Elevated Glutamine but Not Glutamate is Associated with Clozapine Eligibility in an Early Psychosis Sample

Maxwell Seward¹Esther Puiras²Temi Toba-Oluboka²Candice E Crocker^1,2,3Philip G Tibbo^1,2Kara Dempster^1,2*

• ¹Dalhousie University, Department of Psychiatry, Halifax, Canada
• ²Nova Scotia Health Authority, Halifax, Canada
• ³Dalhousie University, Department of Diagnostic Radiology, Halifax, Canada

Introduction: Approximately one third of individuals with schizophrenia will meet criteria for treatment resistant schizophrenia (TRS), the majority of whom demonstrate poor pharmacological response early in their course of illness. Clozapine response is higher when used early in the illness trajectory, thus there is a need to characterize the neurobiological underpinnings of TRS to support early stratification to clozapine. We hypothesized that elevated glutamate in the Anterior Cingulate Cortex (ACC), measured by in vivo magnetic resonance spectroscopy (MRS), would be associated with clozapine-eligibility in an early phase psychosis (EPP) cohort. Methods: Clozapine eligible (CE) individuals and treatment responders (TR) with non-affective EPP were recruited from the Nova Scotia Early Psychosis Program. Clinical assessments were completed as well as 3T 1H-MRS to measure glutamate in the bilateral dorsal ACC. 1H-MRS acquisitions were performed using Point RESsolved Spectroscopy (TE=40ms, TR=2000ms; 128 averages). Results: 46 EPP individuals completed the study with 24 meeting criteria for clozapine eligibility (mean age= 24), and 22 as treatment responders (mean age=22).The CE group had higher PANSS scores, a longer duration of untreated psychosis, worse social functioning, and were taking a higher burden of antipsychotic treatment (chlorpromazine (cpz) equivalencies). Glutamate was compared between the groups using a one-way ANOVA, and glutamine was compared using ANCOVA. While ACC glutamate was not found to be significantly different between the groups, glutamine, a precursor for glutamate, was higher in the CE group (M = 4.43, SD = 0.73) relative to the TR group (M=4.02, SD = 0.64); F(1,40) = 5.44, p = 0.043. Discussion: While elevated ACC glutamate has been associated with poor response to antipsychotic medications in early psychosis samples, this is the first study to explore the association with clozapine-eligibility. Contrary to our hypothesis, ACC glutamate was not higher in the CE group. However, glutamine, a precursor to glutamate, was higher in the CE group, in line with previous studies that have found elevated glutamatergic metabolites to be associated with poor treatment response. Our results support future studies to further characterize the neurobiology of clozapine eligibility in EPP to assist in the timely initiation of clozapine to maximize outcomes.