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

We investigated the longstanding idea that the onset of psychotic symptoms in schizophrenia arises from an early phase of glutamate neurotoxicity, possibly related to loss of GABA restraint, oxidative stress or inflammation, that cumulatively results in a later phase of synaptic loss in keeping with magnetic resonance spectroscopy (MRS) evidence of reduced glutamate in schizophrenia, especially in older patients. We evaluated this hypothesis in a 3-centre MRS study to determine whether abnormalities in glutamate in dorsal anterior cingulate cortex (dACC) differed between people with minimally treated 'Recent' onset schizophrenia and an 'Established' group with > 10 years of illness. We tested the hypothesised mechanisms of reduced GABA in either or both dACC and occipital cortex, and depletion of dACC glutathione, a measure of central inflammation. We explored predicted associations between MRS variables, circulating cytokines and clinical symptoms. The Established group showed significantly greater dACC glutamate deficit than the Recent group which was not accounted for by lifetime exposure to antipsychotic drugs or by their greater CRP or IL-6 levels nor was the deficit associated with glutathione depletion. The greater dACC glutamate deficit in established illness is compatible with loss of synapses occurring after onset of symptoms but there was little to suggest underpinning excitotoxicity, inflammation, or oxidative stress. GABA was reduced in patients versus controls across dACC and occipital voxels. Only dACC GABA content correlated significantly with symptoms, lower content with greater positive and negative symptoms across both groups and this is supportive of a pathophysiological role of GABA in psychosis.

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Publication Details

Journal
Molecular Psychiatry
Published
2025-11-19
DOI
https://doi.org/10.1038/s41380-025-03337-x
Primary Topic
Tryptophan and brain disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Loes Koelewijn, Mohanbabu Rathnaiah, John Evans, J.F.W. Deakin et al.
Molecular Psychiatry
Tryptophan and brain disorders
article

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

Loes Koelewijn, Mohanbabu Rathnaiah, John Evans, J.F.W. Deakin, James Walters, Elizabeth B. Liddle, Carol Gregory, Bernard Lanz, Peter F. Liddle, Peter Morris, Naghmeh Nikkheslat, Richard Smallman, Silke Conen, Lauren E. Gascoyne, Peter S. Talbot, Krish D. Singh, Mohammad Zia Ul Haq Katshu, Adriana Anton, Gemma Williams, Chen Chen, Jyothika Kumar, Lena Palaniyappan, S. R. Williams
article en

Abstract

We investigated the longstanding idea that the onset of psychotic symptoms in schizophrenia arises from an early phase of glutamate neurotoxicity, possibly related to loss of GABA restraint, oxidative stress or inflammation, that cumulatively results in a later phase of synaptic loss in keeping with magnetic resonance spectroscopy (MRS) evidence of reduced glutamate in schizophrenia, especially in older patients. We evaluated this hypothesis in a 3-centre MRS study to determine whether abnormalities in glutamate in dorsal anterior cingulate cortex (dACC) differed between people with minimally treated 'Recent' onset schizophrenia and an 'Established' group with > 10 years of illness. We tested the hypothesised mechanisms of reduced GABA in either or both dACC and occipital cortex, and depletion of dACC glutathione, a measure of central inflammation. We explored predicted associations between MRS variables, circulating cytokines and clinical symptoms. The Established group showed significantly greater dACC glutamate deficit than the Recent group which was not accounted for by lifetime exposure to antipsychotic drugs or by their greater CRP or IL-6 levels nor was the deficit associated with glutathione depletion. The greater dACC glutamate deficit in established illness is compatible with loss of synapses occurring after onset of symptoms but there was little to suggest underpinning excitotoxicity, inflammation, or oxidative stress. GABA was reduced in patients versus controls across dACC and occipital voxels. Only dACC GABA content correlated significantly with symptoms, lower content with greater positive and negative symptoms across both groups and this is supportive of a pathophysiological role of GABA in psychosis.

Molecular PsychiatryVol. 31(4)
Western University (CA), Lawson Health Research Institute (CA), University of Nottingham (GB), King's College London (GB), Douglas Mental Health University Institute (CA), Manchester Academic Health Science Centre (GB), Nottinghamshire Healthcare NHS Foundation Trust (GB), University of Manchester (GB), Institute of Mental Health (GB), Robarts Clinical Trials (CA), Centre d'Imagerie BioMedicale (CH), McGill University (CA), École Polytechnique Fédérale de Lausanne (CH), Cardiff University (GB)
McGill University, Fonds de Recherche du Québec - Santé, Medical Research Council
Openalex Percentile: Top 64%
Tryptophan and brain disorders
DOIOpen Access PDFOpenAlex
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