Abstract
BACKGROUND AND HYPOTHESIS: The brain age gap (BAG) quantifies the difference between predicted brain age and chronological age. Prior research implicates higher BAG in psychotic disorders, suggesting accelerated brain aging. We hypothesized distinct brain aging profiles among biological subtypes of psychosis and intermediate BAG in their relatives. STUDY DESIGN: Brain age gap values were quantified in 348 healthy controls (HCs), 950 psychosis probands classified by both DSM diagnoses of psychotic bipolar disorder, type I (BP, n = 247), schizoaffective disorder (SAD, n = 313), and schizophrenia (SZ, n = 390), and Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Biotypes (301 Biotype 1, 304 Biotype 2, and 345 Biotype 3), and 491 of their non-psychotic first-degree relatives. We calculated brain age values from structural T1-weighted images using the pre-trained, open-source brain age package, brainageR. In probands, we assessed associations between BAG and clinical characteristics, comorbid disorders, medications, and polygenic risk scores for SZ (PRS-SZ). STUDY RESULTS: All DSM diagnosis and Biotype groups had higher BAG than HC. While no significant differences were observed between BP, SAD, or SZ, Biotypes 1 and 2 had significantly higher BAG compared to Biotype 3. Relatives exhibited intermediate BAG values between HC and probands, with the highest BAG in relatives of those with SAD. Brain age gap was not linked to comorbid disorders or PRS-SZ, but was associated with symptom severity, cognition, functioning, and psychotropic medication use. CONCLUSIONS: Bipolar-Schizophrenia Network for Intermediate Phenotypes Biotypes better captured age-related brain structural differences in psychosis than DSM diagnoses. Associations between BAG and medication underscore the potential influence of pharmacotherapy on brain aging in psychosis.