Alessandro Miola ¹ Michele De Prisco ² Marialaura Lussignoli ¹ Nicola Meda ³ Elisa Dughiero ³ Riccardo Costa ³ Nicolas A. Nunez ⁴ Michele Fornaro ⁵ Marin Veldic ⁶ Mark A. Frye ⁶ Eduard Vieta ² Marco Solmi ⁷ Joaquim Radua ⁸ Fabio Sambataro ^1*

• ¹ Padua Neuroscience Center, University of Padua, Padua, Italy
• ² Hospital Clinic of Barcelona, Barcelona, Catalonia, Spain
• ³ Clinica Psichiatrica, Azienda Ospedaliera Universitaria di Padova, Padova, Italy
• ⁴ The University of Utah, Salt Lake City, Utah, United States
• ⁵ University of Naples Federico II, Naples, Campania, Italy
• ⁶ Mayo Clinic, Rochester, Minnesota, United States
• ⁷ University of Ottawa, Ottawa, Ontario, Canada
• ⁸ Center for Biomedical Research in Mental Health Network (CIBERSAM), Madrid, Madrid, Spain

Objective: Bipolar Disorder (BD) is a severe mental illness associated with high rates of general medical comorbidity, reduced life expectancy, and premature mortality. Although BD has been associated with high medical hospitalization, the factors that contribute to this risk remain largely unexplored. We used baseline medical and psychiatric records to develop a supervised machine learning model to predict general medical admissions after discharge from psychiatric hospitalization. Methods: In this retrospective three-year cohort study of 71 patients diagnosed with BD (mean age=52.19 years, females=56.33%), lasso regression models combining medical and psychiatric records, as well as those using them separately, were fitted and their predictive power was estimated using a leave-one-out cross-validation procedure. Results: The proportion of medical admissions in patients with BD was higher compared with age- and sex-matched hospitalizations in the same region (25.4% vs. 8.48%). The lasso model fairly accurately predicted the outcome (area under the curve [AUC]= 69.5%, 95%C.I.=55-84.1%; sensitivity=61.1%, specificity=75.5%, balanced accuracy=68.3%). Notably, pre-existing cardiovascular, neurological, or osteomuscular diseases collectively accounted for more than 90% of the influence on the model. The accuracy of the model based on medical records was slightly inferior (AUC=68.7%, 95%C.I.=54.6-82.9), while that of the model based on psychiatric records only was below chance (AUC=61.8%, 95%C.I.=46.2-77.4%). Conclusion: Our findings support the need to monitor medical comorbidities during clinical decision-making to tailor and implement effective preventive measures in people with BD. Further research with larger sample sizes and prospective cohorts is warranted to replicate these findings and validate the predictive model.