Impaired verbal memory function is related to anterior cingulate glutamate levels in schizophrenia: findings from the STRATA study

Abstract

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Histamine-3 Receptor Availability and Glutamate Levels in the Brain: A PET-1H-MRS Study of Patients With Schizophrenia and Healthy Controls

“…Meta-analytic studies have identified lower glutamate levels in voxels, including the ACC of patients with schizophrenia compared with healthy volunteers ( Marsman et al, 2013 ; Merritt et al, 2023 ). Moreover, studies have found that lower glutamate metabolite levels in the ACC of patients with schizophrenia are correlated to poorer cognitive task performance ( Ohrmann et al, 2008 ; Bojesen et al, 2021 ; Coughlin et al, 2021 ; Griffiths et al, 2022 ). The findings that we report, together with existing evidence of lower ACC glutamate levels being associated with impaired cognition, suggest that H3R antagonism in patients with schizophrenia may improve cognitive impairment, which is a feature of the disorder, by increasing glutamate transmission.…”

Defining the disturbance in cortical glutamate and GABA function in psychosis and its origins and consequences

“…Nevertheless, there was no evidence that IL-6 increases directly mediated the late phase decrease in ACC glutamate (Figure 3D). Indeed, low ACC glutamate was recently associated with polygenic risk for reduced NMDA receptor function shared with treatment resistance albeit in a younger cohort than the Established group [59].…”

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

“…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. In fact, dynamic causal models (DCM) of brain connectivity that recovers parameters reflecting interneuron-mediated inhibitory tone, indicates that higher MRS glutamate in dACC relates to higher inhibitory interneuron tone, not disinhibition(62).…”