From genetics to psychosocial functioning: unraveling the mediating roles of cognitive reserve, cognition, and negative symptoms in first-episode psychosis

Background: Studies have shown associations between polygenic risk scores for educational attainment (PRSEA), cognitive reserve (CR), cognition, negative symptoms (NS), and psychosocial functioning in first-episode psychosis (FEP). However, theirspecific interactions remain unclear. This study aimed to investigate the mediating roles of CR, cognition, and NS in the relationship between PRSEA and psychosocial functioning one year after a FEP. Additionally, we sought to explore the impact of two NSsubtypes on this relationship: diminished Expression (EXP-NS) and Motivation and Pleasure (MAP-NS). Methods: A total of 138 FEP participants, predominantly male (70%), with a mean age of 24.77 years (SD = 5.29), underwent genetic, clinical, and cognitive assessments two months after study enrollment. Functioning evaluation followed at one-year follow-up. To investigate the mediating role of CR, cognition, and NS in the relationship between PRSEA and functioning, a serial mediation model was employed. Two further mediation models were tested to explore the differential impact of EXP-NS and MAP-NS. Mediation analysis was performed using the PROCESS macro version 4.1 within SPSS version 26. Results: The serial mediation model revealed a causal chain for PRSEA > CR > cognition > NS > Functioning (β = −3.08, 95%CI[−5.73, −0.43], p = 0.023). When differentiating by type of NS, only EXP-NS were significantly associated in the casual chain (β = −0.17, 95% CI [−0.39, −0.01], p < 0.05). Conclusions: CR, cognition and NS -specifically EXP-NS- mediate the association between PRSEA and psychosocial functioning at one-year follow-up in FEP patients. These results highlight the potential for personalized interventions based on genetic predisposition.