Acute ketamine administration modulates glutamatergic neurotransmission and functional brain activation in prefrontal cortex implications for major depression

Background: Ketamine is a potent NMDA receptor antagonist with rapid antidepressant properties at subanaesthetic doses. This multimodal imaging study reveals the effects of a subanaesthetic ketamine infusion on fMRI-BOLD responses during an emotional processing task and their relationship to glutamatergic metabolite concentrations in the pregenual anterior cingulate cortex (PACC) assessed by proton magnetic resonance spectroscopy (1H-MRS). Methods: 23 healthy subjects were asked to judge photographs from the International Affective Picture System (IAPS) by button press according to their valence in two separate fMRI sessions (baseline/ketamine) on a Philips 3T MR unit. S-ketamine was administered as an i.v. bolus of 0.12 mg/kg, followed by an infusion of 0.25 mg/kg/h over 60 min. 1H-MRS spectra from the bilateral PACC could be obtained in 16 subjects immediately after the task using a JPRESS sequence. Results and Conclusion: In the PACC, changes in NBRs correlated with glutamine to glutamate ratios as a putative marker of glutamatergic neurotransmission after ketamine administration compared to baseline. These changes are most likely interpreted in terms of an increased glutamate-glutamine-cycling rate after ketamine administration. Thus, the antidepressant effect of ketamine might be linked to a beneficial short-term influence on glutamatergic neurotransmission.