Cited by 219Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchTryptophan and brain disorders

The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?

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Abdallah, Chadi G., Sanacora, Gerard, Duman, Ronald S., Krystal, John H.·2018·Pharmacology & Therapeutics

Abstract

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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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)
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
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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