Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.
Neuropsychopharmacology (Impact Factor: 7.05). 09/2008; 33(9):2187-99. DOI: 10.1038/sj.npp.1301624
Source: PubMed


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.

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    • "MMN has demonstrated utility for forecasting the duration of time to conversion of psychosis in at risk individuals (Bodatsch et al., 2011; Perez et al., 2014b). In addition, MMN is sensitive to pharmacologic (Javitt et al., 1996; Umbricht et al., 2000, 2002; Engeland et al., 2002; Inami et al., 2005, 2007; Baldeweg et al., 2006; Dunbar et al., 2007; Lavoie et al., 2007; Ehrlichman et al., 2008; Martin et al., 2009; Dulude et al., 2010; Nakamura et al., 2011; Gil-da-Costa et al., 2013; Preskorn et al., 2014) and cognitive challenges (Rissling et al., 2013b) and predicts a positive response to some treatments (e.g., Kawakubo et al., 2007). This paper demonstrates the feasibility of using MMN (and P3a) in multi-site studies of SZ patients and HCS and multi-site treatment trials with centralized quality assurance, data management, and analysis. "
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    ABSTRACT: Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test–retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n = 824, SZ n = 966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d = 0.96) and P3a (d = 0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.
    Schizophrenia Research 10/2014; 163(1-3). DOI:10.1016/j.schres.2014.09.042 · 3.92 Impact Factor
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    • "Glutathione (GSH) is an important antioxidant and free radical scavenger that has been found to be decreased in the brains of people with schizophrenia [25, 26]. Although oral GSH supplementation has poor bioavailability [27], N-Acetyl Cysteine (NAC) has been shown to successfully raise plasma glutathione levels in those with schizophrenia [28]. In a case study of a 24-year old woman with chronic and worsening paranoid-type schizophrenia that was generally unresponsive to anti-psychotic treatment, the addition of NAC supplementation improved the patient’s symptomatology in seven days. "
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    ABSTRACT: Schizophrenia is a chronic condition that impacts significantly not only on the individual and family, but the disorder also has wider consequences for society in terms of significant costs to the economy. This highly prevalent condition affects approximately 1% of the worldwide population, yet there are few therapeutic options. The predominant treatment strategy for schizophrenia is anti-psychotic medication (with or without additional talking therapy) even though this approach lacks efficacy in managing the negative symptoms of the condition, is not effective in one-third of the patient group and the side effects of the medication can be severe and debilitating. In recent years, a number of pathophysiological processes have been identified in groups of people with schizophrenia including oxidative stress, one-carbon metabolism and immune-mediated responses. A number of studies have shown that these altered physiological mechanisms can be ameliorated by nutritional interventions in some individuals with schizophrenia. This review briefly describes the aforementioned processes and outlines research that has investigated the utility of nutritional approaches as an adjunct to anti-psychotic medication including antioxidant and vitamin B supplementation, neuroprotective and anti-inflammatory nutrients and exclusion diets. Whilst none of these interventions provides a ‘one-size-fits-all’ therapeutic solution, we suggest that a personalised approach warrants research attention as there is growing agreement that schizophrenia is a spectrum disorder that develops from the interplay between environmental and genetic factors. Electronic supplementary material The online version of this article (doi:10.1186/1475-2891-13-91) contains supplementary material, which is available to authorized users.
    Nutrition Journal 09/2014; 13(1):91. DOI:10.1186/1475-2891-13-91 · 2.60 Impact Factor
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    • "MMN was significantly different among groups, with NAC treatment improving MMN in NVHL rats (Figures 7A and 7B). This observation is consistent with the effect of NAC on MMN in patients (Lavoie et al., 2008) and indicates the NVHL model reproduces an important disease marker that can be prevented by juvenile antioxidant treatment. As MMN depends on NMDA receptor function (Umbricht et al., 2000) and NMDA hypofunction in PVI is suspected in schizophrenia, it is possible that MMN improvement with NAC results from restored PVI activity. "
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    ABSTRACT: Abnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention.
    Neuron 08/2014; 83(5). DOI:10.1016/j.neuron.2014.07.028 · 15.05 Impact Factor
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