Investigating the relationships between risk factors and brain glutamate in schizophrenia

Glutamate is a key neurotransmitter implicated in the neurobiology of schizophrenia. Within the living human brain, the concentration of glutamate can be measured within pre-selected brain areas using the MRI-based technique of proton magnetic resonance spectroscopy (1H-MRS). There are now over 80 1H-MRS studies of glutamate in schizophrenia. These individual studies have observed various results, finding increases, decreases or no change in glutamate levels. Amongst other factors, this may relate to differences in patient characteristics, the brain regions investigated and measurement variability within the relatively small sample sizes of individual studies. Knowledge can be developed by studies examining larger, well-characterised patient samples or by applying mega- or meta- analytical techniques to combine data from individual studies. For example, recent meta and mega-analyses led by Prof Egerton's group have shown elevations in glutamate in schizophrenia in distinct brain regions (Merritt et al., 2018), and that elevations may be most marked shortly after onset of psychosis, or patients who have highest symptom burden (Merritt et al., 2021). Our most recent meta-analysis (Merritt et al., in preparation) shows that glutamate levels in schizophrenia are more variable than in healthy volunteers. The causes and clinical consequences of this variability are currently unclear. Understanding these processes may have translational implications, as it could indicate patient subgroups for whom glutamate-acting therapeutics may have greatest efficacy, and thus inform stratified medicine approaches.

This PhD will extend this work in three ways.

1. Our group and others have also shown that elevations in glutamate in the anterior cingulate cortex (ACC) are more marked in patients who have not responded well to antipsychotic treatment (Egerton et al., 2012, 2018, 2020; Iwata et al., 2018; Tarumi et al., 2021), although some other studies have not detected the same finding (Goldstein et al., 2015; Horne et al., 2021). The first study of the PhD will consist of a meta-analysis and participant level mega-analysis, to determine whether glutamate is elevated in treatment-non-responsive schizophrenia when all the existing information is considered. The translational implication is that this could indicate that glutamate-lowering drugs may have efficacy in those who have not responded well to existing antipsychotics.

2. It is not clear how specific abnormalities in glutamate are to schizophrenia. Glutamate is the major excitatory neurotransmitter in the brain and is thus intricately involved in all aspects of heathy cognition, thus abnormalities in glutamate have been suggested across the psychiatric disorders. In addition to meta-analyses from our group (Merritt et al., 2018; Merritt et al., in prep) and others (Nakahara et al., 2022 ) in schizophrenia, meta-analysis have shown decreases in MFC glutamate in major depressive disorder (Moriguchi et al, 2019), increases in glutamate across brain regions in bipolar disorder (Gigante et al., 2012) and no difference in alcohol use disorder (Kirkland et al., 2022). The second study of the PhD will use meta-analytical approaches to compare brain glutamate abnormalities across two or more psychiatric disorders. This will provide initial, novel information on the extent to which glutamate dysfunction may represent a shared or distinct mechanism, in a transdiagnostic approach.

3. Third, several environmental and genetic risk factors have been associated with the development of psychosis and with more severe forms of schizophrenia, but the biological mechanisms are unclear. Our group has recently shown that polygenetic risk for pathways involving NMDA receptor dysfunction are associated with ACC glutamate levels (Griffiths et al., submitted). The third study of the PhD will investigate whether the presence of other risk factors, including family history, early...