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Duration of index episode, Clinical Global Impression-Bipolar Version-Depression (CGI-BP-D) and Global Assessment of Functioning (GAF) were used as clustering variables. MANOVA and post-hoc ANOVAs examined between-group differences in clustering variables. A stepwise backward regression model explored the relationship with the 56 clinical-demographic variables available. Agglomerative hierarchical clustering with two clusters was shown as the best fit and separated the study population (<jats:italic>n<\/jats:italic>\u2009=\u20092314) into 65.73% (Cluster 1 (C1)) and 34.26% (Cluster 2 (C2)). MANOVA showed a significant main effect for cluster group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) but ANOVA revealed that significant between-group differences were restricted to CGI-BP-D (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and GAF (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), showing greater severity in C2. Psychotic features and a minimum of three DSM-5 criteria for mixed features (DSM-5-3C) had the strongest association with C2, that with greater disease burden, while non-mixed depression in bipolar disorder (BD) type II had negative association. Mixed affect defined as DSM-5-3C associates with greater acute severity and overall impairment, independently of the diagnosis of bipolar or unipolar depression. In this study a pure, non-mixed depression in BD type II significantly associates with lesser burden of clinical and functional severity. The lack of association for less restrictive, researched-based definitions of mixed features underlines DSM-5-3C specificity. If confirmed in further prospective studies, these findings would warrant major revisions of treatment algorithms for both unipolar and bipolar depression.<\/jats:p>","DOI":"10.1038\/s41398-020-00922-2","type":"journal-article","created":{"date-parts":[[2020,7,19]],"date-time":"2020-07-19T06:03:28Z","timestamp":1595138608000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Deconstructing major depressive episodes across unipolar and bipolar depression by severity and duration: a cross-diagnostic cluster analysis on a large, international, observational study"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6807-0617","authenticated-orcid":false,"given":"Filippo","family":"Corponi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6798-4054","authenticated-orcid":false,"given":"Gerard","family":"Anmella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Pacchiarotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Samalin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma","family":"Verdolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Popovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Azorin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jules","family":"Angst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Bowden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-3964","authenticated-orcid":false,"given":"Sergey","family":"Mosolov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2291-6952","authenticated-orcid":false,"given":"Allan H.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Perugi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0548-0053","authenticated-orcid":false,"given":"Eduard","family":"Vieta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6320-4420","authenticated-orcid":false,"given":"Andrea","family":"Murru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,19]]},"reference":[{"key":"922_CR1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association. 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I.P. has received CME-related honoraria, or consulting fees from ADAMED, Janssen-Cilag, and Lundbeck. L.S. has received grants, honoraria, or consulting fees from Janssen-Cilag, Lundbeck, and Otsuka. D.P. has served as a speaker and\/or medical writer for Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen-Cilag, and Ferrer. J.M.A. has received research support and has acted as a consultant and\/or served on a speaker\u2019s bureau for Janssen, Lundbeck, Otsuka, Roche, Servier, and Takeda, and reports no financial or other relationship relevant to the subject of this article. C.L.B. has received grant support from Sunovion and the NIMH, and has consulted for Takeda, and reports no financial or other relationship relevant to the subject of this article. S.M. has received research grants from, and been involved in clinical trials for Servier, Eli Lilly, Lundbeck, AstraZeneca, Janssen-Cilag, Sanofi-Aventis, and Geodon Richter and reports no financial or other relationship relevant to the subject of this article. A.H.Y. is honorary Consultant SLaM (NHS, UK). He provided lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Janssen, Lunbeck, Sunovion, Servier, Livanova, and Janssen. He does not share holdings in pharmaceutical companies. He is Lead Investigator for Embolden Study (AZ), BCI Neuroplasticity study and Aripiprazole Mania Study, he did investigator initiated studies from AZ, Eli Lilly, Lundbeck, Wyeth. Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK);UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK). He reports no financial or other relationship relevant to the subject of this article. G.P. has acted as consultant of Lundbeck, Angelini, FBHealth. He received grant\/research support from Lundbeck and Angelini. He is on the speaker\/advisory board of Sanofi-Aventis, Lundbeck, FBHealth, Angelini, and reports no financial or other relationship relevant to the subject of this article. E.V. has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics,Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the EU Horizon 2020, and the Stanley Medical Research Institute. A.M. has received grants, honoraria, or consulting fees from, Janssen, Lundbeck, and Otsuka.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"241"}}