The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS

Abstract

The NMDA receptor antagonist ketamine can induce a rapid improvement in depressive symptoms that often endures for days after a single intravenous dose. The pharmacodynamic basis for this effect is poorly understood. Using a proton magnetic resonance spectroscopy ([(1)H]-MRS) method that previously detected a normalization of amino acid neurotransmitter (AANt) content after chronic treatment with conventional antidepressant treatments, we examined whether the acute action of ketamine is associated with alterations in AANt content as well. Ten subjects with major depressive disorder (MDD) received saline, then ketamine in a fixed order, one week apart, under single-blind conditions. Each infusion was associated with three [(1)H] MRS scans (baseline, 3h and 48 h post-infusion) that measured glutamate, GABA and glutamine within the occipital cortex. Rating scales were administered before, during and after each infusion. The rapid (1h) and sustained (at least 7 days) antidepressant effect we observed after ketamine infusion was not associated with either baseline measures of, or changes in, occipital AANt content. Dissociative symptoms were not correlated with changes in depression scores. While our results indicate that changes in occipital AANt content are not a correlate of ketamine's antidepressant action, this may only apply to the regional and temporal windows of our MRS measurements.

Figure 1

Study Design. MRS (4) was acquired either 7 or 8 days after MRS (1).

Figure 2. Representative MR spectra from a single subject

The data are shown with gray lines, the spectral fits with black lines superimposed on the data, and the residuals are shown immediately beneath in black. (A) Pre-treatment subspectrum obtained without the editing pulse, yielding glutamate, glutamine and metabolites other than GABA. (B) Post-treatment subspectrum. (C) Pre-treatment J-edited difference spectrum, yielding GABA levels. (D) Post-treatment J-edited difference spectrum. The subspectra were fitted only to just beyond the myoinositol resonances, and the difference spectra were fitted only around the GABA resonance.

Figure 3

Scores on 25-item Hamilton Depression Rating Score (HDRS) over 7 days after each infusion (n=10). The difference in baseline scores was not significant. Values are represented as mean scores +/− s.e.m. * indicates P<.05; + P<.01; ‡ P<0.001.

Figure 4

[ ¹H]-MRS measurements of amino acid neurotransmitter content in the occipital cortex of MDD subjects before and after ketamine infusion. Values represent mean values of the ratio of each metabolite to creatine (Cr). error bars = +/− s.e.m.