**5. Conclusions**

Bipolar disorder that occurs in comorbidity with substance use disorder represents a severe clinical phenotype of bipolar illness. Alcohol use disorder is the most frequent comorbid substance use disorder in individuals with bipolar disorder, and it frequently presents in co-occurrence with other substance use. Machine-learning models might be used to predict the risk of having a comorbid substance use disorder in bipolar disorder, but their accuracy is limited when they include socio-demographical or clinical factors alone, as done in this study. Complex models integrating biological and clinical predictors represent a promising alternative to improve the performance of prediction.

**Author Contributions:** Data curation, V.O., G.F. (Giuseppe Fanelli) and G.F. (Giovanna Fico); Formal analysis, V.O., M.D.P. and G.F. (Giovanna Fico); Methodology, C.F., A.S. and G.F. (Giovanna Fico); Supervision, E.V.; Writing—original draft, G.F. (Giovanna Fico); Writing—review & editing, M.T.P.-C., P.G., G.A., D.H.-M., I.G., M.F., F.I., A.d.B., A.M. and G.F. (Giovanna Fico). All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee (Drug Research Ethics Committee (CEIm); Approval Code: HCB/2017/0432; Approval Date: 7 June 2017).

**Informed Consent Statement:** Informed consent was obtained from all of the subjects involved in the study.

**Data Availability Statement:** Data are available upon request.

**Acknowledgments:** G.A.'s research is supported by a Rio Hortega 2021 gran<sup>t</sup> (CM21/00017) financed by the Instituto de Salud Carlos III (ISCIII) and cofinanced by the Fondo Social Europeo Plus (FSE+). I.G. thanks the support of the Spanish Ministry of Science and Innovation (MCIN) (PI19/00954) integrated into the Plan Nacional de I+D+I and cofinanced by the ISCIII-Subdirección General de Evaluación y el Fondos Europeos de la Unión Europea (FEDER, FSE, Next Generation EU/Plan de Recuperación Transformación y Resiliencia\_PRTR); the Instituto de Salud Carlos III; the CIBER of Mental Health (CIBERSAM); and the the Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2017 SGR 1365), CERCA Programme /Generalitat de Catalunya. E.V. thanks the support of the Spanish Ministry of Science and Innovation (PI15/00283, PI18/00805) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the Instituto de Salud Carlos III; the CIBER of Mental Health (CIBERSAM); the Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2017 SGR 1365), the CERCA Programme, and the Departament de Salut de la Generalitat de Catalunya for the PERIS gran<sup>t</sup> SLT006/17/00357. A.M. has received a gran<sup>t</sup>

(PI19/00672) from the Instituto de Salud Carlos III Subdirección General de Evaluación y Fomento de la investigación, Plan Nacional 2019–2022. The project that gave rise to these results received the support of a fellowship from "La Caixa" Foundation (ID 100010434). G.F. (Giovanna Fico) fellowship code is LCF/BQ/DR21/11880019.

**Conflicts of Interest:** I.G. has received grants and served as consultant, advisor, or CME speaker for the following identities: Angelini, Casen Recordati, Ferrer, Janssen Cilag, and Lundbeck, Lundbeck-Otsuka, Luye, SEI Healthcare outside the submitted work. C.F. was a speaker for Janssen. A.S. is or has been a consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier. G.A. has received CME-related honoraria, or consulting fees from Janssen-Cilag, Lundbeck, Lundbeck/Otsuka, and Angelini, with no financial or other relationship relevant to the subject of this article. A.M. has received funding unrelated to the present work for research projects and/or honoraria as a consultant or speaker from the following entities: Angelini, Janssen, Lundbeck, Otsuka, Sanofi-Aventis and Spanish Ministry of Science and Innovation-Instituto de Salud Carlos III. E.V. has received grants and served as consultant, advisor, or CME speaker unrelated to the present work for the following entities: AB-Biotics, Abbott, Abbvie, Adamed, Angelini, Biogen, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris. G.F. (Giovanna Fico) has received CMErelated honoraria, or consulting fees from Angelini, Janssen-Cilag and Lundbeck. M.F. has none to disclose in conjunction with the present piece of work. A.d.B. has received unrestricted research support from Janssen, Lundbeck, and Otsuka and lecture honoraria for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria.
