Glutamate levels and symptom burden in high-risk and first-episode schizophrenia: a dual-voxel study of the anterior cingulate cortex

Lejia Fan; Zhenmei Zhang; Xiaoqian Ma; Liangbing Liang; Yujue Wang; Liu Yuan; Lijun Ouyang; Zongchang Li; Xiaogang Chen; Ying He; Lena Palaniyappan

doi:10.1503/jpn.240094

Glutamate levels and symptom burden in high-risk and first-episode schizophrenia: a dual-voxel study of the anterior cingulate cortex

J Psychiatry Neurosci. 2024 Nov 14;49(6):E367-E376. doi: 10.1503/jpn.240094. Print 2024 Nov-Dec.

Authors

Affiliations

¹ From the Department of Psychiatry and Psychology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China (Fan); the Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China (Fan, Zhang, Ma, Wang, Yuan, Ouyang, He, Li, Chen); the Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, Que. (Fan, Palaniyappan); the Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ont. (Liang, Palaniyappan).
² From the Department of Psychiatry and Psychology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China (Fan); the Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China (Fan, Zhang, Ma, Wang, Yuan, Ouyang, He, Li, Chen); the Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, Que. (Fan, Palaniyappan); the Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ont. (Liang, Palaniyappan) [email protected] [email protected].

PMID: 39542650
DOI: 10.1503/jpn.240094

Abstract

Background: Reduced glutamatergic excitability of the anterior cingulate cortex (ACC) has been long suspected in schizophrenia; recent observations support low glutamatergic tone as the primary pathophysiology contributing to subtle early features of this illness, with a secondary disinhibition (higher glutamate tone) resulting in more prominent clinical symptoms later in its course. We sought to investigate whether people with genetic high risk (GHR) for schizophrenia have lower glutamate levels in the ACC than those at later stages of clinical high risk (CHR) and those with first-episode schizophrenia (FES), among whom symptoms are already prominent.

Methods: We recruited people with CHR, GHR, or FES, as well as healthy controls. Using proton magnetic resonance spectroscopy, we determined glutamate levels in the perigenual ACC (pACC) and dorsal ACC (dACC) using a 3 T scanner.

Results: We recruited 302 people across multiple stages of psychosis, including 63 with CHR, 76 with GHR, and 96 with FES, as well as 67 healthy controls. Those with GHR had lower glutamate levels in the dACC than those with CHR, while those with CHR had higher glutamate levels in the pACC than those with FES. Higher disorganization, but not any other symptom domain, was associated with lower levels of glutamate in the GHR group (dACC and pACC) and in the CHR group (pACC).

Limitations: The cross-sectional design precluded inferences regarding individual clinical trajectory and resolution at 3 T was insufficient to separate spectra of glutamine from glutamate.

Conclusion: Reduced glutamatergic tone among people genetically predisposed to schizophrenia supports diminished excitability as an early feature of schizophrenia, contributing to the subtle symptom of disorganization across high-risk states. Higher glutamate levels become apparent when psychotic symptoms become prominent, possibly as a disinhibitory effect and, at the full-blown stage of psychosis, the relationship between glutamate concentrations and symptoms ceases to be simply linear.