Previous findings in psychosis have revealed mixed findings on glutamate (Glu) levels in the dorsal anterior cingulate cortex (dACC). Factors such as illness chronicity, methodology, and medication status have impeded a more nuanced evaluation of Glu in psychosis. The goal of this longitudinal neuroimaging study was to investigate the role of antipsychotics on Glu in the dACC in antipsychotic-naïve first-episode psychosis (FEP) patients.

We enrolled 117 healthy controls (HCs) and 113 antipsychotic-naïve FEP patients for this study. 3T proton magnetic resonance spectroscopy (1H-MRS; PRESS; TE = 80 ms) data from a voxel prescribed in the dACC were collected from all participants at baseline, 6, and 16 weeks following antipsychotic treatment. Glutamate levels were quantified using the QUEST algorithm and analyzed longitudinally using linear mixed-effects models.

We found that baseline dACC glutamate levels in FEP were not significantly different than those of HCs. Examining Glu levels in FEP revealed a decrease in Glu levels after 16 weeks of antipsychotic treatment; this effect was weaker in HC. Finally, baseline Glu levels were associated with decreases in positive symptomology.

We report a progressive decrease of Glu levels over a period of 16 weeks after initiation of treatment and a baseline Glu level association with a reduction in positive symptomology, suggestive of a potential mechanism of antipsychotic drug (APD) action. Overall, these findings suggest that APDs can influence Glu within a period of 16 weeks, which has been deemed as an optimal window for symptom alleviation using APDs.