Abstract
RationaleN-Acetylcysteine (NAC) is currently under investigation as an adjunctive treatment for schizophrenia. The therapeutic potential of NAC may involve modulation of brain glutamate function, but its effects on brain glutamate levels in schizophrenia have not been evaluated.ObjectivesThe aim of this study was to examine whether a single dose of NAC can alter brain glutamate levels. A secondary aim was to characterise its effects on regional brain perfusion.MethodsIn a double-blind placebo-controlled crossover study, 19 patients with a diagnosis of schizophrenia underwent two MRI scans, following oral administration of 2400 mg NAC or matching placebo. Proton magnetic resonance spectroscopy was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling was used to assess the effects of NAC on resting cerebral blood flow (rCBF) in the same regions.ResultsRelative to the placebo condition, the NAC condition was associated with lower levels of Glx/Cr, in the ACC (P < 0.05), but not in the caudate nucleus. There were no significant differences in CBF in the NAC compared to placebo condition.ConclusionsThese data provide preliminary evidence that NAC can modulate ACC glutamate in patients with schizophrenia. In contrast, physiological effects of NAC on the brain were not detectable as between session changes in rCBF. Future studies assessing the effects of a course of treatment with NAC on glutamate metabolites in schizophrenia are indicated.
Highlights
Two-thirds of patients with schizophrenia show a suboptimal symptomatic response to standard antipsychotic administration (Meltzer 1997; Lindenmayer 2000)
Using 1H-MRS, we evaluated glutamate levels in the anterior cingulate cortex (ACC) and right caudate nucleus, the brain areas where an elevation in glutamate has been linked to a poor antipsychotic response (Egerton et al 2012; Demjaha et al 2014; Goldstein et al 2015; Mouchlianitis et al 2016), and where, in preclinical studies, the administration of NAC reduces glutamate levels (Baker et al 2008; Durieux et al 2015)
Symptom severity was assessed during the health screen using the Positive and Negative Syndrome Scale (PANSS; (Kay and Qpjer 1982)), Clinical Global Impression-Severity (CGI-S; (Guy, 1976)), and functioning was assessed using Global Assessment of Functioning scale (GAF; (Hall 1995))
Summary
Two-thirds of patients with schizophrenia show a suboptimal symptomatic response to standard antipsychotic administration (Meltzer 1997; Lindenmayer 2000). There are substantial on-going efforts to develop alternative pharmacological interventions for this group, with a major focus on compounds that can modulate glutamatergic neurotransmission (Buchanan et al 2007; Kinon and Gómez 2013; BugarskiKirola et al 2016, 2017) The ability of such compounds to modulate glutamate levels can be tested in animal models during early stages of drug development (Moghaddam and Krystal 2012), but it is not known whether similar effects occur in patients with schizophrenia. Glutamatergic theories of schizophrenia predict an elevation in cortical glutamate, and a therapeutic potential for compounds that can facilitate NMDA function and decrease glutamate release (Moghaddam and Javitt 2012)
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