A Meta-Analysis of Placebo-Controlled Trials of NAC Augmentation in Schizophrenia

Background: Several studies have reported that schizophrenia is associated with abnormalities of glutathione metabolism and increased brain oxidative stress (free radicals). N-acetylcysteine (NAC) is a strong anti-oxidant with potential therapeutic benefit in schizophrenia. We conducted a meta-analysis of the published control studies with the goal of determining the efficacy profile of NAC as an adjunctive treatment in schizophrenia. Methods: An online search was conducted for all placebo-controlled, randomized, double-blind, clinical trials of NAC in schizophrenia and a meta-analysis was conducted. Results: Two studies met the criteria for inclusion. Berk et al. 2008 used NAC as an adjunctive treatment to typical and atypical antipsychotics (45% clozapine, 20% olanzapine) in stable chronic subjects (N=140, mean duration of illness 12.4±8.2 years). NAC treatment at 8 weeks was less efficacious than placebo, but 24 weeks of treatment with NAC produced significant reductions vs. placebo in PANSS negative (d=0.52), general (d=0.46), and total score (d=0.57). The second trial by Farokhnia et al. 2013 used NAC as an adjunctive treatment to risperidone in chronic subjects with active psychosis (N=42, mean duration of illness 6.94±3.42 years). 8 weeks of treatment led to clinically significant reductions vs. placebo in PANSS negative (d=0.96), general (d=0.59), and total score (d=0.88). Conclusion: The data suggest that adjunctive NAC may be efficacious in reducing negative and general symptoms in schizophrenia. Based on studies so far, adjunctive NAC treatment may be useful in schizophrenia. Controlled trials in first episode patients and the effects of NAC on elevated oxidative stress biomarkers are needed.