1H-MRS metabolites in antipsychotic-responsive versus non-responsive psychosis: a meta- and mega-analysis.

Understanding the mechanisms underlying the response to antipsychotic medications is critical for refining targets for new interventions and predicting clinical outcomes. This study presents a mega-analysis of individual participant data (N = 1,189) from 18 {superscript 1}H-MRS datasets to examine differences in neurometabolites in antipsychotic non-responsive compared to antipsychotic-responsive psychosis, accompanied by complementary meta-analyses across the wider published literature (23 studies, N = 1,844). The mega-analysis revealed that antipsychotic non-response is associated with elevated levels of glutamate, Glx (the sum of glutamate and glutamine), choline, and myo-inositol (mI) in the medial frontal cortex (MFC) compared to individuals who showed a good antipsychotic response and healthy controls. Follow-up analyses revealed that elevated MFC Glx in antipsychotic non-responders, compared with responders, is already evident prospectively in first-episode psychosis, whereas elevated mI is most pronounced in individuals meeting criteria for treatment resistance following antipsychotic treatment. The elevations in MFC choline and mI associated with antipsychotic non-response were also detected in the meta-analysis. In both the meta- and mega-analysis, several metabolites were more variable in the patient than the healthy control groups. Collectively, these data provide the most robust evidence to date linking antipsychotic non-response in psychosis to elevations in medial frontal glutamate, choline and mI. The findings support the continued investigation of glutamate-acting and inflammatory pathway-associated interventions for psychosis and schizophrenia, and particularly for patients who have not responded to antipsychotic treatment.