Objective: Understanding the neurobiology of cognitive dysfunction in psychotic disorders remains elusive, as does developing effective interventions. Limited knowledge about the biological heterogeneity of cognitive dysfunction hinders progress. This study aimed to identify subgroups of patients with psychosis with distinct patterns of functional brain alterations related to cognition (cognitive biotypes). Methods: B-SNIP consortium data (2,270 participants including participants with psychotic disorders, relatives, and controls) was analyzed. Researchers used reference-informed independent component analysis and the NeuroMark 100k multi-scale intrinsic connectivity networks (ICN) template to obtain subject-specific ICNs and whole-brain functional network connectivity (FNC). FNC features associated with cognitive performance were identified through multivariate joint analysis. K-means clustering identified subgroups of patients based on these features in a discovery set. Subgroups were further evaluated in a replication set and in relatives. Results: Two biotypes with different functional brain alteration patterns were identified. Biotype 1 exhibited brain-wide alterations, involving hypoconnectivity in cerebellar-subcortical and somatomotor-visual networks and worse cognitive performance. Biotype 2 exhibited hyperconnectivity in somatomotor-subcortical networks and hypoconnectivity in somatomotor-high cognitive processing networks, and better preserved cognitive performance. Demographic, clinical, cognitive, and FNC characteristics of biotypes were consistent in discovery and replication sets, and in relatives. 70.12% of relatives belonged to the same biotype as their affected family members. Conclusions: These findings suggest two distinctive psychosis-related cognitive biotypes with differing functional brain patterns shared with their relatives. Patient stratification based on these biotypes instead of traditional diagnosis may help to optimize future research and clinical trials addressing cognitive dysfunction in psychotic disorders.

PAC has received travel support from Neuraxpharm and ROVI. CDC has received honoraria or travel support from Angelini and Janssen. JC, RB, VC, and AI report no financial relationships with commercial interests.

PAC has received grant support from Programa Intramural de Impulso a la I+D+i 2023 (Instituto de Investigacion Sanitaria Gregorio Maranon). CDC has received grant support from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (PI20/00721, JR19/00024) and the European Commission (grant 101057182, project Youth-GEMs). VC has received grant support from the National Institutes of Health (R01MH123610). AI has received grant support from the National Institutes of Health (R01MH123610).

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The storage and management of the data and access procedures are overseen by the National Institute of Mental Health (NIMH) through the National Data Archive (NDA). The Institutional Review Board approved the project at each participating institution: Athens, GA (University of Georgia, B-SNIP2 only); Baltimore, MD (University of Maryland School of Medicine, B-SNIP1 only); Boston, MA (Harvard Medical School), Chicago IL (University of Illinois-Chicago for B-SNIP1 and University of Chicago for B-SNIP2); Dallas, TX (University of Texas Southwestern Medical Center), Detroit MI (Wayne State University, B-SNIP1 only); and Hartford, CT (Yale University School of Medicine).

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The storage and management of the data and access procedures are overseen by the National Institute of Mental Health (NIMH) through the National Data Archive (NDA).

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