Extensive research has shown that schizophrenia is a complex disorder with multiple factors contributing to its aetiology. Prominent among these are neurochemical abnormalities and the two leading theories of neurochemical dysfunction are – 1) the NMDAR hypofunction hypothesis which relates to an aberrant glutamate (Glu)/glutamine (Gln) system¹ and 2) the neuro-inflammation hypothesis which relates to altered redox balance and glutathione (GSH) levels.² These two theories are now thought to be related. However, studies investigating levels of Glu, Gln or GSH using MR spectroscopy (MRS) in schizophrenia have reported conflicting results. There is no clear evidence in humans as to how these two systems are related to each other, or to clinical aspects of the illness. However, current evidence raises the possibility that the nature of abnormalities in these neurochemicals might change with advancing phase of illness.^2,3In this study we specifically aim to investigate whether deficits in GSH, Glu and Gln are more pronounced in patients with residual schizophrenia (defined in the ICD-10 as the chronic stage in the development of the illness in which there has been a clear progression from an early stage (with psychotic symptoms) to a later stage characterized by long-term negative symptoms).⁴45 healthy volunteers, 15 patients with residual schizophrenia and 13 patients with non-residual schizophrenia participated in this study. All scans were conducted on a Philips Achieva 7T MR scanner (Philips Healthcare, Best, Netherlands) using a volume transmit head coil and a 32 channel receive head coil. An MPRAGE sequence (isotropic resolution = 1 mm³, TE/TR = 3/7 ms, FA = 8°) was used for voxel positioning. 1^H STEAM spectra were obtained from the anterior cingulate cortex (ACC) (20x18x25 mm³) – the main region of interest and also from the visual cortex (20x22x20 mm³) and the left insula (40x12x18 mm³) for comparison. A sample spectrum is shown in Figure 1 and voxel placements are shown in Figure 2. The following acquisition parameters were used: TE/TM/TR = 17/17/2000 ms, 256 averages, 4096 samples and BW = 4 kHz. MRS data were reformatted, phase-corrected, averaged across coil-elements and repeats and realigned to account for frequency drifts. The data were then combined using the coil-averaging technique reported by Hall et al.⁵ LCModel⁶ was used for absolute metabolite quantification and concentrations were corrected for partial volume effects.⁷ Statistical analyses were performed using SPSS (IBM). Three univariate ANOVAS were performed to explore differences in GSH, Glu and Gln between the three groups. Partial correlations with age and current medication intake as covariates were used to examine the relationship between GSH and Glu in the ACC in the three groups. Patients with residual schizophrenia had significantly less GSH, Glu and Gln in the ACC compared to healthy volunteers (p < 0.05) and less Glu compared to patients with non-residual schizophrenia (p < 0.05) (Figure 3). No significant differences were found in the insula or the visual cortex. There was a strong positive correlation between GSH and Glu in the ACC in healthy controls (r = 0.68, p < 0.05) and in patients with residual schizophrenia (r = 0.80, p < 0.05) (Figure 4). Although not statistically significant, there was a trend toward positive correlation between GSH and Glu in the ACC in patients with non-residual schizophrenia.Our findings are consistent with two alternate hypotheses: in the first hypothesis the primary problem in schizophrenia is a long standing deficit in GSH and an associated tendency to NMDAR hypofunction; in the other, the primary problem is an acute event that triggers glutamatergic over-activity, excitotoxicity, neural damage and a subsequent deficit state. We also found a strong positive correlation between GSH and Glu in healthy controls, consistent with a mechanistic link between the antioxidant and glutamatergic systems in the human brain. These findings, as well as correlations between these neurochemicals in both patient groups in the stable state, support the hypothesis that under steady state conditions, low levels of GSH are usually associated with low levels of glutamatergic neurotransmission. This finding provides scope for further investigations into the relationship between oxidative stress and NMDAR hypofunction and brings together the neuroinflammatory and glutamatergic excitotoxicity theories of schizophrenia.