The Association of Anterior Cingulate Cortex Glutamate and Clozapine Eligibility In an Early Psychosis Sample
Abstract
Background: The ability to identify patients who may benefit from clozapine at the earliest opportunity is important for maximizing long term outcomes in schizophrenia. Patients that meet criteria for treatment resistance demonstrate poor antipsychotic medication response from the onset of illness. This poor response to dopamine blocking medications may be due to an inherent lack of dopaminergic elevation. It has been speculated that treatment resistance may be associated with elevated glutamatergic metabolites. Despite individuals meeting criteria, clozapine initiation is frequently delayed. There are currently no objective biomarkers available to support clinicians in accurately identifying individuals who may benefit from a clozapine trial. We hypothesized that elevated glutamate in the Anterior Cingulate Cortex (ACC) would be associated with clozapine eligibility in an early psychosis sample.
Methods: The present study compared glutamate levels in the ACC between clozapine-eligible (CE) patients with early phase psychosis, and those who have responded to traditional treatment (Treatment Responders, TR) using 3T proton magnetic resonance spectroscopy (1H-MRS). Clozapine eligible patients continued to have psychotic symptoms after two antipsychotic medication trials, while treatment responders had minimal symptoms and were taking a single antipsychotic medication. The sample consisted of individuals with non-affective psychotic disorders who were followed by the Nova Scotia Early Psychosis Program (NSEPP) and were within the first five years of their initial presentation of psychotic symptoms.
Results: A total sample size of 30 patients participated (TR= 19 and CE= 11). The TR group (M=15, F=4) had an average age of 26 and PANSS score of 36.63. The CE group (M=8, F=3), had an average age of 26 and PANSS score of 68.64. There was not a significant difference between the two groups for glutamate levels, 10.28 (SD= 0.77) and 9.85 (SD= 0.83) for TR and CE respectively, with an effect size of R2= 0.138. PANSS was significantly different between the two groups and this significance carried over into all 3 categories of symptomatology on the scale. Antipsychotic dose was also significantly different between the two groups, 270.57mg and 532.39mg for CE and TR.
Discussion: This is the first study to investigate the association of brain glutamate with clozapine eligibility in an early psychosis sample. While we did not find an association between ACC glutamate and clozapine eligibility, we did replicate trends from previous studies. While elevated ACC glutamate has been associated with poor antipsychotic response, it is unclear whether elevated glutamate is associated with clozapine eligibility, a clinically meaningful outcome. It is important that future studies are sufficiently powered to assess this potential association reliably. The ability to prospectively identify clozapine eligibility could lead to reformulation of current guidelines regarding clozapine use and may inform the development of additional treatment options for individuals with treatment resistant schizophrenia.