N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study

Abstract

N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen’s d = 0.81; p = 0.15, Cohen’s d = 0.49), and negatively associated with total (rho = −0.47, p = 0.04), depressive (rho = −0.67, p = 0.002), and general symptom severity (rho = −0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.

Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance

“…Meta-analysis shows MMN is lower in patients with schizophrenia compared to healthy controls with a large effect size (82), with a recent study showing reduced MMN amplitude was associated with reduced glutamate levels in this patient group, measured with magnetic resonance spectroscopy (83). This is consistent with findings of lower NMDA receptor levels in schizophrenia (84). Notwithstanding this, post-mortem studies show lower levels of GABAergic markers in cortical brain regions (85).…”

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls

“…We included two measures of NMDAR availability in the analysis (DVR and V T ). DVR is our primary outcome measure as it had been used as the primary outcome in a prior study (Pilowsky et al, 2006) and because we found greater noise in the V T values, which showed more than double the variability seen with DVR (coefficients of variation for the hippocampus in healthy controls were 18.2% and 7.1%, respectively) (Beck et al, 2021;McGinnity et al, 2014). However, we include V T as well for completeness.…”

“…A total of 40 individuals participated, including 21 patients ( n = 12 antipsychotic-free and n = 9 treated with antipsychotics) and 19 healthy controls. The PET but not MRS data for 19 patients and 18 controls have been published previously (Beck et al, 2021).…”

“…The DVR was calculated for the hippocampus and frontal cortex using the whole brain as the normative region. Full details of the PET acquisition and analysis are in a previous publication (Beck et al, 2021).…”

“…Post-mortem data report reduced MK801 binding (Beneyto et al, 2007) and lower mRNA and protein levels of the essential NMDAR subunit, NR1, in the hippocampus (Vrajová et al, 2010). Moreover, in vivo evidence from single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies show lower binding of NMDAR selective tracers in the hippocampus relative to the whole brain (Beck et al, 2021; Pilowsky et al, 2006).…”