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An additional burden arises from treatment-resistance, defined by a lack of response to two or more adequate pharmacotherapeutic treatment trials. Unlike in MDD, where the serotonin 1A receptor subtype (5-HT<jats:sub>1A<\/jats:sub>) has commonly been used to study pathophysiological alterations, treatment-resistant depression (TRD) subjects represent a less investigated cohort. In this cross-sectional study, 5-HT<jats:sub>1A<\/jats:sub> receptor binding was assessed in 33 subjects with TRD with stable medication and 44 healthy control (HC) subjects. Positron emission tomography scans with the radioligand [<jats:italic>carbonyl<\/jats:italic>-<jats:sup>11<\/jats:sup>C]WAY-100635 were acquired and 5-HT<jats:sub>1A<\/jats:sub> receptor nondisplaceable binding potential (BP<jats:sub>ND<\/jats:sub>) was quantified using the multilinear reference tissue model 2. Regional BP<jats:sub>ND<\/jats:sub> in amygdala, anterior cingulate cortex, hippocampus, insula, orbitofrontal cortex, dorsal raphe nucleus and median raphe nucleus was assessed using a multivariate analysis of covariance (MANCOVA). The MANCOVA showed a significant effect of group (F\u2009=\u20093.349, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and sex (F\u2009=\u20092.428, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). The subsequent pairwise comparison revealed a lower BP<jats:sub>ND<\/jats:sub> by 17.45% in the TRD group in the dorsal raphe nucleus (mean difference\u2009\u00b1\u2009SE\u2009=\u2009\u22120.59\u2009\u00b1\u20090.24, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and by 18.39% in the median raphe nucleus (mean difference\u2009\u00b1\u2009SE\u2009=\u2009\u22120.71\u2009\u00b1\u20090.30, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Our results extend previously reported alterations of 5-HT<jats:sub>1A<\/jats:sub> receptor distribution in non-resistant depression to TRD. Ultimately, this knowledge may contribute to clarifying the role of serotonin and help to address the urgent issue of treatment resistance in depression.<\/jats:p>","DOI":"10.1038\/s41398-025-03406-3","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T16:19:09Z","timestamp":1748967549000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["In vivo serotonin 1A receptor distribution in treatment-resistant depression"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7643-2182","authenticated-orcid":false,"given":"Matej","family":"Murga\u0161","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1347-0744","authenticated-orcid":false,"given":"Christian","family":"Milz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7324-0414","authenticated-orcid":false,"given":"Peter","family":"St\u00f6hrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9274-6990","authenticated-orcid":false,"given":"Jakob","family":"Unterholzner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Nics","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3892-1804","authenticated-orcid":false,"given":"Georg S.","family":"Kranz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9727-7580","authenticated-orcid":false,"given":"Andreas","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4222-4083","authenticated-orcid":false,"given":"Marcus","family":"Hacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8278-191X","authenticated-orcid":false,"given":"Siegfried","family":"Kasper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4641-9539","authenticated-orcid":false,"given":"Rupert","family":"Lanzenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9739-0724","authenticated-orcid":false,"given":"Godber M.","family":"Godbersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"3406_CR1","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.jpsychires.2019.08.002","volume":"126","author":"Q Liu","year":"2020","unstructured":"Liu Q, He H, Yang J, Feng X, Zhao F, Lyu J. 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Kasper has received grant\/research support from Lundbeck; he has served as a consultant or on advisory boards for Angelini, Biogen, Esai, Janssen, IQVIA, Lundbeck, Mylan, Recordati, Sage and Schwabe; and he has served on speaker bureaus for Abbott, Angelini, Aspen Farmaceutica S.A., Biogen, Janssen, Lundbeck, Recordati, Sage, Sanofi, Schwabe, Servier, Sun Pharma and Vifor. Without any relevance to this work, R. Lanzenberger received investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET\/MR and travel grants and\/or conference speaker honoraria from Bruker BioSpin, Shire, AstraZeneca, Lundbeck A\/S, Dr. Willmar Schwabe GmbH, Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, Heel and Roche Austria GmbH. in the years before 2020. He has been a shareholder of the start-up company BM Health GmbH, Austria since 2019. M. Hacker received consulting fees and\/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, Siemens Healthineers. G.S. Kranz declares that he received a conference speaker honorarium from Roche, AOP Orphan and Pfizer. The other authors do not report any conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"186"}}