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Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants
Open accessAbstract
For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.
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“Given that the evidence of PCP, MK-801, and memantine exerting antidepressant-like effects in rodents is mixed, with clinical studies either failing or lacking”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gould et al., 2019
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“It appears that increased strength of excitatory neurotransmission, in particular involving AMPARs, represents a common downstream target that is necessary for antidepressant efficacy among classical and rapid-acting antidepressants (Alt et al., 2006; Gould et al., 2019; Thompson et al., 2015).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gould et al., 2019
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“NMDAR antagonism may not fully explain the antidepressant effects of ketamine”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gould et al., 2019
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“Preclinical studies suggest that the beneficial actions of ketamine are mediated by activation of both BDNF-TrkB signaling and endogenous synaptic strengthening mechanisms [114].”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [114]
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Self-citationMicroglial ERK-NRBP1-CREB-BDNF Signaling in Sustained Antidepressant Actions of (R)-Ketamine
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BackgroundSelf-citationEsketamine for treatment resistant depression
Swainson, J., Thomas, R. K., Archer, S., Chrenek, C., MacKay, M.-A., Baker, G., Dursun, S., Klassen, L. J., Chokka, P., & Demas, M. L. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1640604 · Cited by 151
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Self-citationPersonalized use of ketamine and esketamine for treatment-resistant depression
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“This effect has been explained with disinhibition of presynaptic release of glutamate in the hippocampus and PFC (through the reduced activation of GABAergic neurons), thus leading to the activation of postsynaptic AMPA receptors and neurotrophic pathways (Lener et al., 2017; Zanos and Gould, 2018; Duman et al., 2019;…”
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“The following mechanisms have been thought to underlie the antidepressant effects of ketamine: (1) inhibition of NMDARs localized to GABA inhibitory interneurons, (2) a cascade of intracellular changes due to transient inhibition of postsynaptic NMDAR activity, (3) activation of cellular plasticity cascades from inhib…”
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“Further, ketamine is able to reverse depressive symptoms in profoundly depressed and treatment-resistant patients, with the additional advantage of reducing suicide risk (Gould et al., 2019).”
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“Ketamine and its metabolites are believed to exert antidepressant effects primarily by inducing a prefrontal glutamate neurotransmission surge leading to activation of synaptic α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR), which increases brain-derived neurotrophic factor (BDNF) leve…”
BackgroundThe Effect of Ketamine on Electrophysiological Connectivity in Major Depressive Disorder
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“This leads to disinhibition of the pyramidal neurons, resulting in a glutamate surge in the synapse and enhanced a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) throughput, leading to downstream changes that enhance synaptic plasticity (2).”
BackgroundSelf-citationAntidepressants and type 2 diabetes: highways to knowns and unknowns
Alruwaili, N. S., Al-Kuraishy, H. M., Al-Gareeb, A. I., Albuhadily, A. K., Ragab, A. E., Alenazi, A. A., Alexiou, A. T., Papadakis, M., & Batiha, G. E. (2023) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-023-01149-z · Cited by 36
“The clinical effects of antidepressants take several weeks to manifest their clinical effects, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression [67, 111, 112].”
BackgroundThe Role of Glutamate Underlying Treatment-resistant Depression
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Targeting metabotropic glutamate receptors for rapid-acting antidepressant drug discovery
Musazzi, L. (2020) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2020.1822814 · Cited by 26
Vakhitova, Y. V., Kalinina, T. S., Zainullina, L. F., Lusta, A. Y., Volkova, A. V., Kudryashov, N. V., Gudasheva, T. A., Shimshirt, A. A., Kadnikov, I. A., Voronin, M. V., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413381 · Cited by 21
“A rapidly developing and sustained antidepressant effect of ketamine which depends on the NMDA receptors inhibition, leads to the activation of mTORC1 complex followed by an increase in the translation and release of BDNF, an enhancement of BDNF/TrkB signaling, and a subsequent activation of the related cellular plast…”
BackgroundBurgdorf, J. S., Zhang, X., Stanton, P. K., Moskal, J. R., & Donello, J. E. (2022) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac043 · Cited by 23
“A new class of antidepressant medication that can act rapidly and effectively would offer significant advantages over the current standard of care (Gould et al., 2019).”
BackgroundSartim, A. G., Marques, J., Silveira, K. M., Gobira, P. H., Guimarães, F. S., Wegener, G., & Joca, S. R. L. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108679 · Cited by 22
“It has been described in humans that CBD administration can increase some psychotomimetic effects of ketamine while decreasing others (depersonalization) (Hallak et al., 2011).”
BackgroundKetamine alleviates NMDA receptor hypofunction through synaptic trapping
Villega, F., Fernandes, A., Jézéquel, J., Uyttersprot, F., Bénac, N., Zenagui, S., Bastardo, L., Gréa, H., Bouchet, D., Villetelle, L., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.06.028 · Cited by 22
“63,64 These mechanisms involve either NMDAR inhibition on principal cells or interneurons, causing release of BDNF, or direct binding of the drug to TrkB, all of which elicit TrkB activation and mammalian target of rapamycin (mTOR) signaling, allowing protein synthesis and synaptic adaptation.”
BackgroundFreo, U., Brugnatelli, V., Turco, F., & Zanette, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.584649 · Cited by 19
Fine-tuning neural excitation/inhibition for tailored ketamine use in treatment-resistant depression
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Self-citationRiggs, L. M., An, X., Pereira, E. F. R., & Gould, T. D. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01685-0 · Cited by 18
“In addition, while other NMDAR antagonists reproduce the hyperlocomotor and cognitive deficits of ketamine [102, 103], they do not share its rapid or sustained antidepressant effects [1, 104] that are mimicked by (2R,6R)-HNK [36, 38].”
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“In animal studies; AA and ketamine [26,52] should be compared”
BackgroundNeuronal mTOR Outposts: Implications for Translation, Signaling, and Plasticity
Altas, B., Romanowski, A. J., Crutcher, G. W., & Poulopoulos, A. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.853634 · Cited by 18
“Fast-acting antidepressants, such as scopolamine and ketamine (Gould et al., 2019), lose their efficacy when mTOR is inhibited by local rapamycin infusion into the rodent prefrontal cortex (PFC; Li et al.”
BackgroundA focus on Rho/ROCK signaling pathway: An emerging therapeutic target in depression
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Role of group II metabotropic glutamate receptors in ketamine's antidepressant actions
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“The discovery of the rapid antidepressant efficacy of (R, S)-ketamine has reconceptualized how depression could be treated and studied in the future [6].”
Brown, K. A., Ajibola, M. I., & Gould, T. D. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-025-02085-4 · Cited by 15
“Yet, clinical trials with alternative NMDAR inhibitors have failed to mimic ketamine ’ s rapid and/or sustained clinical antidepressant effects [19].”
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Neuroprotection vs. Neurotoxicity: The Dual Impact of Brain Lipids in Depression
Yan, Y., Zhang, Y., Liu, M., Li, L., & Zheng, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062722 · Cited by 17
“However, the known risks of abuse and toxicity associated with long-term ketamine use [3,4] highlight the urgent need for novel pharmacological agents that can deliver rapid antidepressant effects without these adverse side effects [5].”
Riggs, L. M., Pereira, E. F. R., Thompson, S. M., & Gould, T. D. (2023) · Journal of Neurophysiology · doi:10.1152/jn.00326.2023 · Cited by 14
Self-citationExploring the impact of music on response to ketamine/esketamine: A scoping review
Kheirkhah, M., Nugent, A. C., Livinski, A. A., Neely, L., Johnson, S. C., Henter, I. D., Varnosfaderani, S. D., Price, R. B., Hejazi, N. S., Yavi, M., et al. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105693 · Cited by 14
Self-citationKey considerations in the pharmacological management of treatment-resistant depression
Yavi, M., Henter, I. D., Park, L. T., & Zarate, C. A. (2021) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2021.1951225 · Cited by 14
“get of rapamycin (mTOR), cellular proliferation, and neuroplasticity cascades [67].”
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Self-citationPsychedelic Therapy: A Primer for Primary Care Clinicians—Ketamine
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“Further, ketamine can bring relief in profoundly-depressed and in TRD patients, resulting in a reduction of suicide risk (Gould et al. 2019).”
BackgroundMingardi, J., Ndoj, E., Bonifacino, T., Misztak, P., Bertoli, M., Via, L. L., Torazza, C., Russo, I., Milanese, M., Bonanno, G., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310814 · Cited by 13
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“Based on these data, it was argued that the sustained antidepressant effects of ketamine may not depend on the blockade of NMDARs, but on its metabolite HNK [24,158], even though the rapid antidepressant effects cannot be accounted for by the latter.”
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“In particular, in a phase 2 clinical trial, decoglurant, a mixed mGlu2/3 negative allosteric modulator did not differentiate from placebo in patients suffering from depression (Gould et al., 2019).”
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“(2R,6R)-HNK lacks the sensory dissociative effects and abuse potential that limit the broader therapeutic use of ketamine (Figure 1; Gould et al 2019).”
Glutamate modulators and beyond: A neuroscience revolution in the making
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“(25) indicate that “ideally, a rapid-acting antidepressant drug would exert its effects within hours or days, as opposed to weeks or months.”
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Introduction to the Theme “New Therapeutic Targets”
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“(16) in their discussion of the experimental use of ketamine and its possible mechanism of action for this disorder.”
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Self-citationPutative effects of cannabidiol in depression and synaptic plasticity
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Metadata
- Authors
- Gould, T. D., Zarate, C. A., & Thompson, S. M.
- Affiliations
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- Corresponding author
- Gould, Todd D.
- Venue
- Annual Review of Pharmacology and Toxicology
- Publisher
- Annual Reviews
- Published
- 2019-01-06
- Volume
- 59
- Issue
- 1
- Pages
- 213-236
- ISSN
- 0362-1642 (ISSN-L)
- 1545-4304
- PMC
- PMC6364552
- OpenAlex
- W2897395578
- Cited by
- 133
- References
- 163
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 16 · 2023: 21 · 2022: 17 · 2021: 22 · 2020: 24 · 2019: 12
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Annual Review of Pharmacology and Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01MH086828, R01MH107615, ZIAMH002857)
- 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
- rapid-acting antidepressants, ketamine, depression, mechanism of action, hydroxynorketamine, NMDA receptor modulators, anhedonia, suicidal ideation
- MeSH terms
- Animals, Antidepressive Agents, Brain, Depression, Humans, Ketamine
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