Hippocampal glutamate and hippocampus subfield volumes in antipsychotic-naive first episode psychosis subjects and relationships to duration of untreated psychosis

Abstract

Evidence points toward a relationship between longer duration of untreated psychosis (DUP) and worse long-term outcomes in patients with first episode psychosis (FEP), but the underlying neurobiology remains poorly understood. Proton magnetic resonance spectroscopy studies have reported altered hippocampus glutamatergic neurotransmission, and structural MRI as reported hippocampal atrophy that may be associated with memory impairment in schizophrenia. Here, we quantify left hippocampus glutamate (Glx) and left hippocampus subfield volumes in 54 antipsychotic-naive FEP and 41 healthy controls (HC), matched on age, sex, and parental occupation. While there were no significant group difference in Glx levels, hippocampal Glx levels were significantly higher in those who underwent a long DUP (>12 months) compared to those with a short DUP, and compared to HC. Compared to HC, FEP had significantly reduced whole hippocampus volume, as well as of CA1, CA4, granule cell layer, subiculum, and presubiculum subfields. Smaller whole hippocampal volume, as well as CA1, molecular layer, subiculum, presubiculum, and hippocampal tail volumes were significantly associated with longer DUP. However, we found no significant association between hippocampal Glx levels and hippocampal volume or subfields, suggesting that these alterations are not related, or their relationship does not follow a linear pattern. However, our results strongly suggest that one or several pathophysiological processes underlie the DUP. Importantly, our data highlight the critical need for reducing the DUP and for early pharmacological intervention with the hope to prevent structural deficits and, hopefully, improve clinical outcomes.

Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

“…Our finding is in agreement with a later study that reported a negative relationship between glutamate excess and brain volumes in the caudate nucleus in first episode psychosis patients (91). In contrast, we did not observe a linear relationship between hippocampus subfield volumes and glutamate levels in antipsychotic medication-naïve first episode psychosis patients (69). Interestingly though, those with a longer duration of untreated psychosis showed lower hippocampus subfield volumes.…”

“…In magnetic resonance spectroscopy studies, we found elevated choline and a disruption of the relationship between NAA and glutamate in the left striatum, indicating possible mitochondrial, membrane, and glial dysfunction ( 72 ). However, we reported no neurometabolite abnormalities in the medial prefrontal cortex or the hippocampus when contrasting antipsychotic medication-naïve first episode patients and controls in the overall group ( 31 , 69 ). It is important to note that glutamate levels in both areas showed a greater variance in patients compared to controls, suggesting heterogeneity in glutamatergic metabolism in first episode psychosis.…”

“…Using structural neuroimaging techniques, we found that a number of alterations are already present in medication-naive patients. Alterations include decreased gyrification in the pre- and post-central gyri, decreased total hippocampus and hippocampus subfield volumes, a trend level decrease in cortical thickness, as well as a decrease in whole brain fractional anisotropy and axial diffusivity ( 17 , 18 , 62 , 69 ). Additionally, an increase in mean diffusivity in the hippocampal part of the cingulum, which is often interpreted as evidence of neuroinflammation, is already evident in first episode patients ( 18 ).…”

“…Additionally, an increase in mean diffusivity in the hippocampal part of the cingulum, which is often interpreted as evidence of neuroinflammation, is already evident in first episode patients ( 18 ). Importantly, the duration of untreated psychosis, which is the time between first onset of psychotic symptoms and the first antipsychotic treatment, seems to be an important modulatory factor for structural integrity, as a longer duration of untreated psychosis is associated with greater gray and white matter alterations ( 62 , 68 , 69 ).…”

MK-801-induced behavioral and dopaminergic responses in the shell part of the nucleus accumbens in adult rats are disrupted after neonatal blockade of the ventral subiculum

“…In this context, it is important to note that the ventral subiculum (VSub), which is part of the hippocampal formation allowing the output of the signals from the CA1 region of the hippocampus, seems to be particularly sensitive to neurodevelopmental alterations in schizophrenia (Rioux et al, 2003; Moyer et al, 2015). Moreover, a reduction in the volume of the left VSub volume was observed in patients with first episode psychosis (Briend et al, 2020). In other respects regarding this conceptual framework, it is worth mentioning that anatomical projections from the VSub towards the shell subregion have been described, as well as NMDA-type glutamatergic receptors present at the presynaptic level on the DAergic terminals in this part of the Nacc (Meredith and Totterdell, 1999).…”