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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Evidence that PCP, MK-801, and memantine produce antidepressant-like effects in rodents is mixed, and clinical studies are failing or lacking.
“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
The Pharmacology section says NMDAR channel blockers such as MK-801 typically have not shown ketamine’s sustained antidepressant effects in preclinical models, and the Clinical Studies section reports that memantine failed in multiple placebo-controlled MDD trials. The copy does not establish mixed rodent findings for all three named drugs or state that clinical studies of PCP and MK-801 are lacking; its reference to phencyclidine concerns NMDAR activity, not antidepressant effects. Page numbers were not provided. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStronger excitatory neurotransmission, especially via AMPARs, appears to be a shared requirement for antidepressant efficacy across classical and rapid-acting drugs.
“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
The 'Antidepressant Expression Mechanisms' section says AMPARs are required for rapid antidepressant actions and links sustained effects to stronger synapses. But 'Future Medication Development for the Rapid Treatment of Depression' says classical monoamine-acting antidepressants appear insensitive to acute AMPAR blockade. The paper therefore does not support an AMPAR requirement shared across classical and rapid-acting drugs; page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNMDAR antagonism may not fully account for ketamine's antidepressant effects.
“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
Animal work suggests ketamine's benefits involve both BDNF-TrkB signaling and the brain's own synaptic strengthening processes.
“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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BackgroundLally, N., Nugent, A. C., Luckenbaugh, D. A., Ameli, R., Roiser, J. P., & Zarate, C. A. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.105 · Cited by 271 · cited 1× · see citing works
“Ketamine also rapidly improves anhedonia in depressed patients (29, 30).”
BackgroundSelf-citationAn excitatory synapse hypothesis of depression
Thompson, S. M., Kallarackal, A. J., Kvarta, M. D., Van Dyke, A. M., LeGates, T. A., & Cai, X. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.03.003 · Cited by 265 · cited 4× · see citing works
“It is hypothesized that antidepressant-mediated synaptic potentiation occurs selectively in circuits that are abnormally weakened in depression (5, 123) (Figure 3).”
BackgroundInfluentialSelf-citationVoleti, B., Navarria, A., Liu, R.-J., Banasr, M., Li, N., Terwilliger, R., Sanacora, G., Eid, T., Aghajanian, G., & Duman, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.04.025 · Cited by 264 · cited 1× · see citing works
“Scopolamine administered to rodents also increases mTORC1 signaling, synaptogenesis, and antidepressant behavioral responses that are mTORC1 activation–dependent (115) and that have been functionally linked to disinhibition of somatostatin interneurons in the medial prefrontal cortex, a result that converges with the…”
BackgroundZarate, C. A., Mathews, D., Ibrahim, L., Chaves, J. F., Marquardt, C., Ukoh, I., Jolkovsky, L., Brutsche, N. E., Smith, M. A., & Luckenbaugh, D. A. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.10.019 · Cited by 255 · cited 2× · see citing works
“However, the response rate was low and was not as robust or sustained as that typically observed with ketamine (42).”
BackgroundResultSelf-citationLateral habenula in the pathophysiology of depression
Yang, Y., Wang, H., Hu, J., & Hu, H. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.10.024 · Cited by 254 · cited 1× · see citing works
“A fourth, more recent, putative NMDARdependent mechanism proposes ketamine inhibition of NMDAR-dependent high-frequency burst firing of a specific neuronal population in the lateral habenula, which will result in a decreased activity of negative valence brain circuits that are proposed to be abnormally enhanced in dep…”
BackgroundAntidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine
Fukumoto, K., Toki, H., Iijima, M., Hashihayata, T., Yamaguchi, J.-I., Hashimoto, K., & Chaki, S. (2017) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.239228 · Cited by 252 · see citing works
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“Indeed, there is extensive evidence that numerous growth-promoting signaling pathways are activated by ketamine and other rapid-acting antidepressants (72, 122, 123, 131).”
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“More recent controlled studies observed antidepressant actions of intravenous scopolamine 3–5 days following a single treatment (53, 54).”
BackgroundA role for AMPA receptors in mood disorders
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“Another placebo-controlled study of repeated adjunctive AZD6765 infusions administered daily over three weeks to subjects with treatment-resistant MDD found that AZD6765 (given at doses of either 100 mg or 150 mg) had antidepressant effects without dissociative side effects but was not rapid acting, as measured at ear…”
BackgroundAntidepressant-like actions of an AMPA receptor potentiator (LY392098)
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Neural correlates of change in major depressive disorder anhedonia following open-label ketamine
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“Ketamine also rapidly improves anhedonia in depressed patients (29, 30).”
BackgroundSelf-citationAMPA Receptor Potentiators for the Treatment of CNS Disorders
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“No other treatment for depression—especially for TRD—has demonstrated comparable effects in terms of the magnitude of response following a single administration.”
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NMDA Receptors in the Central Nervous System
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“A functional NMDAR in brain cortical regions is most typically composed of two GluN1 (historically referred to as NR1) subunits and two GluN2 (historically referred to as NR2) subunits (60).”
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“While ketamine’s antidepressant effects have been consistently replicated over the past decade (14), efforts to develop novel or more effective agents that mimic ketamine’s mechanism of action have proven difficult.”
BackgroundSelf-citationMiller, O. H., Moran, J. T., & Hall, B. J. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.07.028 · Cited by 200 · cited 1× · see citing works
“A third hypothesis proposes a role for extrasynaptic NMDARs composed primarily of GluN2B that are tonically activated by ambient glutamate and, when inhibited, lead to activation of cellular plasticity cascades (75, 76).”
BackgroundThe role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine
Monteggia, L. M., Gideons, E., & Kavalali, E. T. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.09.006 · Cited by 198 · cited 1× · see citing works
“elongation factor 2 (eEF2)] that result in an increase in translation and release of BDNF and subsequent synaptic potentiation (73, 74).”
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“To date, the observed human clinical effects of GLYX-13 have been ambiguous and have yet to be fully reported, but they do suggest potential rapid and sustained antidepressant effects (49, 50).”
BackgroundSubunit-specific mechanisms and proton sensitivity of NMDA receptor channel block
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“However, other studies suggest no such selectivity (62, 63).”
BackgroundDifferent sensitivities of NMDA receptor channel subtypes to non-competitive antagonists
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“However, other studies suggest no such selectivity (62, 63).”
BackgroundKallarackal, A. J., Kvarta, M. D., Cammarata, E., Jaberi, L., Cai, X., Bailey, A. M., & Thompson, S. M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2588-13.2013 · Cited by 181 · see citing works
Self-citationEffects of a ketamine metabolite on synaptic NMDAR function
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Convergent Mechanisms Underlying Rapid Antidepressant Action
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mTOR activation is required for the antidepressant effects of mGluR2/3 blockade
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Ketamine: new uses for an old drug?
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“Since the discovery of the rapid antidepressant actions of ketamine, most studies assessing ketamine’s antidepressant effects have been designed, conducted, and analyzed using a commonly accepted view that ketamine and, possibly, norketamine are the active agents with clinical effects that are due to inhibition of the…”
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Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials
Ballard, E. D., Wills, K. E., Lally, N., Richards, E. M., Luckenbaugh, D. A., Walls, T. L., Ameli, R., Niciu, M. J., Brutsché, N. E., Park, L., et al. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.04.057 · Cited by 146 · cited 1× · see citing works
“The reduction in thoughts of suicide associated with ketamine treatment is correlated with the antianhedonic response, independent of depression improvement (31).”
BackgroundSelf-citationGABA interneurons mediate the rapid antidepressant-like effects of scopolamine
Wohleb, E. S., Wu, M., Gerhard, D. M., Taylor, S. R., Picciotto, M. R., Alreja, M., & Duman, R. S. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85033 · Cited by 144 · see citing works
Ketamine-induced anesthesia involves the N-methyl-d-aspartate receptor-channel complex in mice
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“This focus originates from anesthesia-focused experiments, where an early seminal study found that ketamine and norketamine exert anesthetic actions, but that the 6-HNKs do not, which parallels the potencies of ketamine, norketamine, and the 6-HNKs to inhibit the NMDAR (93, 94).”
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Pham, T. H., Defaix, C., Xu, X., Deng, S.-X., Fabresse, N., Alvarez, J.-C., Landry, D. W., Brachman, R. A., Denny, C. A., & Gardier, A. M. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.020 · Cited by 131 · see citing works
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“To date, the observed human clinical effects of GLYX-13 have been ambiguous and have yet to be fully reported, but they do suggest potential rapid and sustained antidepressant effects (49, 50).”
BackgroundA Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders
Wilkinson, S. T., Toprak, M., Turner, M. S., Levine, S. P., Katz, R. B., & Sanacora, G. (2017) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2017.17020239 · Cited by 125 · cited 1× · see citing works
“These data have led to ketamine’s off-label use and the emergence of specialized ketamine clinics and emergency room protocols to treat severely depressed and suicidal individuals (32).”
BackgroundNMDAR-independent, cAMP-dependent antidepressant actions of ketamine
Wray, N. H., Schappi, J. M., Singh, H., Senese, N. B., & Rasenick, M. M. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0083-8 · Cited by 125 · see citing works
Signaling networks in the pathophysiology and treatment of mood disorders
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“However, a larger 12-week course, adjunctive, repeateddose study of AZD6765 (50 mg or 150 mg) found that this agent did not separate from placebo (44).”
BackgroundNavarria, A., Wohleb, E. S., Voleti, B., Ota, K. T., Dutheil, S., Lepack, A. E., Dwyer, J. M., Fuchikami, M., Becker, A., Drago, F., et al. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.06.012 · Cited by 118 · cited 1× · see citing works
“Antagonists of M1 and M2 receptors have also produced an antidepressant and antianhedonic effect in animal models, similar to the actions of scopolamine (113, 114).”
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“However, ketamine has relatively low affinity for the majority of these targets, and in most cases, subanesthetic doses of ketamine are not expected to reach the brain levels necessary for effective interactions (37, 89, 90).”
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“The NMDAR glycine site antagonist brainpenetrant prodrug 4-chlorokynurenine has been shown to exert antidepressant activity in preclinical models and is in human phase II clinical trials with results not yet reported (88).”
BackgroundSelf-citationGhosal, S., Bang, E., Yue, W., Hare, B. D., Lepack, A. E., Girgenti, M. J., & Duman, R. S. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.06.017 · Cited by 111 · see citing works
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“Upregulation of AMPAR synaptic expression has been measured in immunoblots from animals within 24 hours after treatment with ketamine and other putative rapid-acting antidepressant drugs (68, 71, 107, 129, 139).”
BackgroundChou, D., Peng, H.-Y., Lin, T.-B., Lai, C.-Y., Hsieh, M.-C., Wen, Y.-C., Lee, A.-S., Wang, H.-H., Yang, P.-S., Chen, G.-D., et al. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.06.033 · Cited by 104 · cited 1× · see citing works
“The (2R,6R)-HNK metabolite [formed exclusively from (R)-ketamine] exerts rapid and sustained ketamine-like behavioral and cellular actions in vivo (68, 95, 96).”
BackgroundDefining the role of NMDA receptors in anesthesia: Are we there yet?
Petrenko, A. B., Yamakura, T., Sakimura, K., & Baba, H. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.11.039 · Cited by 103 · cited 1× · see citing works
“However, there is evidence that other targets contribute to anesthetic actions (65), such as ketamine blockade of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel (66).”
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“Antagonists of M1 and M2 receptors have also produced an antidepressant and antianhedonic effect in animal models, similar to the actions of scopolamine (113, 114).”
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AMPA Receptor Potentiators: Application for Depression and Parkinsons Disease
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Glutamatergic Modulators in Depression
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“Past treatment approaches (such as total sleep deprivation and ECT) and emerging findings with other medications, including scopolamine, (S)-ketamine, and GLYX-13, support the notion that depression can be treated rapidly, provided that the correct receptors, synapses, and/or circuits are targeted.”
BackgroundInfluentialBDNF Release and Signaling Are Required for the Antidepressant Actions of GLYX-13
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“Deletion of forebrain BDNF or TrkB and prevention of TrkB activation hinder the actions of rapid-acting antidepressant compounds in preclinical models (74, 110, 131, 132, 135).”
BackgroundOral Scopolamine Augmentation in Moderate to Severe Major Depressive Disorder
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“It was subsequently reported that oral, twice-daily scopolamine had a small but superior antidepressant effect, compared to placebo, within 4 days of treatment initiation (55).”
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“Historically, ECT, when efficacious, has a faster onset than monoamine-targeting antidepressants (8).”
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“An early study found that intramuscular administration of scopolamine resulted in an antidepressant effect following the second of three administrations (52).”
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mGlu2/3 Receptor Antagonists as Novel Antidepressants
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Rapid Acting Antidepressants in Chronic Stress Models: Molecular and Cellular Mechanisms
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Enhancing ketamine translational pharmacology via receptor occupancy normalization
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“However, ketamine has relatively low affinity for the majority of these targets, and in most cases, subanesthetic doses of ketamine are not expected to reach the brain levels necessary for effective interactions (37, 89, 90).”
BackgroundEfficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain
Kroin, J. S., Das, V., Moric, M. M., & Buvanendran, A. (2019) · Regional Anesthesia & Pain Medicine · doi:10.1136/rapm-2018-000013 · Cited by 49 · cited 1× · see citing works
“Additional studies have identified biological effects of (2R,6R)-HNK relevant to depression (98, 101–105) as well as effectiveness of (2R,6R)-HNK in ameliorating chronic pain symptoms in mice (106).”
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“Furthermore, GLYX-13 administered at antidepressant-relevant doses prevented the NMDAR inhibition–mediated cognitive side effects of ketamine (112).”
BackgroundIntracellular Signaling Pathways Involved in ( S )- and ( R )-Ketamine Antidepressant Actions
Zanos, P., & Gould, T. D. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.026 · Cited by 42 · cited 1× · see citing works
“It is critically important for future human clinical trials to assess the antidepressant efficacy of (R)ketamine and to compare the potency of (R)-ketamine to that of (S)-ketamine (83).”
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“Since the discovery of the rapid antidepressant actions of ketamine, most studies assessing ketamine’s antidepressant effects have been designed, conducted, and analyzed using a commonly accepted view that ketamine and, possibly, norketamine are the active agents with clinical effects that are due to inhibition of the…”
BackgroundSelf-citationPark, L., Furey, M., Nugent, A. C., Farmer, C., Ellis, J., Szczepanik, J. E., Lener, M. S., & Zarate, C. A. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy051 · Cited by 37 · cited 12× · see citing works
“Overall, MDD subjects had a 60% response rate to CP-101,606, compared to 20% in the placebo group (45).”
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Tolerance to the discriminative stimulus and reinforcing effects of ketamine
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“Ketamine is abused because of its dissociative and psychotomimetic effects (34), and rodents will self-administer ketamine (67, 68).”
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Add-on memantine to valproate treatment increased HDL-C in bipolar II disorder
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Hashimoto, K. (2019) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12902 · Cited by 335 · see citing works
Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor
Wei, Y., Chang, L., & Hashimoto, K. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01121-1 · Cited by 248 · see citing works
“It has been recognized that the rapid-acting antidepressantlike effects of (R,S)-ketamine are mediated through blockade of NMDARs located on γ-aminobutyric acid (GABA) ergic inhibitory interneurons, and that subsequent activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is required…”
BackgroundMolecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine
Hashimoto, K. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113935 · Cited by 239 · see citing works
The role of dissociation in ketamine’s antidepressant effects
Ballard, E. D., & Zarate, C. A. (2020) · Nature Communications · doi:10.1038/s41467-020-20190-4 · Cited by 221 · see citing works
Self-citationMicroglial ERK-NRBP1-CREB-BDNF Signaling in Sustained Antidepressant Actions of (R)-Ketamine
Yao, W., Cao, Q., Luo, S., He, L., Yang, C., Chen, J., Qi, Q., Hashimoto, K., & Zhang, J.-C. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01377-7 · Cited by 216 · see citing works
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Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin
Abdallah, C. G., Averill, L. A., Gueorguieva, R., Goktas, S., Purohit, P., Ranganathan, M., Sherif, M., Ahn, K.-H., D’Souza, D. C., Formica, R., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0644-9 · Cited by 184 · see citing works
“Neuronal plasticity is thought to be critical in the pathology and treatment of depression, particularly in the mechanisms of rapid acting antidepressants [7].”
BackgroundChang, L., Zhang, K., Pu, Y., Qu, Y., Wang, S.-M., Xiong, Z., Ren, Q., Dong, C., Fujita, Y., & Hashimoto, K. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.04.008 · Cited by 176 · see citing works
Mechanisms of ketamine and its metabolites as antidepressants
Hess, E. M., Riggs, L. M., Michaelides, M., & Gould, T. D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114892 · Cited by 169 · see citing works
Self-citationKetamine Treatment for Depression: A Review
Yavi, M., Lee, H., Henter, I. D., Park, L. T., & Zarate, C. A. (2022) · Discover Mental Health · doi:10.1007/s44192-022-00012-3 · Cited by 161 · see citing works
“, AMPA, mGluR); mediation via opioidergic mechanisms; the interplay between the glutamatergic and GABA-ergic systems; and downstream effects on signal transduction cascades such as mTOR, cellular proliferation, and neuroplasticity cascades [88].”
BackgroundSelf-citationA historical review of antidepressant effects of ketamine and its enantiomers
Wei, Y., Chang, L., & Hashimoto, K. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.172870 · Cited by 158 · see citing works
Zanos, P., Highland, J. N., Stewart, B. W., Georgiou, P., Jenne, C. E., Lovett, J., Morris, P. J., Thomas, C. J., Moaddel, R., Zarate, C. A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819540116 · Cited by 152 · see citing works
“High-frequency oscillations in vivo have parallels to many forms of activity-dependent plasticity, such as long-term potentiation, in which high-frequency stimuli induce sustained strengthening of excitatory synapses via an enhanced synchrony between limbicconnected brain regions, likely necessary for antidepressant b…”
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 · see citing works
Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression
Ling, S., Ceban, F., Lui, L. M. W., Lee, Y., Teopiz, K. M., Rodrigues, N. B., Lipsitz, O., Gill, H., Subramaniapillai, M., Mansur, R. B., et al. (2022) · CNS Drugs · doi:10.1007/s40263-021-00877-y · Cited by 127 · see citing works
“Although there is no well-characterized time frame of therapeutic action for RAADs, these treatments show therapeutic efficacy within a few days to a week [9].”
BackgroundZhang, K., Yang, C., Chang, L., Sakamoto, A., Suzuki, T., Fujita, Y., Qu, Y., Wang, S., Pu, Y., Tan, Y., et al. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0733-x · Cited by 119 · see citing works
Zanos, P., Brown, K. A., Georgiou, P., Yuan, P., Zarate, C. A., Thompson, S. M., & Gould, T. D. (2023) · The Journal of Neuroscience · doi:10.1523/jneurosci.1316-22.2022 · Cited by 115 · see citing works
Self-citationA Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics
Savalia, N. K., Shao, L.-X., & Kwan, A. C. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.11.008 · Cited by 104 · see citing works
Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals
Mkrtchian, A., Evans, J. W., Kraus, C., Yuan, P., Kadriu, B., Nugent, A. C., Roiser, J. P., & Zarate, C. A. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-00878-1 · Cited by 110 · see citing works
Self-citationNeurobiological Basis of Increased Risk for Suicidal Behaviour
Wisłowska-Stanek, A., Kołosowska, K., & Maciejak, P. (2021) · Cells · doi:10.3390/cells10102519 · Cited by 115 · see citing works
Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications
Highland, J. N., Zanos, P., Riggs, L. M., Georgiou, P., Clark, S. M., Morris, P. J., Moaddel, R., Thomas, C. J., Zarate, C. A., Pereira, E. F. R., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000149 · Cited by 92 · see citing works
“…2019b; Chou et al., 2018; Highland et al., 2019; Pham et al., 2018; Fukumoto et al., 2019; Lumsden et al., 2019; Rahman et al., 2020; Yokoyama et al., 2020), leading to a growing interest in understanding their biologic activities (Abdallah, 2017; Aleksandrova et al., 2017; Gould et al., 2019).”
BackgroundSelf-citationKetamine and the Future of Rapid-Acting Antidepressants
Riggs, L. M., & Gould, T. D. (2021) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-072120-014126 · Cited by 87 · see citing works
Self-citationKetamine treatment for refractory anxiety: A systematic review
Tully, J. L., Dahlén, A. D., Haggarty, C. J., Schiöth, H. B., & Brooks, S. J. (2022) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.15374 · Cited by 87 · see citing works
“therapeutic option for treatment-resistant mood disorders.(7) The antidepressant effects of ketamine were first reported in 2000, where subanesthetic IV doses of 0.”
BackgroundFarmer, C. A., Gilbert, J. R., Moaddel, R., George, J., Adeojo, L., Lovett, J., Nugent, A. C., Kadriu, B., Yuan, P., Gould, T. D., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0663-6 · Cited by 85 · see citing works
Self-citationJoffe, M. E., Santiago, C. I., Oliver, K. H., Maksymetz, J., Harris, N. A., Engers, J. L., Lindsley, C. W., Winder, D. G., & Conn, P. J. (2019) · Neuron · doi:10.1016/j.neuron.2019.09.044 · Cited by 75 · see citing works
Medeiros, G. C., Gould, T. D., Prueitt, W. L., Nanavati, J., Grunebaum, M. F., Farber, N. B., Singh, B., Selvaraj, S., Machado-Vieira, R., Achtyes, E. D., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01652-1 · Cited by 75 · see citing works
“Initially developed in the early 1960s as an anesthetic agent [13], ketamine is a NMDA receptor antagonist with a unique antidepressant mechanism of action that may ultimately result in enhanced glutamatergic neurotransmission and strengthening of excitatory synapses [14, 15].”
BackgroundSelf-citationWitkin, J. M., Martin, A. E., Golani, L. K., Xu, N. Z., & Smith, J. L. (2019) · Advances in pharmacology · doi:10.1016/bs.apha.2019.03.002 · Cited by 75 · see citing works
Treatment-resistant depression: molecular mechanisms and management
Kajumba, M. M., Kakooza‐Mwesige, A., Nakasujja, N., Attix, D. K., & Canli, T. (2024) · Molecular Biomedicine · doi:10.1186/s43556-024-00205-y · Cited by 86 · see citing works
“Thus, the finding that ketamine induces DA release [261, 264], and a rapid therapeutic action in TRD [265] with relief of the motor and motivational symptoms [36, 91, 99, 101, 102], further supports the assertion that the dopaminergic system is central in the etiology of TRD and may be involved in…”
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Page, C. E., Epperson, C. N., Novick, A. M., Duffy, K. A., & Thompson, S. M. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02625-2 · Cited by 80 · see citing works
“Preclinical studies suggest that the bene fi cial actions of ketamine are mediated by activation of both BDNF-TrkB signaling and endogenous synaptic strengthening mechanisms [114].”
Self-citationHighland, J. N., Morris, P. J., Zanos, P., Lovett, J., Ghosh, S., Wang, A. Q., Zarate, C. A., Thomas, C. J., Moaddel, R., & Gould, T. D. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881118812095 · Cited by 62 · see citing works
“This suggests that some rapid change is induced while the drug is present, and this change leads to a sustained alteration in brain function that persists long after the drug is cleared (Gould et al., 2018).”
Self-citationPark, L. T., Kadriu, B., Gould, T. D., Zanos, P., Greenstein, D., Evans, J. W., Yuan, P., Farmer, C. A., Oppenheimer, M., George, J. M., et al. (2020) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyaa025 · Cited by 63 · see citing works
“Recent preclinical investigations, including comprehensive mechanistic cellular and molecular studies, support efforts to develop novel treatment approaches that robustly improve depressive symptoms within hours instead of weeks without ketamine’s most concerning adverse effects (Abdallah et al., 2018; Gould et al., 2…”
BackgroundSelf-citationSerial Prefrontal Pathways Are Positioned to Balance Cognition and Emotion in Primates
Joyce, M. K. P., García‐Cabezas, M. Á., John, Y. J., & Barbas, H. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.0860-20.2020 · Cited by 60 · see citing works
“Whether the antidepressant effects of NMDAR antagonists are mediated by populations of NMDARs on excitatory or inhibitory neurons in A25 remains an open question (for review, see Gould et al., 2019).”
BackgroundKetamine and esketamine in suicidal thoughts and behaviors: a systematic review
Jollant, F., Colle, R., Nguyen, T. M. L., Corruble, E., Gardier, A. M., Walter, M., Abbar, M., & Wagner, G. (2023) · Therapeutic Advances in Psychopharmacology · doi:10.1177/20451253231151327 · Cited by 56 · see citing works
“In secondary RCTs, durations of follow-up were also highly variable: 24 h (N = 1), below 30 days (9), 3 weeks (1), 4 weeks (1), 6 weeks (1), and 6 months (1).”
BackgroundZhang, H., Sun, Y., Yau, S., Zhou, Y., Song, X., Zhang, H., Zhu, B., Wu, H., & Chen, G. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15847 · Cited by 52 · see citing works
“However, owing to the well-known abuse potential and toxicity associated with long-term use of ketamine (Li et al., 2013; Shyu et al., 2016; Zhu et al., 2016), novel pharmacological agents with a rapid antidepressant action are still urgently needed (Gould et al., 2019; Wilkinson & Sanacora, 2019).”
BackgroundMa, L., Zhang, J., Fujita, Y., Qu, Y., Shan, J., Wan, X., Wang, X., Ishima, T., Kobayashi, K., Wang, L., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01803-6 · Cited by 52 · see citing works
Targeting metaplasticity mechanisms to promote sustained antidepressant actions
Brown, K. A., & Gould, T. D. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02397-1 · Cited by 49 · see citing works
“Furthermore, many clinical studies have revealed that NMDAR antagonists do not induce robust, rapid, and/or sustained antidepressant effects [23 – 34] compared to what has been observed with ketamine [10, 12, 41, 42].”
InfluentialSelf-citationWang, Y., Zhang, N., Liu, L., Jiang, H., Hu, D., Wang, Z., Chen, N., & Zhang, Y. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.01.024 · Cited by 46 · see citing works
Biological Factors Underpinning Suicidal Behaviour: An Update
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“Approved therapeutics include several drugs administered to depressed patients to decrease the possibility of SI and SA, such as Lithium (mood-stabilizing drug), Clozapine (reduces suicidality, aggressive/impulsive behaviours), and Ketamine/Esketamine (antidepressant) [124].”
BackgroundEffects of pharmacological treatment on metabolomic alterations in animal models of depression
Pu, J., Liu, Y., Gui, S., Tian, L., Yu, Y., Wang, D., Zhong, X., Chen, W., Chen, X., Chen, Y., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01947-5 · Cited by 46 · see citing works
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Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition
Lüscher, B., Feng, M., & Jefferson, S. J. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.03.002 · Cited by 41 · see citing works
Brymer, K. J., Johnston, J. N., Botterill, J. J., Romay-Tallón, R., Mitchell, M. A., Allen, J., Pinna, G., Caruncho, H. J., & Kalynchuk, L. E. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0609-z · Cited by 41 · see citing works
Plasticity of synapses and reward circuit function in the genesis and treatment of depression
Thompson, S. M. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-022-01422-1 · Cited by 40 · see citing works
Self-citationPersonalized use of ketamine and esketamine for treatment-resistant depression
Medeiros, G. C., Demo, I., Goes, F. S., Zarate, C. A., & Gould, T. D. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03180-8 · Cited by 41 · see citing works
Self-citationSala, N., Paoli, C., Bonifacino, T., Mingardi, J., Schiavon, E., Via, L. L., Milanese, M., Tornese, P., Datusalia, A. K., Rosa, J., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.759626 · Cited by 38 · see citing works
“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;…”
BackgroundSakurai, H., Yonezawa, K., Tani, H., Mimura, M., Bauer, M., & Uchida, H. (2022) · Pharmacopsychiatry · doi:10.1055/a-1714-9097 · Cited by 38 · see citing works
“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…”
BackgroundRepurposing of Drugs–The Ketamine Story
Das, J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01193 · Cited by 35 · see citing works
Witkin, J. M. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.172854 · Cited by 36 · see citing works
Wang, M., Zhang, B., Zhou, Y., Wang, C., Zheng, W., Liu, W., Zhan, Y., Lan, X., & Ning, Y. (2021) · Pharmacological Reports · doi:10.1007/s43440-020-00203-1 · Cited by 35 · see citing works
Averill, L. A., Averill, C. L., Gueorguieva, R., Fouda, S., Sherif, M., Ahn, K.-H., Ranganathan, M., D'Souza, D. C., Southwick, S. M., Sanacora, G., et al. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.01.104 · Cited by 33 · see citing works
Depoortère, R., Papp, M., Gruca, P., Łasoń, M., Niemczyk, M., Varney, M. A., & Newman‐Tancredi, A. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881119860666 · Cited by 33 · see citing works
“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).”
BackgroundTroppoli, T. A., Zanos, P., Georgiou, P., Gould, T. D., Rudolph, U., & Thompson, S. M. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.11.024 · Cited by 29 · see citing works
Self-citationAbdallah, C., Averill, L. A., Gueorguieva, R., Goktas, S., Purohit, P., Ranganathan, M., D'Souza, D. C., Formica, R., Southwick, S. M., Duman, R. S., et al. (2018) · doi:10.1101/500959 · Cited by 30 · see citing works
“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
Nugent, A. C., Ballard, E. D., Gilbert, J. R., Tewarie, P. K. B., Brookes, M. J., & Zarate, C. A. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00519 · Cited by 30 · see citing works
“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 30 · see citing works
“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
Kim, J., Kim, T.-E., Lee, S., & Koo, J. W. (2023) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.22.1034 · Cited by 30 · see citing works
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“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…”
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“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).”
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“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 21 · see citing works
“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.”
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Fine-tuning neural excitation/inhibition for tailored ketamine use in treatment-resistant depression
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“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
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“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 · see citing works
“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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Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models
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Neuroprotection vs. Neurotoxicity: The Dual Impact of Brain Lipids in Depression
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“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 · see citing works
Self-citationExploring the impact of music on response to ketamine/esketamine: A scoping review
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“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).”
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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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- 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 · 2018: 3
- 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 › 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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