title: 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 (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.
authors.affiliation: Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.
authors.forename: Suzie
authors.initials: S
authors.lastname: Lavoie
authors.forename: Micah M
authors.initials: MM
authors.lastname: Murray
authors.forename: Patricia
authors.initials: P
authors.lastname: Deppen
authors.forename: Maria G
authors.initials: MG
authors.lastname: Knyazeva
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Olivier
authors.initials: O
authors.lastname: Boulat
authors.forename: Pierre
authors.initials: P
authors.lastname: Bovet
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: Philippe
authors.initials: P
authors.lastname: Conus
authors.forename: David
authors.initials: D
authors.lastname: Copolov
authors.forename: Eleonora
authors.initials: E
authors.lastname: Fornari
authors.forename: Reto
authors.initials: R
authors.lastname: Meuli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Solida
authors.forename: Pascal
authors.initials: P
authors.lastname: Vianin
authors.forename: Michel
authors.initials: M
authors.lastname: Cuénod
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Kim Q
authors.initials: KQ
authors.lastname: Do
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000161:Acoustic Stimulation / Q000379:methods; D000328:Adult; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003265:Contingent Negative Variation / Q000187:drug effects*; D018592:Cross-Over Studies; D004192:Discrimination, Psychological / Q000187:drug effects; D004311:Double-Blind Method; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011930:Reaction Time / Q000187:drug effects; D012189:Retrospective Studies; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D016166:Free Radical Scavengers; D005978:Glutathione; D000111:Acetylcysteine