Psychosis brain subtypes validated in first-episode cohorts and related to illness remission: results from the PHENOM consortium

Dominic B. Dwyer, Ganesh B. Chand, Alessandro Pigoni, Adyasha Khuntia, Junhao Wen, Mathilde Antoniades, Gyujoon Hwang, Guray Erus, Jimit Doshi, Dhivya Srinivasan, Erdem Varol, Rene S. Kahn, Hugo G. Schnack, Eva Meisenzahl, Stephen J. Wood, Chuanjun Zhuo, Aristeidis Sotiras, Russell T. Shinohara, Haochang Shou, Yong FanMaristela Schaulfelberger, Pedro Rosa, Paris A. Lalousis, Rachel Upthegrove, Antonia N. Kaczkurkin, Tyler M. Moore, Barnaby Nelson, Raquel E. Gur, Ruben C. Gur, Marylyn D. Ritchie, Theodore D. Satterthwaite, Robin M. Murray, Marta Di Forti, Simone Ciufolini, Marcus V. Zanetti, Daniel H. Wolf, Christos Pantelis, Benedicto Crespo-Facorro, Geraldo F. Busatto, Christos Davatzikos, Nikolaos Koutsouleris, Paola Dazzan

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Using machine learning, we recently decomposed the neuroanatomical heterogeneity of established schizophrenia to discover two volumetric subgroups—a ‘lower brain volume’ subgroup (SG1) and an ‘higher striatal volume’ subgroup (SG2) with otherwise normal brain structure. In this study, we investigated whether the MRI signatures of these subgroups were also already present at the time of the first-episode of psychosis (FEP) and whether they were related to clinical presentation and clinical remission over 1-, 3-, and 5-years. We included 572 FEP and 424 healthy controls (HC) from 4 sites (Sao Paulo, Santander, London, Melbourne) of the PHENOM consortium. Our prior MRI subgrouping models (671 participants; USA, Germany, and China) were applied to both FEP and HC. Participants were assigned into 1 of 4 categories: subgroup 1 (SG1), subgroup 2 (SG2), no subgroup membership (‘None’), and mixed SG1 + SG2 subgroups (‘Mixed’). Voxel-wise analyses characterized SG1 and SG2 subgroups. Supervised machine learning analyses characterized baseline and remission signatures related to SG1 and SG2 membership. The two dominant patterns of ‘lower brain volume’ in SG1 and ‘higher striatal volume’ (with otherwise normal neuromorphology) in SG2 were identified already at the first episode of psychosis. SG1 had a significantly higher proportion of FEP (32%) vs. HC (19%) than SG2 (FEP, 21%; HC, 23%). Clinical multivariate signatures separated the SG1 and SG2 subgroups (balanced accuracy = 64%; p < 0.0001), with SG2 showing higher education but also greater positive psychosis symptoms at first presentation, and an association with symptom remission at 1-year, 5-year, and when timepoints were combined. Neuromorphological subtypes of schizophrenia are already evident at illness onset, separated by distinct clinical presentations, and differentially associated with subsequent remission. These results suggest that the subgroups may be underlying risk phenotypes that could be targeted in future treatment trials and are critical to consider when interpreting neuroimaging literature.

Original languageEnglish
Pages (from-to)2008-2017
Number of pages10
JournalMolecular Psychiatry
Issue number5
StatePublished - May 2023


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