Glutamate concentrations and cognitive deficits in ultra-treatment-resistant schizophrenia: An exploratory and comparative 1H-MRS study

Background and aims: Glutamate plays a crucial role in cognition, learning, and mood regulation, with studies suggesting glutamatergic dysfunction in chronic schizophrenia. This study explored glutamate levels in the occipital cortex (OCC) and cognitive function in ultra-treatment resistant schizophrenia (uTRS) compared to healthy controls. Methods: Fifteen uTRS participants and 19 healthy controls underwent 3T proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate levels in the OCC. Cognitive performance was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Results: No significant differences in OCC glutamate levels were found between uTRS participants and healthy controls. uTRS participants performed significantly worse on the MCCB compared to healthy controls, with a large effect size (eta 2 = 0.72). Although no significant direct relationships were observed between Glu levels and cognitive performance, significant regression models for certain cognitive domains suggest a modest association between Glu levels and cognitive outcomes. Conclusion: Participants with uTRS exhibited significant cognitive deficits compared to healthy controls, though no significant differences in OCC Glu levels were found. While no clear linear or quadratic relationships emerged, Glu explained a small portion of the variance in cognitive performance, indicating a more complex role for Glu in cognition that warrants further investigation.