Mapping schizophrenia progression: cognitive, clinical, and functional trajectories and their prognostic value - a Padua University Hospital follow-up study

Background Schizophrenia is a severe and complex psychiatric disorder characterized by a wide range of symptoms and heterogeneous clinical presentations. The neurodevelopmental hypothesis is the prevailing theory that explains the onset and progression of the disorder. Multiple factors are believed to contribute to this process. Although establishing causative roles remains challenging, individual developmental trajectories illustrate how early insults and deviations can influence later functioning. Particularly, premorbid adjustment and age of onset are believed to influence cognitive functioning and psychopathological symptoms, which in turn affect functional outcomes. Exploring these relationships was the primary aim of this work. Method A preliminary literature review was conducted using PubMed. Subsequently, correlation, structural equation modelling (SEM), principal component analysis (PCA), and Random Forest analyses were performed to examine cognitive (assessed by MCCB MATRICS, CAI and GAF-CogS), clinical (assessed by PANSS and BNSS), and real-life functioning indices (SLOF and UCSD UPSA-B) in individuals with schizophrenia (n = 25), healthy controls (n = 26), and unaffected relatives (n = 8). The study employed a dual design: a cross-sectional comparison between individuals with schizophrenia (SZ), healthy controls (HC), and unaffected relatives (UR), and a longitudinal follow-up involving only the patient group, identifying potential prognostic factors. Results In the cross-sectional study (Study 1), SZ patients showed greater impairment and heterogeneity across cognitive, clinical, and functional domains compared to HC, with UR displaying intermediate profiles. Late adolescence premorbid adjustment (PAS) predicted SZ risk and directly influenced cognition and functional outcomes. Cognition predicted self-care and functional capacity (SLOF), moderated by age of onset for self-care and social functioning but not community functioning. At 4-year follow-up (Study-2), SZ patients improved in social/community functioning, verbal learning (HVLT, MCCB MATRICS), while negative symptoms remained prominent and mediated the impact of cognitive impairment on self-care. PAS correlated with PANSS scores. Patient and informant cognitive ratings largely overlapped, with minor differences in specific domains. Positive symptoms correlated with cognitive and functional measures. Employment status was associated with social cognition and baseline cognition. Functional performance (UCSD UPSA-B) at both time points was primarily predicted by baseline cognitive abilities, with stronger associations emerging at follow-up. Key contributing factors included processing speed, working memory, and global cognitive functioning (MCCB); general and positive symptom severity (PANSS); as well as insight into cognitive deficits (CAI), and informant-rated cognitive functioning (GAF-CogS). Conclusions The findings support a hierarchical neurodevelopmental model of schizophrenia, highlighting the critical roles of premorbid adjustment, cognitive impairment, and symptom severity in functional outcomes. Age of onset moderates these relationships, underscoring the importance of early interventions targeting cognition and negative symptoms. Different assessment methods (performance-based, self-report, and informant-report) yielded varying results, likely reflecting distinct aspects of the same cognitive and functional domains. The complex interplay between cognitive impairment, negative symptoms, and functional outcomes (particularly self-care), points to comprehensive assessment and targeted interventions in schizophrenia management.