The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects.
Chadi G. Abdallah, Henk M De Feyter, Lynnette A. Averill, Lihong Jiang, Christopher L. Averill, Golam M I Chowdhury, Prerana Purohit, Robin A De Graaf, Irina Esterlis, Christoph Juchem, Brian Pittman, John H. Krystal, Douglas L Rothman, Gerard Sanacora, Graeme F. Mason
Neuropsychopharmacology September 2018 DOI: 10.1038/s41386-018-0136-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pilot study Peer reviewed |
|---|---|
| Sample size | 21 |
| Population | 14 healthy participants and 7 depressed participants |
| Interventions | Ketamine normal saline |
| Dose | subanesthetic doses of ketamine |
| Measures | 13C glutamine enrichment, 13C glutamate enrichment, 13C glutamate/glutamine enrichment ratio, Clinician-Administered Dissociative States Scale |
| Topics | Esketamine Ketamine |
| Key points | Ketamine increased prefrontal glutamate-glutamine cycling relative to placebo, shown by a 13% rise in 13C glutamine enrichment, with no evidence of an effect on oxidative energy production. The ratio of 13C glutamate to glutamine enrichment correlated with dissociative symptoms during infusion. The authors argue these findings provide the most direct human evidence to date that ketamine increases prefrontal glutamate release. |
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.
Comparable studies
Other non-randomized and open-label trials on ketamine, most cited first.
Citations in the library
Cited by 95
- Ketamine: a paradigm shift for depression research and treatment Neuron March 1, 2019
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Pharmacology, Biochemistry, and Behavior December 9, 2019
- Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia JAMA Network Open May 1, 2020
- General Anesthesia: A Probe to Explore Consciousness Frontiers in Systems Neuroscience August 14, 2019
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Cites 16
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and 11 more in the library