Exposotypes in psychotic disorders.

Psychiatry lags in adopting etiological approaches to diagnosis, prognosis, and outcome prediction compared to the rest of medicine. Etiological factors such as childhood trauma (CHT), substance use (SU), and socioeconomic status (SES) significantly affect psychotic disorder symptoms. This study applied an agnostic clustering approach to identify exposome clusters "Exposotypes (ETs)" and examine their relationship with clinical, cognitive, and functional outcomes. Using data from individuals with psychotic disorders (n = 1,350), and controls (n = 623), we assessed the relationship between the exposotypes and outcomes. Four exposotypes were identified: ET1 characterized by high CHT and SU; ET2, high CHT; ET3, high SU; ET4, low exposure. Compared to ET4, ET1 demonstrated higher positive and general symptoms, anxiety, depression, impulsivity, and mania; ET2 had higher anxiety, depression, and impulsivity; ET3 had better cognitive and functional outcomes with lower negative symptoms. Intracranial volume was largest in ET3, and smallest in ET2. No group differences in schizophrenia polygenic risk scores were found. The age of onset was 5 years earlier in ET1 than in ET4. These findings provide insight into the complex etiological interplay between trauma, and SU, as well as their unique effects on clinical symptoms, cognition, neurobiology, genetic risk, and functioning.