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Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients
Open accessAbstract
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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“In addition, NAC normalized neuronal activity and connectivity and improved mismatch-negativity (Lavoie et al., 2008), an auditory-related, NMDA-dependent evoked potential typically impaired in schizophrenia (Umbricht et al., 2000).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Lavoie et al., 2008
In the citing paper
“Published studies have revealed beneficial effects in schizophrenia patients as an add-on to maintenance medication [100][101][102][103] and ongoing studies are following up their results and including additional metrics of efficacy such as brain GSH imaging in order to reflect the BBB permeability analyses of NAC that have been performed in rodents 104 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [102]
In the citing paper
“Other compounds that may reverse MMN deficits in schizophrenia include N-acetylcysteine, a precursor of the brain antioxidant glutathione (59) and D-serine, an endogenous NMDAR modulator (60).”
From Sensory Processing Dysfunction in the Personal Experience and Neuronal Machinery of Schizophrenia (2015) · cites this paper as [59]
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Metadata
- Authors
- Lavoie, S., Murray, M. M., Deppen, P., Knyazeva, M. G., Berk, M., Boulat, O., Bovet, P., Bush, A. I., Conus, P., Copolov, D., Fornari, E., Meuli, R., Solida, A., Vianin, P., Cuénod, M., Buclin, T., & Do, K. Q.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- Mental Health Research Institute (AU)
- Monash University (AU)
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2007-11-14
- Volume
- 33
- Issue
- 9
- Pages
- 2187-2199
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2003906510
- Cited by
- 371
- References
- 67
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 4 · 2023: 15 · 2022: 10 · 2021: 22 · 2020: 21 · 2019: 33 · 2018: 16 · 2017: 27 · 2016: 19 · 2015: 28 · 2014: 31 · 2013: 23 · 2012: 28
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Own your potential (DEAKIN) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- IRIS (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Stanley Medical Research Institute
- Centre d'Imagerie BioMédicale
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- N-acetylcysteine, glutathione, schizophrenia, mismatch negativity, NMDA receptor hypofunction, auditory evoked potentials, P300, auditory sensory processing, glutathione precursor
- MeSH terms
- Acetylcysteine, Acoustic Stimulation, Adult, Brain Mapping, Cerebral Cortex, Contingent Negative Variation, Discrimination, Psychological, Double-Blind Method, Electroencephalography, Evoked Potentials, Auditory, Female, Glutathione, Humans, Male, Middle Aged, Neuropsychological Tests, Reaction Time, Retrospective Studies, Schizophrenia, Time Factors, Free Radical Scavengers, Cross-Over Studies
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