1. ¹Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland
2. ²Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
3. ³EEG Core, Center for Biomedical Imaging of Lausanne and Geneva, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland
4. ⁴Radiology Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
5. ⁵Functional Electrical Neuroimaging Laboratory, Neuropsychology and Neurorehabilitation Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
6. ⁶Mental Health Research Institute of Victoria, Victoria, Australia
7. ⁷Department of Clinical and Biomedical Sciences, University of Melbourne, Melbourne, Australia
8. ⁸Central Laboratory for Clinical Chemistry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
9. ⁹Monash University, Clayton, Australia
10. ¹⁰Department of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

Correspondence: Dr KQ Do, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly 1008, Switzerland. Tel: +41 21 643 6565; Fax: +41 21 643 6562; E-mail: Kim.Do@CHUV.ch

¹¹These two authors have contributed equally to this work.

Received 10 May 2007; Accepted 9 October 2007; Published online 14 November 2007.

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.