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We aimed to develop and validate a machine learning (ML) model to predict relapse in FEBD patients and assess whether pharmacotherapy effectiveness varies across predicted risk strata. We used nationwide registry data from Sweden (n\u2009=\u200930,402; follow-up\u2009=\u20092006\u20132021) and Finland (n\u2009=\u200913,790; follow-up\u2009=\u20091996\u20132018). The developed ML model achieved an area under the receiver operating characteristic curve (AUROC) of 0.71 (95% CI\u2009=\u20090.69\u20130.72, highest for relapse due to psychotic mania [AUROC\u2009=\u20090.85, 95% CI\u2009=\u20090.80\u20130.89]) in the Swedish cohort (internal validation) and 0.68 (95% CI\u2009=\u20090.66\u20130.69, highest for nonpsychotic mania [AUROC\u2009=\u20090.74, 95% CI\u2009=\u20090.69\u20130.78]) in the Finnish cohort (external validation). The model incorporated only seven accessible predictors, including pharmacotherapies during the first 30 days post-FEBD (lithium, combination treatments, and antipsychotics), outpatient follow-up within 30 days post-FEBD, prolonged initial hospitalization for FEBD, history of prior psychiatric hospitalizations, and sickness absence days. Among high-risk patients (N\u2009=\u200910,119, 31.77%), long-acting injectable (LAI) antipsychotics were associated with the greatest reduction in psychiatric rehospitalization risk (HR\u2009=\u20090.44, 95% CI 0.29\u20130.67). In the low-risk group (n\u2009=\u200921,736, 68.23%), only combinations of quetiapine with valproate (HR\u2009=\u20090.79, 95% CI\u2009=\u20090.65\u20130.95) or lamotrigine (HR\u2009=\u20090.86, 95% CI\u2009=\u20090.74\u20130.99) were associated with reduced rehospitalization risk. Available online for research purposes, our internally and externally validated prognostic model may inform clinical decision-making by identifying high-risk individuals who could benefit from early initiation of LAI antipsychotics, promoting a shift toward proactive, risk-guided treatment in FEBD patients.<\/jats:p>","DOI":"10.1038\/s41380-025-03316-2","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T17:45:53Z","timestamp":1761241553000},"page":"5722-5730","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Relapse risk prediction in patients with first-episode bipolar disorder: development, external validation, and pharmacotherapy associations of a machine learning model"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6030-0249","authenticated-orcid":false,"given":"Johannes","family":"Lieslehto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0400-6798","authenticated-orcid":false,"given":"Jari","family":"Tiihonen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7244-145X","authenticated-orcid":false,"given":"Markku","family":"L\u00e4hteenvuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Kautzky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aemal","family":"Akhtar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ridwanul","family":"Amin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bergn\u00fd","family":"\u00c1rmannsd\u00f3ttir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4934-4352","authenticated-orcid":false,"given":"Stefan","family":"Leucht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph U.","family":"Correll","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellenor","family":"Mittendorfer-Rutz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antti","family":"Tanskanen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3281-934X","authenticated-orcid":false,"given":"Heidi","family":"Taipale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"3316_CR1","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1016\/j.euroneuro.2015.07.013","volume":"25","author":"GH V\u00e1zquez","year":"2015","unstructured":"V\u00e1zquez GH, Holtzman JN, Lolich M, Ketter TA, Baldessarini RJ. 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JL owns shares for the publicly traded companies Orion, Aiforia, and Optomed. JT has been a consultant and\/or advisor to and\/or received honoria and\/or support for attending meetings from Healthcare Global Village, HLS Therapeutics, Janssen-Cilag, Lundbeck, Orion Pharma, Otsuka, Teva, and WebMD Global. HTs report personal fees from Gedeon Richter, Janssen-Cilag, Lundbeck and Otsuka. ML is a board member of Genomi Solutions Ltd. and Springflux Ltd. and has received honoraria from Sunovion, Orion Pharma, Camurus, Lundbeck, Otsuka Pharma, Recordati, Janssen and Janssen-Cilag and research funding from the Finnish Cultural Foundation and the Emil Aaltonen Foundation. CUC has been a consultant and\/or advisor to or has received honoraria from AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen\/J&J, Karuna, and Luxbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, Teva and Xenon. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder for Cardio Diagnostics, Kuleon Biosciences, LB Pharma, MindLink, Mindpax, Terran and Quantic. SL has received honoraria as an advisor and\/or for lectures and\/or for educational material from Alkermes, Angelini, Apsen, Eisai, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Merck Sharp and Dohme, Mitshubishi, Neurotorium, NovoNordisk, Otsuka, Recordati, Roche, Rovi, Sanofi Aventis, and TEVA. JL owns shares for Orion. The other coauthors report no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}