The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects

Abstract

The ability of ketamine administration to activate prefrontal glutamate neurotransmission is thought to be a key mechanism contributing to its transient psychotomimetic effects and its delayed and sustained antidepressant effects. Rodent studies employing carbon-13 magnetic resonance spectroscopy (¹³C MRS) methods have shown ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists to transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex. However, there are not yet direct measures of glutamate neurotransmission in vivo in humans to support these hypotheses. The current first-level pilot study employed a novel prefrontal ¹³C MRS approach similar to that used in the rodent studies for direct measurement of ketamine effects on glutamate-glutamine cycling. Twenty-one participants (14 healthy and 7 depressed) completed two ¹³C MRS scans during infusion of normal saline or subanesthetic doses of ketamine. Compared to placebo, ketamine increased prefrontal glutamate-glutamine cycling, as indicated by a 13% increase in ¹³C glutamine enrichment (t = 2.4, p = 0.02). We found no evidence of ketamine effects on oxidative energy production, as reflected by ¹³C glutamate enrichment. During ketamine infusion, the ratio of ¹³C glutamate/glutamine enrichments, a putative measure of neurotransmission strength, was correlated with the Clinician-Administered Dissociative States Scale (r = -0.54, p = 0.048). These findings provide the most direct evidence in humans to date that ketamine increases glutamate release in the prefrontal cortex, a mechanism previously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects.

Fig. 1

Prefrontal ¹³C magnetic resonance spectroscopy (MRS) acquisition and ¹³C spectrum. Sagittal (a) and axial (b) view of the region of interest—based on the radius of the carbon coil—primarily rostral Brodmann Area 10. c ¹³C magnetic resonance spectrum acquired at 4 T from the prefrontal region of a study participant during infusion of [U ¹³C]-glucose. Color code: blue—raw; red—fitted; green—residual. Abbreviations: GluC45 ¹³C-Glutamate C45, GlnC45 ¹³C-Glutamine C45, and AspC34 ¹³C-Aspartate C34

Fig. 2

Carbon-13 (¹³C) labeling of glutamate and glutamine via the TCA and glutamate–glutamine cycle. Following glycolysis, ¹³C-Glucose (¹³C-Glc) metabolites (i.e., acetyl-CoA) enter the mitochondrial tricarboxylic acid (TCA) cycle (also known as Krebs cycle) and subsequently label glutamate through exchange with α-ketoglutarate. Next, ¹³C-glutamate is released into the synaptic cleft and taken up by astrocytes, where the ¹³C-glutamate is converted to ¹³C-glutamine and transferred to neurons. Hence, the rate of ¹³C-glutamate enrichment is primarily affected by neuroenergetics (the neuronal TCA cycle) and the rate of ¹³C-glutamine enrichment primarily reflects the rate of glutamate–glutamine cycling. The development of this metabolic model and potential impact of other metabolic pathways on the measured labeling are discussed in reference [10]. The figure was adapted with permission from the Emerge Research Program (emerge.care)

Fig. 3

Effects of ketamine on prefrontal glutamate–glutamine cycling and neuroenergetics. In the first 20 min post infusion, ketamine induced a rapid increase in ¹³C-glutamine enrichment, indicating an acute surge in prefrontal glutamate–glutamine cycling. The enrichment of ¹³C-glutamate remained stable, suggesting no changes in oxidative energy production early during ketamine infusion

Fig. 4

Separate effects of ketamine on prefrontal glutamate–glutamine cycling and neuroenergetics in healthy and major depressive disorder (MDD) subjects. a Mean and SEM of ¹³C-glutamate and ¹³C-glutamine during placebo (Plc) and during ketamine (Ket). b Individual values, as well as mean and SEM, of percent change in enrichment of ¹³C-glutamine during ketamine compared to placebo in each group. The pattern of changes in ¹³C-glutamine and ¹³C-glutamate enrichments was comparable between healthy and depressed subjects, with no statistically significant differences between the two groups. The similarities indicate that while the impacts of ketamine on glutamate–glutamine cycling were significant, both groups were affected to about the same extent

Fig. 5

Association between glutamate neurotransmission and the psychotomimetic effects of ketamine in healthy participants. a Reduced neuroenergetics relative to neurotransmitter cycling, as measured by the ¹³C-glutamate/¹³C-glutamine (¹³C Glu/Gln) ratio, is associated with the psychotomimetic effects of ketamine, as measured by the Clinician-Administered Dissociative States Scale (CADSS). b The association with the Brief Psychiatric Rating Scale (BPRS) positive symptoms was comparable in effect size, but did not reach statistical significance in this sample of 14 subjects