Elevated glutamine but not glutamate is associated with clozapine eligibility in an early psychosis sample

Approximately one-third of individuals with schizophrenia will meet the 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 using in vivo magnetic resonance spectroscopy (MRS), would be associated with clozapine eligibility in an early-phase psychosis (EPP) cohort.

Criteria-defined clozapine-eligible (CE) individuals and treatment responders (TR) with non-affective EPP were recruited from the Nova Scotia Early Psychosis Program (within the first 5 years of illness onset). 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 RESolved Spectroscopy (TE = 40 ms, TR = 2,000 ms; 128 averages).

Forty-six EPP individuals completed the study, with 24 meeting the criteria for clozapine eligibility (mean age = 24) and 22 as treatment responders (mean age = 22). Twenty-six individuals (56.5%) in the total sample were receiving treatment with a long-acting injectable antipsychotic (LAI) medication. The TR group (16 men, 6 women) did not differ from the CE group (19 men, 5 women) in age, years of education, family history of psychosis, or regular nicotine and cannabis use. The CE group had higher PANSS scores, a longer duration of untreated psychosis, and worse social functioning and were taking a higher burden of antipsychotic treatment [chlorpromazine (cpz) equivalencies]. Clinical variables that were significantly different between groups were added to the linear model, and nested model comparisons were used to select the final model for analysis of each metabolite. 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 = 0.02].

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 to antipsychotic medication. Our results support future studies to further characterize the neurobiology of clozapine eligibility in early-phase psychosis to assist in the timely initiation of clozapine to maximize outcomes.