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The in the 1960s approved mineralocorticoid antagonist spironolactone has been shown to be effective to modulate (NRG1)-ERBB4 signaling in preclinical and animal models. Thus, a proof-of-concept drug repurposing trial in patients with schizophrenia was justified.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We conducted a multi-site proof-of-concept randomized controlled trial. 90 patients with schizophrenia were randomized to a three-week trial of two different spironolactone dosages (100\u2009mg or 200\u2009mg) or placebo. The primary endpoint was predefined as change in working memory performance after three weeks of treatment. A naturalistic follow-up was performed nine weeks after the end of intervention. The trial was registered at the WHO International Clinical Trials Registry platform (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/apps.who.int\/trialsearch\/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE\" ext-link-type=\"uri\">http:\/\/apps.who.int\/trialsearch\/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Despite large numerical improvements in working memory functions, particularly in the spironolactone 200\u2009mg group, the pre-specified analyses do not demonstrate significant superiority of either intervention over placebo. However, post-hoc sensitivity analyses suggest a significant advantage of spironolactone for the primary endpoint. Safety measures show that both interventions are well tolerated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>This finding suggests a potential positive effect of spironolactone on working memory in people with schizophrenia and the good safety outcomes may justify further trials with longer intervention periods or higher spironolactone dosages.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s43856-026-01714-3","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T09:03:15Z","timestamp":1781600595000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Antagonizing NRG1-ERBB4 signaling pathway with spironolactone for the treatment of schizophrenia: results of a randomized controlled drug repositioning clinical 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Cells 9, 1887 (2020).","DOI":"10.3390\/cells9081887"}],"container-title":["Communications Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43856-026-01714-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43856-026-01714-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43856-026-01714-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T09:03:32Z","timestamp":1781600612000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43856-026-01714-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1714"],"URL":"https:\/\/doi.org\/10.1038\/s43856-026-01714-3","relation":{},"ISSN":["2730-664X"],"issn-type":[{"value":"2730-664X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]},"assertion":[{"value":"16 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.H. was a member of the advisory boards of Axunio, Boehringer-Ingelheim, Lundbeck, Janssen, Otsuka, Rovi, Recordati, Teva and received paid speakership by these companies as well as by AbbVie and Advanz. He is the editor of the German schizophrenia guideline. S.L. has received honoraria for advising, consulting, and for lectures and\/or for educational material from Angelini, Apsen, Boehringer Ingelheim, Eisai, Ekademia, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Neurotorium, Otsuka, Novo Nordisk, Recordati, Rovi, and Teva. W.S. has received a paid speakership from Mag & More (Neurocare), Recordati, Boehringer Ingelheim, and Rovi. He was a member of an advisory board of Recordati and Rovi. E.W. was a member of the advisory boards of Recordati and Boehringer-Ingelheim. S.H. has accepted speaker honoraria from Johnson & Johnson, Boehringer-Ingelheim, Recordati and Otsuka\/Lundbeck; services as consultant in clinical trials were provided for the companies TEVA, ROVI, Merck und Boehringer-Ingelheim. I.M. received speaker fees from Boehringer-Ingelheim.\n                      Maximilian Hansbauer\n                      is a member of the sounding board of Rovi. Berthold Langguth was a member of the sounding board of Rovi, has received speaker honoraria from Rovi, ad contributed to the German schizophrenia guideline.\n                      SK Greiner\n                      is an advisor to the GOLDKIND Foundation. M.W. and M.R. report a relationship with Systasy Bioscience GmbH that includes employment and equity or stocks. B.D. reports a relationship with Node Biosciences, Inc that includes employment and equity or stocks. P.F. was co-editor of the German (DGPPN) schizophrenia treatment guidelines, and co-author of the WFSBP schizophrenia treatment guidelines. He was on advisory boards and received speaker fees from Janssen, Lundbeck, Otsuka, Servier, and Richter. All other authors have no competing interests to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"337"}}