# Molecular Mechanisms and Biomarkers for Disease Progression from Prodrome to Early Psychosis

> **NIH NIH R01** · MCLEAN HOSPITAL · 2022 · $496,117

## Abstract

Project Summary
Despite its public health impact and a century of biological research, the pathophysiology of Schizophrenia
(SZ) remains poorly understood. One major barrier is the lack of validated and biologically relevant in vivo
measures reflecting SZ progression. Accumulating evidence suggests that a central “immuno-oxidative”
pathway involving redox dysregulation, oxidative stress, and NMDA receptor hypofunction, may play a key role
in the emergence of neuronal dysfunction and information processing abnormalities characteristic of the
disorder. The redox state, reflected by the balance between oxidized NAD+ and reduced NADH, is a key
parameter in biological systems indicating the system's ability to carry out energy production; the redox ratio
(RR=NAD+/NADH) is thus intimately linked to ATP synthesis processes. The RR is particularly important in the
human brain, our most metabolically active organ whose fragile balance of oxidation-reduction is easily
disrupted. During intensive energy metabolism, toxic reactive oxygen species are formed; these are eliminated
by the antioxidant glutathione (GSH), a critical molecule in resisting oxidative stress. In addition, strong
bidirectional influences exist between redox balance and energy metabolism on the one hand and
glutamatergic transmission and NMDA receptor function on the other. Thus, the widely-reported abnormalities
in glutamatergic function in SZ may be related to abnormal redox balance and bioenergetics. In this proposal,
we implement recently developed Magnetic Resonance Spectroscopy (MRS) techniques to measure RR,
GSH, and glutamate/glutamine levels in the same brain regions in the same scan, providing convergent
evidence on redox dysregulation and glutamatergic function simultaneously in SZ. The current literature
suggests that these abnormalities are critical in the early phases of SZ but it is not known how they evolve and
influence one another over time. To address this key issue, we will recruit a cohort of individuals at clinical
high risk (CHR) and another experiencing a first episode (FE) of psychosis and follow both groups over a 2-
year period. Because rate of conversion to frank psychosis is low in CHR groups, we will examine community
outcomes in this group as well as conversion. We will also compare findings in this group with those from FE
where all individuals have developed frank psychosis. This will allow us to observe unfolding abnormalities at
critical stages of the emergence of SZ. We aim to outline the trajectories of biological development in early
phases of psychotic disorders and to identify a sensitive predictor for the prodrome and transition to psychosis.
The identification of a biomarker associated with CHR which could predict subsequent dysfunction would be a
major boost to the development of early intervention and prevention strategies as well as to measuring the
impact of early intervention. This proposal uses innovative MRS approaches to ask mechanistic q...

## Key facts

- **NIH application ID:** 10312102
- **Project number:** 5R01MH114982-04
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** FEI DU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $496,117
- **Award type:** 5
- **Project period:** 2019-02-18 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312102

## Citation

> US National Institutes of Health, RePORTER application 10312102, Molecular Mechanisms and Biomarkers for Disease Progression from Prodrome to Early Psychosis (5R01MH114982-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10312102. Licensed CC0.

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