Placebo-controlled augmentation trials of the antioxidant NAC in schizophrenia: A review

Ann Clin Psychiatry. 2016 Aug;28(3):190-6.


Background: Several studies have reported that schizophrenia is associated with mitochondrial abnormalities, glutathione deficit, and increased brain oxidative stress (free radicals). N-acetylcysteine (NAC) is a strong antioxidant with potential therapeutic benefit in schizophrenia, according to some reports. We conducted a review of the published controlled studies, with the goal of determining the efficacy profile of NAC as an adjunctive treatment for schizophrenia.

Methods: An online search was conducted for all placebo-controlled, double-blind, randomized clinical trials of NAC in schizophrenia, and a review was conducted.

Results: Two studies met the criteria for inclusion. Berk et al (2008) used NAC as an adjunctive treatment to atypical antipsychotics in subjects with chronic schizophrenia who were stable on antipsychotic medications. Treatment at 8 weeks was less efficacious than placebo, but at 24 weeks produced significant reductions vs placebo in Positive and Negative Syndrome Scale (PANSS) negative (d = 0.52), general (d = 0.46), and total (d = 0.57) scores. Farokhnia et al (2013) used NAC as an adjunctive treatment to risperidone in subjects with chronic schizophrenia who were experiencing an acute exacerbation episode. Eight weeks of treatment led to clinically significant reductions vs placebo in PANSS negative (d = 0.96), general (d = 0.59), and total (d = 0.88) scores.

Conclusions: The data suggest that adjunctive NAC may be efficacious in reducing negative and general symptoms in schizophrenia.

Publication types

  • Review

MeSH terms

  • Acetylcysteine / therapeutic use*
  • Antipsychotic Agents / therapeutic use
  • Double-Blind Method
  • Drug Therapy, Combination*
  • Free Radical Scavengers / therapeutic use*
  • Humans
  • Psychiatric Status Rating Scales
  • Randomized Controlled Trials as Topic*
  • Risperidone / therapeutic use
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology


  • Antipsychotic Agents
  • Free Radical Scavengers
  • Risperidone
  • Acetylcysteine