Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

A growing body of evidence has emerged demonstrating a pathological link between oxidative stress and schizophrenia. This evidence identifies oxidative stress as a convergence point or central hub for schizophrenia genetic and environmental risk factors. Here we review the existing experimental and translational research pinpointing the complex dynamics of oxidative stress mechanisms and their modulation in relation to schizophrenia pathophysiology. We focus on evidence supporting the crucial role of either redox dysregulation, N-methyl-D-aspartate receptor hypofunction, neuroinflammation or mitochondria bioenergetics dysfunction, initiating vicious circles centered on oxidative stress during neurodevelopment. These processes would amplify one another in positive feed-forward loops, leading to persistent impairments of the maturation and function of local parvalbumin-GABAergic neurons microcircuits and myelinated fibers of long-range macrocircuitry. This is at the basis of neural circuit synchronization impairments and cognitive, emotional, social and sensory deficits characteristic of schizophrenia. Potential therapeutic approaches that aim at breaking these different vicious circles represent promising strategies for timely and safe interventions. In order to improve early detection and increase the signal-to-noise ratio for adjunctive trials of antioxidant, anti-inflammatory and NMDAR modulator drugs, a reverse translation of validated circuitry approach is needed. The above presented processes allow to identify mechanism based biomarkers guiding stratification of homogenous patients groups and target engagement required for successful clinical trials, paving the way towards precision medicine in psychiatry.

Automated summary

There is a pathological link between oxidative stress and schizophrenia, with oxidative stress playing a central role in the impairment of neural circuits and subsequent cognitive, emotional, social, and sensory deficits characteristic of the disorder. Redox dysregulation, NMDA receptor hypofunction, neuroinflammation, and mitochondria dysfunction exacerbate this damage, creating a vicious cycle that leads to persistent impairments in neural circuit synchronization. Therapeutic approaches targeting these cycles show promise for interventions, and a reverse translation of circuitry approaches is needed for improved early detection and successful clinical trials in precision medicine for psychiatry.