Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients
- 14 November 2007
- journal article
- clinical trial
- Published by Springer Science and Business Media LLC in Neuropsychopharmacology
- Vol. 33 (9), 2187-2199
- https://doi.org/10.1038/sj.npp.1301624
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=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.Keywords
This publication has 64 references indexed in Scilit:
- Impaired glutathione synthesis in schizophrenia: Convergent genetic and functional evidenceProceedings of the National Academy of Sciences of the United States of America, 2007
- Neurophysiological Endophenotypes of Schizophrenia: The Viability of Selected Candidate MeasuresSchizophrenia Bulletin, 2006
- Schizophrenia and Oxidative Stress: Glutamate Cysteine Ligase Modifier as a Susceptibility GeneAmerican Journal of Human Genetics, 2006
- Cluster Validation by Prediction StrengthJournal of Computational and Graphical Statistics, 2005
- The antioxidants α‐lipoic acid and N‐acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 miceJournal of Neurochemistry, 2003
- An event-related potential study on the impairment of automatic processing of auditory input in schizophreniaBrain Topography, 1996
- Mapping event-related brain potential microstates to sentence endingsBrain Topography, 1995
- NMDA receptor channels: Subunit-specific potentiation by reducing agentsNeuron, 1994
- Dose dependent pharmacokinetics of N‐ACETYLCYSTEINE AFTER ORAL DOSING TO MANBiopharmaceutics & Drug Disposition, 1990
- Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteineEuropean Journal of Clinical Pharmacology, 1988