Highlights
- Glutamate levels in the medial prefrontal cortex (mPFC) are significantly elevated in treatment-naive individuals during their first episode of psychosis (FEP) compared to both healthy controls and patients with chronic schizophrenia.
- In never-medicated chronic schizophrenia patients, glutamate levels do not significantly differ from healthy controls, suggesting that glutamatergic dysregulation may be a transient feature of the early illness phase rather than a persistent trait.
- Higher mPFC glutamate levels in the FEP group are inversely correlated with cognitive performance, specifically in verbal and visual learning domains.
- The findings underscore the necessity of stage-specific clinical trials, particularly for medications targeting the glutamatergic system, such as mGluR2/3 agonists.
Background: The Evolution of the Glutamate Hypothesis
For decades, the pathophysiology of schizophrenia was viewed primarily through the lens of the dopamine hypothesis. However, the persistence of negative symptoms and cognitive deficits despite effective dopaminergic blockade led researchers to explore the glutamatergic system. The glutamate hypothesis suggests that N-methyl-D-aspartate (NMDA) receptor hypofunction on inhibitory interneurons leads to a disinhibition of pyramidal neurons, causing a downstream surge in glutamate release, particularly in the prefrontal cortex.
While neuroimaging studies have frequently reported altered glutamate levels in psychosis, results have been inconsistent. A major confounding factor has been the influence of antipsychotic medication, which is known to modulate glutamatergic signaling. By studying never-medicated individuals across different stages of the illness, researchers can finally isolate the natural progression of glutamatergic alterations without the interference of pharmacological treatment.
Study Design and Methodology
This cross-sectional study, conducted at the Instituto Nacional de Neurología y Neurocirugía in Mexico City, utilized proton magnetic resonance spectroscopy (1H-MRS) to quantify glutamate levels in the mPFC. The study period spanned from November 2017 to July 2025, with data analysis finalized in August 2025.
The researchers recruited 181 individuals, categorized into three distinct groups:
- First-Episode Psychosis (FEP): 65 individuals experiencing their first nonaffective psychotic episode.
- Chronic Schizophrenia: 42 individuals with a long-term diagnosis who remained treatment-naive.
- Healthy Controls: 74 age- and sex-matched individuals with no psychiatric history.
Following rigorous quality control of the spectral data—rejecting participants with excessive movement or poor signal-to-noise ratios—the final analysis included 51 FEP patients, 32 chronic patients, and 60 controls. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive function was evaluated via the MATRICS Consensus Cognitive Battery (MCCB).
Key Findings: The Early Glutamatergic Peak
The primary finding of the study was a statistically significant difference in glutamate levels across the three groups (F2,136 = 7.5; P = .001). Post hoc analysis revealed a specific pattern of elevation that was exclusive to the early phase of the disease.
1. Elevated Glutamate in First-Episode Psychosis
Individuals in the FEP group exhibited significantly higher glutamate levels in the mPFC compared to both the healthy control group (P = .008; Cohen d = 0.83) and the chronic schizophrenia group (P = .003; Cohen d = 0.69). This suggests a “glutamatergic storm” characterizes the onset of psychotic symptoms.
2. Normalization in Chronic, Untreated Schizophrenia
One of the most striking results was that glutamate levels in the chronic schizophrenia group did not differ significantly from healthy controls (P > .99). Because these patients were also never-medicated, this decline from the early-stage peak cannot be attributed to antipsychotic effects. Instead, it suggests a naturalistic shift in the glutamatergic system as the disease progresses, possibly reflecting a transition from an acute excitatory state to a state of chronic neurobiological adaptation or exhaustion.
3. Cognitive Impact
The study found that higher glutamate levels were not benign. In the FEP group, elevated mPFC glutamate was associated with lower scores in verbal learning (ρ = -0.29; P = .04) and visual learning (ρ = -0.29; P = .04). This correlation supports the theory that excessive glutamatergic activity may interfere with the fine-tuned neural plasticity required for memory and learning.
Expert Commentary: Implications for Precision Psychiatry
These findings provide a compelling explanation for the mixed results seen in previous clinical trials of glutamatergic agents. For instance, trials involving mGluR2/3 agonists—which inhibit glutamate release—have shown promise in some phases but failed to meet primary endpoints in others. If glutamatergic elevation is only present during the first episode, administering these drugs to chronic patients (who may have normal or even low glutamate levels) would logically yield poor results.
The data suggests that 1H-MRS could serve as a vital biomarker for patient stratification. Clinicians could potentially use imaging to identify “high-glutamate” candidates who are most likely to benefit from glutamate-modulating therapies. Furthermore, the association between glutamate levels and cognitive decline in the FEP group suggests that early intervention to normalize glutamate might not only treat psychotic symptoms but also preserve cognitive function, which is a major determinant of long-term functional recovery.
However, the study is not without limitations. The cross-sectional design prevents a definitive conclusion about individual trajectories; a longitudinal study following the same patients from FEP to chronic stages would be necessary to confirm the decline in glutamate levels over time. Additionally, the focus on the mPFC does not rule out different glutamatergic patterns in other brain regions, such as the thalamus or basal ganglia.
Conclusion
The study by Rivera-Chávez and colleagues provides critical evidence that the glutamatergic pathology of schizophrenia is dynamic and stage-dependent. The finding that mPFC glutamate is only elevated in the early, never-medicated stages of psychosis offers a clear target for early intervention strategies. It calls for a paradigm shift in drug development: moving away from a “one-size-fits-all” approach toward a precision medicine model that accounts for the illness phase and individual neurochemical profiles. Future research should focus on whether early pharmacological normalization of glutamate can prevent the transition to the cognitive and functional deficits seen in chronic schizophrenia.
References
1. Rivera-Chávez LF, González-Sangabriel D, González-Manríquez L, et al. Glutamate Levels in Medial Prefrontal Cortex According to Illness Phase of Never-Medicated Individuals With Psychosis. JAMA Psychiatry. 2026; doi:10.1001/jamapsychiatry.2025.4091.
2. Hu W, MacDonald ML, Elswick DE, Sweet RA. The glutamate hypothesis of schizophrenia: evidence from human genetic studies. Fitoterapia. 2015;103:266-273.
3. Merritt K, Egerton A, Kempton MJ, Taylor MJ, McGuire PK. Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies. JAMA Psychiatry. 2016;73(7):665-674.
