THE EVOLUTION OF KETAMINE: FROM A DISSOCIATIVE ANESTHETIC TO A RAPID-ACTING ANTIDEPRESSANT AND NEW THERAPEUTIC HORIZONS
DOI:
https://doi.org/10.11603/1811-2471.2026.v.i1.16129Keywords:
ketamine, esketamine, antidepressants, treatment-resistant depression, NMDA antagonist, neuroplasticity, glutamate hypothesis, anesthesiaAbstract
SUMMARY. Ketamine, known for over 60 years as a dissociative anesthetic, possesses a unique multimodal pharmacological profile extending beyond classic NMDA antagonism. This complex action has underpinned its clinical evolution and «rediscovery» in new therapeutic niches, particularly psychiatry.
The aim – to systematize and analyze scientific data on the clinical evolution of ketamine: from its initial use in anesthesiology and pain medicine to its current revolutionary role as a rapid-acting antidepressant for treatment-resistant depression (TRD) and acute suicidality.
Material and Methods. A narrative review of scientific literature was conducted, including foundational preclinical studies, pivotal clinical trials (e.g., Berman et al., 2000; Zarate et al., 2006), systematic reviews, and meta-analyses, highlighting the pharmacological mechanisms and clinical applications of ketamine throughout its “eras” of use.
Results. The analysis identified three key eras of evolution. The first era (1970s-2000s) is characterized by ketamine’s use as an anesthetic (especially in military medicine and pediatrics) due to its hemodynamic stability. The second era (1990s-present) involves the use of sub-anesthetic doses for acute and chronic pain management. The third, «psychiatric» era (since 2000), began with the demonstration of its rapid (within hours) and robust antidepressant effect in TRD and acute suicidality. The mechanism is linked to the induction of synaptic plasticity (the BDNF-TrkB-mTOR cascade). Results also cover the approval of the S-enantiomer (esketamine, Spravato), new therapeutic targets (PTSD, OCD), and current challenges (safety, abuse potential, pharmacoeconomics).
Conclusions. Ketamine has followed a unique evolutionary path from a “battlefield anesthetic” to the first new class of antidepressant in decades. Its ability to rapidly induce neuroplasticity has shifted the paradigm for treating affective disorders. Further research and resolution of safety concerns will define its future place in medicine.
References
Mion G, Villevieille T. Ketamine: A long and winding road. European Journal of Anaesthesiology. 2013; 30(10):596-602. DOI: 10.1097/EJA.0b013e328362678c
Li L, Vlisides PE. Ketamine: 50 Years of Clinical Application, Current Science, and Future Directions. Journal of Cardiothoracic and Vascular Anesthesia. 2016;30(6):1628-1637. DOI: 10.1053/j.jvca.2016.03.013
Domino EF. Taming the ketamine tiger. Anesthesiology. 2010;113(3):678-684. DOI: 10.1097/ALN. 0b013e3181e41125
Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacologica Sinica. 2016; 37(7):865-872. DOI: 10.1038/aps.2016.54
Kim J, Farchione T, Sung H, et al. Esketamine Nasal Spray for Treatment-Resistant Depression: First FDA-Approved Antidepressant in a New Class. American Journal of Psychiatry. 2019;176(6):429-441. DOI: 10.1176/appi.ajp.2019.19030278
Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481-486. DOI: 0.1038/ nature17998
Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Archives of General Psychiatry. 1994;51(3):199-214. DOI: 10.1001/archpsyc.1994.03950030035004
MacDonald JF, Miljkovic Z, Kotecha S, et al. Ketamine as a use-dependent antagonist of the NMDA receptor. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2006;30(1):11-19. DOI: 10.1016/j.pnpbp.2005.09.006
Anand A, Vose B, Zope M, et al. Ketamine-induced disruption of thalamo-cortical connectivity: A potential neurobiological mechanism of dissociation. Neuropsychopharmacology. 2012;37(5):1227-1236. DOI: 10.1038/npp. 2011.309
Anand A, Singh H, Kumar P, et al. Role of the opioid system in the effects of ketamine. Indian Journal of Psychological Medicine. 2014;36(4):337-342. DOI: 10.4103/ 0253-7176.140723
Nadesan S, Ljou T, Loo C. Ketamine as an opioid-sparing agent in the perioperative setting: A review of the literature. Journal of Opioid Management. 2019;15(4):331-340. DOI: 10.5055/jom.2019.0520
Keppel G, Szu P. The role of sigma receptors in the action of ketamine. Current Pharmaceutical Design. 2018; 24(15):1615-1624. DOI: 10.2174/1381612824666180417161825
Szałach Ł, Karbownik A, Łys-Tyszerg L, et al. The contribution of the sigma-1 receptor to the antidepressant and neuroprotective effects of ketamine. Pharmacological Reports. 2021;73(1):164-175. DOI: 10.1007/s43440-020-00171-8
Iken K, Chaki S, Yoshikawa R. Ketamine as a monoamine reuptake inhibitor. European Journal of Pharmacology. 2011;668(1-2):148-154. DOI: 10.1016/j.ejphar.2011. 06.052
Marland S, G. R. The cholinergic-anesthetic interface: ketamine and muscarinic antagonism. Anesthesia & Analgesia. 2008;106(2):473-479. DOI: 10.1213/01.ane. 0000299432.54885.a3
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and the rapid antidepressant action of ketamine. Science. 2016;354(6312):594-598. DOI: 10.1126/science.aah4640
Moghaddam B, Krystal JH. The ‘Glutamate Surge’ and ‘Synaptic Recovery’ Hypotheses of Ketamine’s Rapid Antidepressant Action. Neuropsychopharmacology. 2020;45(1):210-211. DOI: 10.1038/s41386-019-0520-y
Maeng S, Zarate CA Jr. The role of AMPA receptors in the antidepressant effects of ketamine. Biological Psychiatry. 2007;62(1):4-11. DOI: 10.1016/j.biopsych.2006. 06.001
Lepack AE, Fuchikami M, Dwyer JM, et al. BDNF-TrkB signaling mediates the rapid-acting antidepressant-like effects of ketamine. Neuropharmacology. 2014; 85:398-406. DOI: 10.1016/j.neuropharm.2014.05.031
Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-964. DOI: 10.1126/science.1190287
Moda-Sava RN, Mundt JM, Panda M, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced new spines. Science. 2019; 364(6436):eaat8078. DOI: 10.1126/science.aat8078
Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry. 2006;63(8):856-864. DOI: 10.1001/archpsyc. 63.8.856
Morris RW, Corssen G. Ketamine in the field. Anesthesiology. 1972;37(3):362-363.
Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with phencyclidine. Anesthesia & Analgesia. 1966; 45(1):29-40.
Mautner S, Tendler A, Fruchter E, et al. Ketamine in the Field: The Lure of the «Ideal» Anesthetic and a Tale of Caution. Anesthesia & AnalgesIA. 2018;127(4):854-858. DOI: 10.1213/ANE.0000000000003598
Green SM, Krauss B. Ketamine for pediatric procedural sedation and analgesia: A review of the literature. Pediatric Emergency Care. 2001;17(4):270-281. DOI: 10.1097/00006565-200108000-00018
Green SM, Roback MG, Krauss B, et al. Predictors of adverse events with procedural sedation in the emergency department. Annals of Emergency Medicine. 2007;49(1):23-31. DOI: 10.1016/j.annemergmed.2006.08.019
Sherwin TS, Green SM, Stremski ES. The incidence of emergence reactions in children after ketamine sedation. Annals of Emergency Medicine. 1995;26(3):309-313. DOI: 10.1016/s0196-0644(95)70077-8
White PF. Ketamine: a role for this controversial agent in the future of anesthesia? F1000 Medicine Reports. 2010;2:63. DOI: 10.3410/M2-63
Gries D, Richter J, Eich W, et al. [Ketamine vs etomidate for induction of anesthesia in emergency medicine. A prospective, randomized, comparative study]. Der Anaesthesist. 2007;56(11):1107-1113. DOI: 10.1007/s00101-007-1249-4
Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. The Lancet. 2009;374(9686):293-300. DOI: 10.1016/S0140-6736(09)60949-1
Allen JY, Macias CG. The efficacy of ketamine in pediatric emergency department patients who present with acute severe asthma. Annals of Emergency Medicine. 2005;46(1):43-50. DOI: 10.1016/j.annemergmed. 2005.01.026
Cole JB, Moore JC, Nystrom PC, et al. A prospective study of ketamine versus haloperidol for the treatment of severe prehospital agitation. Annals of Emergency Medicine. 2016;68(5):575-582. DOI: 10.1016/j.annemergmed. 2016.03.045
Bell RF, Kalso EA. Ketamine for the treatment of pain. Pain. 2013;154(1):1. DOI: 10.1016/j.pain.2012.11.002
Motov S, Rockoff B, Cohen V, et al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Annals of Emergency Medicine. 2015;66(3):222-229.e1. DOI: 10.1016/j.annemergmed.2015. 03.004
Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients with acute pain in the emergency department: a propensity score analysis. Academic Emergency Medicine. 2014;21(11):1193-1200. DOI: 10.1111/acem.12501
Brinck T, Tiippana E, Heesen M, et al. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database of Systematic Reviews. 2018; 12(12):CD012033. DOI: 10.1002/14651858.CD012033. pub3
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-S15. DOI: 10.1016/j.pain.2010.09.030
Schwartzman RJ, Alexander GM, Grothusen JR, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo-controlled study. Pain. 2009;147(1-3):107-115. DOI: 10. 1016/j.pain.2009.08.019
Correll GE, Maleki J, Gracely EJ, et al. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Medicine. 2004;5(3):263-275. DOI: 10.1111/j.1526-4637.2004.04035.x
Noppers I, Niesters M, Sweder van der Heijde P, et al. Ketamine for the treatment of chronic pain conditions: a systematic review of the clinical utility in fibromyalgia and complex regional pain syndrome. Expert Opinion on Pharmacotherapy. 2010;11(17):2861-2869. DOI: 10.1517/ 14656566.2010.534575
Mao J. Opioid-induced hyperalgesia: a persistent issue in clinical practice. The Journal of Pain. 2016; 17(3):257-258. DOI: 10.1016/j.jpain.2015.11.007
Bodnar RJ. Endogenous opiates and behavior: 2015. Peptides. 2017;88:111-151. DOI: 10.1016/j.peptides. 2016.12.010
Jansen KLR. «K-hole» and the ketamine experience. In: Ketamine: Dreams and Realities. Sarasota, FL: Multidisciplinary Association for Psychedelic Studies; 2001: 187-213.
Shahani R, Streutker C, Dickson B, et al. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology. 2007;69(5):810-812. DOI: 10.1016/j.urology.2007.01.005
Chung C, Waine E, Bae E, et al. Ketamine-associated urinary tract dysfunction: A review of the clinical and basic science evidence. Neurourology and Urodynamics. 2019;38(1):42-50. DOI: 10.1002/nau.23847
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry. 2006;163(11):1905-1917. DOI: 10.1176/appi.ajp.163.11.1905
Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry. 2000;47(4):351-354. DOI: 10.1016/s0006-3223(99)00230-9
DiazGranados N, Ibrahim LA, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry. 2010;67(8):793-802. DOI: 10.1001/archgenpsychiatry.2010.90
Grunebaum MF, Galfalvy H, Choo TH, et al. Ketamine for Rapid Reduction of Suicidal Ideation: A Randomized Controlled Trial. American Journal of Psychiatry. 2018;175(4):327-335. DOI: 10.1176/appi.ajp. 2017.17060647
Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study (TRANSFORM-2). American Journal of Psychiatry. 2019;176(6):458-468. DOI: 10.1176/appi.ajp.2019.19010091
Feder A, Parides MK, Murrough JW, et al. Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2014;71(6):681–688. DOI: 10.1001/jamapsychiatry.2014.62
Feder A, Rutter SB, Charney DS, et al. A Randomized Trial of Repeated Ketamine Administration in Chronic Posttraumatic Stress Disorder. American Journal of Psychiatry. 2021;178(2):193-202. DOI: 10.1176/appi.ajp.2020.20050596
Rodriguez CI, Kegeles LS, Levinson A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: from target engagement to clinical effects. Biological Psychiatry. 2013;74(12):938-946. DOI: 10.1016/j.biopsych.2013.06.019
Dore J, Turnipseed B, Dwyer S, et al. Ketamine Assisted Psychotherapy (KAP): A Review of the Results of a Large Case Series. Journal of Psychoactive Drugs. 2019;51(2):189-198. DOI: 10.1080/02791072.2019.1583256
Kohtala S. Ketamine-assisted psychotherapy: A narrative review of the therapeutic model and the evidence. Frontiers in Psychology. 2021;12:707204. DOI: 10.3389/fpsyg.2021.707204
Daws RE, P. A. C, Giribaldi B, et al. Ketamine-assisted psychotherapy for alcohol use disorder: A randomized controlled trial. American Journal of Psychiatry. 2022; 179(7):483-492. DOI: 10.1176/appi.ajp. 20220023
Winstock AR, Mitcheson L, Gillatt DA, et al. The prevalence and natural history of ketamine-induced ulcerative cystitis: a longitudinal study. BJU International. 2012; 110(11):1760-1764. DOI: 10.1111/j.1464-410X.2012. 11225.x
Wiver T, Wanscher M, Bonnet U, et al. Long-term safety of ketamine in treatment-resistant depression: A systematic review. European Neuropsychopharmacology. 2018;28(Suppl1):S88-S89. DOI: 10.1016/j.euroneuro.2017. 12.203
Olney JW, Labruyere J, Wang G, et al. NMDA antagonist neurotoxicity: mechanism and prevention. Science. 1991;254(5038):1515-1518. DOI: 10.1126/science. 1835779
Kvam TM, Stewart LM, G. D. C. Cognitive effects of ketamine in depression: A review of the evidence. Journal of Affective Disorders. 2019;245:1023-1033. DOI: 10.1016/ j.jad.2018.12.016
Li L, Zhao K, J. L. Ketamine use disorder. Current Addiction Reports. 2019;6:421–427. DOI: 10.1007/s40429-019-00271-z
Wilkinson ST, Sanacora G. The Past, Present, and Future of Ketamine-Like Drugs in the Treatment of Mood Disorders. Focus (Am Psychiatr Publ). 2019;17(2):120-128. DOI: 10.1176/appi.focus.17202
Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy and tolerability of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders. 2021;278:542-555. DOI: 10.1016/j.jad.2020.09.083
Zanos P, Gould TD. The tantalizing quest for a new generation of rapidly acting antidepressants: A review of ketamine and its metabolites. Philosophical Transactions of the Royal Society B. 2018;373(1745):20170165. DOI: 10.1098/rstb.2017.0165
Downloads
Published
How to Cite
Issue
Section
Accepted 2026-04-08
Published 2026-04-22
