Skip to Main Content
Skip Nav Destination
Open Access License / Drug Dosage / Disclaimer
This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Schizophrenia is a major psychiatric brain disease with potentially devastating effects. It strikes in adolescence and young adulthood and can last a lifetime. It affects about 1% of the world's population, is destructive for the individual, family and society, and constitutes a major costly public health problem. It develops progressively, most often undetected during childhood and adolescence in a pre-morbid phase. This usually leads to the onset of psychosis at between 18 and 25 years of age, often evolving toward invalidity. Approximately two-thirds of those who develop schizophrenia require assistance from health care providers (such as government and social security systems) within a few years of onset. The majority of people who develop schizophrenia are unable to return to work or school and may have difficulties in maintaining normal social interactions [1].

The symptoms of schizophrenia are classically divided into categories of positive symptoms (delusions, hallucinations, thought disorder) and negative ones (e.g. deficits in social abilities, poverty of speech, affective flattening). The patients also present other discrete, but more permanent dysfunctions, such as cognitive deficits (problems with attention, specific forms of memory, executive functions) and perceptual instability (basic symptoms) that are now thought to be central to patients’ behavioral disturbances and functional disability. Moreover, patients with schizophrenia also present non-specific symptoms such as anxiety, depression, obsessive behavior, drug and alcohol abuse and suicidal tendency (10% incidence). While present antipsychotic treatments are relatively effective against positive symptoms, they are almost ineffectual for negative and cognitive ones. Indeed, even in patients stabilized with present antipsychotics, these negative and cognitive symptoms are impediments to the social and professional integration of young individuals from the time of disease onset [13].

Despite a growing understanding of its neurochemical anomalies, schizophrenia remains an elusive and multifaceted disorder and available evidence regarding its onset and etiology point to a complex interplay of genetic, environmental and developmental factors. Various pathophysiological hypotheses have been put forward, which account for available evidence to varying degrees. Globally, they involve dysfunctions in neurotransmission and impairments of functional connectivity.

It is well established from twin and adoption studies that schizophrenia is highly heritable, but in a complex manner, with a concordance rate of ~50% for monozygotic twins and a heritability of 80% [4]. Numerous studies have focused on identifying genetic vulnerability factors. Results from several genome-wide scans [58] have identified chromosomal regions of interest, and cumulative evidence from replication efforts suggest that schizophrenia susceptibility genes may be found on chromosomes 1, 6, 8, 10, 13 and 22 [see reviews in 911]. Very recent studies from large genome-wide scans in multiple, large cohorts that have identified both rare high-risk mutations (RR: 2–14) [1215] and common low-risk variations on chromosome 2 (ZnF804A) and 11 (RR: 1.09–1.19) [16] and in the HLA and histone regions on chromosome 6 [17]. Similarly, studies that have adopted a family-based approach have identified a balanced translocation that disrupts the DISC1 gene [18], as well as the neuregulin gene [19], while hypothesis-driven approaches based on biological findings of deficits in the ability to cope with oxidative stress in patients with schizophrenia have implicated gene variants in the biosynthesis of glutathione as susceptibility factors of the illness [20, 21]. Moreover, understanding how genetic variation at each locus confers susceptibility and/or protection, or what is the contribution of each gene, their relationship with the phenotype and their interaction with environmental risk factors [22, 23] remains a great challenge.

These include exposure to viral infections [24], autoimmune, toxic or traumatic insults and stress during gestation, birth or childhood [2527] that have been implicated in the pathogenesis of schizophrenia. Recently, models based on epigenetic factors and an interaction between a susceptible genotype and environmental factors have been proposed for this puzzlingly complex disease [28].

In attempting to produce a unifying concept of the etiology of schizophrenia, researchers have posited that these biological mechanisms have their origins in developmental processes that emerge prior to the onset of clinical symptoms. Indeed, evidence for pre- and perinatal epidemiological risk factors of schizophrenia, and for premorbid dysfunction during infancy and childhood have led to the formulation of the so-called neurodevelopmental hypothesis: schizophrenia is viewed as resulting from etiological events acting between conception and birth, and interfering with normal maturational processes of the central nervous system [2931]. Moreover, it is also hypothesized that the interaction between a hereditary predisposition and early neurodevelopmental insults results in defective connectivity between a number of brain regions, including the midbrain, nucleus accumbens, thalamus, temporo-limbic (including hippocampus) and prefrontal cortices [2, 3234]. This defective neural circuitry is then vulnerable to dysfunction when unmasked by developmental processes and events of adolescence (myelination, synaptic pruning and hormonal effects of puberty on the central nervous system) and exposure to stressors as the individual enters high-risk ages [3, 31, 35].

A number of theories implicate aberrant neurotransmission systems in schizophrenia, in particular, aberrant dopaminergic [3638], glutamatergic [3941] and γ-aminobutyric acid (GABA)-ergic systems [4246] involving dysfunctions in presynaptic storage, vesicular transport, release, re-uptake and metabolic mechanisms [3, 47]. It is unclear, however, to what extent such neurochemical findings reflect primary causes rather than secondary effects of the pathology, including compensatory mechanisms or environmental interactions.

Multiple lines of evidence suggest that schizophrenia is associated with abnormalities in neural circuitry and impaired structural connectivity. Post-mortem histological studies have shown anomalies at the level of dendritic spines [4851] and decreases in numbers of inhibitory GABA-parvalbumin interneurons in the prefrontal cortex [46, 52]. Moreover, recent advances in diffusion tensor imaging have allowed in vivo explorations of anatomical connectivity in the human brain. These have pointed to connectivity abnormalities in fronto-parietal and fronto-temporal circuitry in schizophrenia [for reviews see 53, 54]. Further evidence for anomalies in information integration across brain networks is accumulating.

This is based on the study of dynamic, context-dependent processes, which require the preferential recruitment of context-relevant networks over others [5557]. Evidence is emerging in schizophrenia for an impairment in both local and long-range synchronization in a range of cognitive and perceptual tasks [5861]. Such perturbation of brain connectivity might be associated with functional anomalies of dopaminergic, glutamatergic and GABA-ergic systems [6264]. The connectivity argument is reinforced by the fact that the age of onset of full-blown psychosis corresponds to the maturation of myelinated pathways, in particular those involving the prefrontal cortex.

In summary, existing neuroanatomical, neurochemical, neurophysiological and psychopathological arguments converge to suggest that schizophrenia may be considered as a developmental syndrome involving faulty connectivity and neurotransmission and it is likely to have complex origins deriving from multiple genetic and environmental factors.

In the present review, we will emphasize the need to identify a ‘hub’ or ‘final common pathway’ leading to schizophrenia, a hub on which various known causal factors converge and from which established patho-physiological impairments originate. Through a reverse translational approach [65], we have identified a candidate hub related to redox dysregulation. The hub of redox dysregulation/oxidative stress resulting from a genetic impairment of glutathione (GSH) synthesis fulfills such requirements: it represents a complex interplay between genetic and environmental factors during brain development, which leads to impaired neuronal integrity and connectivity and sets off a cascade of events that extend into adult life (fig. 1).

The tripeptide GSH (γ-glutamyl-cysteine-glycine), known as the major intracellular non-protein antioxidant, is required (1) for protection against cellular damage due to reactive oxygen and nitrogen species (ROS and RNS) and detoxification of environmental toxins and reactive metabolites [66], and (2) for the maintenance of the thiol redox status which is critical for redox-sensitive processes [67] such as cell cycle regulation and cell differentiation [68], receptor activation (e.g. N-methyl-daspartate, NMDA, receptor [69]), signal transduction (e.g. H-Ras, PTP-1B) and transcription factor binding to DNA (e.g. Nrf-2, NF-κB) [67]. GSH deficiency will induce oxidative stress, leading to deleterious peroxidations of lipids, proteins and DNAs, altering lipid metabolism and affecting mitochondrial function [70].

Substantial evidence of oxidative damage has been observed in peripheral tissues and post-mortem brain of schizophrenia patients [7178]. However, variability in these results highlights the contribution of the diverse genotypes and tissues studied [for review see 79]. It remains unclear if the responsible oxidative stress was due to environmental factors or was of genetic origin, preventing the affected brain areas from reacting adequately to oxidative stress. We propose that a primary genetic defect of GSH synthesis is at the origin of the failure of antioxidant defenses in schizophrenia. This implies the involvement of a critical neurodevelopmental component in schizophrenia when compared with neurodegenerative disorders. Indeed, there is also increasing evidence for the involvement of oxidative stress-induced cellular damage in the pathogenesis of various neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's. However, in these cases, ROS/RNS increase and GSH depletion appears to be a downstream consequences of other primary causes (such as mitochondrial complex I dysfunction in Parkinson's disease, amyloid-β peptide toxicity in Alzheimer's disease, and huntingtin-related mitochondrial dysfunction in Huntington's disease) [70].

Fig. 1.
Role of GSH/redox dysregulation in schizophrenia, focusing on genetic and environmental causal factors and their pathophysiological consequences. GABA =: γ-aminobutyric acid; GCL = glutamate-cysteine ligase; gclc = catalytic unit of GCL gene; gclm = modulatory unit of GCL; NAC = N-acetyl-cysteine; NADPH = nicotinamide adenine dinucleotide phosphate; NMDAR = N-methyl-Daspartate receptor; PV = parvalbumine.
Fig. 1.
Role of GSH/redox dysregulation in schizophrenia, focusing on genetic and environmental causal factors and their pathophysiological consequences. GABA =: γ-aminobutyric acid; GCL = glutamate-cysteine ligase; gclc = catalytic unit of GCL gene; gclm = modulatory unit of GCL; NAC = N-acetyl-cysteine; NADPH = nicotinamide adenine dinucleotide phosphate; NMDAR = N-methyl-Daspartate receptor; PV = parvalbumine.
Close modal

An association between schizophrenia and a trinucleotide repeat polymorphism in the key gene responsible for GSH synthesis has been recently demonstrated, which suggests a genetic origin for the dysregulation of the redox system seen in the disease [21]. Indeed, patients suffering from schizophrenia present a brain deficit in the GSH system which is of genetic origin: (1) GSH levels in the brain and cerebrospinal fluid are decreased [8082]; (2) glutamate cysteine ligase (GCL) activity and GSH synthesis are decreased in patients’ fibroblasts under oxidative stress conditions [21], and (3) allelic variants of the key GSH-synthesizing enzyme the GCL-modulatory subunit (GCLM) [20] and catalytic subunit (GCLC) [21] are associated with the disease. In particular, in 2 case-control studies with a total of 570 patients and 797 controls, a GAG trinucleotide with 7, 8 or 9 repeat polymorphisms in the GCLC gene showed a significant intergroup difference regarding the overall genotype distribution [21]: the GCLC genotypes 7/7 and 7/9 are more frequent in controls (‘low risk’ genotypes), while 8/7, 8/8, 8/9 and 9/9 are more frequent in patients (‘high risk’ genotypes). This polymorphism has functional consequences: the high-risk genotypes had lower GCL activity, GCLC protein expression and GSH content than subjects with low risk. Interestingly, the high-risk genotype is present in 36–40% of patients and is 3 times more frequent in patients. This is consistent with the decreased GSH levels in the cerebrospinal fluid and medial prefrontal cortex in vivo [80, 82], as well as in post-mortem striatum [81]. Furthermore, high-risk genotype patients have lower fibroblast GSH levels and higher plasmatic free oxidized cysteine levels than low-risk ones (Gysin et al., in preparation), pointing to generalized oxidative systemic conditions [76, 83].

Taken together, these results provide evidence that polymorphisms in the key GSH-synthesizing genes are associated with schizophrenia, leading to a redox dysregulation favoring oxidative and nitrosative stress consequences. These results inspired the development of the ‘glutathione hypothesis’ [84]: brain deficits in the GSH system would lead to both a functional and a structural disconnectivity, which could be a basis of the disease etiology. Moreover, results gathered in experimental models, revealed that a decrease in GSH, particularly during development, induces morphological [85, 86], electrophysiological [87, 88] and behavioral [8991] anomalies analogous to those observed in the disease (see ‘Developmental animal models with redox dysregulation’, below), thus providing additional support to the hypothesis.

We thus propose that a redox/antioxidant dysregulation due to GSH deficit could represent a vulnerability factor in the early phase of brain development in schizophrenia. Combined with other genetic and environmental factors, it could favor the development of the disease [84]. Life event stresses, through hypothalamic-pituitaryadrenal axis stimulation, induce substantial dopamine release [9294]. This could result, when combined with GSH deficit, in an increase in ROS and thus in oxidative damage to lipids, proteins and DNA [95], leading during brain development and maturation to progressive structural and functional disconnectivity.

As GSH is the main non-protein cellular redox regulator, protecting against cell damage due to ROS, this deficit would be particularly damaging in brain regions rich in dopamine (e.g. prefrontal cortex), whose metabolism generates ROS. This mechanism could be responsible for morphological alterations such as anomalies of dendritic spines and of parvalbumin-positive inhibitory interneurones in prefrontal cortex [46, 49, 96].

A GSH deficit would also depress NMDA (glutamate) receptor responses [97], a phenomenon known to be involved in perturbations of sensory and cognitive functions in schizophrenia [64], as demonstrated by the psychotomimetic action of the NMDA antagonist phencyclidine [98]. Indeed, GSH potentiates the glutamate response of the NMDA receptor (NMDAR) through interaction at the redox site [97]. This action could be depressed in case of a GSH deficit, leading to effects similar to those induced by phencyclidine. In summary, the framework of the ‘glutathione hypothesis’ can integrate both dopamine and glutamate theories.

The etiological hub of GSH deficit can have many causes via an interaction between genetic and environmental factors [84] (fig. 1). Besides the GSH regulatory genes described above, some other genetic factors identified as implicated in schizophrenia could also lead to a redox imbalance and an oxidative stress. Indeed, a positive association with schizophrenia has been found for a SNP in PRODH which increases the proline oxidase (PRODH) activity, reported to promote ROS generation [99, 100]. On the other hand, various environmental insults known to be schizophrenia risk factors all lead to a GSH deficit: viral infections [24], inflammation, toxic or traumatic insults and stress during gestation or birth or childhood, psycho-social stress and perhaps even diet and post-natal exposure to toxins [2527]. It is thus likely that such insults, particularly when combined with a genetically deficient redox system, will cause oxidative stress and damaging peroxidations. Impacts during early development may become apparent only in adulthood. Exposure to oxidative stress at various developmental stages affects at least 2 essential cerebral processes that are dysfunctional in schizophrenia (fig. 1): (1) reductions in parvalbumin (PV) fast spiking GABAergic interneurons (FSGI) [46] known to be crucial for brain oscillatory activity [101], and (2) deficient myelination [102].

The NMDAR, which is essential for synaptic plasticity, learning and memory, possesses a redox site which modulates its activity: it is depressed under oxidizing conditions and thus hypoactive when GSH is low [97]. Antagonists of the NMDAR (phencyclidine, ketamine) are known to induce psychotic states in normal subjects and worsen the symptoms of patients [98]. At the cellular level, the prefrontal cortex FSGI show a decrease of PV and GAD67 in post-mortem brains of patients [46]. The same result is obtained in animal models under low GSH conditions [85] or after treatment with NMDAR antagonists [103, 104, 105]. It thus appears that GSH deficit induces an impaired function in FSGI, particularly during brain development. This NMDAR hypofunction induced FSGI defect is mediated by activation of NAPDH oxidases [106, 107]. The latter also produces ROS, which will not be sufficiently reduced when GSH is low. The FSGI are critically involved in the functional cortical circuitry responsible for synchronization and gamma band EEG oscillations during cognitive tasks [59, 101, 108]. Their impairment could potentially lead to decreased synchronization and γ-oscillation power and to cognitive deficits both in patients and in animal models. This chain of events is likely to be causally involved in the generation of schizophrenia phenotype.

In addition, oxidative stress is likely to affect the development of progenitor cells in the central nervous system, and the precursors of oligodendrocytes are particularly sensitive to redox balance. A tendency toward the oxidative side of the balance favors differentiation over proliferation, leading to a deficit in oligodendrocytes and to anomalies of myelination [109, 110]. The development of appropriate levels of myelin is affected in the schizophrenic brain and the resulting errors in conduction speed of action potentials is likely to contribute to the deficits in connectivity and synchronization in diverse pathways which would underlie the cognitive and negative symptoms.

As noted above, schizophrenia is a multifaceted disorder, with evidence concerning its onset and etiology pointing to a complex interplay of genetic, environmental and developmental factors. Several approaches have been taken to develop animal models of schizophrenia [for review see 111, 112]. These include:

  • Specific pharmacological or genetic manipulations that aim at modeling a particular aspect of the pathophysiology observed in schizophrenia in order to assess the consequences of these defects. These are applicable to post-pubertal and chronic stages of the disease.

  • Disruptions of normal brain development and maturation, focusing on those which lead to behavioral impairments related to schizophrenia that only appear after puberty.

  • Animal models with obstetrical complications and prenatal maternal infections, two conditions known to increase the risk of schizophrenia.

However, none of these models by itself addresses in a comprehensive manner the complexity and heterogeneity of schizophrenia and its multiple stages of development. Integration of results obtained from models of these different elements are needed to determine the conditions and defects that can produce the various symptoms of schizophrenia. It is becoming apparent that several different defects independently or in combination can converge to provoke similar behavioral dysfunctions related to schizophrenia. There is thus a strong need to develop new models that combine several manipulations (e.g. combining genetic or pharmacological manipulations with a developmental environmental factor). A unifying pathogenesis concept was proposed [31]: ‘genetic susceptibility in concert with particular stressors during development, may lead to a critical threshold that, when crossed, produces the clinical syndrome at a later stage in life.’

We review here results concerning 2 animal models which explore such convergence of both genetic and environmental risk factors during development, based on impairment of GSH synthesis, redox dysregulation and increased oxidative stress.

We have established a pharmacological model in rats based on inducing transient redox dysregulation during development involving specific inhibition of GSH synthesis with t-butyl sulfoximide (BSO) leading to a 50–60% decrease of brain GSH levels from postnatal days (PN) 5 to 16. Alone or combined with oxidative stress (induced by a blockade of dopamine uptake with GBR12909 leading to high levels of extracellular dopamine and thus to ROS production), this treatment leads to following morphological, electrophysiological and behavioral anomalies:

  • In prefrontal cortex neurons, we observed a decrease in dendritic spine density [86, 113], as well as in parvalbumin immunoreactivity [85]. These observations are similar to those reported in the brain of schizophrenia patients [49, 96].

  • Memory and sensory integration are perturbed (later in female rats than in males [8991]), reproducing some of the cognitive deficits observed in schizophrenia.

  • In rat hippocampal slices, GSH depletion impairs NMDA-dependent synaptic plasticity [87]. In neuronal cultures, while dopamine enhanced NMDA responses in control, it depressed them in GSH-depleted neurons. Antagonist of D2-Rs prevented this depression, a mechanism contributing to the efficacy of antipsychotics [88].

All of these anomalies are quite similar to those reported in schizophrenia and show that an insult imposed in the developmental period of PN 5–16 has long-term behavioral consequences. This pharmacological model has, however, some technical limitations, in particular bound to the fact that the period at which BSO can be applied systemically is restricted by its transitory permeability across the blood brain barrier.

This preclinical animal model permits exploration of how interaction between this susceptibility gene and environmental insults during brain development will result in impaired neuronal integrity and connectivity, setting off a cascade of events that extend to adult life. As discussed above, the fact that the GCLM gene has allelic variations associated with schizophrenia in patients [20] indicates that the GCLM-/- mouse is a useful model. Its GSH level is low (20% of wild type) throughout development, rendering it at permanent risk for oxidative stress (note that a knockout of the gene coding the catalytic subunit GCLC is lethal in mice). At the other end, environmental stress, through hypothalamic-pituitary-adrenal axis stimulation, induces substantial dopamine release [9294]. This would result in an augmentation in ROS and thus further increase oxidative stress. We thus investigated an animal model which involves GCLM as a risk gene causing redox dysregulation and employ hyperdopaminergia as an environmental stressor which can be applied at various stages during neural development. GCLM-/- mice showed selective and region-specific anomalies in the GABAergic system. As in the BSO-treated rats, PV immunoreactive interneurons in GCLM-/- mice were particularly affected.

In anterior cingulate of GCLM-/- mice, concomitantly to an increase in oxidative stress as revealed by 8-oxo-dG (marker of DNA oxidation), the developmental expression of PV was impaired at PN 10, but normalized at PN 20. Additional stress (GBR treatment) during postnatal development (from PN 10–20) prevents this normalization at PN 20 [114]. Moreover, myelination is also impaired as revealed by a weaker myelin basic protein immunolabelling intensity and thinner myelin basic protein immunoreactivity profiles [114].

In ventral but not dorsal hippocampus of adult GCLM-/- mice, oxidative stress marker 8-hydroxy-2-deoxyguanosine was increased while PV immunoreactivity of GABA interneurons and kainate-induced γ-oscillations were reduced. These effects were severe in the dentate gyrus and CA3 region but not CA1. Furthermore, GCLM– /– had no impairment in dorsal hippocampus-related spatial learning and memory (rewarded alternation and Morris water maze) while they display novelty-induced hyperactivity, reduced anxiety, alterations in social behavior and deficiency in object memory, all tasks related to ventral hippocampus [114, 115].

Altogether, these observations confirm that PV immunoreactive interneurons are particularly sensitive to a GSH deficit but their vulnerability depends on brain region and correlates with the level of oxidative stress. This also supports the notion that PV immunoreactive fast-spiking interneurons are highly vulnerable to oxidative stress [116]. As noted above, patients with schizophrenia are characterized by decreases in PV containing GABAergic interneurons that are crucially involved in the generation of high-frequency oscillations. Moreover the synchronization of such oscillatory activity which is at the basis of neural activity coordination during perceptual and cognitive processes is also impaired in schizophrenia [108, for review see 117]. The impairment of PV interneurons and neural synchronization in GCLM-/- mice suggests that GSH deficit and redox dysregulation underly cognitive and behavioral anomalies observed in schizophrenia, at least in high-risk GCLC genotype patients.

The myelination anomalies observed in GCLM-/- mice are consistent with the impairment of oligodendroglia-mediated myelination in schizophrenia as evidenced from gene expression profiling, neurocytochemical and neuroimaging studies [54, 118, 119]. A deficit in myelination would influence the axonal conduction velocity and thus prevent precise synchronizations. It also would have an impact on the association pathways essential for intermodal sensory integration and the ‘binding’ process [117], underlying the cognitive and negative symptoms. As cortical myelination extends until late adolescence for the temporal and prefrontal regions, its deficit could be related to the delayed onset of the disease in early adulthood. As discussed above, intracellular redox state appears to be a necessary and sufficient modulator of the balance between self-renewal and differentiation in dividing oligodendrocyte-type-2 astrocyte progenitor cells [109, 110]. More specifically, cells that are more oxidized tend to differentiate, whereas those that are more reduced undergo self-renewal. Therefore the redox dysregulation observed in schizophrenia may lead to myelination perturbation through oligodendrocytes mitogenic signaling disruption [109].

N-acetyl cysteine (NAC) is a commercial drug approved as an add-on treatment for bronchitis and as an antidote in paracetamol intoxication. Recently, biological effects of NAC have been studied in order to explore potential additional clinical indications, such as graft rejection [120], cystic fibrosis [121], chronic obstructive pulmonary disease [122], arthritis [120], some forms of cancer [120], neurodegenerative disorders [123125] and cocaine and heroin dependency [126, for review see 127]. Various NAC characteristics suggest it is a very promising candidate in the context of a potential GSH-redox dysregulation linked to schizophrenia, through its influence on the GSH system as well as through a direct antioxidant effect. These characteristics can be defined as follows:

  • Induction of in vivo biosynthesis of GSH: cysteine, an NAC metabolite, is essential for GSH synthesis. Availability of cysteine is therefore a crucial factor for constitution of adequate intracerebral reserves of GSH, considering glutathione itself does not cross the blood-brain barrier.

  • Gene expression modulation by oxidative stress: NAC plays an important modulating role in expression of genes linked to oxidative stress through its effect on transcription factors such as NF-κB and AP1 [128].

  • Antioxidant effect of NACNAC reduces concentration of free radicals and other oxidants through direct inactivation of reactive oxygenated compounds through the molecule's free thiol group and formation of NAC-disulfide as the final product.

  • Protection of nerve cells: numerous studies, both in vitro and in vivo, have shown that administration of NAC protects nervous cells against free radicals [120, 128].

In a double-blind, placebo-controlled study, NAC has proven to be efficient at improving schizophrenia symptoms. Indeed, NAC, as an add-on treatment to antipsychotics, decreased negative symptoms and reduced side effects (akathisia) in a cohort of 140 chronic patients [129]. Moreover, this GSH precursor is also effective in improving mismatch negativity [130], an auditory related, NMDA-dependent evoked potential typically impaired in schizophrenia [62, 131]. This is encouraging since present antipsychotic treatments are rather ineffective against cognitive and negative symptoms and have no effect on certain biomarkers like mismatch negativity, a pre-attentional component which is proposed to gate some cognitive and functional modules.

It is of interest to note that the high-risk GAG trinucleotide polymorphism is also associated with bipolar patients [Gysin et al., unpubl. observations], but not with major depression, supporting the view that various genetic anomalies are common to several psychoses. This is consistent with the observation that NAC supplementation improves bipolar patients [132], and is consistent with the concept of a psychosis continuum, as proposed by Crow [133].

Early intervention in psychosis has become an important focus of interest in psychiatry [134, 135]. Prospective studies conducted in first episode psychosis patients [136139] have identified long delays between onset of psychotic symptoms and initiation of adequate treatment and lack of specificity in treatment of the early phase of psychosis (fig. 2). Two additional concepts emerged from this research: first, that full-blown psychosis is preceded by a ‘prodromal phase’ [140143], and second, that the first few years after onset of the major symptoms constitute a ‘critical phase’ where outcome is more likely to be influenced [144]. However, the diagnosis of the prodromal phase still relies exclusively on clinical assessment [145] with limited specificity and hence a high rate of false positives, which raises important ethical issues when designing therapeutic strategies [146, 147] and underlines the need for valid biomarkers.

Our present knowledge indicates that the maximal efficacy of our treatments would be in the early psychosis and prodromal phase before redox dysregulation/ oxidative stress has done major damage. Considering NAC has negligible side effects, its efficacy in early psychosis and prodromal phase will be a first step towards identifying pharmacological agents that are much more acceptable to patients and may therefore improve adherence to treatment. Moreover, NAC supplementation has very promising potential in children and adolescents who suffer from neurodevelopmental psychotic disorders, because neuroprotection could be crucial at the critical ages of adolescence when pathological processes are interfering with ongoing brain development. Finally, the presence of a GSH-redox dysregulation or its genetic correlates may prove to be a useful marker in the frame of early detection of schizophrenia.

Fig. 2.
Phases of schizophrenia.
Fig. 2.
Phases of schizophrenia.
Close modal

Disturbances in single-carbon metabolism appear to be related to a variety of neuropsychiatric disorders, covering a broad spectrum that includes depression [148], autism [149] and psychosis [150, 151]. Indeed, the enzymes and metabolites of the methionine and folate cyle are associated with schizophrenia [152155]. However, we do not know yet whether an observed disturbance is a primary event that is fundamentally related to the pathogenesis or a secondary phenomenon reflecting a nonpathogenic mechanism.

Interestingly, methionine given per os has been shown to be the only amino acid that exacerbates the psychotic symptoms in schizophrenic patients [154]. Experimental methionine loading brings about various effects on the single-carbon cycle as it lowers serum folate concentration [156], induces oxidative stress [157], and lowers the amino acid cysteine [158], the rate-limiting precursor in the GSH synthesis. The exacerbation of psychosis could thus be the consequences of an aggravation of the impairment of the GSH deficit and redox dyregulation hub, at least in the high-risk GCLC genotype schizophrenia patients. Moreover, GSH is a cofactor for the function of methionine adenosyltransferase (MAT), which is a sensitive target for oxidation, and MAT activity is therefore strongly dependent on cellular GSH levels [159]. MAT has been reported to be significantly underactive in red blood cells and brains of schizophrenic patients [160]. In addition, GSH deficit, through methionine and the transmethylation pathway could contribute to the dysregulation of DNA methylation thus affecting epigenetic processes (fig. 3). Indeed, under oxidative stress conditions, methionine synthase is inactivated, allowing homocysteine to be shunted into the transsulfuration pathway in order to favour GSH synthesis [161]. As GSH synthesis is impaired in the high-risk genotype, both transmethylation and transsulfuration pathways will be depressed, leading to perturbations of the DNA methylation process and increase of homocysteine levels often observed in schizophrenia [28, 162, 163].

Fig. 3.
Single-carbon metabolism and glutathione in schizophrenia. GSH dysregulation might play a role in the framework of the single-carbon hypothesis of schizophrenia originally proposed by Smythies et al. [183]. In the transmethylation pathway, methionine is converted to homocysteine providing methyl groups to DNA, lipids and proteins. Homocysteine can be either remethylated to methionine through activation of methionine synthase, which depends on folate and vitamin B12, or metabolized to cystathionine and cysteine through the transsulfuration pathway. Cysteine can then be used as a precursor of GSH. Thus, homocysteine is in a central position, going either to transmethylation or to transsulfuration and GSH synthesis. Deth et al. [155] proposed that methionine synthase can act as a ‘redox sensor’. Under oxidative stress conditions, methionine synthase is inactivated (dotted arrow line 1), allowing homocysteine to be shunted into the transsulfuration pathway to increase GSH synthesis and thus neutralize oxidative stress. This mechanism is of particular interest in the perspective of schizophrenia, as hyperhomocysteinemia has been reported in subgroups of patients. Such a hyperhomocysteinemia could be related to a partial block of both transmethylation and transsulfuration pathways. A GSH deficit due to the impairment of GCL could thus interfere with the transsulfuration pathway, and inhibit the methionine synthase affecting the transmethylation pathway. In addition, hyperhomocysteinemia exercises an inhibition on GPX1 activity (dotted arrow line 2), further depressing the reduction effect of GSH [184], and testosterone has been shown to depress the β-cystationase (dotted arrow line 3), possibly contributing to gender differences in severity [185]. These mechanisms are likely to be exacerbated by an enhancement of oxidative stress during the acute phases of psychosis.
Fig. 3.
Single-carbon metabolism and glutathione in schizophrenia. GSH dysregulation might play a role in the framework of the single-carbon hypothesis of schizophrenia originally proposed by Smythies et al. [183]. In the transmethylation pathway, methionine is converted to homocysteine providing methyl groups to DNA, lipids and proteins. Homocysteine can be either remethylated to methionine through activation of methionine synthase, which depends on folate and vitamin B12, or metabolized to cystathionine and cysteine through the transsulfuration pathway. Cysteine can then be used as a precursor of GSH. Thus, homocysteine is in a central position, going either to transmethylation or to transsulfuration and GSH synthesis. Deth et al. [155] proposed that methionine synthase can act as a ‘redox sensor’. Under oxidative stress conditions, methionine synthase is inactivated (dotted arrow line 1), allowing homocysteine to be shunted into the transsulfuration pathway to increase GSH synthesis and thus neutralize oxidative stress. This mechanism is of particular interest in the perspective of schizophrenia, as hyperhomocysteinemia has been reported in subgroups of patients. Such a hyperhomocysteinemia could be related to a partial block of both transmethylation and transsulfuration pathways. A GSH deficit due to the impairment of GCL could thus interfere with the transsulfuration pathway, and inhibit the methionine synthase affecting the transmethylation pathway. In addition, hyperhomocysteinemia exercises an inhibition on GPX1 activity (dotted arrow line 2), further depressing the reduction effect of GSH [184], and testosterone has been shown to depress the β-cystationase (dotted arrow line 3), possibly contributing to gender differences in severity [185]. These mechanisms are likely to be exacerbated by an enhancement of oxidative stress during the acute phases of psychosis.
Close modal

A most encouraging feature of single-carbon metabolism is its potential modification by natural means, such as B vitamins and antioxidants. In one case report, cobalamine treatment alleviated psychotic symptoms [152]. However, this clinical effect diminished with time, and the metabolic abnormality was thus not wholly cobalamin dependent. In a double-blind, placebo-controlled trial, methylfolate supplementation significantly improved clinical and social recovery among both depressed and schizophrenic patients [164].

Another potential alternative and adjunctive to current antipsychotic treatments is the use of certain polyunsaturated fatty acids (PUFA), the omega-3 and omega-6, which play key roles in brain structure and function but which must be derived from dietary sources [165]. A high dietary ratio of omega-6, found in soft margarine, most vegetable oils and animal fats, to omega-3, found principally in oily fish and seafood, has been linked with vulnerability to many disorders of physical and mental health [166].

In our context, GSH deficit and redox dysregulaton in schizophrenia could lead to oxidative stress and ROS-mediated injury as supported by increased lipid peroxidation products and reduced membrane PUFAs. Decrease in membrane phospholipids in blood cells of psychotic patients [167, 168] and fibroblasts from drug-naïve patients [169] and in post-mortem brain [170] were indeed reported. It has been also suggested that peripheral membrane anomalies correlate with abnormal central phospholipid metabolism in first-episode and chronic schizophrenia patients [171, 172]. Recently, a microarray and proteomic study on post-mortem brain showed anomalies of mitochondrial function and oxidative stress pathways in schizophrenia [76]. Mitochondrial dysfunction in schizophrenia has also been observed [74, 173]. As main ROS producers, mitochondria are particularly susceptible to oxidative damage. Since the brain is highly vulnerable to oxidative damage because of its high oxygen consumption, its high content of oxidizable PUFAs and the presence of redox-active metals (Cu, Fe), a deficit in GSH could be particularly damaging to the neuronal function.

There is increasing evidence that dietary supplementation with omega-3 fatty acids may be beneficial in psychiatric conditions [174]. This evidence includes randomized controlled trials in conditions such as schizophrenia, depression and borderline personality disorder [175178]. However, recent meta-analyses of these studies show little evidence of a robust clinically relevant effect of omega-3 PUFA in schizophrenia, while the most convincing evidence for beneficial effects of omega-3 PUFA is to be found in depression [179]. Moreover, supplementation with omega-3 PUFA and vitamins C and E appear to exacerbate the positive symptoms in a subgroup of schizophrenia patients with low plasma PUFA [180]. These puzzling results might be explained by assuming an intrinsic GSH deficit of genetic origin in these patients. Indeed, antioxidants such as vitamins C and E might become pro-oxidants in an oxidizing environment [181, 182] as they require GSH to be reduced and regenerated [70]. The same argument can be applied for the short-term effect of the above-described cobalamine treatment. Thus, nutritional approachs must take into account the genetic and epigenetic background of individual patients. Nutrigenetics research will offer a strong foundation for future clinical investigations towards alternative treatment and prevention of psychiatric diseases.

Redox dysregulation may constitute a hub where genetic and environmental vulnerability factors converge, and their timing in brain development is likely to play a decisive role in the phenotype of schizophrenia patients. In experimental models, such redox dysregulation induces anomalies strikingly similar to those observed in patients. A treatment restoring redox balance, deprived of side-effects, yields improvements in chronic patients. Its application in early psychosis and prodrome, intended to halt pathological developmental processes, is promising. The proposed mechanisms should provide biomarkers for early detection, paving the way for prevention perspectives in which nutrigenetics would play a primordial role.

Insel TR: Disruptive insights in psychiatry: transforming a clinical discipline. J Clin Invest 2009;119:700-705
Andreasen NC: Schizophrenia: the fundamental questions. Brain Res Brain Res Rev 2000;31:106-112
Lewis DA, Lieberman JA: Catching up on schizophrenia: natural history and neurobiology. Neuron 2000;28:325-334
Cardno AG, Gottesman, II: Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 2000;97:12-17
Barr CL, Kennedy JL, Pakstis AJ, et al: Progress in a genome scan for linkage in schizophrenia in a large Swedish kindred. Am J Med Genet 1994;54:51-58
Coon H, Jensen S, Holik J, et al: Genomic scan for genes predisposing to schizophrenia. Am J Med Genet 1994;54:59-71
Blouin JL, Dombroski BA, Nath SK, et al: Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998;20:70-73
Brzustowicz LM, Honer WG, Chow EW, et al: Linkage of familial schizophrenia to chromosome 13q32. Am J Hum Genet 1999;65:1096-1103
Pulver AE: Search for schizophrenia susceptibility genes. Biol Psychiatry 2000;47:221-230
Mcguffin P, Tandon K, Corsico A: Linkage and association studies of schizophrenia. Curr Psychiatry Rep 2003;5:121-127
Carlson CS, Eberle MA, Kruglyak L, Nickerson DA: Mapping complex disease loci in whole-genome association studies. Nature 2004;429:446-452
Stefansson H, Rujescu D, Cichon S, et al: Large recurrent microdeletions associated with schizophrenia. Nature 2008;455:232-236
Rujescu D, Ingason A, Cichon S, et al: Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet 2009;18:988-996
International Schizophrenia Consortium: Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008;455:237-241
Hoogendoorn ML, Vorstman JA, Jalali GR, et al: Prevalence of 22q11 2 deletions in 311 Dutch patients with schizophrenia. Schizophr Res 2008;98:84-88
O’Donovan MC, Craddock N, Norton N, et al: Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008;40:1053-1055
Sklar P: Genomewide association for schizophrenia: the Broad/Stanley study. World Congress of Psychiatric Genetics 2008;
Blackwood DH, Fordyce A, Walker MT, et al: Schizophrenia and affective disorders: cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 2001;69:428-433
Tosato S, Dazzan P, Collier D: Association between the neuregulin 1 gene and schizophrenia: a systematic review. Schizophr Bull 2005;31:613-617
Tosic M, Ott J, Barral S, et al: Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet 2006;79:586-592
Gysin R, Kraftsik R, Sandell J, et al: Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci USA 2007;104:16621-16626
Caspi A, Moffitt TE, Cannon M, et al: Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 2005;57:1117-1127
Nicodemus KK, Straub RE, Egan MF, Weinberger DR: Evidence for statistical epistasis between (COMT) Val158Met polymorphism and multiple putative schizophreia susceptibility genes. Am J Med Genet B Neuropsychiatr Genet 2005;138B:130-131
Leweke FM, Gerth CW, Koethe D, et al: Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 2004;254:4-8
Cannon TD, Rosso IM, Hollister JM, et al: A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr Bull 2000;26:351-366
Rosso IM, Cannon TD, Huttunen T, et al: Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort. Am J Psychiatry 2000;157:801-807
Marcelis M, Van Os J, Sham P, et al: Obstetric complications and familial morbid risk of psychiatric disorders. Am J Med Genet 1998;81:29-36
Petronis A: The origin of schizophrenia: genetic thesis, epigenetic antithesis and resolving synthesis. Biol Psychiatry 2004;55:965-970
Weinberger DR: Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44:660-669
Murray RM, Lewis SW: Is schizophrenia a neurodevelopmental disorder?. Br Med J (Clin Res Ed) 1987;295:681-682
Lewis DA, Levitt P: Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002;25:409-432
Selemon LD, Goldman-Rakic PS: The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 1999;45:17-25
Parnas J, Bovet P, Innocenti GM: Schizophrenic trait features binding and cortico-cortical connectivity: a neurodevelopmental pathogenetic hypothesis. Neurol Psychiatry Brain Res 1996;4:185-196
Friston KJ: The disconnection hypothesis. Schizophrenia Res 1998;30:115-125
Raedler TJ, Knable MB, Weinberger DR: Schizophrenia as a developmental disorder of the cerebral cortex. Curr Opin Neurobiol 2000;8:157-161
Matthysse S: Antipsychotic drug actions: a clue to the neuropathology of schizophrenia?. Fed Proc 1973;32:200-205
Carlsson A: The current status of the dopamine hypothesis of schizophrenia. Neuropsycho-pharmacology 1988;1:179-186
Lewis DA, Gonzalez-Burgos G: Pathophysiologically based treatment interventions in schizophrenia. Nat Med 2006;12:1016-1022
Tamminga CA, Lahti AC, Medoff DR, Gao XM, Holcomb HH: Evaluating glutamatergic transmission in schizophrenia. Ann NY Acad Sci 2003;1003:113-118
Moghaddam B: Bringing order to the glutamate chaos in schizophrenia. Neuron 2003;40:881-884
Coyle JT: Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 2006;26:365-384
Benes FM, Berretta S: GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001;25:1-27
Volk DW, Pierri JN, Fritschy JM, et al: Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb Cortex 2002;12:1063-1070
Beasley CL, Zhang ZJ, Patten I, Reynolds GP: Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol Psychiatry 2002;52:708-715
Hashimoto T, Volk DW, Eggan SM, et al: Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 2003;23:6315-6326
Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005;6:312-324
Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT: Neurobiology of schizophrenia. Neuron 2006;52:139-153
Garey LJ, Ong WY, Patel TS, et al: Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 1998;65:446-453
Glantz LA, Lewis DA: Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000;57:65-73
Rosoklija G, Toomayan G, Ellis SP, et al: Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. Arch Gen Psychiatry 2000;57:349-356
Kolluri N, Sun Z, Sampson AR, Lewis DA: Laminaspecific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am J Psychiatry 2005;162:1200-1202
Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA: Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 2000;57:237-245
Lim KO, Helpern JA: Neuropsychiatric applications of DTI-a review. NMR Biomed 2002;15:587-593
Kanaan RA, Kim JS, Kaufmann WE, et al: Diffusion tensor imaging in schizophrenia. Biol Psychiatry 2005;58:921-929
Engel AK, Konig P, Kreiter AK, Singer W: Interhemispheric synchronization of oscillatory neuronal responses in cat visual cortex. Science 1991;252:1177-1179
Singer W, Gray CM: Visual feature integration and the temporal correlation hypothesis. Annu Rev Neurosci 1995;18:555-586
Tallon-Baudry C, Bertrand O: Oscillatory gamma activity in humans and its role in object representation. Trends Cogn Sci 1999;3:151-162
Spencer KM, Nestor PG, Niznikiewicz MA, et al: Abnormal neural synchrony in schizophrenia. J Neurosci 2003;23:7407-7411
Uhlhaas PJ, Singer W: Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology. Neuron 2006;52:155-168
Jalili M, Lavoie S, Deppen P, et al: Dysconnection topography in schizophrenia revealed with statespace analysis of EEG. PLoS ONE 2007;2:e1059
Knyazeva MG, Jalili M, Meuli R, et al: Alpha rhythm and hypofrontality in schizophrenia. Acta Psychiatr Scand 2008;118:188-199
Shelley AM, Ward PB, Catts SV, et al: Mismatch negativity: an index of a preattentive processing deficit in schizophrenia. Biol Psychiatry 1991;30:1059-1062
Umbricht D, Javitt D, Novak G, et al: Effects of clozapine on auditory event-related potentials in schizophrenia. Biol Psychiatry 1998;44:716-725
Umbricht D, Schmid L, Koller R, et al: Ketamineinduced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry 2000;57:1139-1147
Insel TR: Translating scientific opportunity into public health impact: a strategic plan for research on mental illness. Arch Gen Psychiatry 2009;66:128-133
Lu SC: Regulation of glutathione synthesis. Mol Aspects Med 2008;30:42-59
Jones DP: Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 2008;295:C849-C868
Shi ZZ, Osei-Frimpong J, Kala G, et al: Glutathione synthesis is essential for mouse development but not for cell growth in culture. Proc Natl Acad Sci USA 2000;97:5101-5106
Lipton SA, Choi YB, Takahashi H, et al: Cysteine regulation of protein function as exemplified by NMDA-receptor modulation. Trends Neurosci 2002;25:474-480
Valko M, Leibfritz D, Moncol J, et al: Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84
Mahadik SP, Mukherjee S: Free radical pathology and antioxidant defense in schizophrenia: a review. Schizophrenia Res 1996;19:1-17
Yao JK, Reddy RD, van Kammen DP: Oxidative damage and schizophrenia: an overview of the evidence and its therapeutic implications. CNS Drugs 2001;15:287-310
Herken H, Uz E, Ozyurt H, et al: Evidence that the activities of erythrocyte free radical scavenging enzymes and the products of lipid peroxidation are increased in different forms of schizophrenia. Mol Psychiatry 2001;6:66-73
Ben-Shachar D: Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine. J Neurochem 2002;83:1241-1251
Zhang XY, Tan YL, Cao LY, et al: Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophrenia Res 2006;81:291-300
Prabakaran S, Swatton JE, Ryan MM, et al: Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 2004;9:684-697
Evans DR, Parikh VV, Khan MM, et al: Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent Fatty Acids 2003;69:393-399
Marchbanks RM, Ryan M, Day IN, et al: A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress. Schizophrenia Res 2003;65:33-38
Do KQ, Bovet P, Cabungcal JH, et al: Redox dysregulation in schizophrenia: genetic susceptibility and pathophysiological mechanisms. Lajtha A: Handbook of Neurochemistry and Molecular Neurobiology New York, Springer, 27:2009;
Do KQ, Trabesinger AH, Kirsten-Kruger M, et al: Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 2000;12:3721-3728
Yao JK, Leonard S, Reddy R: Altered glutathione redox state in schizophrenia. Dis Markers 2006;22:83-93
Matsuzawa D, Obata T, Shirayama Y, et al: Negative correlation between brain glutathione level and negative symptoms in schizophrenia: a 3T 1H-MRS study. PLoS ONE 2008;3:e1944
Raffa M, Mechri A, Othman LB, et al: Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1178-1183
Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M: Redox dysregulation neurodevelopment and schizophrenia. Curr Opin Neurobiol 2009;19:220-230
Cabungcal JH, Nicolas D, Kraftsik R, et al: Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: relevance to schizophrenia. Neurobiol Dis 2006;22:624-637
Grima G, Benz B, Parpura V, Cuenod M, Do KQ: Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia. Schizophr Res 2003;62:213-224
Steullet P, Neijt HC, Cuenod M, Do KQ: Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. Neuroscience 2006;137:807-819
Steullet P, Lavoie S, Kraftsik R, et al: A glutathione deficit alters dopamine modulation of L-type calcium channels via D2 and ryanodine receptors in neurons. Free Radic Biol Med 2008;44:1042-1054
Castagne V, Rougemont M, Cuenod M, Do KQ: Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat's development induce long-term cognitive deficit: relevance to schizophrenia. Neurobiol Dis 2004;15:93-105
Castagne VV, Cuenod M, Do KQ: An animal model with relevance to schizophrenia: sex-dependent cognitive deficits in osteogenic disorder: Shionogi rats induced by glutathione synthesis and dopamine uptake inhibition during development. Neuroscience 2004;123:821-834
Cabungcal JH, Preissmann D, Delseth C, et al: Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia. Neurobiol Dis 2007;26:634-645
Piazza PV, Le Moal ML: Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress glucocorticoids and dopaminergic neurons. Annu Rev Pharmacol Toxicol 1996;36:359-378
Barrot M, Abrous DN, Marinelli M, et al: Influence of glucocorticoids on dopaminergic transmission in the rat dorsolateral striatum. Eur J Neurosci 2001;13:812-818
Ganguli R, Singh A, Brar J, Carter C, Mintun M: Hydrocortisone induced regional cerebral activity changes in schizophrenia: a PET scan study. Schizophrenia Res 2002;56:241-247
Liu J Wang X, Shigenaga MK, Yeo HC, Mori A, Ames BN: Immobilization stress causes oxidative damage to lipid protein and DNA in the brain of rats. FASEB J 1996;10:1532-1538
Harrison PJ: The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain 1999;122:593-624
Kohr G, Eckardt S, Luddens H, Monyer H, Seeburg PH: NMDA receptor channels: subunit-specific potentiation by reducing agents. Neuron 1994;12:1031-1040
Krystal JH, Karper LP, Seibyl JP, et al: Subanesthetic effects of the noncompetitive NMDA antagonist ketamine in humans: psychotomimetic perceptual cognitive and neuroendocrine responses. Arch Gen Psychiatry 1994;51:199-214
Kempf L, Nicodemus KK, Kolachana B, et al: Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and frontostriatal structure and function. PLoS Genet 2008;4:e1000252
Phang JM, Donald SP, Pandhare J, Liu Y: The metabolism of proline a stress substrate modulates carcinogenic pathways. Amino Acids 2008;35:681-690
Fuchs EC, Zivkovic AR, Cunningham MO, et al: Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior. Neuron 2007;53:591-604
Davis KL, Haroutunian V: Global expression-profiling studies and oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 2003;362:758
Abekawa T, Ito K, Nakagawa S, Koyama T: Prenatal exposure to an NMDA receptor antagonist MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to metham-phetamine in postpubertal rats. Psychopharmacology (Berl) 2007;192:303-316
Rujescu D, Bender A, Keck M, et al: A pharmacological model for psychosis based on N-methyl-daspartate receptor hypofunction: molecular cellular functional and behavioral abnormalities. Biol Psychiatry 2006;59:721-729
Wang CZ, Yang SF, Xia Y, Johnson KM: Postnatal phencyclidine administration selectively reduces adult cortical parvalbumin-containing interneurons. Neuropsychopharmacology 2008;33:2442-2455
Behrens MM, Ali SS, Dao DN, et al: Ketamineinduced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 2007;318:1645-1647
Bedard K, Krause KH: The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007;87:245-313
Uhlhaas PJ, Linden DE, Singer W, et al: Dysfunctional long-range coordination of neural activity during Gestalt perception in schizophrenia. J Neurosci 2006;26:8168-8175
Li Z, Dong T, Proschel C, Noble M: Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biol 2007;5:e35
Smith J, Ladi E, Mayer-Proschel M, Noble M: Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci USA 2000;97:10032-10037
Robertson GS, Hori SE, Powell KJ: Schizophrenia: an integrative approach to modelling a complex disorder. J Psychiatry Neurosci 2006;31:157-167
O’tuathaigh CM, Babovic D, O’meara G, et al: Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. Neurosci Biobehav Rev 2007;31:60-78
Rougemont M, Do KQ, Castagne V: A new model of glutathione deficit during development: effect of glutathione deficit on lipid peroxidation in the rat brain. J Neurosci Res 2003;70:774-783
Steullet P, Cabungcal JH, Kulak A, et al: Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations and related behaviours. J Neurosci 2010;30:2547-2558
Do KQ, Conus P, Bovet P, et al: developmental critical period in genetic redox dysregulation: animal and human studies in schizophrenia. Schizophr Bull 2009;35:106-107
Behrens MM, Ali SS, Dao DN, et al: Ketamineinduced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 2007;318:1645-1647
Uhlhaas PJ, Haenschel C, Nikolic D, Singer W: The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophr Bull 2008;34:927-943
Kubicki M, McCarley R, Westin CF, et al: A review of diffusion tensor imaging studies in schizophrenia. J Psychiatr Res 2007;41:15-30
Kyriakopoulos M, Vyas NS, Barker GJ, Chitnis XA, Frangou S: A diffusion tensor imaging study of white matter in early-onset schizophrenia. Biol Psychiatry 2008;63:519-523
Zafarullah M, Li WQ, Sylvester J, Ahmad M: Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 2003;60:6-20
Tirouvanziam R, Conrad CK, Bottiglieri T, et al: High-dose oral N-acetylcysteine a glutathione prodrug modulates inflammation in cystic fibrosis. Proc Natl Acad Sci USA 2006;103:4628-4633
Decramer M, Rutten-van Molken M, Dekhuijzen PN, et al: Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005;365:1552-1560
Arakawa M, Ito Y: N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology. Cerebellum 2007;1-7
Adair JC, Knoefel JE, Morgan N: Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology 2001;57:1515-1517
Andreassen OA, Dedeoglu A, Klivenyi P, Beal MF, Bush AI: N-acetyl-l-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Clin Neurosci 2000;11:2491-2493
Zhou W, Kalivas PW: N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking. Biol Psychiatry 2008;63:338-340
Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA: N-Acetylcysteine: a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007;7:355-359
Cotgreave IA: N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Adv Pharmacol 1997;38:205-227
Berk M, Copolov D, Dean O, et al: N-acetyl cysteine as a glutathione precursor for schizophrenia: a dou-bleblind randomized placebo-controlled trial. Biol Psychiatry 2008;64:361-368
Lavoie S, Murray MM, Deppen P, et al: Glutathione precursor N-acetyl-cysteine improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 2008;33:2187-2199
Javitt DC, Doneshka P, Zylberman I, Ritter W, Vaughan HG, Jr: Impairment of early cortical processing in schizophrenia: an event-related potential confirmation study. Biol Psychiatry 1993;33:513-519
Berk M, Copolov DL, Dean O, et al: N-acetyl cysteine for depressive symptoms in bipolar disorder: a double-blind randomized placebo-controlled trial. Biol Psychiatry 2008;64:468-475
Crow TJ: The continuum of psychosis and its implication for the structure of the gene. Br J Psychiatry 1986;149:419-429
McGorry PD, Yung AR: Early intervention in psychosis: an overdue reform. Aust NZ J Psychiatry 2003;37:393-398
Killackey E, Yung AR, McGorry PD: Early psychosis: where we’ve been, where we still have to go. Epidemiol Psichiatr Soc 2007;16:102-108
Falloon IR: Early intervention for first episodes of schizophrenia: a preliminary exploration. Psychiatry 1992;55:4-15
Loebel AD, Lieberman JA, Alvir JM, et al: Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 1992;149:1183-1188
McGlashan TH: Early detection and intervention in schizophrenia: research. Schizophr Bull 1996;22:327-345
McGorry PD, Edwards J, Mihalopoulos C, Harrigan SM, Jackson HJ: EPPIC: an evolving system of early detection and optimal management. Schizophr Bull 1996;22:305-326
Yung AR, McGorry PD: The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull 1996;22:353-370
Yung AR, Nelson B, Stanford C, et al: Validation of ‘prodromal’ criteria to detect individuals at ultra high risk of psychosis: 2 year follow-up. Schizophr Res 2008;105:10-17
McGorry PD, Yung AR, Bechdolf A, Amminger P: Back to the future: predicting and reshaping the course of psychotic disorder. Arch Gen Psychiatry 2008;65:25-27
Cannon TD, Cadenhead K, Cornblatt B, et al: Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry 2008;65:28-37
Birchwood M, Todd P, Jackson C: Early intervention in psychosis: the critical period hypothesis. Br J Psychiatry Suppl 1998;172:(suppl 33)53-59
Conus P, Montagrin Y, Bircher R, et al: TIPPLausanne first episode psychosis program: patients’ baseline characteristics and impact of the program on adherence to psychosocial treatment. Schizophr Res 2008;98:(suppl 1)81
McGlashan TH, Miller TJ, Woods SW: Pre-onset detection and intervention research in schizophrenia psychoses: current estimates of benefit and risk. Schizophr Bull 2001;27:563-570
Phillips LJ, McGorry PD, Yung AR, et al: Prepsychotic phase of schizophrenia and related disorders: recent progress and future opportunities. Br J Psychiatry Suppl 2005;48:s33-s44
Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM: Folate vitamin B12 homocysteine and the MTHFR 677C→T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry 2003;60:618-626
James SJ, Cutler P, Melnyk S, et al: Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004;80:1611-1617
Smythies JR, Gottfries CG, Regland B: Disturbances of one-carbon metabolism in neuropsychiatric disorders: a review. Biol Psychiatry 1997;41:230-233
Muskiet FA, Kemperman RF: Folate and long-chain polyunsaturated fatty acids in psychiatric disease. J Nutr Biochem 2006;17:717-727
Regland B, Johansson BV, Gottfries CG: Homocysteinemia and schizophrenia as a case of methylation deficiency. J Neural Transm Gen Sect 1994;98:143-152
Regland B: Schizophrenia and single-carbon metabolism. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1124-1132
Park LC, Baldessarini RJ, Kety SS: Methionine effects on chronic schizophrenics. Arch Genet Psychiatry 1965;12:346-351
Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M: How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 2008;29:190-201
Connor H, Newton DJ, Preston FE, Woods HF: Oral methionine loading as a cause of acute serum folate deficiency: its relevance to parenteral nutrition. Postgrad Med J 1978;54:318-320
Ventura P, Panini R, Verlato C, Scarpetta G, Salvioli G: Peroxidation indices and total antioxidant capacity in plasma during hyperhomocysteinemia induced by methionine oral loading. Metabolism 2000;49:225-228
Raijmakers MT, Schilders GW, Roes EM, et al: N-acetylcysteine improves the disturbed thiol redox balance after methionine loading. Clin Sci (Lond) 2003;105:173-180
Avila MA, Corrales FJ, Ruiz F, et al: Specific interaction of methionine adenosyltransferase with free radicals. Biofactors 1998;8:27-32
Gomes-Trolin C, Yassin M, Gottfries CG, et al: Erythrocyte and brain methionine adenosyltransferase activities in patients with schizophrenia. J Neural Transm 1998;105:1293-1305
Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M: How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 2008;29:190-201
Abdolmaleky HM, Smith CL, Faraone SV, et al: Methylomics in psychiatry: modulation of geneenvironment interactions may be through DNA methylation. Am J Med Genet 2004;127B:51-59
Abdolmaleky HM, Cheng KH, Russo A, et al: Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 2005;134:60-66
Godfrey PS, Toone BK, Carney MW, et al: Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336:392-395
Yehuda S, Rabinovitz S, Mostofsky DI: Essential fatty acids are mediators of brain biochemistry and cognitive functions. J Neurosci Res 1999;56:565-570
Simopoulos AP: Importance of the ratio of omega-6/ omega-3 essential fatty acids: evolutionary aspects. World Rev Nutr Diet 2003;92:1-22
Keshavan MS, Mallinger AG, Pettegrew JW, Dippold C: Erythrocyte membrane phospholipids in psychotic patients. Psychiatry Res 1993;49:89-95
Reddy RD, Keshavan MS, Yao JK: Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neurolepticnaive baseline. Schizophr Bull 2004;30:901-911
Mahadik SP, Mukherjee S, Correnti EE, et al: Plasma membrane phospholipid and cholesterol distribution of skin fibroblasts from drug-naive patients at the onset of psychosis. Schizophr Res 1994;13:239-247
Horrobin DF, Manku MS, Hillman H, Iain A, Glen M: Fatty acid levels in the brains of schizophrenics and normal controls. Biol Psychiatry 1991;30:795-805
Pettegrew JW, Keshavan MS, Panchalingam K, et al: Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode drug-naive schizophrenics: a pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 1991;48:563-568
Yao J, Stanley JA, Reddy RD, Keshavan MS, Pettegrew JW: Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites. Biol Psychiatry 2002;52:823-830
Altar CA, Jurata LW, Charles V, et al: Deficient hippocampal neuron expression of proteasome ubiquitin and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry 2005;58:85-96
Freeman MP, Hibbeln JR, Wisner KL, et al: Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 2006;67:1954-1967
Peet M, Horrobin DF: A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 2002;36:7-18
Peet M, Horrobin DF: A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002;59:913-919
Nemets B, Stahl Z, Belmaker RH: Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477-479
Su KP, Huang SY, Chiu CC, Shen WW: Omega-3 fatty acids in major depressive disorder: a preliminary double-blind placebo-controlled trial. Eur Neuropsychopharmacol 2003;13:267-271
Ross BM, Seguin J, Sieswerda LE: Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid?. Lipids Health Dis 2007;6:21
Bentsen H, Lingjaerde O, Solberg DK, Murck H: A multicentre placebo-controlled trial of eicosapentaenoic acid and antioxidant supplementation in the treatment of schizophrenia and related disorders. Schizophr Res 2006;81:29
Gerster H: High-dose vitamin C: a risk for persons with high iron stores?. Int J Vitam Nutr Res 1999;69:67-82
Podmore ID, Griffiths HR, Herbert KE, et al: Vitamin C exhibits pro-oxidant properties. Nature 1998;392:559
Smythies JR, Gottfries CG, Regland B: Disturbances of one-carbon metabolism in neuropsychiatric disorders: a review. Biol Psychiatry 1997;41:230-233
Handy DE, Zhang Y, Loscalzo J: Homocysteine down-regulates cellular glutathione peroxidase (GPx1) by decreasing translation. J Biol Chem 2005;280:15518-15525
Vitvitsky V, Prudova A, Stabler S, et al: Testosterone regulation of renal cystathionine beta-synthase: implications for sex-dependent differences in plasma homocysteine levels. Am J Physiol Renal Physiol 2007;293:F594-F600

Send Email

Recipient(s) will receive an email with a link to 'Personalized NutritionTranslating Nutrigenetic/Nutrigenomic Research into Dietary Guidelines > 131 - 153: Redox Dysregulation and Oxidative Stress in Schizophrenia: Nutrigenetics as a Challenge in Psychiatric Disease Prevention' and will not need an account to access the content.

Subject: Personalized NutritionTranslating Nutrigenetic/Nutrigenomic Research into Dietary Guidelines > 131 - 153: Redox Dysregulation and Oxidative Stress in Schizophrenia: Nutrigenetics as a Challenge in Psychiatric Disease Prevention

(Optional message may have a maximum of 1000 characters.)

Close Modal

or Create an Account

Close Modal
Close Modal