Glutamate and Oxidative Stress: A novel approach to pathophysiology in schizophrenia

It is well accepted that a combination of genetic and environmental factors is implicated in the risk of psychosis, but the complex interplay between these two etiologies remains incompletely understood. Oxidative stress has been suggested as the pathophysiologic point of convergence bridging “nature and nurture” pathways and the risk of schizophrenia. During a scientific symposium titled ‘Redox, glutamate and oxidative stress in the pathogenesis of psychiatric disorders: From genetic to novel drug target,’ Prof Kim Do from Lausanne University in Switzerland discussed the effects of dysregulated redox pathways on parvalbumin interneurons in the prefrontal cortex and genetic susceptibility to schizophrenia. She also discussed two recently identified novel brain biomarkers that are paving the way towards precision psychiatry.

Oxidative stress is a ‘central hub’ for schizophrenia pathophysiology

Functional impairments in cortical parvalbumin interneurons (PVI) have been a consistent observation in preclinical studies investigating the pathophysiology of schizophrenia.1 More recently, oxidative stress has been shown to be a common pathway in which both genetic and environmental stimuli can lead to PVI impairment via the generation of damaging reactive oxygen species.


Reverse translational approach: From mechanistic pathways to generic risk scores

Whereas most genetic studies use a genome-wide association approach to derive mechanistic hypotheses, Prof Do and colleagues used a reverse translational approach to examine the genetic susceptibility associated with redox pathways involved in psychosis. They identified relevant genes, variants and regulatory elements involved in redox pathways, then looked for single nucleotide polymorphism (SNP) and identified expression quantitative gene loci (eQTLs) in each pathway to derive a polygenic risk score (PRS) associated with early psychosis.

Oxidative stress and neuroinflammation drive gene-environment interactions

The next step was to validate the PRS score in patients with early psychosis. Two patient cohorts were analyzed, the Treatment and early Intervention Psychosis Program (TIPP) cohort in Lausanne, which includes 208 early psychosis patients and 132 matched controls, and the Cantabria Program of First Episodes of Psychosis (PAFIP) cohort in Spain, which consists of 224 early psychosis patients and 128 matched controls. These cohorts demonstrated that there was a strong enrichment for oxidative stress and neuroinflammation pathways in patients with early psychosis relative to healthy controls.


Biomarkers of mitochondrial dysfunction in schizophrenia

Increased oxidative stress was associated with upregulation of two mitochondrial biomarkers

Prof Do then discussed recent research investigating mitochondrial damage in schizophrenia. Functionally impaired PVIs have an increased firing rate that contributes to the neural dys-synchrony and disrupted cognitive-behavioral processes that are frequently observed in patients with schizophrenia.1 Defective PVIs have high mitochondrial content to fuel the metabolic demands of this increased activity, which could render them to be more susceptible to oxidative stress. Using a murine model of redox vulnerability, increased oxidative stress was associated with upregulation of miR-137 and reduction in COX6A2, two biomarkers of mitochondrial dysfunction that can be measured in the blood.

Biomarkers could be used to select the right intervention for the right patient at the right time, rather than applying a conventional “one size fits all” approach

Prof Do and colleagues then used brain-derived exosomes from patients with early psychosis to translate these preclinical observations to humans. Using partition analysis, they found that miR-137 and COX6A2 were highly accurate for identifying a population of patients with early psychosis at high risk of mitochondrial damage. Correlational analysis showed that these biomarkers were associated with worse cognition, socio-functional outcomes and psychopathology.

Prof Do posited that exosomal miR-137 and COX6A2 could be used as biomarkers to identify a subgroup of patients with early psychosis who could benefit from mitochondrial targeted antioxidant treatment. She concluded that this work represents a promising step towards precision medicine in psychiatry, where biomarkers could be used to select the right intervention for the right patient at the right time, rather than applying a conventional “one size fits all” approach to medicine.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

  1. Khadimallah, et al. Mol Psychiatry 2021; 27(2): 1192-1204.
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