Hostname: page-component-f554764f5-44mx8 Total loading time: 0 Render date: 2025-04-12T06:27:26.258Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  24 July 2019

Michael D. Banov ,
Jonathan R. Young Open the ORCID record for Jonathan R. Young [Opens in a new window] ,
Tyler Dunn  and
Steven T. Szabo
Michael D. Banov*
Affiliation:
Psychatlanta/Northwest Behavioral Research Center, 1012 Coggins Place NE, Marietta, GA 30060, United States Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA30912, United States
Jonathan R. Young
Affiliation:
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, 40 Duke Medicine Circle, Durham, NC27710, United States
Tyler Dunn
Affiliation:
Psychatlanta/Northwest Behavioral Research Center, 1012 Coggins Place NE, Marietta, GA 30060, United States
Steven T. Szabo
Affiliation:
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, 40 Duke Medicine Circle, Durham, NC27710, United States Durham Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC27705, United States
*
*Address correspondence to: Michael D. Banov, Psychatlanta/Northwest Behavioral Research Center, 1012 Coggins Place NE, Marietta, GA 30060, USA. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

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.

Keywords

Ketamineanxietygeneralized anxiety disorderGADOCDpanic disorderPTSDsocial anxiety disorder
Type
Review
Information
CNS Spectrums , Volume 25 , Issue 3 , June 2020 , pp. 331 - 342
Copyright
© Cambridge University Press 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

References:

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): 16–23.Google Scholar
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): 1605–1611.Google Scholar
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): 950–966.Google Scholar
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): 169–184.Google Scholar
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.Google Scholar
Kaufman, J, Charney, D.Comorbidity of mood and anxiety disorders. Depress anxiety. 2000; 12(S1): 69–76.Google Scholar
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): 342–351.Google Scholar
Wiethoff, K, Bauer, M, Baghai, T, et al.Prevalence and treatment outcome in anxious versus nonanxious depression. J Clin Psychiatry. 2010; 71(08): 1047–1054.Google Scholar
Gorman, JM, Kent, JM.SSRIs and SNRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry. 1999; 60(4): 33–38. discussion, 39.Google Scholar
Roy-Byrne, P.Treatment-refractory anxiety; definition, risk factors, and treatment challenges. Dialogues Clin Neurosci. 2015; 17(2): 191–206.Google Scholar
Cassano, G, Rossi, N, Pini, S.Psychopharmacology of anxiety disorders. Dialogues Clin Neurosci. 2002; 4(3): 271–285.Google Scholar
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): 998–1007.Google Scholar
Madaan, V, Wilson, DR.Neuropeptides: relevance in treatment of depression and anxiety disorders. Drug News Perspect. 2009; 22(6): 319.Google Scholar
Uys, JDK, Stein, DJ, Daniels, WMU.Neuroproteomics: relevance to anxiety disorders. Curr Psychiatry Rep. 2006; 8(4): 286–290.Google Scholar
Duman, RS, Aghajanian, GK.Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012; 338(6103): 68–72.Google Scholar
Trullas, R, Skolnick, P.Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J. Pharmacol. 1990; 185: 1–10.Google Scholar
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): 271–281.Google Scholar
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): 140–144.Google Scholar
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): 23–26.Google Scholar
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: 153–155.Google Scholar
Autry, AE, Adachi, M, Nosyreva, E, et al.NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011; 475(7354): 91–95.Google Scholar
Collingridge, GL, Olsen, RW, Peters, J, et al.A nomenclature for ligand-gated ion channels. Neuropharmacology. 2009; 56(1): 2–5.Google Scholar
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): 1199–1203.Google Scholar
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): 754–761.Google Scholar
Murrough, JW.Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther. 2011; 91(2): 303–309.Google Scholar
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): 903–908.Google Scholar
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): 958–965.Google Scholar
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): e932–e938.Google Scholar
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: 161–166.Google Scholar
Goldberg, D, Fawcett, J.The importance of anxiety in both major depression and bipolar disorder. Depress Anxiety. 2012; 29(6): 471–478.Google Scholar
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): 868–876.Google Scholar
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).Google Scholar
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): 1302–1305.Google Scholar
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): 663–667.Google Scholar
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): 939–946.Google Scholar
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): 793–802.Google Scholar
El-Mallakh, RS, Hollifield, M.Comorbid anxiety in bipolar disorder alters treatment and prognosis. Psychiatr Q. 2008; 79(2): 139–150.Google Scholar
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): 438–443.Google Scholar
Grant, BF, Hasin, DS, Blanco, C, et al.The epidemiology of social anxiety disorder in the United States. J Clin Psychiatry. 2005; 66(11): 1351–1361.Google Scholar
Schneier, FR.Social Phobia. Arch Gen Psychiatry. 1992; 49(4): 282–288.Google Scholar
Stein, MB, Liebowitz, MR, Lydiard, RB, et al.Paroxetine treatment of generalized social phobia (social anxiety disorder). JAMA. 1998; 280(8): 708.Google Scholar
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): 1368–1371.Google Scholar
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): 128–134.Google Scholar
Taylor, JH, Landeros-Weisenberger, A, Coughlin, C, et al.Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial. Neuropsychopharmacology. 2017; 43(2): 325–333.Google Scholar
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): 354–361.Google Scholar
Eisen, JL, Sibrava, NJ, Boisseau, CL, et al.Five-year course of obsessive-compulsive disorder. J Clin Psychiatry. 2013; 74(03): 233–239.Google Scholar
Skoog, G, Skoog, I.A 40-year follow-up of patients with obsessive-compulsive disorder. Arch Gen Psychiatry. 1999; 56(2): 121–127.Google Scholar
Pittenger, C, Bloch, MH, Williams, K.Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther. 2011; 132(3): 314–332.Google Scholar
Adams, TG, Bloch, MH, Pittenger, C.Intranasal ketamine and cognitive-behavioral therapy for treatment-refractory obsessive-compulsive disorder. J Clin Psychopharmacol. 2017; 37(2): 269–271.Google Scholar
Bloch, MH, Wasylink, S, Landeros-Weisenberger, A, et al.Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012; 72(11): 964–970.Google Scholar
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): 651–654.Google Scholar
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): 2475–2483.Google Scholar
Nair, J, Ajit, SS.The role of the glutamatergic system in posttraumatic stress disorder. CNS Spectr. 2008; 13(07): 585–59.Google Scholar
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): 411–420.Google Scholar
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): 420–425.Google Scholar
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): 493–497.Google Scholar
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): S195–S199.Google Scholar
D’Andrea, D, Andrew Sewell, R.Transient resolution of treatment-resistant posttraumatic stress disorder following ketamine infusion. Biol Psychiatry. 2013; 74(9): e13–e14.Google Scholar
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.Google Scholar
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): e37–e38.Google Scholar
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).Google Scholar
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): 94–101.Google Scholar
Malhi, GS, Byrow, Y, Cassidy, F, et al.Ketamine: stimulating antidepressant treatment? BJPsych Open. 2016; 2(03): e5–e9.Google Scholar
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): 38–52.Google Scholar
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): 1306–1311.Google Scholar
Serafini, G, Howland, R, Rovedi, F, et al.The role of ketamine in treatment-resistant depression: a systematic review. Curr Neuropharmacol. 2014; 12(5): 444–461.Google Scholar
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): 710–727.Google Scholar
Girish, B, Prutha, D, Prahlad, P.Ketamine-induced affective switch in a patient with treatment-resistant depression. Indian J Pharmacol. 2015; 47(4): 454–455.Google Scholar
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): 247–252.Google Scholar
Krishnan, V, Nestler, EJ.The molecular neurobiology of depression. Nature. 2008; 455(7215): 894–902.Google Scholar
Riaza Bermudo-Soriano, C, Perez-Rodriguez, MM, Vaquero-Lorenzo, C, et al.New perspectives in glutamate and anxiety. Pharmacol Biochem Behav. 2012; 100(4): 752–774.Google Scholar
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): 2023–2034.Google Scholar