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. 2025 May;151(5):600-612.
doi: 10.1111/acps.13779. Epub 2024 Dec 25.

From Genetics to Psychosocial Functioning: Unraveling the Mediating Roles of Cognitive Reserve, Cognition, and Negative Symptoms in First-Episode Psychosis

M Florencia Forte  1   2   3   4 , Derek Clougher  1   2   4 , Àlex G Segura  1   2 , Gisela Mezquida  2   3   4   5 , Ana Maria Sánchez-Torres  6 , Eduard Vieta  1   2   4 , Marina Garriga  1   2   3   4 , Antonio Lobo  4   7 , Ana M González-Pinto  4   8   9 , Covadonga M Diaz-Caneja  4   10 , Alexandra Roldan  4   11 , Anabel Martínez-Arán  1   2   4 , Elena de la Serna  4   12 , Anna Mané  4   13 , Sergi Mas  2   3   14 , Carla Torrent  1   2   4 , Kelly Allott  15 , Miquel Bernardo  2   3   4 , Silvia Amoretti  1   3   4   16 ; PEPs Group
Collaborators, Affiliations

From Genetics to Psychosocial Functioning: Unraveling the Mediating Roles of Cognitive Reserve, Cognition, and Negative Symptoms in First-Episode Psychosis

M Florencia Forte et al. Acta Psychiatr Scand. 2025 May.

Abstract

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, their specific 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 NS subtypes 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.

Keywords: cognition; cognitive reserve; first‐episode psychosis; functioning; negative symptoms; polygenic risk score.

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Conflict of interest statement

E. Vieta has received grants and served as consultant, advisor or CME speaker for the following entities (unrelated to the present work): AB‐Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi‐Aventis, and Takeda. M. Garriga has received support from Ferrer, Janssen and Lundbeck. G. Mezquida has received support from Boehringer Ingelheim. Dr. Gonzalez‐Pinto has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen‐Cilag, Lundbeck, Otsuka, Alter, Angelini, Novartis, Rovi, Takeda, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, and the European Framework Program of Research. Dr. R. Rodriguez‐Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de InvestigaciónBiomédicaen Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/ BMD‐2422 AGES; S2017/BMD‐3740; S2022/BMD‐7216), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen‐Recordati, Angelini, Rovi. MPGP has been a consultant to and/or has received honoraria/grants from Angelini, Alianza Otsuka‐Lundbeck, Instituto de Salud Carlos III, Janssen‐Cilag, Lundbeck, Otsuka, and Pfizer. FDS has received grants from the Spanish Foundation of Psychiatry and Mental Health and the European Psychiatric Association. C. Diaz‐Caneja has received funding from Instituto de Salud Carlos III (PI17/00481, PI20/00721, PI23/00625) and the European Union (Grant No. 101057182, project Youth‐GEMs) and honoraria or travel support to attend conferences from Angelini, Janssen, and Viatris. R. Rodriguez‐Jimenez has received funding from Madrid Regional Government (S2022/BMD‐7216). A. Roldán has served as advisor or speaker for the companies Otsuka, Rovi, Angelini and Casen Recordati (unrelated to the present work). A. Mané has received financial support to attend meetings, travel support, and served as a speaker/advisory board from Otsuka, Lundbeck, Angelini, Neuraxpharm and Janssen Cilag. The rest of the authors report no biomedical financial interests or potential conflicts of interest.

Figures

FIGURE 1
FIGURE 1
The serial mediating effect of cognitive reserve, cognition and negative symptoms in the relationship between PRSEA and functioning. All presented effects are standardized. C′ is the unstandardized direct effect coefficient of PRSEA on functionality. *p < 0.05, **p < 0.01, ***p < 0.001. Grey lines represent path with significant indirect effect. Continuous lines denoted significant regression. Abbreviations: CR = Cognitive Reserve; NS=Negative Symptoms; PRSEA = Polygenic risk score for educational attainment.
FIGURE 2
FIGURE 2
The serial mediating effect of cognitive reserve, cognition and negative symptoms (EXP‐NS and MAP‐NS) in the relationship between PRSEA and functioning. All presented effects are standardized. C′ is the unstandardized direct effect coefficient of PRSEA on functionality. *p < 0.05, **p < 0.01, ***p < 0.001. Grey lines represent path with significant indirect effect. Continuous lines denoted significant regression. Abbreviations: CR = Cognitive Reserve; PRSEA = Polygenic risk score for educational attainment.
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