Glutamatergic basis of antipsychotic response in first-episode psychosis: a dual voxel study of the anterior cingulate cortex

Neuropsychopharmacology. 2023 Sep 26. doi: 10.1038/s41386-023-01741-x. Online ahead of print.


A subgroup of patients with schizophrenia is believed to have aberrant excess of glutamate in the frontal cortex; this subgroup is thought to show poor response to first-line antipsychotic treatments that focus on dopamine blockade. If we can identify this subgroup early in the course of illness, we can reduce the repeated use of first-line antipsychotics and potentially stratify first-episode patients to intervene early with second-line treatments such as clozapine. The use of proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate and Glx (glutamate plus glutamine) may provide a means for such a stratification. We must first establish if there is robust evidence linking elevations in anterior cingulate cortex (ACC) glutamate metabolites to poor response, and determine if the use of antipsychotics worsens the glutamatergic excess in eventual nonresponders. In this study, we estimated glutamate levels at baseline in 42 drug-naive patients with schizophrenia. We then treated them all with risperidone at a standard dose range of 2-6 mg/day and followed them up for 3 months to categorize their response status. We expected to see baseline "hyperglutamatergia" in nonresponders, and expected this to worsen over time at the follow-up. In line with our predictions, nonresponders had higher glutamate than responders, but patients as a group did not differ in glutamate and Glx from the healthy control (HC) group before treatment-onset (F1,79 = 3.20, p = 0.046, partial η2 = 0.075). Glutamatergic metabolites did not change significantly over time in both nonresponders and responders over the 3 months of antipsychotic exposure (F1,31 = 1.26, p = 0.270, partial η2 = 0.039). We conclude that the use of antipsychotics without prior knowledge of later response delays symptom relief in a subgroup of first-episode patients, but does not worsen the glutamatergic excess seen at the baseline. Given the current practice of nonstratified use of antipsychotics, longer-time follow-up MRS studies are required to see if improvement in symptoms accompanies a dynamic shift in glutamate profile.