In a groundbreaking study shedding new light on the biochemical underpinnings of psychosis, researchers have identified serum concentrations of NR1 and NR2 subunits as potential biomarkers for early detection of schizophrenia and individuals at clinical high risk (CHR) for psychosis. Published in the prestigious journal BMC Psychiatry, this research opens promising avenues for objective diagnosis and cognitive assessment in psychiatric practice, an area historically challenged by subjective symptom evaluation.
Schizophrenia and psychotic disorders have long baffled clinicians and neuroscientists alike, partly due to the elusive nature of their biomarkers. Traditional diagnosis heavily relies on clinical interviews and symptomatic ratings, which often delay intervention until the disease has significantly progressed. The novel approach presented in this study leverages circulating levels of NR1 and NR2 receptor subunits, components of the N-methyl-D-aspartate receptor (NMDAR) complex that play critical roles in synaptic transmission and plasticity in the central nervous system.
The researchers employed a cross-sectional design incorporating three distinct cohorts: individuals experiencing their first episode of schizophrenia (FES), those identified as clinical high risk (CHR) for psychosis, and healthy controls (HC). Blood samples were analyzed using enzyme-linked immunosorbent assay (ELISA) to quantify serum NR1 and NR2 concentrations. Cognitive performance was concurrently assessed through the MATRICS Consensus Cognitive Battery (MCCB), a standardized tool evaluating multiple cognitive domains affected in schizophrenia.
Statistical analyses revealed significant differences in serum NR1 levels across all three groups. Strikingly, patients with first-episode schizophrenia exhibited markedly distinct NR1 concentrations compared to both high-risk individuals and healthy controls, suggesting an elevated or dysregulated expression correlating with disease onset. This delineation highlights the potential of NR1 as a discriminator between active psychosis and prodromal states or unaffected individuals.
Meanwhile, serum NR2 levels displayed a notable difference between the CHR and healthy groups, pinpointing NR2 as a sensitive marker potentially reflective of the transitional phase toward psychosis. This finding is particularly relevant as identifying at-risk populations before full-blown clinical symptoms manifest remains a critical challenge in psychiatric medicine. The stability of NR2 concentrations supports its viability as a biomarker in longitudinal monitoring and early intervention strategies.
Delving deeper, the study uncovers intriguing correlations between these biomarkers and cognitive functioning. Within the schizophrenia cohort, elevated NR1 levels were inversely correlated with speed of processing, an essential cognitive domain affecting daily functioning. Similarly, NR2 concentrations negatively correlated with verbal learning abilities, further corroborating the role of NMDAR subunits in cognitive deficits characteristic of schizophrenia.
Conversely, among those at clinical high risk, higher serum NR1 concentrations were positively linked to overall cognitive performance as gauged by the MCCB total score. This paradoxical association may hint at compensatory neurobiological mechanisms or differential receptor regulation during the prodromal phase. Such nuanced insights could pave the way for targeted cognitive therapies tailored to biomarker profiles.
To evaluate the diagnostic utility of these findings, receiver operating characteristic (ROC) curve analyses were conducted. Serum NR2 emerged as a superior discriminator for both FES and CHR groups, boasting area under the curve (AUC) values of 69% and 74%, respectively, coupled with high specificity (85%) albeit moderate sensitivity. Optimal cutoff values for NR2 concentration were established around 32.8 ng/mL, offering a quantifiable threshold for clinical application.
These findings collectively signify a paradigm shift towards objective biochemical markers in psychiatry, transcending traditional symptom-based frameworks. The use of peripheral blood measurements ensures minimally invasive procedures, enhancing practical feasibility in clinical settings. Furthermore, the dual correlation with cognitive domains underscores the functional relevance of these biomarkers beyond mere diagnostic categorization.
Despite the promising implications, the authors emphasize the necessity for larger-scale studies and longitudinal designs to validate these preliminary findings fully. Variabilities in sample size, demographic factors, and assay methodologies warrant cautious interpretation. Additionally, mechanistic investigations exploring the pathophysiological pathways linking NR1 and NR2 alterations to psychotic pathology remain imperative.
Integrating serum NR1 and NR2 concentrations into routine psychiatric evaluation holds transformative potential. Early identification of high-risk individuals could facilitate timely interventions, potentially altering disease trajectories and improving long-term outcomes. Moreover, individualized treatment paradigms based on biomarker profiles may optimize therapeutic efficacy while minimizing side effects.
As neuroscience continues to unravel the molecular intricacies of psychosis, studies like this reinforce the hopeful vision of precision psychiatry. Bridging molecular biomarkers with cognitive phenotypes equips clinicians with powerful tools for diagnosis, prognosis, and personalized care. This research constitutes a significant step toward demystifying the biochemical landscape of schizophrenia and psychosis risk, fostering advancements that may ultimately alleviate the global burden of these debilitating disorders.
In conclusion, serum concentrations of NR1 and NR2 subunits represent promising biomolecular candidates for distinguishing first-episode schizophrenia and clinical high-risk states from healthy individuals. Their correlations with cognitive impairments further validate their clinical relevance, while the relative stability and diagnostic accuracy of NR2 highlight its biomarker potential. While additional research is essential to cement their clinical utility, these findings herald a new era in biomarker-driven psychiatric assessment.
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Subject of Research: Identification and validation of serum NR1 and NR2 subunits as biomarkers for first-episode schizophrenia and clinical high risk for psychosis, including their relationship with cognitive functions.
Article Title: Serum NR1 and NR2 concentrations in first-episode schizophrenia and clinical high-risk for psychosis
Article References:
Mao, Z., Li, F., Ge, L. et al. Serum NR1 and NR2 concentrations in first-episode schizophrenia and clinical high-risk for psychosis. BMC Psychiatry 25, 493 (2025). https://doi.org/10.1186/s12888-025-06950-w
Image Credits: AI Generated
DOI: https://doi.org/10.1186/s12888-025-06950-w
