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

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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

DOI 10.1016/j.pharmthera.2018.05.010PMC PMC6165688

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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.
ORCID: Abdallah, Chadi G.
Sanacora, Gerard
Duman, Ronald S.
Krystal, John H.
Venue: Pharmacology & Therapeutics
Publisher: Elsevier BV
Published: 2018-10
Volume: 190
Pages: 148-158
ISSN: 0163-7258 (ISSN-L)
DOI: 10.1016/j.pharmthera.2018.05.010
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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 (medical) › 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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The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?

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