Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities

Abstract

The anterior cingulate cortex (ACC) has shown decreased glutamate levels in patients with major depressive disorder. Subanesthetic doses of ketamine were repeatedly shown to improve depressive symptoms within 24 h after infusion and this antidepressant effect was attributed to increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) throughput. To elucidate ketamine's mechanism of action, we tested whether the clinical time course of the improvement is mirrored by the change of glutamine/glutamate ratio and if such effects show a regional and temporal specificity in two distinct subdivisions of ACC with different AMPA/N-methyl-D-aspartate receptor profiles. In a double-blind, placebo-controlled intravenous infusion study of ketamine, we measured glutamate and glutamine in the pregenual ACC (pgACC) and the anterior midcingulate cortex at 1 and 24 h post infusion with magnetic resonance spectroscopy at 7 T. A significant interaction of time, region, and treatment was found for the glutamine/glutamate ratios (placebo, n=14; ketamine, n=12). Post-hoc analyses revealed that the glutamine/glutamate ratio increased significantly in the ketamine group, compared with placebo, specifically in the pgACC after 24 h. The glutamine/glutamate increase in the pgACC caused by ketamine at 24 h post infusion was reproduced in an enlarged sample (placebo, n=24; ketamine, n=20). Our results support a significant temporal and regional response in glutamine/glutamate ratios to a single subanesthetic dose of ketamine, which mirrors the time course of the antidepressant response and reversal of the molecular deficits in patients and which may be associated with the histoarchitectonical receptor fingerprints of the ACC subregions.

Figure 1

Magnetic resonance spectroscopy (MRS) voxel locations and exemplary spectrum showing metabolites and the corresponding model fit for our metabolites of interest. The anterior midcingulate cortex (aMCC, a) and pregenual anterior cingulate cortex (pgACC, b) voxel positioning in yellow and the exemplary spectrum (c) acquired from a study participant, showing the raw spectrum, the corresponding model fit, and baseline from LCModel analysis. A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 2

Results of regional comparison from the primary analysis. The change of glutamine/glutamate ratio at 24 h after intravenous ketamine infusion over baseline in the two anterior cingulate cortex subregions (aMCC, anterior middle cingulate cortex, in red; pgACC, pregenual anterior cingulate cortex, in dark green) in placebo (n=14, saline) and verum groups (n=12, ketamine), respectively. Asterisks denote statistically significant changes in glutamine/glutamine relative to baseline levels. Error bars denote one SEM. A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 3

Validation of the effects in the pregenual anterior cingulate cortex (pgACC): significant increase in change of the glutamine/glutamate ratio after 24 h compared with the baseline in the ketamine group corresponds to a significant difference in the ketamine (n=20) vs placebo (n=24) in pgACC. Asterisks denote statistically significant change in the glutamine/glutamate relative to the baseline levels. Error bars denote SEM.

Figure 4

Correlation of the glutamine/glutamate ratio with the glutamate and the glutamine levels at 24 h post ketamine infusion (n=20) in the validation analysis. The glutamine/glutamate ratios are predicted by the glutamate levels (r=−0.751, p<0.001) and the glutamine levels (r=0.904, p<0.001).