7T 1H-MRS in major depressive disorder: a Ketamine Treatment Study

Abstract

The glutamatergic modulator ketamine has striking and rapid antidepressant effects in major depressive disorder (MDD), but its mechanism of action remains unknown. Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive method able to directly measure glutamate levels in vivo; in particular, glutamate and glutamine metabolite concentrations are separable by 1H-MRS at 7T. This double-blind, placebo-controlled, crossover study that included 1H-MRS scans at baseline and at 24 h post ketamine and post-placebo infusions sought to determine glutamate levels in the pregenual anterior cingulate (pgACC) of 20 medication-free MDD subjects and 17 healthy volunteers (HVs) 24 h post ketamine administration, and to evaluate any other measured metabolite changes, correlates, or predictors of antidepressant response. Metabolite levels were compared at three scan times (baseline, post-ketamine, and post-placebo) in HVs and MDD subjects at 7T using a 1H-MRS sequence specifically optimized for glutamate. No significant between-group differences in 1H-MRS-measured metabolites were observed at baseline. Antidepressant response was not predicted by baseline glutamate levels. Our results suggest that any infusion-induced increases in glutamate at the 24-h post ketamine time point were below the sensitivity of the current technique; that these increases may occur in different brain regions than the pgACC; or that subgroups of MDD subjects may exist that have a differential glutamate response to ketamine.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1

a Schematic of the double-blind, placebo-controlled, crossover study illustrating the timing of the medication taper, ketamine and placebo infusions (triangle), and magnetic resonance spectroscopy (MRS) imaging (circle). b (i) Example voxel location (yellow box) shown overlaid on an anatomical image slice in the saggital (left), axial (middle), and coronal directions. (ii) Centroid locations of all MRS voxels overlaid on a glass brain. (iii) Example segmentation into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) with overlaid voxel location in red. (c) Example voxel spectrum labeled with modeled metabolites

Fig. 2

a Group mean glutamate (Glu) concentrations referenced to creatine for the healthy volunteer (HV, red) and major depressive disorder (MDD, blue) groups for each scan. Each filled circle represents the value for a subject. The open circle is the group mean, and the error bars are the standard error. b Glutamate values for each MDD subject are shown joined with a line across scans. Solid dark blue lines are subjects where the glutamate value was larger at baseline than after ketamine administration and the light dotted blue line are subjects whose glutamate levels increased after ketamine (only subjects with completed baseline scans are shown)