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

Abstract

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 (2g/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 ¼ 0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p ¼ 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.

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

“…If such activation of the IL-6/Nox2 pathway occurs in situations of genetically diminished brain-GSH levels, such as those described in some schizophrenia cohorts, it will lead to further decrease in GSH levels, NMDA-R hypofunction and increased oxidative damage to macromolecules and lipids (Do et al, 2009). Recent results showing that treatment with N-acetyl-cysteine, a precursor of GSH, improves negative symptoms, and corrects mismatch negativity in schizophrenia patients further support the idea of a redox imbalance in schizophrenia Lavoie et al, 2008).…”

Oxidative stress in psychiatric disorders: evidence base and therapeutic implications

“…NAC has been studied as an adjunctive treatment in schizophrenia in a recently completed 6-month, double-blind, randomized, placebo-controlled trial (n=140), which found significant advantages of NAC over placebo on several scales that include the Clinical Global Impressions (CGI) (effect size of 0.43), the Positive and Negative Symptoms Scale (PANSS) (effect size of 0.57) and the Barnes Akathisia Scale (BAS) (effect size of 0.44) (Berk et al, unpublished observations). In a subset of patients enrolled in this study (n=11), NAC was also associated with an increase in plasma glutathione and the amelioration of mismatch negativity, an auditory evoked potential component characteristically impaired in schizophrenia, which may indicate the ability of NAC to correct more fundamental neurophysiological dysfunction (Lavoie et al, 2007).…”

N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice

“…In this context, it is also important to note that activation of mGluRs reduces the loss of cellular GSH (Sagara and Schubert, 1998). Interestingly, antioxidants including omega-3 fatty acids (Sivrioglu et al, 2007) and NAC have already demonstrated clinical efficacy in the treatment of schizophrenia symptoms (Berk et al, 2008a;Lavoie et al, 2008), obsessive-compulsive disease (Grant et al, 2009;Odlaug and Grant, 2007), and bipolar disorder (Berk et al, 2008b). Our findings provide a rationale for this treatment effect and suggest a therapeutic option for the therapy of G72-associated psychiatric disorders.…”