Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders

Schizophr Res. 2018 Sep;199:395-402. doi: 10.1016/j.schres.2018.03.012. Epub 2018 Mar 24.


Background: Currently approved medications for schizophrenia are relatively ineffective for negative symptoms and cognitive impairment. N-Acetyl Cysteine (NAC) is a neuroprotective agent that improved general symptoms, cognitive impairment and negative symptoms in some but not all studies, but failed to improve positive symptoms in patients with schizophrenia. Progressive brain mass loss (PBML) has been consistently observed in early phase schizophrenia. NAC mitigates the deleterious effects oxidative stress, inflammation and glutamatergic excitotoxicity and these three pathological processes are hypothesized to contribute to PBML.

Methods: In this study, we assessed the effects NAC (3600mg/day) in a 52-week, double-blind, placebo controlled trial on symptoms, and cognition in early phase schizophrenia spectrum disorders (N=60). In the context of the clinical trial, we explored the effects of NAC on brain morphology.

Results: NAC significantly improved (time×group) PANSS total (F=14.7, p<0.001), negative (F=5.1, p=0.024) and disorganized thought (F=13.7, p<0.001) symptom scores. NAC failed to improve PANSS positive symptoms and BACS cognitive scores. In preliminary analyses, baseline right (r=-0.48, p=0.041) and left (r=-0.45, p=0.018) total cortical thickness, and thickness in other cortical regions, were associated with NAC related improvement in PANSS total scores, but NAC, as compared to placebo, did not significantly impact brain morphology over the study treatment period.

Conclusions: These results replicate some but not all previous findings of NAC efficacy. Preliminary results suggest that NAC's symptom effects may be related to structural integrity, but NAC failed to demonstrate treatment effects on longitudinal measures of brain morphology. ClinicalTrials.gov Identifier: NCT01339858.

Keywords: Cognitive impairment; Early phase schizophrenia spectrum disorders; N-acetyl cysteine; Negative symptoms; Positive symptoms; Progressive brain mass loss.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / adverse effects
  • Acetylcysteine / therapeutic use*
  • Adult
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / therapeutic use*
  • Brain / diagnostic imaging
  • Brain / drug effects*
  • Cognition / drug effects*
  • Double-Blind Method
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Schizophrenia / diagnostic imaging
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology
  • Time Factors
  • Treatment Outcome
  • Young Adult


  • Antipsychotic Agents
  • Acetylcysteine

Associated data

  • ClinicalTrials.gov/NCT01339858