N-acetylcysteine for the treatment of glutathione deficiency and oxidative stress in schizophrenia.

F o r s c s s v a w a D espite decades of intense research and development, current treatments for schizophrenia (SZ) have not only met with limited efficacy but are also often associated with serious side effects, justifying the heightened interest in the development of alternate therapies (1). With mounting experimental evidence implicating glutathione (GSH) deficiency and increased oxidative stress in the pathophysiology of most major psychiatric disorders (2), novel neuroprotective strategies that aim to limit oxidative stress-mediated cellular damage in such disorders, including SZ, are being increasingly scrutinized (2,3). Building upon a prior study that found significant GSH deficits in the medial prefrontal cortex and cerebrospinal fluid of antipsychotic-free patients with SZ compared with healthy controls (4), Duarte et al. (5) report in this issue the results of a study of a transgenic mouse model of GSH deficiency as a putative model of the interplay between N-methyl-D-aspartate receptor antagonism and redox dysregulations, which may offer new targets for the development of novel treatments in schizophrenia. Briefly, the GSH-deficient mouse model in the study by Duarte et al. (5) has knockout (KO) of glutamate-cysteine ligase modulatory subunit (GCLM) in the ratelimiting GSH synthetic enzyme. Using H magnetic resonance spectroscopy (H MRS) at 14.1 T, the investigators longitudinally meaured the levels of several major neurometabolites in the anterior ingulate cortex of the resulting GCLM-KO mice, as well as in wildype and heterozygous mice, for comparison. In addition, subsets of nimals in each group were treated with N-acetylcysteine (NAC), a utative GSH precursor, to assess group effects of treatment on ortical GSH and other metabolite levels. In GCLM-KO mice, the investigators found a number of metabolic lterations, including increased glutamate (Glu), glutamine, and gluamine/Glu, which were similar to those found in schizophrenia and hich normalized following treatment with NAC. Because many of hese metabolic alterations and their subsequent normalization with AC treatment occurred in prepubertal animals, the investigators peculated that their results showed the potential of NAC as a treatent of at-risk individuals for schizophrenia and the associated abnoralities as promising biomarkers for early diagnosis and for monitorng treatment response. Significantly, the study did not establish a irect role of GSH in the beneficial effects of NAC treatment because one of the NAC-treated mice showed measurable elevations of cortial GSH. Because the absence of significant elevations of GSH in the CLM-KO mice was due to the lack of a functioning GSH synthetic ngine and because the tight feedback mechanism that inhibits GSH ynthesis in tissue with normal levels (6) had prevented elevations of he antioxidant in wild-type mice, this overall failure of NAC to spur ignificant increases in GSH may be one of the more informative results f this study. It has established experimentally that for treatment stratgies that attempt to elevate cortical GSH levels through NAC supple-