{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:18:56Z","timestamp":1789532336478,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1156072"],"award-info":[{"award-number":["1156072"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT1078928"],"award-info":[{"award-number":["GNT1078928"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT1153607"],"award-info":[{"award-number":["GNT1153607"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Bipolar Disorders"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The aim of this study was to repurpose a drug for the treatment of bipolar depression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal\u2010like (NT2\u2010N) cells. A compound library of 960 approved, off\u2010patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co\u2010cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive\u2010like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal\u2010like cells. Transcriptomic analysis in induced pluripotent stem cell\u2010derived neuron\/astrocyte co\u2010cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive\u2010like behaviours, trimetazidine exhibited antidepressant\u2010like activity with reduced anhedonia and reduced immobility in the forced swim test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bdi.13319","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T05:08:59Z","timestamp":1678338539000},"page":"661-670","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression"],"prefix":"10.1111","volume":"25","author":[{"given":"Chiara C.","family":"Bortolasci","sequence":"first","affiliation":[{"name":"IMPACT The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University  Geelong Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srisaiyini","family":"Kidnapillai","sequence":"additional","affiliation":[{"name":"IMPACT The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University  Geelong Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Briana","family":"Spolding","sequence":"additional","affiliation":[{"name":"IMPACT The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University  Geelong Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9301-5911","authenticated-orcid":false,"given":"Trang T. 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