Anterior cingulate glutamate metabolites as a predictor of antipsychotic response in first episode psychosis: data from the STRATA collaboration

Abstract

Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked to clozapine. Using proton magnetic resonance spectroscopy (¹H-MRS), we examined the ability of glutamate and Glx (glutamate plus glutamine) in the anterior cingulate cortex (ACC) and caudate to predict response to antipsychotic treatment. A total of 89 minimally medicated patients with FEP not meeting symptomatic criteria for remission were recruited across two study sites. ¹H-MRS and clinical data were acquired at baseline, 2 and 6 weeks. Response was defined as >20% reduction in Positive and Negative Syndrome Scale (PANSS) Total score from baseline to 6 weeks. In the ACC, baseline glutamate and Glx were higher in Non-Responders and significantly predicted response (P < 0.02; n = 42). Overall accuracy was greatest for ACC Glx (69%) and increased to 75% when symptom severity at baseline was included in the model. Glutamate metabolites in the caudate were not associated with response, and there was no significant change in glutamate metabolites over time in either region. These results add to the evidence linking elevations in ACC glutamate metabolites to a poor antipsychotic response. They indicate that glutamate may have utility in predicting response during early treatment of first episode psychosis. Improvements in accuracy may be made by combining glutamate measures with other response biomarkers.

Fig. 1. Glutamate metabolite levels in the anterior cingulate cortex and right caudate at baseline in patients classified as Responders or Non-Responders at 6 weeks.

Glu glutamate, Glx glutamate + glutamine. The graphs present the individual values, mean and standard deviations.

Fig. 2. Association between glutamate metabolite levels in the anterior cingulate cortex at baseline and change in PANSS total score from baseline to 6 weeks, covaring for PANSS total score at baseline.

Positive values for the change in PANSS represent increases in symptom severity. Glu_corr glutamate, Glx_corr glutamate + glutamine, PANSS positive and negative syndrome scale for schizophrenia. The relationships between both ACC Glu_corr and Glx_corr at baseline and change in PANSS Total score over 6 weeks were significant, P < 0.001.

Fig. 3. Glutamate metabolite levels in the anterior cingulate cortex (ACC) and right caudate (Caud) at baseline, 2 and 6 weeks in patients classified as Responders or Non-Responders at 6 weeks.

Glu_corr glutamate, Glx_corr glutamate + glutamine. The graphs present the mean and standard deviations. All main effects of time, response, and response-by-time interactions were non-significant.