Glutamate Levels in Medial Prefrontal Cortex According to Illness Phase of Never-Medicated Individuals With Psychosis

Evidence suggests that elevated glutamate levels in the medial prefrontal cortex may be associated with the illness stage, but little is known about whether these effects occur in the absence of antipsychotic treatment.

To evaluate differences in glutamate levels in treatment-naive individuals with psychosis on the schizophrenia spectrum at different stages of the illness.

This cross-sectional study uses proton magnetic resonance spectroscopy in the medial prefrontal cortex of individuals experiencing their first episode of nonaffective psychosis, individuals with chronic schizophrenia, and matched controls at inpatient and outpatient services of the Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico, from November 2017 to July 2025. Data were analyzed from January 28, 2025, to August 8, 2025.

Proton magnetic resonance spectroscopy.

The primary outcome was glutamate levels and scores measured on the Positive and Negative Syndrome Scale for Schizophrenia and the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery.

This cross-sectional study included a total of 181 individuals (65 with first-episode psychosis [FEP], 42 with chronic schizophrenia, and 74 age- and sex-matched healthy controls). Data from 38 participants (14 with FEP, 10 with schizophrenia, and 14 controls) were rejected from all analyses due to excessive movement or poor spectral quality, leaving 83 participants and 60 controls. The mean (SD) age was 25.9 (7.2) years for individuals with FEP, 38.0 (14.5) years for those with chronic schizophrenia, and 30.4 (11.5) years for controls. Sex distribution did not differ (34 male individuals with FEP [67.0%]; 20 male individuals with chronic schizophrenia [62.5%]; and 33 male controls [55.0%]; P = .44). Glutamate levels differed among the 3 groups (F2,136 = 7.5; P = .001). Post hoc pairwise comparisons revealed higher glutamate levels in the FEP group compared with both the chronic schizophrenia group (P = .003; Cohen d = 0.69) and the control group (P = .008; Cohen d = 0.83). There were no significant differences in glutamate levels between the chronic schizophrenia group and the control group (P > .99). Higher glutamate levels were associated with lower verbal (ρ = -0.29; P = .04) and visual learning scores (ρ = -0.29; P = .04) in the FEP group.

These findings suggest that the differences in glutamate levels may indicate that these alterations occur primarily in the early stages of the disease. The results of this study have implications for resuming clinical trials with targeted metabotropic glutamate receptor 2/3 agonists, taking into account both the disease phase and the glutamatergic alterations measured by magnetic resonance imaging.