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New Frontiers in Ketamine Research: From Mechanisms of Action to Novel Psychiatric Treatment Approaches

Ketamine, initially developed as a safer alternative to phencyclidine, has emerged as a groundbreaking treatment in psychiatric practice. It gained popularity after its approval by the FDA in 1970 for its analgesic properties and ability to induce altered consciousness while maintaining vital functions. In the 1990s, researchers discovered its rapid and potent antidepressant effects, especially in patients with treatment-resistant depression. The mechanism of action of ketamine involves blocking N-Methyl-D-Aspartate receptors, leading to the release of inhibitory signals and increased glutamate levels. This process triggers a series of events promoting neuron growth and synaptic plasticity relevant to antidepressant outcomes. Various administration methods have been explored, including intravenous, intranasal, oral, subcutaneous, and intramuscular routes, each with its own advantages and limitations. IV ketamine administration has been widely used, but intranasal and sublingual forms are gaining popularity due to improved accessibility and safety. The FDA and European Medicines Agency approved intranasal S-ketamine for treatment resistant depression and depressive symptoms. Ketamine treatment is being extensively researched for its impact on various psychiatric domains, including resistant depression, suicidal crises, anxiety disorders, substance use disorders, and others. Preliminary evidence suggests potential benefits in conditions such as obsessive compulsive and personality disorders, although further research is needed. Ketamine's safety profile is generally favorable, with mild, temporary, and self-limiting side effects. However, caution is advised in individuals with uncontrolled hypertension, cardiovascular conditions, a history of psychosis, or substance abuse. Contraindications also apply to pregnant women. Ketamine interactions with other medications should be carefully considered, especially regarding benzodiazepines, and lamotrigine use. To optimize ketamine treatment in psychiatric diseases, guidelines recommend it as a third-line option after multiple unsuccessful antidepressant treatments for treatment resistant depression. Intravenous racemic ketamine has Level 1 evidence supporting its efficacy, while the evidence for non-intravenous formulations is limited. International guidelines vary slightly, but overall, the use of ketamine shows great potential in addressing challenging psychiatric conditions. This update highlights the expanding literature on ketamine in psychiatric treatment, focusing on its applications in treatment-resistant depression and its potential to revolutionize acute psychiatric emergency departments. Moreover, it provides insights into administration methods, safety considerations, and international guidelines for optimized ketamine usage in psychiatric practice.

Ketamine, Psychiatry, Treatment Resistance

Marcus Christian Rosenhagen, Julien Elowe, Alberto Forte, Nicolas Schaad. (2023). New Frontiers in Ketamine Research: From Mechanisms of Action to Novel Psychiatric Treatment Approaches. American Journal of Psychiatry and Neuroscience, 11(3), 64-72.

Copyright © 2023 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Domino EF. History and pharmacology of PCP and PCP-related analogs. J Psychedelic Drugs, 1980, 12 (3-4): 223–227.
2. Greifenstein FE, Devault M, Yoshitake J, et al. A study of a 1-aryl cyclo hexyl amine for anesthesia. Anesth Analg, 1958, 37 (5): 283-294.
3. Mion G. History of anaesthesia: the ketamine story- past, present and future. Eur J Anaesthesiol, 2017, 34: 571–75.
4. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 2000, 47 (4): 351–4.
5. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry, 2006, 63 (8): 856-64.
6. Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science, 2012, 338 (6103): 68-72.
7. Krystal JH, Abdallah CG, Sanacora G, et al. Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 2019, 101 (5): 774-778.
8. Monteggia LM, Zarate CAJ. Antidepressant actions of ketamine: from molecular mechanisms to clinical practice. Curr Opin Neurobiol, 2015, 30: 139–43.
9. Mkrtchian A, Evans JW, Kraus C, et al. Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals. Mol Psychiatry, 2021, 26: 3292–301.
10. Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med, 2016, 46: 1459–72.
11. Singh JB, Daly EJ, Mathews M, et al. Approval of esketamine for treatment resistant depression. Lancet Psychiatry, 2020, 7 (3): 232-5.
12. EMA:
13. SPRAVATO (esketamine) nasal spray, CIII HIGHLIGHTS OF PRESCRIBING IN FORMATION. Available at: Accessed August 31, 2022.
14. Swainson J, McGirr A, Blier P, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder. Can J Psychiatry, 2021, 66 (2): 113-125.
15. Hassan K, Struthers WM, Sankarabhotla A, et al. Safety, effectiveness and tolerability of sublingual ketamine in depression and anxiety: A retrospective study of off-label, at-home use. Front Psychiatry, 2022, 13: 992624.
16. Anis NA, Berry SC, Burton NR, et al. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol, 1983, 79 (2): 565-75.
17. Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 2016, 533 (7604): 481-6.
18. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev, 2018, 70: 621-660.
19. Abdallah CG, Adams TG, Kelmendi B, et al. KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID-ACTING ANTIDEPRESSANTS. Depress Anxiety, 2016, 33 (8): 689-97.
20. Irwin MN, VandenBerg A. Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action. Ment Health Clin, 2021, 11 (3): 200-210.
21. Duman RS, Aghajanian GK, Sanacora G, et al. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med, 2016, 22 (3): 238.
22. Scotton E, Antqueviezc B, Vasconcelos MF, et al. Is (R)-ketamine a potential therapeutic agent for treatment-resistant depression with less detrimental side effects? A review of molecular mechanisms underlying ketamine and its enantiomers. Biochem Pharmacol, 2022, 198: 114963.
23. Halaris A, Cook J. The Glutamatergic System in Treatment-Resistant Depression and Comparative Effectiveness of Ketamine and Esketamine: Role of Inflammation? Adv Exp Med Biol, 2023, 1411: 487-512.
24. Johnston JN, Greenwald MS, Henter ID, et al. Inflammation, stress and depression: An exploration of ketamine's therapeutic profile. Drug Discov Today, 2023, 28 (4): 103518.
25. Andrade C. Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? J Clin Psychiatry, 2017, 78 (7): e852-e857.
26. McIntyre RS, Carvalho IP, Lui LMW, et al. The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis. J Affect Disord, 2020, 276: 576-584.
27. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry, 2013, 74: 250-256.
28. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry, 2021, 178: 383-399.
29. Meshkat S, Haikazian S, Di Vincenzo JD, et al. Oral ketamine for depression: An updated systematic review. World J Biol Psychiatry, 2023, 31: 1-13.
30. Tham JCW, Do A, Fridfinnson J, et al. Repeated subcutaneous racemic ketamine in treatment-resistant depression: case series. Int Clin Psychopharmacol, 2022, 37 (5): 206-214.
31. Vasiliu O. Esketamine for treatment-resistant depression: A review of clinical evidence (Review). Exp Ther Med, 2023, 25 (3): 111.
32. Peters EM, Halpape K, Cheveldae I, et al. Intranasal racemic ketamine for patients hospitalized with treatment-resistant depression: A retrospective analysis. Exp Clin Psychopharmacol, 2023, 31 (3): 593-598.
33. Hietamies TM, McInnes LA, Klise AJ, et al. The effects of ketamine on symptoms of depression and anxiety in real-world care settings: A retrospective controlled analysis. J Affect Disord, 2023, 335: 484-492.
34. Zheng W, Zhou YL, Wang CY, et al. A comparative analysis of antidepressant and anti-suicidal effects of repeated ketamine infusions in elderly and younger adults with depression. J Affect Disord, 2023, 334: 145-151.
35. Ahmed GK, Elserogy YM, Elfadl GMA, et al. Antidepressant and anti-suicidal effects of ketamine in treatment-resistant depression associated with psychiatric and personality comorbidities: A double-blind randomized trial. J Affect Disord, 2023, 325: 127-134.
36. Danayan K, Chisamore N, Rodrigues NB, et al. Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder. Psychiatry Res, 2023, 323: 115133.
37. Alnefeesi Y, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. J Psychiatr Res, 2022, 151: 693-709.
38. Nikayin S, Murphy E, Krystal JH, et al. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opin Drug Saf, 2022, 21 (6): 777-787.
39. Smith-Apeldoorn SY, Veraart JK, Spijker J, et al. Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Lancet Psychiatry, 2022, 9 (11): 907-921.
40. Singh B, Kung S, Pazdernik V, et al. Comparative Effectiveness of Intravenous Ketamine and Intranasal Esketamine in Clinical Practice Among Patients with Treatment-Refractory Depression: An Observational Study. J Clin Psychiatry, 2023, 84 (2): 22m14548.
41. Levinta A, Meshkat S, McIntyre RS, et al. The association between stage of treatment-resistant depression and clinical utility of ketamine/esketamine: A systematic review. J Affect Disord, 2022, 318: 139-149.
42. Kew BM, Porter RJ, Douglas KM. Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review. BJPsych Open, 2023, 9 (3): e79.
43. Kwaśny A, Włodarczyk A, Ogonowski D, et al. Effect of Ketamine on Sleep in Treatment-Resistant Depression: A Systematic Review. Pharmaceuticals (Basel), 2023, 16 (4): 568.
44. Ibrahim L, Diazgranados N, Luckenbaugh DA, et al. Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry, 2011, 35 (4): 1155-9.
45. Payette O, Lespérance P, Desbeaumes Jodoin V, et al. Intravenous ketamine for treatment-resistant depression patients who have failed to respond to transcranial magnetic stimulation: A case series. J Affect Disord, 2023, 333: 18-20.
46. Turner EH. Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval. Lancet Psychiatry, 2019, 6 (12): 977-979.
47. de A Simoes Moreira D, Gauer LE, Teixeira G, et al. Efficacy and adverse effects of ketamine versus electroconvulsive therapy for major depressive disorder: A systematic review and meta-analysis. J Affect Disord, 2023, 330: 227-238.
48. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. N Engl J Med, 2023, 388 (25): 2315-2325.
49. Menon V, Varadharajan N, Faheem A, et al. Ketamine vs Electroconvulsive Therapy for Major Depressive Episode: A Systematic Review and Meta-analysis. JAMA Psychiatry, 2023, 80 (6): 639-642.
50. Le TT, Di Vincenzo JD, Teopiz KM, et al. Ketamine for psychotic depression: An overview of the glutamatergic system and ketamine's mechanisms associated with antidepressant and psychotomimetic effects. Psychiatry Res, 2021, 306: 114231.
51. Gałuszko-Węgielnik M, Chmielewska Z, Jakuszkowiak-Wojten K, et al. Ketamine as Add-On Treatment in Psychotic Treatment-Resistant Depression. Brain Sci, 2023, 13 (1): 142.
52. Martinotti G, Dell'Osso B, Di Lorenzo G, et al. REAL-ESK Study Group. Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression. Bipolar Disord, 2023, 25 (3): 233-244.
53. Fancy F, Rodrigues NB, Di Vincenzo JD, et al. Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. Bipolar Disord, 2023, 25 (2): 99-109.
54. Singh B, Vande Voort JL, Frye MA, et al. Can ketamine be a safe option for treatment-resistant bipolar depression? Expert Opin Drug Saf, 2022, 21 (6): 717-720.
55. Jollant F, Colle R, Nguyen TML, et al. Ketamine and esketamine in suicidal thoughts and behaviors: a systematic review. Ther Adv Psychopharmacol, 2023, 13: 1-25.
56. Anzolin AP, Goularte JF, Pinto JV, et al. Ketamine study: Protocol for naturalistic prospective multicenter study on subcutaneous ketamine infusion in depressed patients with active suicidal ideation. Front Psychiatry., 2023, 14: 1147298.
57. Chen CC, Zhou N, Hu N, et al. Acute Effects of Intravenous Sub-Anesthetic Doses of Ketamine and Intranasal Inhaled Esketamine on Suicidal Ideation: A Systematic Review and Meta-Analysis. Neuropsychiatr Dis Treat, 2023, 19: 587-599.
58. Abbar M, Demattei C, El-Hage W, et al. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ, 2022, 376: e067194.
59. Tully JL, Dahlén AD, Haggarty CJ, et al. Ketamine treatment for refractory anxiety: A systematic review. Br J Clin Pharmacol, 2022, 88 (10): 4412-4426.
60. Hartland H, Mahdavi K, Jelen LA, et al. A transdiagnostic systematic review and meta-analysis of ketamine's anxiolytic effects. J Psychopharmacol, 2023 Apr 2: 2698811231161627. doi: 10.1177/02698811231161627. Epub ahead of print. PMID: 37005739.
61. Jones JL, Mateus CF, Malcolm RJ, et al. Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review. Front Psychiatry, 2018, 9: 277.
62. Martinotti G, Chiappini S, Pettorruso M, et al. Therapeutic Potentials of Ketamine and Esketamine in Obsessive-Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature. Brain Sci, 2021, 11 (7): 856.
63. Goldfine CE, Tom JJ, Im DD, et al. The therapeutic use and efficacy of ketamine in alcohol use disorder and alcohol withdrawal syndrome: a scoping review. Front Psychiatry, 2023, 14: 1141836.
64. Garel N, McAnulty C, Greenway KT, et al. Efficacy of ketamine intervention to decrease alcohol use, cravings, and withdrawal symptoms in adults with problematic alcohol use or alcohol use disorder: A systematic review and comprehensive analysis of mechanism of actions. Drug Alcohol Depend, 2022, 239: 109606.
65. Grabski M, McAndrew A, Lawn W, et al. Adjunctive Ketamine With Relapse Prevention-Based Psychological Therapy in the Treatment of Alcohol Use Disorder. Am J Psychiatry, 2022, 179 (2): 152-162.
66. Joneborg I, Lee Y, Di Vincenzo JD, et al. Active mechanisms of ketamine-assisted psychotherapy: A systematic review. J Affect Disord, 2022, 315: 105-112.
67. Ferguson AA, Khan AI, Abuzainah B, et al. Clinical Effectiveness of N-Methyl-D-Aspartate (NMDA) Receptor Antagonists in Adult Obsessive-Compulsive Disorder (OCD) Treatment: A Systematic Review. Cureus, 2023, 15 (4): e37833.
68. Swierkosz-Lenart K, Dos Santos JFA, Elowe J, et al. Therapies for obsessive-compulsive disorder: Current state of the art and perspectives for approaching treatment-resistant patients. Front Psychiatry, 2023, 14: 1065812.
69. van Roessel PJ, Grassi G, Aboujaoude EN, et al. Treatment-resistant OCD: Pharmacotherapies in adults. Compr Psychiatry, 2023, 120: 152352.
70. Fineberg SK, Choi EY, Shapiro-Thompson R, et al. A pilot randomized controlled trial of ketamine in Borderline Personality Disorder. Neuropsychopharmacology, 2023, 48 (7): 991-999.
71. Liriano F, Hatten C, Schwartz TL. Ketamine as treatment for post-traumatic stress disorder: a review. Drugs Context, 2019, 8: 212305.
72. Philipp-Muller AE, Stephenson CJ, Moghimi E, et al. Combining Ketamine and Psychotherapy for the Treatment of Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis. J Clin Psychiatry, 2023, 84 (2): 22br14564.
73. Veraart JKE, van Westenbrugge M, van Wulfften Palthe JE, et al. Repeated oral esketamine in patients with treatment resistant depression and comorbid posttraumatic stress disorder. Heliyon, 2023, 9 (5): e15883.
74. Burback L, Brémault-Phillips S, Nijdam MJ, et al. Treatment of Posttraumatic Stress Disorder: a State-of-the-art Review. Curr Neuropharmacol, 2023 Apr 28. doi: 10.2174/1570159X21666230428091433. Epub ahead of print. PMID: 37132142.
75. Mitchell JS, Hermens DF, Bennett MR, et al. Ketamine and Zinc: Treatment of Anorexia Nervosa Via Dual NMDA Receptor Modulation. CNS Drugs, 2023, 37 (2): 159-180.
76. Schep LJ, Slaughter RJ, Watts M, et al. The clinical toxicology of ketamine. Clin Toxicol (Phila), 2023, 2: 1-14.
77. Williamson D, Turkoz I, Wajs E, et al. Adverse Events and Measurement of Dissociation After the First Dose of Esketamine in Patients With TRD. Int J Neuropsychopharmacol, 2023, 26 (3): 198-206.
78. Orsolini L, Salvi V, Volpe U. Craving and addictive potential of esketamine as side effects? Expert Opin Drug Saf, 2022, 21 (6): 803-812.
79. Lin F, He Y, Zhang L, Zhang M, Zhang Y, Wen C. Assessment of the effect of ketamine on cytochrome P450 isoforms activity in rats by cocktail method. Int J Clin Exp Med, 2015, 8 (3): 4335-41.
80. Uchaipichat V, Raungrut P, Chau N, et al. Effects of ketamine on human UDP-glucuronosyltransferases in vitro predict potential drug-drug interactions arising from ketamine inhibition of codeine and morphine glucuronidation. Drug Metab Dispos, 2011, 39 (8): 1324-8.
81. Lilius TO, Jokinen V, Neuvonen MS, et al. Niemi M, Kalso EA, Rauhala PV. Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat. Br J Pharmacol, 2015, 172 (11): 2799-813.
82. Veraart JKE, Smith-Appledorn SY, Bakker IM, et al. Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: a systematic review. Int J Neuropsychopharmacol, 2021, 24 (19): 808-831.
83. Wallner MA, Eloge JC, Mackey IV, et al. Safety and Tolerability of Concomitant Intranasal Esketamine Treatment with Irreversible, Nonselective MAOIs: A Case Series. J Clin Psychiatry, 2023, 84 (2): 22cr14598.
84. Langmia IM, Just KS, Yamoune S, et al. Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant - implications for precision dosing in a global perspective. Br J Clin Pharmacol, 2022, (12): 5149-5165.
85. Andrashko V, Novak T, Brunovsky M, et al. The antidepressant effect of ketamine is dampened by concomitant benzodiazepine medication. Front Psychiatry, 2020, 11: 1.
86. Andreazza AC, Young LT. The neurobiology of bipolar disorder: identifying targets for specific agents and synergies for combination treatment. Int J Neuropsychopharmacol, 2014, 17 (7): 1039-52.
87. Réus GZ, Matias BI, Maciel AL, et al. Mechanism of synergistic action on behavior, oxidative stress and inflammation following co-treatment with ketamine and different antidepressant classes. Pharmacol Rep, 2017, 69 (5): 1094-1102.
88. Gärtner M, Weigand A, Keicher C, et al. Effects of Ketamine and Lamotrigine on Cognition: Emotion Interaction in the Brain. Neuropsychobiology, 2023, 82 (2): 91-103.
89. Wilkowska A, Wiglusz MS, Jakuszkowiak-Wojten K, et al. Ketamine and Lamotrigine Combination in Psychopharmacology: Systematic Review. Cells, 2022, 11 (4): 645.
90. Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs, 2009, 23 (8): 627-47.
91. López-Díaz Á, Murillo-Izquierdo M, Moreno-Mellado E. Off-label use of ketamine for treatment-resistant depression in clinical practice: European perspective. Br J Psychiatry, 2019, 215 (2): 447-448.
92. Mahase E. NICE reconsiders esketamine for depression. BMJ, 2020, 370: m3479.