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

Abstract

Treatment-resistant schizophrenia is believed to be related to excess prefrontal glutamate. If we can identify these individuals early in the course of illness, the repeated use of rst-line antipsychotics can be reduced and rst-episode patients can be strati ed for accelerated treatments. The use of proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate and Glx (glutamate plus glutamine) provides a means for such a strati cation, but we must rst establish if there is robust evidence linking elevations in anterior cingulate cortex (ACC) glutamate metabolites to poor response, and determine if continuous exposure to antipsychotics worsens the glutamatergic excess in eventual non-responders. In this study, we estimated glutamate levels at baseline in 70 drug-naive patients with schizophrenia. We then treated them (N=42) with risperidone and followed them up for 3 months to categorize their response status. We hypothesized to see "hyperglutamatergia" at baseline in later non-responders and expected this to worsen with treatment. Non-responders had high glutamate before treatment-onset (F1,79=3.20, p=0.046, partial η2 = 0.075); However, glutamate levels did not change signi cantly over time in both non-responders and responders over the 3 months of treatment (F1,31=1.26, p=0.270, partial η2 = 0.039). Antipsychotic use without prior knowledge of later response delays symptom relief in a subgroup of rst-episode patients, but does not worsen the glutamatergic excess seen at baseline. Given the current practice of non-strati ed use of antipsychotics, longer-time follow-up MRS studies are required to see if improvement in symptoms accompanies a shift in glutamate pro le.

A multistage, dual voxel study of glutamate in the anterior cingulate cortex in schizophrenia supports a primary pyramidal dysfunction model of disorganization

“…Consistent with our previous research(60), we observed that pACC had higher glutamatergic level than dACC, a detailed discussion on this founding can be found in that article. Glu has been now consistently negatively associated with age(8), aligned with our results as well.…”

“…While interindividual variation in symptom severity has not mapped on glutamate differences in ACC in FES in many other studies(56, 57), at a meta-analytic level, studies where samples had higher positive symptoms also reported higher patient-control differences in glutamate levels(8). High glutamate in ACC has been now consistently linked with the status of being a non-responder (58–60) or being treatment-resistant, both indicating persistent high levels of positive symptoms. The lack of Glu-symptom correlation may reflect MRS glutamate measures being an indirect measure for NMDA receptor dysfunction(61), but not the secondary disinhibition that is likely mediated via interneuron downregulation.…”