Glutamate dysfunction in first episode psychosis and relationship with the response to treatment

• Main Author: Merritt, Kate Sky
• Other Authors: McGuire, Philip ; Taylor, Matthew John ; Egerton, Alice
• Published: King's College London (University of London) 2016
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754878

Abnormal glutamatergic neurotransmission is strongly implicated in the pathophysiology of schizophrenia. The main technique available for assessing central glutamate function in man in vivo is proton magnetic resonance spectroscopy (1H-MRS), which can be used to measure glutamate, its metabolite glutamine, or their combination (Glx). Although around sixty 1H-MRS studies in schizophrenia have been published, the findings have been inconsistent, and the extent to which these vary with the brain region examined, the stage of the disorder, the severity of symptoms and the effects of treatment is unclear. Nevertheless, data from recent cross-sectional studies suggest that glutamate concentrations may relate to the degree to which patients respond to antipsychotic medication. However, it is not yet known whether glutamate is predictive of the future therapeutic response, or whether glutamate concentrations change as a consequence of treatment. This issue can be addressed through the longitudinal assessment of glutamate concentrations in patients with psychosis before and after antipsychotic treatment. A meta-analysis of the entire literature to date indicates that schizophrenia is associated with elevated 1H-MRS glutamate metabolites in the medial temporal cortex, basal ganglia, and thalamus, and that these findings vary with the stage of the disorder. The relationship between 1H-MRS glutamate metabolites and symptom severity was examined in a large dataset of individual patient data, pooled from multiple research samples. However this did not identify robust associations between glutamate measures and symptom scores, consistent with the findings from a systematic review of studies that had examined this issue. To investigate whether glutamatergic differences between antipsychotic responders and non-responders are predictive or consequential to the therapeutic response, a longitudinal (10 month) 1H-MRS study in FEP was conducted. This revealed that Glx levels in the thalamus declined with antipsychotic treatment in patients who responded well, but did not change in patients with a poor response after both 5 weeks and 10 months. Parallel work involving repeated 1H-MRS scanning of healthy volunteers indicated that these findings were not attributable to non-specific time effects. Overall, the results from this thesis suggest that alterations in glutamatergic function are evident in a number of brain regions in schizophrenia, and that these differ between patients who do and do not respond to treatment with antipsychotic medication. These findings have implications for our understanding of the pathophysiology of the disorder, the stratification of patients, and the development of novel treatments.