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

Neuropsychopharmacology. 2018 Sep;43(10):2154-2160. doi: 10.1038/s41386-018-0136-3. Epub 2018 Jun 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antidepressive Agents / pharmacology*
  • Depressive Disorder / physiopathology*
  • Energy Metabolism / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Glutamates / physiology*
  • Hallucinogens / pharmacology
  • Healthy Volunteers
  • Humans
  • Ketamine / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Male
  • Middle Aged
  • Pilot Projects
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Synaptic Transmission / drug effects*
  • Young Adult


  • Antidepressive Agents
  • Excitatory Amino Acid Antagonists
  • Glutamates
  • Hallucinogens
  • Ketamine