Glutamatergic Metabolites, Volume and Cortical Thickness in Antipsychotic-Naive Patients with First-Episode Psychosis: Implications for Excitotoxicity

Abstract

Neuroimaging studies investigating patients with schizophrenia often report appreciable volumetric reductions and cortical thinning, yet the cause of these deficits is unknown. The association between subcortical and cortical structural alterations, and glutamatergic neurometabolites is of particular interest due to glutamate's capacity for neurotoxicity; elevated levels may be related to neuroanatomical compromise through an excitotoxic process. To this end, we explored the relationships between glutamatergic neurometabolites and structural measures in antipsychotic-naive patients experiencing their first non-affective episode of psychosis (FEP). Sixty antipsychotic-naive patients with FEP and 60 age- and sex-matched healthy controls underwent a magnetic resonance imaging session, which included a T1-weighted volumetric image and proton magnetic resonance spectroscopy in the precommissural dorsal caudate. Group differences in precommissural caudate volume (PCV) and cortical thickness (CT), and the relationships between glutamatergic neurometabolites (ie, glutamate+glutamine (Glx) and glutamate) and these structural measures, were examined. PCV was decreased in the FEP group (p<0.001), yet did not differ when controlling for total brain volume. Cortical thinning existed in the FEP group within frontal, parietal, temporal, occipital, and limbic regions at a 5% false discovery rate. Glx levels were negatively associated with PCV only in the FEP group (p=0.018). The observed relationship between Glx and PCV in the FEP group is supportive of a focal excitotoxic mechanism whereby increased levels of glutamatergic markers are related to local structural losses. This process may be related to the prominent structural deficits that exist in patients with schizophrenia.

Inefficient Neural Self-Stabilization: A theory of spontaneous resolutions and recurrent relapses in psychosis

“…The current model of inefficient self-stabilization predicts that in early stages, higher levels of glutamate signal can be found in the loci of hyperconnectivity and anomalously increased neural activity whereas lower levels of glutamate signal should accompany grey matter loss in schizophrenia, especially in later stages of illness, with excitatory synapses undergoing structural elimination. While several studies are in agreement 69,75,229,234,235 , opposite results also exist 236 . Cautious interpretation is required nevertheless as it is unclear how much of spectroscopic glutamate refers to synaptic activity.…”

The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [11C]‐raclopride and [11C]‐(+)‐PHNO PET

“…For example, increased striatal glutamate levels measured with proton magnetic resonance spectroscopy ( 1 H‐MRS) have also been observed in patients with first‐episode psychosis [Plitman et al, ]. In turn, striatal glutamate levels were found to be negatively correlated with dorsal caudate volumes in these patients [Plitman et al, ]. Given the potential interactions between striatal DA and glutamate [Caravaggio et al, ; Stone et al, ], it can be inferred that the dopaminergic changes observed in schizophrenia may also be related changes in brain morphology.…”

“…The procedure for total brain volume (TBV) analysis has been published elsewhere [Plitman et al, ]. TBV was obtained using the Brain Extraction based on non‐local Segmentation Technique (BEaST) method [Eskildsen et al, ], which is based on non‐local segmentation in a multi‐resolution framework.…”

Amotivation is associated with smaller ventral striatum volumes in older patients with schizophrenia

“…The procedure for total brain volume (TBV) analysis has been published elsewhere . Total brain volume was obtained using the brain extraction based on a nonlocal segmentation technique method .…”