Effect of single dose N-acetylcysteine administration on resting state functional connectivity in schizophrenia

Psychopharmacology (Berl). 2020 Feb;237(2):443-451. doi: 10.1007/s00213-019-05382-1. Epub 2019 Nov 30.


Rationale: There is interest in employing N-acetylcysteine (NAC) in the treatment of schizophrenia, but investigations of the functional signatures of its pharmacological action are scarce.

Objectives: The aim of this study was to identify the changes in resting-state functional connectivity (rs-FC) that occur following administration of a single dose of NAC in patients with schizophrenia. A secondary aim was to examine whether differences in rs-FC between conditions were mediated by glutamate metabolites in the anterior cingulate cortex (ACC).

Methods: In a double-blind, placebo-controlled crossover design, 20 patients with schizophrenia had two MRI scans administered 7 days apart, following oral administration of either 2400 mg NAC or placebo. Resting state functional fMRI (rsfMRI) assessed the effect of NAC on rs-FC within the default mode network (DMN) and the salience network (SN). Proton magnetic resonance spectroscopy was used to measure Glx/Cr (glutamate plus glutamine, in ratio to creatine) levels in the ACC during the same scanning sessions.

Results: Compared to the placebo condition, the NAC condition was associated with reduced within the DMN and SN, specifically between the medial pre-frontal cortex to mid frontal gyrus, and ACC to frontal pole (all p < 0.04). There were no significant correlations between ACC Glx/Cr and rs-FC in either condition (p > 0.6).

Conclusions: These findings provide preliminary evidence that NAC can reduce medial frontal rs-FC in schizophrenia. Future studies assessing the effects of NAC on rs-FC in early psychosis and on repeated administration in relation to efficacy would be of interest.

Keywords: Functional connectivity; Glutamate; Magnetic resonance imaging; Magnetic resonance spectroscopy; Resting state; Schizophrenia; n-Acetylcysteine.

Publication types

  • Clinical Trial

MeSH terms

  • Acetylcysteine / administration & dosage*
  • Adult
  • Brain / diagnostic imaging*
  • Brain / drug effects
  • Brain / metabolism
  • Cross-Over Studies
  • Double-Blind Method
  • Female
  • Gyrus Cinguli / diagnostic imaging
  • Gyrus Cinguli / drug effects
  • Gyrus Cinguli / metabolism
  • Humans
  • Magnetic Resonance Imaging / methods*
  • Male
  • Middle Aged
  • Nerve Net / diagnostic imaging*
  • Nerve Net / drug effects
  • Nerve Net / metabolism
  • Proton Magnetic Resonance Spectroscopy / methods
  • Rest / physiology*
  • Schizophrenia / diagnostic imaging*
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism


  • Acetylcysteine