.332"},{"key":"S0007125024000977_ref25","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-311835"},{"key":"S0007125024000977_ref21","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.859123"},{"key":"S0007125024000977_ref28","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2010.04.002"},{"key":"S0007125024000977_ref1","unstructured":"1 World Health Organization (WHO). 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Published by Cambridge University Press on behalf of Royal College of Psychiatrists","name":"copyright","label":"Copyright","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http:\/\/creativecommons.org\/licenses\/by\/4.0\/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.","name":"license","label":"License","group":{"name":"copyright_and_licensing","label":"Copyright and Licensing"}},{"value":"This content has been made available to all.","name":"free","label":"Free to read"}]}}