Background: The glutamate hypothesis of schizophrenia postulates that dysfunction of glutamate circuits in the prefrontal cortex may contribute to negative symptoms, which are closely related to functional outcomes of patients. N-acetylcysteine (NAC), a dietary supplement, can potentially both normalize glutamate levels and increase glutathione levels to improve glutamate receptor functioning. The present study used magnetic resonance spectroscopy (MRS) to investigate whether NAC treatment can alter glutamate and glutathione concentrations in the prefrontal cortex and improve negative symptoms and cognitive performance in patients with schizophrenia.
Method: Patients meeting DSM-5 criteria for schizophrenia or schizoaffective disorder were recruited and randomized to either NAC or placebo treatment group. Patients underwent MRS scans to measure glutathione and glutamate concentrations in medial prefrontal cortex (MPFC) and dorsolateral prefrontal cortex (DLPFC), and completed clinical symptom assessments and cognitive performance measures at baseline and after treatment. Exploratory analyses were performed using baseline data from 23 subjects.
Results: Exploratory analyses revealed no significant correlations between glutathione levels in the MPFC or the DLPFC and clinical or cognitive measures. However, glutamate concentration in the MPFC was significantly correlated with general psychopathology as well as several cognitive domains including speed of processing, visual learning, and reasoning and problem solving. Glutamate concentration in the DLPFC was also correlated with reasoning and problem solving.
Discussion: We demonstrate successful measurement of glutamate levels in prefrontal cortex in patients with schizophrenia, and a possible correlation between cognitive performance and glutamate. These preliminary findings are consistent with a small number of studies which have implicated glutamate in cognitive functioning in patients with schizophrenia, and may support the glutamate hypothesis of schizophrenia. Increased sample size and examination of the effects of NAC, which influences glutamate concentration at the synapse, on cognition, will further illuminate these relationships.