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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.

Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients' blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients' group with mitochondrial dysfunction "Psy-D", having high miR-137 and low COX6A2 levels in exosomes, and (b) a "Psy-ND" subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials.

Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.

Processing speed (PS) impairment is one of the most severe and common cognitive deficits in schizophrenia. Previous studies have reported correlations between PS and white matter diffusion properties, including fractional anisotropy (FA), in several fiber bundles in schizophrenia, suggesting that white matter alterations could underpin decreased PS. In schizophrenia, white matter alterations are most prevalent within inter-hub connections of the rich club. However, the spatial and topological characteristics of this association between PS and FA have not been investigated in patients. In this context, we tested whether structural connections comprising the rich club network would underlie PS impairment in 298 patients with schizophrenia or schizoaffective disorder and 190 healthy controls from the Australian Schizophrenia Research Bank. PS, measured using the digit symbol coding task, was largely (Cohen's d = 1.33) and significantly (P < .001) reduced in the patient group when compared with healthy controls. Significant associations between PS and FA were widespread in the patient group, involving all cerebral lobes. FA was not associated with other cognitive measures of phonological fluency and verbal working memory in patients, suggesting specificity to PS. A topological analysis revealed that despite being spatially widespread, associations between PS and FA were over-represented among connections forming the rich club network. These findings highlight the need to consider brain network topology when investigating high-order cognitive functions that may be spatially distributed among several brain regions. They also reinforce the evidence that brain hubs and their interconnections may be particularly vulnerable parts of the brain in schizophrenia.

Early intervention in psychosis is crucial to improving patient response to treatment and the functional deficits that critically affect their long-term quality of life. Stratification tools are needed to personalize functional deficit prevention strategies at an early stage. In the present study, we applied topological tools to analyze symptoms of early psychosis patients, and detected a clear stratification of the cohort into three groups. One of the groups had a significantly better psychosocial outcome than the others after a 3-year clinical follow-up. This group was characterized by a metabolic profile indicative of an activated antioxidant response, while that of the groups with poorer outcome was indicative of oxidative stress. We replicated in a second cohort the finding that the three distinct clinical profiles at baseline were associated with distinct outcomes at follow-up, thus validating the predictive value of this new stratification. This approach could assist in personalizing treatment strategies.

Early intervention in psychosis is crucial to improving patient response to treatment and the functional deficits that critically affect their long-term quality of life. Stratification tools are needed to personalize functional deficit prevention strategies at an early stage. In the present study, we applied topological tools to analyze symptoms of early psychosis patients, and detected a clear stratification of the cohort into three groups. One of the groups had a significantly better psychosocial outcome than the others after a 3-year clinical follow-up. This group was characterized by a metabolic profile indicative of an activated antioxidant response, while that of the groups with poorer outcome was indicative of oxidative stress. We replicated in a second cohort the finding that the three distinct clinical profiles at baseline were associated with distinct outcomes at follow-up, thus validating the predictive value of this new stratification. This approach could assist in personalizing treatment strategies., QC 20201230

Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress "hub" affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258-70); (Nat Rev Neurosci. 2016;17:125-34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm-/-), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721-8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to pr

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Exposure to childhood trauma (CT) increases the risk for psychosis and affects the development of brain structures, possibly through oxidative stress. As oxidative stress is also linked to psychosis, it may interact with CT, leading to a more severe clinical phenotype. In 133 patients with early psychosis (EPP), we explored the relationships between CT and hippocampal, amygdala, and intracranial volume (ICV); blood antioxidant defenses [glutathione peroxidase (GPx) and thioredoxin/peroxiredoxin (Trx/Prx)]; psychopathological results; and neuropsychological results. Nonadjusted hippocampal volume correlated negatively with GPx activity in patients with CT, but not in patients without CT. In patients with CT with high GPx activity (high-GPx+CT), hippocampal volume was decreased compared with that in patients with low-GPx+CT and patients without CT, who had similar hippocampal volumes. Patients with high-GPx+CT had more severe positive and disorganized symptoms than other patients. Interestingly, Trx and oxidized Prx levels correlated negatively with GPx only in patients with low-GPx+CT. Moreover, patients with low-GPx+CT performed better than other patients on cognitive tasks. Discriminant analysis combining redox markers, hippocampal volume, clinical scores, and cognitive scores allowed for stratification of the patients into subgroups. In conclusion, traumatized EPP with high peripheral oxidation status (high-GPx activity) had smaller hippocampal volumes and more severe symptoms, while those with lower oxidation status (low-GPx activity) showed better cognition and regulation of GPx and Trx/Prx systems. These results suggest that maintained regulation of various antioxidant systems allowed for compensatory mechanisms preventing long-term neuroanatomical and clinical impacts. The redox marker profile may thus represent important biomarkers for defining treatment strategies in patients with psychosis.

Mechanism-based treatments for schizophrenia are needed, and increasing evidence suggests that oxidative stress may be a target. Previous research has shown that N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor almost devoid of side effects, improved negative symptoms, decreased the side effects of antipsychotics, and improved mismatch negativity and local neural synchronization in chronic schizophrenia. In a recent double-blind randomized placebo-controlled trial by Conus et al., early psychosis patients received NAC add-on therapy (2700 mg/day) for 6 months. Compared with placebo-treated controls, NAC patients showed significant improvements in neurocognition (processing speed) and a reduction of positive symptoms among patients with high peripheral oxidative status. NAC also led to a 23% increase in GSH levels in the medial prefrontal cortex (GSHmPFC) as measured by 1H magnetic resonance spectroscopy. A subgroup of the patients in this study were also scanned with multimodal MR imaging (spectroscopy, diffusion, and structural) at baseline (prior to NAC/placebo) and after 6 months of add-on treatment. Based on prior translational research, we hypothesized that NAC would protect white matter integrity in the fornix. A group × time interaction indicated a difference in the 6-month evolution of white matter integrity (as measured by generalized fractional anisotropy, gFA) in favor of the NAC group, which showed an 11% increase. The increase in gFA correlated with an increase in GSHmPFC over the same 6-month period. In this secondary study, we suggest that NAC add-on treatment may be a safe and effective way to protect white matter integrity in early psychosis patients.

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

Several lines of evidence implicate the fornix-hippocampus circuit in schizophrenia. In early-phase psychosis, this circuit has not been extensively investigated and the underlying mechanisms affecting the circuit are unknown. The hippocampus and fornix are vulnerable to oxidative stress at peripuberty in a glutathione (GSH)-deficient animal model. The purposes of the current study were to assess the integrity of the fornix-hippocampus circuit in early-psychosis patients (EP), and to study its relationship with peripheral redox markers. Diffusion spectrum imaging and T1-weighted magnetic resonance imaging (MRI) were used to assess the fornix and hippocampus in 42 EP patients compared with 42 gender- and age-matched healthy controls. Generalized fractional anisotropy (gFA) and volumetric properties were used to measure fornix and hippocampal integrity, respectively. Correlation analysis was used to quantify the relationship of gFA in the fornix and hippocampal volume, with blood GSH levels and glutathione peroxidase (GPx) activity. Patients compared with controls exhibited lower gFA in the fornix as well as smaller volume in the hippocampus. In EP, but not in controls, smaller hippocampal volume was associated with high GPx activity. Disruption of the fornix-hippocampus circuit is already present in the early stages of psychosis. Higher blood GPx activity is associated with smaller hippocampal volume, which may support a role of oxidative stress in disease mechanisms.

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

BACKGROUND: The dysconnection hypothesis has been proposed to account for pathophysiological mechanisms underlying schizophrenia. Widespread structural changes suggesting abnormal connectivity in schizophrenia have been imaged. A functional counterpart of the structural maps would be the EEG synchronization maps. However, due to the limits of currently used bivariate methods, functional correlates of dysconnection are limited to the isolated measurements of synchronization between preselected pairs of EEG signals. METHODS/RESULTS: To reveal a whole-head synchronization topography in schizophrenia, we applied a new method of multivariate synchronization analysis called S-estimator to the resting dense-array (128 channels) EEG obtained from 14 patients and 14 controls. This method determines synchronization from the embedding dimension in a state-space domain based on the theoretical consequence of the cooperative behavior of simultaneous time series-the shrinking of the state-space embedding dimension. The S-estimator imaging revealed a specific synchronization landscape in schizophrenia patients. Its main features included bilaterally increased synchronization over temporal brain regions and decreased synchronization over the postcentral/parietal region neighboring the midline. The synchronization topography was stable over the course of several months and correlated with the severity of schizophrenia symptoms. In particular, direct correlations linked positive, negative, and general psychopathological symptoms to the hyper-synchronized temporal clusters over both hemispheres. Along with these correlations, general psychopathological symptoms inversely correlated within the hypo-synchronized postcentral midline region. While being similar to the structural maps of cortical changes in schizophrenia, the S-maps go beyond the topography limits, demonstrating a novel aspect of the abnormalities of functional cooperation: namely, regionally reduced or enhanced connectivi