Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression

Lener, Marc S.; Kadriu, Bashkim; Zarate, Carlos A.

doi:10.1007/s40265-017-0702-8

Cited by 133Treatment of Major DepressionElectroconvulsive Therapy StudiesNeuroscience and Neuropharmacology Research

Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression

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Lener, Marc S., Kadriu, Bashkim, Zarate, Carlos A.·2017·Drugs

DOI 10.1007/s40265-017-0702-8PMC PMC5342919

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Abstract

Clinical and preclinical studies suggest that dysfunction of the glutamatergic system is implicated in mood disorders such as major depressive disorder and bipolar depression. In clinical studies of individuals with major depressive disorder and bipolar depression, rapid reductions in depressive symptoms have been observed in response to subanesthetic-dose ketamine, an agent whose mechanism of action involves the modulation of glutamatergic signaling. The findings from these studies have prompted the repurposing and/or development of other glutamatergic modulators for antidepressant efficacy, both as monotherapy or as an adjunct to conventional monoaminergic antidepressants. This review highlights the evidence supporting the antidepressant effects of subanesthetic-dose ketamine as well as other glutamatergic modulators, such as D-cycloserine, riluzole, CP-101,606, CERC-301 (previously known as MK-0657), basimglurant, JNJ-40411813, dextromethorphan, nitrous oxide, GLYX-13, and esketamine.

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Esketamine has nearly fourfold greater affinity for the NMDAR than (R)-ketamine but induces fewer and weaker psychotomimetic and dissociative effects.
“Esketamine has nearly fourfold greater affinity for the NMDAR than (R)-ketamine but interestingly induces fewer and weaker psychotomimetic and dissociative effects [103].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [103]
In all reports, initial efficacy of memantine, lanicemine, and CERC 301 was either transient or inconsistent in larger studies.
“In all reports, initial efficacy was either transient or inconsistent in larger studies [97,103,144,145,146].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [103]

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Heresco-Levy, U., Gelfin, G., Bloch, B., Levin, R., Edelman, S., Javitt, D. C., & Kremer, I. (2013) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712000910 · Cited by 177 · see citing works
Regulation of Cellular Plasticity Cascades in the Pathophysiology and Treatment of Mood Disorders
Zarate, C. A., Du, J., Quiroz, J. A., GRAY, N. A., Denicoff, K. D., Singh, J., Charney, D. S., & Manji, H. K. (2003) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1300.017 · Cited by 164 · see citing works
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Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?
Sanacora, G., & Schatzberg, A. F. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.261 · Cited by 160 · see citing works
Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder
Niciu, M. J., Ionescu, D. F., Richards, E. M., & Zarate, C. A. (2013) · Journal of Neural Transmission · doi:10.1007/s00702-013-1130-x · Cited by 157 · see citing works
Self-citation
Effects of Propofol and Ketamine as Combined Anesthesia for Electroconvulsive Therapy in Patients With Depressive Disorder
Wang, X., Chen, Y., Zhou, X., Liu, F., Zhang, T., & Zhang, C. (2012) · Journal of Ect · doi:10.1097/yct.0b013e31824d1d02 · Cited by 157 · see citing works
Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder
Ghasemi, M., Kazemi, M., Yoosefi, A., Ghasemi, A., Paragomi, P., Amini‎, H., & Afzali, M. H. (2013) · Psychiatry Research · doi:10.1016/j.psychres.2013.12.008 · Cited by 153 · see citing works
Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study
Hu, Y.-D., Xiang, Y.-T., Fang, J.-X., Zu, S., Sha, S., Shi, H., Ungvari, G. S., Correll, C. U., Chiu, H. F. K., Xue, Y., et al. (2016) · Psychological Medicine · doi:10.1017/s0033291715002159 · Cited by 146 · see citing works
Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial
Murrough, J. W., Burdick, K. E., Levitch, C. F., Perez, A. M., Brallier, J. W., Chang, L. C., Foulkes, A., Charney, D. S., Mathew, S. J., & Iosifescu, D. V. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.298 · Cited by 142 · see citing works
Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression
Lara, D. R., Bisol, L. W., & Munari, L. R. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713000485 · Cited by 140 · see citing works
Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial
Quiroz, J. A., Tamburri, P., Deptula, D., Banken, L., Beyer, U., Rabbia, M., Parkar, N., Fontoura, P., & Santarelli, L. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2016.0838 · Cited by 133 · see citing works
GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists
Moskal, J. R., Burch, R. M., Burgdorf, J. S., Kroes, R. A., Stanton, P. K., Disterhoft, J. F., & Leander, J. D. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.852536 · Cited by 130 · see citing works
A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: Efficacy and tolerability
McGirr, A., Berlim, M. T., Bond, D. J., Neufeld, N. H., Chan, P. Y., Yatham, L. N., & Lam, R. W. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.01.003 · Cited by 127 · see citing works
Rapid Antidepressant Effect of Ketamine in the Electroconvulsive Therapy Setting
Abdallah, C. G., Fasula, M. K., Kelmendi, B., Sanacora, G., & Ostroff, R. B. (2012) · Journal of Ect · doi:10.1097/yct.0b013e31824f8296 · Cited by 123 · see citing works
Neuropsychological and mood effects of ketamine in electroconvulsive therapy: A randomised controlled trial
Loo, C. K. A., Katalinic, N., Garfield, J. B. B., Sainsbury, K., Hadži-Pavlović, D., & MacPherson, R. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.04.032 · Cited by 118 · see citing works
Long-term effects of ketamine: evidence for a persisting impairment of source memory in recreational users
Morgan, C. J. A., Riccelli, M., Heriot-Maitland, C., & Curran, H. V. (2004) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2004.03.006 · Cited by 118 · see citing works
Beyond the K‐hole: a 3‐year longitudinal investigation of the cognitive and subjective effects of ketamine in recreational users who have substantially reduced their use of the drug
Morgan, C. J. A., Monaghan, L., & Curran, H. V. (2004) · Addiction · doi:10.1111/j.1360-0443.2004.00879.x · Cited by 113 · see citing works
Stress, glucocorticoids and glutamate release: Effects of antidepressant drugs
Musazzi, L., Racagni, G., & Popoli, M. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.05.002 · Cited by 113 · see citing works
Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response
Murrough, J. W., Wan, L.-B., Iacoviello, B. M., Collins, K. A., SOLON, C. A., Glicksberg, B. S., Perez, A. M., Mathew, S. J., Charney, D. S., Iosifescu, D. V., et al. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3255-x · Cited by 112 · see citing works
Effect of Baseline Anxious Depression on Initial and Sustained Antidepressant Response to Ketamine
Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J., Richards, E. M., Slonena, E. E., Vande Voort, J. L., Brutsche, N. E., & Zarate, C. A. (2014) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.14m09049 · Cited by 111 · see citing works
Self-citation
Pilot dose–response trial of i.v. ketamine in treatment-resistant depression
Lai, R., Katalinic, N., Glue, P., Somogyi, A. A., Mitchell, P. B., Leyden, J., Harper, S., & Loo, C. K. A. (2014) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2014.922697 · Cited by 109 · see citing works
GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine
Liu, R.-J., Duman, C., Kato, T., Hare, B., Lopresto, D., Bang, E., Burgdorf, J., Moskal, J., Taylor, J., Aghajanian, G., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.202 · Cited by 105 · see citing works
A single infusion of ketamine improves depression scores in patients with anxious bipolar depression
Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J., Richards, E. M., & Zarate, C. A. (2014) · Bipolar Disorders · doi:10.1111/bdi.12277 · Cited by 104 · see citing works
Self-citation
A Word to the Wise About Ketamine
Schatzberg, A. F. (2014) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2014.13101434 · Cited by 102 · see citing works
MK-801-induced neuronal damage in rats
Horváth, Z., Czopf, J., & Buzsáki, G. (1997) · Brain Research · doi:10.1016/s0006-8993(96)01290-5 · Cited by 101 · see citing works
Comparing Effects of Ketamine and Thiopental Administration During Electroconvulsive Therapy in Patients With Major Depressive Disorder
Yoosefi, A., Sepehri, A. S., Kargar, M., Akhondzadeh, S., Sadeghi, M., Rafei, A., Alimadadi, A., & Ghaeli, P. (2013) · Journal of Ect · doi:10.1097/yct.0b013e3182a4b4c6 · Cited by 98 · see citing works
A Brief Overview of the Clinical Pharmacology of “Club Drugs”
Britt, G. C., & McCance‐Katz, E. F. (2005) · Substance Use & Misuse · doi:10.1081/ja-200066730 · Cited by 98 · see citing works
Effects of S-Ketamine as an Anesthetic Adjuvant to Propofol on Treatment Response to Electroconvulsive Therapy in Treatment-Resistant Depression
Järventausta, K., Chrapek, W., Kampman, O., Tuohimaa, K., Björkqvist, M., Häkkinen, H., Yli‐Hankala, A., & Leinonen, E. V. J. (2013) · Journal of Ect · doi:10.1097/yct.0b013e318283b7e9 · Cited by 97 · see citing works
In pursuit of neuroimaging biomarkers to guide treatment selection in major depressive disorder: a review of the literature
Lener, M. S., & Iosifescu, D. V. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12759 · Cited by 96 · see citing works
Self-citation
Dissimilar patterns of degeneration in brain following four different addictive stimulants
Ellison, G. D., & Switzer, R. C. (1993) · Neuroreport · doi:10.1097/00001756-199310000-00004 · Cited by 92 · see citing works
Controlled trial of d-cycloserine adjuvant therapy for treatment-resistant major depressive disorder
Heresco-Levy, U., Javitt, D. C., Gelfin, Y., Gorelik, E., Bar, M., Blanaru, M., & Kremer, I. (2006) · Journal of Affective Disorders · doi:10.1016/j.jad.2006.03.004 · Cited by 89 · see citing works
A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department
Larkin, G. L., Beautrais, A. L., Turelli, R., Sanacora, G., Powsner, S. M., Lippmann, M. J., & Krystal, J. H. (2011) · European Psychiatry · doi:10.1016/s0924-9338(11)73311-9 · Cited by 80 · see citing works
The interplay between rapid and slow corticosteroid actions in brain
Joëls, M., Pasricha, N., & Karst, H. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.07.015 · Cited by 78 · see citing works
Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression
Zhong, X., He, H., Zhang, C., Wang, Z., Jiang, M., Li, Q., Zhang, M., & Huang, X. (2016) · Journal of Affective Disorders · doi:10.1016/j.jad.2016.05.011 · Cited by 76 · see citing works
Single-Dose Ketamine Followed by Daily d-Cycloserine in Treatment-Resistant Bipolar Depression
Kantrowitz, J. T., Halberstam, B., & Gangwisch, J. E. (2015) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.14l09527 · Cited by 73 · see citing works
Fates-shifted is an F-box protein that targets Bicoid for degradation and regulates developmental fate determination in Drosophila embryos
Liu, J., & Ma, J. (2010) · Nature Cell Biology · doi:10.1038/ncb2141 · Cited by 72 · see citing works
Riluzole Augmentation for Treatment-Resistant Depression
Sanacora, G., Kendell, S. F., Fenton, L. R., Coric, V., & Krystal, J. H. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.11.2132 · Cited by 71 · see citing works
Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the monkey subthalamic nucleus
Kuwajima, M., Hall, R. A., Aiba, A., & Smith, Y. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.20158 · Cited by 69 · see citing works
Can Exposure-Based CBT Extend the Effects of Intravenous Ketamine in Obsessive-Compulsive Disorder?
Rodríguez, C. I., Wheaton, M. G., Zwerling, J., Steinman, S. A., Sonnenfeld, D., Galfalvy, H., & Simpson, H. B. (2016) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.15l10138 · Cited by 63 · see citing works
Ketamine regulates the presynaptic release machinery in the hippocampus
Müller, H. K., Wegener, G., Liebenberg, N., Zarate, C. A., Popoli, M., & Elfving, B. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.03.008 · Cited by 61 · see citing works
Self-citation
Impact comparison of ketamine and sodium thiopental on anesthesia during electroconvulsive therapy in major depression patients with drug-resistant; a double-blind randomized clinical trial
Moshiri, I., Salehi, B., Mohammadbeigi, A., Kamali, A., & Taheri-nejad, M. R. (2015) · Annals of Cardiac Anaesthesia · doi:10.4103/0971-9784.166444 · Cited by 61 · see citing works
The Use of a Series of Ketamine Infusions in Two Patients With Treatment-Resistant Depression
Messer, M., Haller, I. V., Larson, P. M., Pattison-Crisostomo, J., & Gessert, C. E. (2010) · Journal of Neuropsychiatry · doi:10.1176/jnp.2010.22.4.442 · Cited by 56 · see citing works
Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression
Kent, J. M., Daly, E., Kezic, I., Lane, R., Lim, P., De Smedt, H., De Boer, P., Van Nueten, L., Drevets, W. C., & Ceusters, M. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.01.009 · Cited by 53 · cited 2× · see citing works
“Among the 100 patients who completed the study, no differences were observed in depression or anxiety rating scale scores via primary outcome measures, although some reductions in anxiety symptoms, as assessed by secondary measures, were noted [119].”
The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS
Kelly, T., & Lieberman, D. Z. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.05.050 · Cited by 50 · see citing works
Developing biomarkers in mood disorders research through the use of rapid-acting antidepressants
Niciu, M. J., Mathews, D. C., Nugent, A. C., Ionescu, D. F., Furey, M. L., Richards, E. M., Machado-Vieira, R., & Zarate, C. A. (2014) · Depression and Anxiety · doi:10.1002/da.22224 · Cited by 45 · see citing works
Self-citation
Expression Profiling of a Genetic Animal Model of Depression Reveals Novel Molecular Pathways Underlying Depressive-Like Behaviours
Blaveri, E., Kelly, F., Mallei, A., Harris, K., Taylor, A. R., Reid, J. L., Razzoli, M., Carboni, L., Piubelli, C., Musazzi, L., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012596 · Cited by 44 · see citing works
Novel Glutamatergic Treatments for Severe Mood Disorders
Park, M., Niciu, M. J., & Zarate, C. A. (2015) · Current Behavioral Neuroscience Reports · doi:10.1007/s40473-015-0050-5 · Cited by 40 · see citing works
Self-citation
Subanesthetic Dose Ketamine Does Not Induce an Affective Switch in Three Independent Samples of Treatment-Resistant Major Depression
Niciu, M. J., Luckenbaugh, D. A., Ionescu, D. F., Mathews, D. C., Richards, E. M., & Zarate, C. A. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.01.038 · Cited by 39 · see citing works
Self-citation
A Bayesian framework systematic review and meta-analysis of anesthetic agents effectiveness/tolerability profile in electroconvulsive therapy for major depression
Fond, G. B., Bennabi, D., Haffen, É., Brunel, L., Micoulaud‐Franchi, J., Loundou, A., Lançon, C., Llorca, P., Auquier, P., & Boyer, L. (2016) · Scientific Reports · doi:10.1038/srep19847 · Cited by 38 · see citing works
The DRD2/ANKK1 gene is associated with response to add-on dextromethorphan treatment in bipolar disorder
Lee, S.-Y., Chen, S.-L., Chang, Y.-H., Chen, S.-H., Chu, C.-H., Huang, S.-Y., Tzeng, N.-S., Wang, C.-L., Lee, I. H., Yeh, T. L., et al. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.01.024 · Cited by 35 · cited 2× · see citing works
“Dextromethorphan NMDA receptor, Sigma-1 receptor, SERT, NET NMDA receptor antagonist, Sigma-1 receptor antagonist, SERT and NET inhibitor BD Weak evidence for antidepressant effects as adjunct to mood stabilizers in BD [120, 121]”
Prescription monitoring programs and emergency department visits involving benzodiazepine misuse: Early evidence from 11 United States metropolitan areas
Bachhuber, M. A., Maughan, B. C., Mitra, N., Feingold, J., & Starrels, J. L. (2016) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2015.08.005 · Cited by 35 · see citing works
Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine
Cho, H. S., D’Souza, D. C., Gueorguieva, R. V., Perry, E. B., Madonick, S. H., Karper, L. P., Abi‐Dargham, A., Belger, A., Abi‐Saab, W., Lipschitz, D. S., et al. (2005) · Psychopharmacology · doi:10.1007/s00213-004-2066-5 · Cited by 35 · see citing works
Ketamine Anesthesia, Efficacy of Electroconvulsive Therapy, and Cognitive Functions in Treatment-Resistant Depression
Rybakowski, J., Bodnar, A., Krzywotulski, M., Chłopocka‐Woźniak, M., Michalak, M., Rosada-Kurasińska, J., & Bartkowska-Śniatkowska, A. (2016) · Journal of ECT · doi:10.1097/yct.0000000000000317 · Cited by 33 · see citing works
Antidepressant Effect of Combined Ketamine and Electroconvulsive Therapy on Patients With Major Depressive Disorder: A Randomized Trial
Alizadeh, N. S., Maroufi, A., Nasseri, K., Najafabadi, S. H. S., Taghiabad, A. M., Gharibi, F., & Esfandiari, G.-R. (2015) · Iranian Journal of Psychiatry and Behavioral Sciences · doi:10.17795/ijpbs-1578 · Cited by 33 · see citing works
WHITHER KETAMINE AS AN ANTIDEPRESSANT: PANACEA OR TOXIN?: Editorial
Newport, D. J., Schatzberg, A. F., & Nemeroff, C. B. (2016) · Depression and Anxiety · doi:10.1002/da.22535 · Cited by 30 · see citing works
The Effects of Stress on Glutamatergic Transmission in the Brain
Yuan, T., & Hou, G. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8783-9 · Cited by 26 · see citing works
Effect of Ketamine, Thiopental and Ketamine–Thiopental Combination during Electroconvulsive Therapy for Depression
Kuşçu, Ö. Ö., Karacaer, F., Biricik, E., Güleç, E., Tamam, L., & Güneş, Y. (2015) · Türk anesteziyoloji ve reanimasyon derneği dergisi · doi:10.5152/tjar.2015.92668 · Cited by 25 · see citing works
Erratum: Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?
Sanacora, G., & Schatzberg, A. F. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.338 · Cited by 25 · see citing works
Riluzole likely lacks antidepressant efficacy in ketamine non-responders
Niciu, M. J., Luckenbaugh, D. A., Ionescu, D. F., Richards, E. M., Voort, J. L. V., Ballard, E. D., Brutsché, N. E., Furey, M. L., & Zarate, C. A. (2014) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.07.022 · Cited by 22 · see citing works
Self-citation
GSK ‐3: A key regulatory target for ketamine's rapid antidepressant effects mediated by enhanced AMPA to NMDA throughput
Zarate, C. A., & Machado‐Vieira, R. (2016) · Bipolar Disorders · doi:10.1111/bdi.12452 · Cited by 19 · see citing works
Self-citation
Comments on "An Innovative Design to Establish Proof of Concept of the Antidepressant Effects of the NR2B Subunit Selective N-Methyl-d-Aspartate Antagonist, CP-101,606, in Patients With Treatment-Refractory Major Depressive Disorder"
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Ketamine for depression relapse prevention following electroconvulsive therapy: protocol for a randomised pilot trial (the KEEP-WELL trial)
Finnegan, M., Ryan, K. M., Shanahan, E., Harkin, A., Daly, L., & McLoughlin, D. M. (2016) · Pilot and Feasibility Studies · doi:10.1186/s40814-016-0080-0 · Cited by 4 · see citing works

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Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression
Cole, E. J., Stimpson, K. H., Bentzley, B. S., Gulser, M., Cherian, K., Tischler, C., Nejad, R., Pankow, H., Choi, E., Aaron, H., et al. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19070720 · Cited by 802 · see citing works
Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial
Cole, E. J., Phillips, A. L., Bentzley, B. S., Stimpson, K. H., Nejad, R., Barmak, F., Veerapal, C., Khan, N., Cherian, K., Felber, E., et al. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2021.20101429 · Cited by 795 · see citing works
Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis
Bahji, A., Vazquez, G. H., & Zarate, C. A. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.09.071 · Cited by 408 · see citing works
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Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review
Molero, P., Ramos-Quiroga, J. A., Martin-Santos, R., Calvo-Sánchez, E., Gutiérrez-Rojas, L., & Meana, J. J. (2018) · CNS Drugs · doi:10.1007/s40263-018-0519-3 · Cited by 280 · see citing works
Major depressive disorder: Validated treatments and future challenges
Karrouri, R., Hammani, Z., Benjelloun, R., & Otheman, Y. (2021) · World Journal of Clinical Cases · doi:10.12998/wjcc.v9.i31.9350 · Cited by 201 · see citing works
A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems
Wilkinson, S. T., & Sanacora, G. (2019) · Drug Discovery Today · doi:10.1016/j.drudis.2018.11.007 · Cited by 173 · see citing works
Ketamine for the treatment of addiction: evidence and potential mechanisms
Ivan Ezquerra-Romano, I., Lawn, W., Krupitsky, E., & Morgan, C. J. A. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.01.017 · Cited by 163 · see citing works
Astroglial correlates of neuropsychiatric disease: From astrocytopathy to astrogliosis
Kim, R., Healey, K. L., Sepulveda-Orengo, M. T., & Reissner, K. J. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.10.002 · Cited by 141 · see citing works
Neuropeptide and small transmitter coexistence: Fundamental studies and relevance to mental illness
Hökfelt, T., Barde, S., Xu, Z.-Q. D., Kuteeva, E., Rüegg, J., Le Maitre, E., Risling, M., Kehr, J., Ihnatko, R., Theodorsson, E., et al. (2018) · Frontiers in Neural Circuits · doi:10.3389/fncir.2018.00106 · Cited by 139 · see citing works
Psychedelic drugs—a new era in psychiatry?
Nutt, D. (2019) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2019.21.2/dnutt · Cited by 132 · see citing works
A brief history of antidepressant drug development: from tricyclics to beyond ketamine
Pereira, V. S., & Sato, V. (2018) · Acta Neuropsychiatrica · doi:10.1017/neu.2017.39 · Cited by 129 · see citing works
The Nucleus Accumbens: A Common Target in the Comorbidity of Depression and Addiction
Xu, L., Nan, J., & Lan, Y. (2020) · Frontiers in Neural Circuits · doi:10.3389/fncir.2020.00037 · Cited by 115 · see citing works
Ketamine 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
The anterior cingulate cortex as a key locus of ketamine’s antidepressant action
Alexander, L., Jelen, L. A., Mehta, M. A., & Young, A. H. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.05.003 · Cited by 83 · see citing works
The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity
Kang, M. J. Y., Hawken, E., & Vazquez, G. H. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.860882 · Cited by 77 · see citing works
Ketamine and nitrous oxide: The evolution of NMDA receptor antagonists as antidepressant agents
Kalmoe, M. C., Janski, A. M., Zorumski, C. F., Nägele, P., Palanca, B. J. A., & Conway, C. R. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.116778 · Cited by 76 · see citing works
Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis
Bahji, A., Zarate, C. A., & Vázquez, G. H. (2022) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2022.2047928 · Cited by 73 · see citing works
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A Review of Nonanesthetic Uses of Ketamine
Pribish, A. M., Wood, N. J., & Kalava, A. (2020) · Anesthesiology Research and Practice · doi:10.1155/2020/5798285 · Cited by 67 · see citing works
Ketamine for Bipolar Depression: A Systematic Review
Bahji, A., Zarate, C. A., & Vázquez, G. H. (2021) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyab023 · Cited by 65 · see citing works
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Riluzole attenuates the efficacy of glutamatergic transmission by interfering with the size of the readily releasable neurotransmitter pool
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On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods
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At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: Findings from a large, prospective, open-label effectiveness trial
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Sex differences in resilience: Experiential factors and their mechanisms
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Efficacy and Safety of a Rapid Intravenous Injection of Ketamine 0.5 mg/kg in Treatment-Resistant Major Depression
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Metabotropic Glutamatergic Receptor 5 and Stress Disorders: Knowledge Gained From Receptor Imaging Studies
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Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression
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“Esketamine has nearly fourfold greater afﬁnity for the NMDAR than (R)-ketamine but interestingly induces fewer and weaker psychotomimetic and dissociative effects [103].”
BackgroundResultInfluential
Behavioral and neuropsychiatric disorders in Alzheimer's disease
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An Update on Glutamatergic System in Suicidal Depression and on the Role of Esketamine
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A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats
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Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders
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Withdrawal from chronic ethanol exposure increases postsynaptic glutamate function of insular cortex projections to the rat basolateral amygdala
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What Is New about New Antidepressants?
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Drug repurposing may generate novel approaches to treating depression
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Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression (SAINT-TRD)
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Modulation of DNA Methylation and Gene Expression in Rodent Cortical Neuroplasticity Pathways Exerts Rapid Antidepressant-Like Effects
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Remembering Mechanosensitivity of NMDA Receptors
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New agents and perspectives in the pharmacological treatment of major depressive disorder
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Proteomics Study Reveals the Anti-Depressive Mechanisms and the Compatibility Advantage of Chaihu-Shugan-San in a Rat Model of Chronic Unpredictable Mild Stress
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Intravenous infusion of xenon‐containing liposomes generates rapid antidepressant‐like effects
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Positive effects of running exercise on astrocytes in the medial prefrontal cortex in an animal model of depression
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Bringing Neuroscience to the Bedside
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Rasool, U., Jan, N., Zahoor, M., Roub, F., Rather, Y. H., Hussain, A., & Najeeb, R. (2023) · International Journal of Research in Medical Sciences · doi:10.18203/2320-6012.ijrms20230029 · Cited by 2 · see citing works
Association of the GRIK4 rs1954787 polymorphism with clinical response in antidepressant-treated depressed patients: results from a prospective cohort and meta-analysis
Chappell, K., Colle, R., Asmar, K. E., Gressier, F., Bouligand, J., Trabado, S., Fève, B., Becquemont, L., Corruble, E., & Verstuyft, C. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02765-5 · Cited by 2 · see citing works
Heterogeneous trajectory of depressive symptoms after repeated subcutaneous esketamine injections
Barbosa, M. G., Sarin, L. M., Tuena, M. A., Sant, L. C. D., Nakahira, C., Magalhães, E. T. P., Fava, V. A. R., Delfino, R. S., Steglich, M. S., Puertas, C. B., et al. (2020) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2020.100053 · Cited by 2 · see citing works
Brain Glutamate Dynamics Predict Positive Agency in Healthy Women: Insights from Combined Application of Pharmacological Challenge, Comprehensive Affective Assessment, and Magnetic Resonance Spectroscopy
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Glutamatergic Modulators in Depression
Henter, I. D., SOUSA, R. T. D., & Zarate, C. A. (2018) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000183 · Cited by 93 · see citing works
Self-citation
Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status
Henter, I. D., Park, L. T., & Zarate, C. A. (2021) · CNS Drugs · doi:10.1007/s40263-021-00816-x · Cited by 142 · see citing works
Self-citation
Glutamatergic approaches in major depressive disorder: focus on ketamine, memantine and riluzole
Owen, R. T. (2012) · Drugs of today · doi:10.1358/dot.2012.48.7.1832873 · Cited by 28 · see citing works
Glutamate Modulators in Major Depressive Disorder
Cooper, T. M., & Iosifescu, D. (2020) · Elsevier eBooks · doi:10.1016/b978-0-323-58131-8.00013-6
Ketamine and Glutamatergic Compounds: Exploring Biomarkers and Mechanisms Related to Rapid Antidepressant Action
(2017) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9781681084732117020010

Authors: Lener, M. S., Kadriu, B., & Zarate, C. A.
Affiliations: National Institutes of Health (US)
Corresponding author: Lener, Marc S.
ORCID: Kadriu, Bashkim
Zarate, Carlos A.
Venue: Drugs
Publisher: Springer Science and Business Media LLC
Published: 2017-02-14
Volume: 77
Issue: 4
Pages: 381-401
ISSN: 0012-6667 (ISSN-L)
1179-1950
DOI: 10.1007/s40265-017-0702-8
PMC: PMC5342919
OpenAlex: W2588408561
Cited by: 131
References: 131
Citations by year: 2026: 2 · 2025: 10 · 2024: 11 · 2023: 16 · 2022: 18 · 2021: 17 · 2020: 19 · 2019: 14 · 2018: 15 · 2017: 9
FWCI: 2.01
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Drugs (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, public-domain)
Funders: National Institute of Mental Health (ZIA-MH002857-10)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: ketamine, depression, major depressive disorder, bipolar depression, antidepressant repurposing, subanesthetic ketamine, D-cycloserine, riluzole, CP-101,606, dextromethorphan, nitrous oxide, esketamine, glutamatergic signaling
MeSH terms: Depression, Humans, Ketamine, Excitatory Amino Acid Agents

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Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression

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