Schizophrenia may be associated with elevations in glutamate levels in the anterior cingulate cortex (ACC), and this may be apparent in patients who have not responded well to conventional antipsychotic treatment. Compounds that can decrease ACC glutamate levels may have therapeutic potential for this group, however before this PhD the extent to which glutamate can be modulated pharmacologically was unknown. This PhD examined the potential of two different drugs to reduce ACC glutamate levels in schizophrenia, N-acetylcysteine (NAC), and clozapine. Study One: N-acetylcysteine. The primary aim of this study was to examine whether a single oral dose of NAC can alter brain glutamate levels, as well as regional cerebral blood flow (CBF) and resting state functional connectivity (rs-FC) in patients with schizophrenia. In the ACC, glutamate + glutamine was significantly reduced in the NAC compared to placebo condition, but this effect was not related to changes in CBF or rs-FC. The results provided preliminary evidence that NAC may reduce ACC glutamate metabolites in schizophrenia. Study Two: Clozapine. Clozapine has been shown to be effective in treating symptoms that have not responded to conventional antipsychotic medication. While the reasons for this superior efficacy is unclear, it may relate to the ability of clozapine to modulate brain glutamate. The primary aim of this study was to measure glutamate levels in the ACC and caudate in patients with TRS before and after 12 weeks of treatment with clozapine. We found that clozapine treatment was associated with a longitudinal reduction in glutamate levels in the caudate, which was associated with symptomatic improvement. Conclusions: The work described in this PhD supports the idea that brain glutamate metabolites can be reduced pharmacologically in schizophrenia. These findings can be translated to future work to determine the extent to which such reductions in glutamate may relate to clinical efficacy.