Peripheral NMDAR subunits as predictors of working memory improvement in schizophrenia

Cognitive dysfunction is a defining characteristic impairing social functioning in schizophrenia (SZ). N-methyl-D-aspartate receptor (NMDAR) hypofunction may underlie these impairments. This study explored the association between peripheral blood levels of the NMDAR subunits NR1 and NR2 and cognitive improvement in SZ, evaluating their potential as biomarkers for the efficacy of cognitive intervention. This secondary analysis of a randomized controlled trial included 60 clinically stable SZ patients and 30 healthy controls (HCs). Patients received five-day transcranial direct current stimulation (tDCS) during cognitive tasks across three groups: the active dorsolateral prefrontal cortex (DLPFC), the active posterior parietal cortex (PPC), and the sham stimulation group. Cognition was evaluated, and blood samples were collected at baseline, week 1, and week 2. Baseline blood samples were also obtained from HCs. NR1 and NR2 concentrations were quantified using enzyme-linked immunosorbent assay (ELISA). We found that baseline NR1 concentration was significantly lower in the patient group than in HCs, with no NR2 differences observed. Compared to the other two groups, the active PPC group demonstrated significant working memory improvements. In the active PPC group, baseline NR1 and NR2 concentrations were negatively correlated with working memory improvements at week 1. Moreover, changes in NR1 at weeks 1 and 2, and NR2 at week 1, were positively associated with working memory improvements at week 1 in the active PPC group. Peripheral NR1 and NR2 levels may serve as biomarkers for predicting cognitive improvement in SZ, supporting the role of NMDAR dysfunction in SZ-related cognitive deficits.