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Efficacy and safety of ketamine in the management of anxiety and anxiety spectrum disorders: a review of the literature

  • Michael D. Banov (a1) (a2), Jonathan R. Young (a3), Tyler Dunn (a1) and Steven T. Szabo (a3) (a4)


Anxiety disorders are among the most prevalent psychiatric conditions. Despite many proven pharmacological and non-pharmacological treatments available, high rates of partial response and low rates of long-term remission remain. Ketamine has been receiving increasing attention as an interventional treatment modality in psychiatry, especially among refractory conditions, including major depressive disorder. There is limited yet growing evidence to support the use of ketamine in anxiety disorders. In this review of the literature, we present case reports, case series, and controlled trials demonstrating proof-of-concept for its potential role in the treatment of anxiety and anxiety spectrum disorders. Its unique mechanism of action, rapid onset, and high rate of response have driven its use in clinical practice. Ketamine is generally well tolerated by patients and has a limited side effect profile; however, the effects of long-term use are unknown. While there is a growing body of research and increasing clinical experience to suggest ketamine may have clinical applications in the treatment of refractory anxiety disorders, further research to determine long-term safety and tolerability is indicated.


Corresponding author

*Address correspondence to: Michael D. Banov, Psychatlanta/Northwest Behavioral Research Center, 1012 Coggins Place NE, Marietta, GA 30060, USA. (Email:


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1. Grady, S, Marsh, T, Tenhouse, A, et al. Ketamine for the treatment of major depressive disorder and bipolar depression: a review of the literature. Mental Health Clin. 2017; 7(1): 1623.
2. Diaz Granados, N, Ibrahim, L, Brutsche, N, et al. Rapid resolution of suicidal ideation after a single infusion of an N-Methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010; 71(12): 16051611.
3. Newport, DJ, Carpenter, LL, McDonald, WM, et al. Ketamine and other NMDA antagonists: early trials and possible mechanisms in depression. Am J Psychiatry. 2015; 172(10): 950966.
4. Kessler, R, Petukhova, M, Sampson, N, et al. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012; 21(3): 169184.
5.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
6. Kaufman, J, Charney, D. Comorbidity of mood and anxiety disorders. Depress anxiety. 2000; 12(S1): 6976.
7. Fava, M, Rush, A, Alpert, J, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008; 165(3): 342351.
8. Wiethoff, K, Bauer, M, Baghai, T, et al. Prevalence and treatment outcome in anxious versus nonanxious depression. J Clin Psychiatry. 2010; 71(08): 10471054.
9. Gorman, JM, Kent, JM. SSRIs and SNRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry. 1999; 60(4): 3338. discussion, 39.
10. Roy-Byrne, P. Treatment-refractory anxiety; definition, risk factors, and treatment challenges. Dialogues Clin Neurosci. 2015; 17(2): 191206.
11. Cassano, G, Rossi, N, Pini, S. Psychopharmacology of anxiety disorders. Dialogues Clin Neurosci. 2002; 4(3): 271285.
12. Davis, M, Myers, KM. The role of glutamate and gamma-aminobutyric acid in fear extinction: clinical implications for exposure therapy. Biol Psychiatry. 2002; 52(10): 9981007.
13. Madaan, V, Wilson, DR. Neuropeptides: relevance in treatment of depression and anxiety disorders. Drug News Perspect. 2009; 22(6): 319.
14. Uys, JDK, Stein, DJ, Daniels, WMU. Neuroproteomics: relevance to anxiety disorders. Curr Psychiatry Rep. 2006; 8(4): 286290.
15. Duman, RS, Aghajanian, GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012; 338(6103): 6872.
16. Trullas, R, Skolnick, P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J. Pharmacol. 1990; 185: 110.
17. Aguado, L, Antonio, AS, Pérez, L, et al. Effects of the NMDA receptor antagonist ketamine on flavor memory: conditioned aversion, latent inhibition, and habituation of neophobia. Behav Neural Biol. 1994; 61(3): 271281.
18. Garcia, LSB, Comim, CM, Valvassori, SS, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008; 32(1): 140144.
19. Skolnick, P, Layer, R, Popik, P, et al. Adaptation of N-Methyl-D-Aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996; 29(01): 2326.
20. Zarate, CA Jr, Singh, JB, Quiroz, JA, et al. A double-blind, placebo controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006; 163: 153155.
21. Autry, AE, Adachi, M, Nosyreva, E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011; 475(7354): 9195.
22. Collingridge, GL, Olsen, RW, Peters, J, et al. A nomenclature for ligand-gated ion channels. Neuropharmacology. 2009; 56(1): 25.
23. Monteggia, LM, Gideons, E, Kavalali, ET. The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine. Biol Psychiatry. 2013; 73(12): 11991203.
24. Li, N, Liu, R-J, Dwyer, JM, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011; 69(8): 754761.
25. Murrough, JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther. 2011; 91(2): 303309.
26. Irwin, SA, Iglewicz, A. Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 2010; 13(7): 903908.
27. Irwin, SA, Iglewicz, A, Nelesen, RA, et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. J Palliat Med. 2013; 16(8): 958965.
28. Ionescu, DF, Luckenbaugh, DA, Niciu, MJ, et al. Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. J Clin Psychiatry. 2014; 75(09): e932e938.
29. Ballard, ED, Ionescu, DF, Vande Voort, JL, et al. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. 2014; 58: 161166.
30. Goldberg, D, Fawcett, J. The importance of anxiety in both major depression and bipolar disorder. Depress Anxiety. 2012; 29(6): 471478.
31. Nock, MK, Hwang, I, Sampson, NA, et al. Mental disorders, comorbidity and suicidal behavior: results from the national comorbidity survey replication. Mol Psychiatry. 2009; 15(8): 868876.
32. Ray, SM, Kious, BM. Sustained resolution of panic disorder, agoraphobia, and generalized anxiety disorder with a single ketamine infusion. Prim Care Companion CNS Disord. 2016; 18(4).
33. Glue, P, Medlicott, NJ, Harland, S, et al. Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017; 31(10): 13021305.
34. Glue, P, Neehoff, SM, Medlicott, NJ, et al. Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders. J Psychopharmacol. 2018; 32(6): 663667.
35. Zarate, CA, Brutsche, NE, Ibrahim, L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012; 71(11): 939946.
36. Diazgranados, N, Ibrahim, L, Brutsche, NE, et al. A randomized add-on trial of an n-methyl-d-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010; 67(8): 793802.
37. El-Mallakh, RS, Hollifield, M. Comorbid anxiety in bipolar disorder alters treatment and prognosis. Psychiatr Q. 2008; 79(2): 139150.
38. Ionescu, DF, Luckenbaugh, DA, Niciu, MJ, et al. A single infusion of ketamine improves depression scores in patients with anxious bipolar depression. Bipolar Disord. 2014; 17(4): 438443.
39. Grant, BF, Hasin, DS, Blanco, C, et al. The epidemiology of social anxiety disorder in the United States. J Clin Psychiatry. 2005; 66(11): 13511361.
40. Schneier, FR. Social Phobia. Arch Gen Psychiatry. 1992; 49(4): 282288.
41. Stein, MB, Liebowitz, MR, Lydiard, RB, et al. Paroxetine treatment of generalized social phobia (social anxiety disorder). JAMA. 1998; 280(8): 708.
42. Katzelnick, D, Kobak, K, Greist, J, et al. Sertraline for social phobia: a double-blind, placebo-controlled crossover study. Am J Psychiatry. 1995; 152(9): 13681371.
43. van Vliet, IM, den Boer, JA, Westenberg, HGM. Psychopharmacological treatment of social phobia; a double blind placebo controlled study with fluvoxamine. Psychopharmacology. 1994; 115(1 –2): 128134.
44. Taylor, JH, Landeros-Weisenberger, A, Coughlin, C, et al. Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial. Neuropsychopharmacology. 2017; 43(2): 325333.
45. Haan, E, Oppen, P, Balkom, AJLM, et al. Prediction of outcome and early vs. late improvement in OCD patients treated with cognitive behaviour therapy and pharmacotherapy. Acta Psychiatr Scand. 1997; 96(5): 354361.
46. Eisen, JL, Sibrava, NJ, Boisseau, CL, et al. Five-year course of obsessive-compulsive disorder. J Clin Psychiatry. 2013; 74(03): 233239.
47. Skoog, G, Skoog, I. A 40-year follow-up of patients with obsessive-compulsive disorder. Arch Gen Psychiatry. 1999; 56(2): 121127.
48. Pittenger, C, Bloch, MH, Williams, K. Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther. 2011; 132(3): 314332.
49. Adams, TG, Bloch, MH, Pittenger, C. Intranasal ketamine and cognitive-behavioral therapy for treatment-refractory obsessive-compulsive disorder. J Clin Psychopharmacol. 2017; 37(2): 269271.
50. Bloch, MH, Wasylink, S, Landeros-Weisenberger, A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012; 72(11): 964970.
51. Niciu, MJ, Grunschel, BD, Corlett, PR, et al. Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after ketamine infusion in patients with obsessive–compulsive disorder and a history of major depressive disorder. J Psychopharmacol. 2013; 27(7): 651654.
52. Rodriguez, CI, Kegeles, LS, Levinson, A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013; 38(12): 24752483.
53. Nair, J, Ajit, SS. The role of the glutamatergic system in posttraumatic stress disorder. CNS Spectr. 2008; 13(07): 585–59.
54. Molero, P, Ramos-Quiroga, JA, Martin-Santos, R, et al. Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CNS Drugs. 2018; 32(5): 411420.
55. Schönenberg, M, Reichwald, U, Domes, G, et al. Effects of peritraumatic ketamine medication on early and sustained posttraumatic stress symptoms in moderately injured accident victims. Psychopharmacology. 2005; 182(3): 420425.
56. Schönenberg, M, Reichwald, U, Domes, G, et al. Ketamine aggravates symptoms of acute stress disorder in a naturalistic sample of accident victims. J Psychopharmacol. 2008; 22(5): 493497.
57. McGhee, LL, Maani, CV, Garza, TH, et al. The correlation between ketamine and posttraumatic stress disorder in burned service members. J Trauma. 2008; 64(Supplement): S195S199.
58. D’Andrea, D, Andrew Sewell, R. Transient resolution of treatment-resistant posttraumatic stress disorder following ketamine infusion. Biol Psychiatry. 2013; 74(9): e13e14.
59. 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): 681688.
60. Zeng, MC, Niciu, MJ, Luckenbaugh, DA, et al. Acute stress symptoms do not worsen in posttraumatic stress disorder and abuse with a single subanesthetic dose of ketamine. Biol Psychiatry. 2013; 73(12): e37e38.
61. Albott, CS, Lim, KO, Forbes, MK, et al. Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J Clin Psychiatry. 2018; 79(3).
62. Gollan, JK, Fava, M, Kurian, B, et al. What are the clinical implications of new onset or worsening anxiety during the first two weeks of SSRI treatment for depression? Depress Anxiety. 2011; 29(2): 94101.
63. Malhi, GS, Byrow, Y, Cassidy, F, et al. Ketamine: stimulating antidepressant treatment? BJPsych Open. 2016; 2(03): e5e9.
64. Suleiman, Z, Kolawole, I, Bolaji, B. Evaluation of cardiovascular stimulation effects after induction of anaesthesia with ketamine. J West Afr Coll Surg. 2012; 2(1): 3852.
65. Castle, C, Gray, A, Neehoff, S, et al. Effect of ketamine dose on self-rated dissociation in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017; 31(10): 13061311.
66. Serafini, G, Howland, R, Rovedi, F, et al. The role of ketamine in treatment-resistant depression: a systematic review. Curr Neuropharmacol. 2014; 12(5): 444461.
67. Katalinic, N, Lai, R, Somogyi, A, et al. Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Aust N Z J Psychiatry. 2013; 47(8): 710727.
68. Girish, B, Prutha, D, Prahlad, P. Ketamine-induced affective switch in a patient with treatment-resistant depression. Indian J Pharmacol. 2015; 47(4): 454455.
69. Wan, L-B, Levitch, CF, Perez, AM, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry. 2014; 76(03): 247252.
70. Krishnan, V, Nestler, EJ. The molecular neurobiology of depression. Nature. 2008; 455(7215): 894902.
71. Riaza Bermudo-Soriano, C, Perez-Rodriguez, MM, Vaquero-Lorenzo, C, et al. New perspectives in glutamate and anxiety. Pharmacol Biochem Behav. 2012; 100(4): 752774.
72. Mathew, AR, Pettit, JW, Lewinsohn, PM, et al. Co-morbidity between major depressive disorder and anxiety disorders: shared etiology or direct causation? Psychol Med. 2011; 41(10): 20232034.


Efficacy and safety of ketamine in the management of anxiety and anxiety spectrum disorders: a review of the literature

  • Michael D. Banov (a1) (a2), Jonathan R. Young (a3), Tyler Dunn (a1) and Steven T. Szabo (a3) (a4)


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