The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?
Open accessAbstract
The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission - reviewing the history of the "glutamate inhibition" and "glutamate activation" hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.
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A main limitation of previous methods is the lack of distinction between presynaptic glutamate release and postsynaptic activation.
“A main limitation of previous methods is the lack of distinction between presynaptic glutamate release and postsynaptic activation, the latter has been related to the RAAD effects of ketamine [14,15].”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [15]
Ketamine affects the PFC, hippocampus and ACC preferentially.
“MDD has been shown to affect, among other areas, the PFC, the hippocampus and the anterior cingulate cortex (ACC), and there is evidence that ketamine affects these areas preferentially.204–206”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [204]
MDD affects the PFC, hippocampus and ACC.
“MDD has been shown to affect, among other areas, the PFC, the hippocampus and the anterior cingulate cortex (ACC), and there is evidence that ketamine affects these areas preferentially.204–206”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [204]
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Self-citationThe Neurobiology of Panic: A Chronic Stress Disorder
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- Authors
- Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H.
- Affiliations
- Yale University (US)
- Corresponding author
- Abdallah, Chadi G.
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 190
- Pages
- 148-158
- ISSN
- 0163-7258 (ISSN-L)
- PMC
- PMC6165688
- OpenAlex
- W2803958441
- Cited by
- 219
- References
- 173
- Citations by year
- 2026: 9 · 2025: 29 · 2024: 22 · 2023: 29 · 2022: 25 · 2021: 24 · 2020: 35 · 2019: 31 · 2018: 15
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k23mh101498-05)
- National Institute of Mental Health (K23MH-101498(, R01MH093897)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- depression, ketamine, rapid-acting antidepressants, glutamatergic neurotransmission, chronic stress, mechanism of action, biomarkers, antidepressant efficacy
- MeSH terms
- Drug Development, Animals, Antidepressive Agents, Depression, Disease Models, Animal, Humans, Ketamine, Synaptic Transmission, Biomarkers, Glutamic Acid
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