A Pilot In Vivo Proton Magnetic Resonance Spectroscopy Study of Amino Acid Neurotransmitter Response to Ketamine Treatment of Major Depressive Disorder

Abstract

The NMDA receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine’s antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate + glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg/kg i.v.) was administered to eleven depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total ≤ 10) within 230 minutes of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 minutes. Mean areas under the curve (AUC) for Glx/W (p = 0.025) and GABA/W (p = 0.005) increased and correlated (r = 0.796; p=0.018). Clinical improvement correlated with 90-minute norketamine concentration (df=6, r=−0.78, p=0.023), but no other measures.

Rapid increases in Glx and GABA in MDD following ketamine administration support the postulated antidepressant role of glutamate and for the first time raises the question of GABA’s role in the antidepressant action of ketamine. These data support the hypothesis ¹ that ketamine administration may cause an initial increase in glutamate that potentially activates mammalian target of rapamycin (mTOR) pathway via AMPA receptors, since ketamine blocks NMDA receptors. The role of the contemporaneous surge in GABA remains to be determined. ²