A longitudinal study of hippocampal subfield volumes and hippocampal glutamate levels in antipsychotic-naïve first episode psychosis patients

Abstract

Background: Previous studies have implicated hippocampal abnormalities in the neuropathology of psychosis spectrum disorders. Reduced hippocampal volume has been reported across all illness stages, and this atrophy has been hypothesized to be the result of glutamatergic excess. To test this hypothesis, we measured hippocampal subfield volumes and hippocampal glutamate levels in antipsychotic naïve first episode psychosis patients (FEP) and the progression of volume decline and changes in glutamate levels over a 16-week antipsychotic drug (APD) trial. We aimed to determine if subfield volumes at baseline were associated with glutamate levels, and if baseline glutamate levels were predictive of change in subfield volumes over time.

Methods: We enrolled ninety-three medication-naïve FEP participants and 80 matched healthy controls (HC). T1 and T2 weighted images and magnetic resonance spectroscopy (MRS) data from a voxel prescribed in the left hippocampus were collected from participants at baseline and after 6 and 16 weeks of APD treatment. Hippocampal subfield volumes were assessed using FreeSurfer 7.1.1., while glutamate levels were quantified using jMRUI version 6.0. Data were analyzed using linear mixed models.

Results: We found regional subfield volume deficits in the CA1, and presubiculum in FEP at baseline, that further expanded to include the molecular and granule cell layer of the dentate gyrus (GC/ML/DG) and CA4 by week 16. Baseline hippocampal glutamate levels in FEP were not significantly different than those of HC, and there was no effect of treatment on glutamate. Glutamate levels were not related to initial subfield volumes or volume changes over 16 weeks.

Conclusion: We report a progressive loss of hippocampal subfield volumes over a period of 16 weeks after initiation of treatment, suggestive of early progression in neuropathology. Our results do not suggest a role for glutamate as a driving factor. This study underscores the need to further research the mechanism(s) underlying this phenomenon as it has implications for early intervention to preserve cognitive decline in FEP participants.

Fig. 1. Consort flow chart.

Presents the number of participants in each of our 10 mixed models (Total hippocampal volume, 8 hippocampal subfield volumes and hippocampal glutamate) at each time point. The flow chart also shows the number of excluded participants in each model at each timepoint and reasons for exclusion. Lastly the flow chart shows the number of participants for our glutamate × volume correlation analyses.

Fig. 2. Hippocampal subfield volume changes over time in first episode psychosis.

A shows a 3D model of the segmentation of all hippocampal subfields segmented for this study color coded by region. Colored boxes marked by an * signify regions with significant group × time interactions (p < 0.05 after Tukey’s HSD). B A scan time × volume graph of the whole bilateral hippocampal volume over time comparing FEP to HC. Post hoc tests showed a significant difference in the main effect for group (p < 0.05 after Tukey’s HSD) with FEP showing greater overall reduction in whole hippocampal volume compared to HC. Meanwhile * signifies a significant difference between baseline and week 16, and week 6 and week 16 within FEP (p < 0.05 after Tukey’s HSD). C Within FEP volume differences over time for each subfield. In short FEP showed a consistent reduction in volume over time for the whole hippocampus as well as the CA1, CA3, CA4, presubiculum, and GC-ML-DG hippocampal subfields.

Fig. 3. Baseline hippocampal glutamate group difference and change in FEP glutamate over time.

Hippocampal glutamate did show significant group × time interaction, F(2,46.9) = 4.60 p = 0.0109. A Glutamate comparisons between HC and FEP showed no significant group differences at baseline. B FEP demonstrated no significant change in glutamate level over time in pot-hoc analyses.