Abstract
RationaleThere is interest in employing N-acetylcysteine (NAC) in the treatment of schizophrenia, but investigations of the functional signatures of its pharmacological action are scarce.ObjectivesThe 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).MethodsIn 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.ResultsCompared 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).ConclusionsThese 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.
Highlights
There is an urgent need to develop new treatments for the large proportion of patients with schizophrenia who do not show an adequate response to standard antipsychotic treatment
We recently reported that a single dose of NAC compared to placebo was associated with lower levels of glutamate plus glutamine (Glx) in the anterior cingulate cortex (ACC) (McQueen et al 2018), similar to findings in cocaine-addicted individuals (Schmaal et al 2012)
This study evaluated brain network resting-state functional connectivity (rs-FC) following a single dose of NAC versus placebo in patients with schizophrenia
Summary
There is an urgent need to develop new treatments for the large proportion of patients with schizophrenia who do not show an adequate response to standard antipsychotic treatment. Antipsychotics are predominantly dopamine D2 receptor antagonists (Nordström et al 1993; Brisch 2014). This raises the possibility that patients who fail to respond to conventional antipsychotic treatment may benefit from mono- or adjunctive therapy with interventions that target non-dopaminergic mechanisms. In addition to dopamine dysfunction, schizophrenia is associated with glutamatergic abnormalities (Moghaddam and Javitt 2012) (Merritt et al 2016), functional dysconnectivity within brain networks (Stephan et al 2006), inflammation (Khandaker et al 2015) and oxidative stress (Flatow et al 2013). Psychopharmacology (2020) 237:443–451 these processes may enhance treatment options for those who do not respond to conventional antipsychotics. N-acetylcysteine (NAC) is an L-cysteine precursor (Arakawa and Ito 2007) and may have therapeutic potential due to its ability to regulate glutathione (GSH) and excessive brain glutamate through the cysteine-glutamate antiporter (Bridges et al 2012), while increasing endogenous antioxidants and reducing inflammation (Berk et al 2013)
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