Pharmacopsychiatry 2020; 53(02): 45-50
DOI: 10.1055/a-0991-0582
Review
© Georg Thieme Verlag KG Stuttgart · New York

Ketamine in the Treatment of Depressive Episodes

Philipp Ritter
1   Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Hannelore Findeis
1   Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
,
Michael Bauer
1   Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
› Author Affiliations
Further Information

Publication History

received 09 May 2019
revised 30 July 2019

accepted 30 July 2019

Publication Date:
21 August 2019 (online)

Abstract

The treatment of depressive episodes remains complicated by the long latency of antidepressant efficacy, insufficient response, and high risk of suicide. Ketamine and esketamine have been proposed as fast-acting substances able to overcome these impediments.

Since the first randomized controlled trial in the year 2000, numerous studies have explored the antidepressant efficacy of ketamine and esketamine. Clear evidence has emerged that a single infusion exerts a significant antidepressant and antisuicidal effect in both unipolar and bipolar depression. A few studies suggest that antidepressant response can be improved and maintained by repeated administration. Although intravenous application has been most common, subcutaneous, intramuscular, and intranasal application has also been successful. There is some evidence that ketamine may accelerate the response to electroconvulsive therapy without improving the overall response rate.

The precise position of ketamine and esketamine within treatment algorithms have yet to be defined, and issues surrounding potential toxicity need to be resolved.

 
  • References

  • 1 Bennabi D, Aouizerate B, El-Hage W. et al. Risk factors for treatment resistance in unipolar depression: A systematic review. J Affect Disord 2015; 171: 137-141
  • 2 Hedegaard H, Warner M, Curtin SC. Increase in suicide in the United States, 1999–2014. NCHS Data Brief 2016; 241: 1-8
  • 3 Hustveit O, Maurset A, Øye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, σ and muscarinic receptors. Pharmacol Toxicol 1995; 77: 355-359
  • 4 Smith DJ, Azzaro AJ, Zaldivar SB. et al. Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines. Neuropharmacology 1981; 20: 391-396
  • 5 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: 411-420
  • 6 Skolnick P, Layer RT, Popik P. et al. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: Implications for the pharmacotherapy of depression. Pharmacopsychiatry 1996; 29: 23-26
  • 7 Prezegalinski E, Tatarczynska E, Deren-Wesolek A. et al. Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and a competitive NMDA receptor antagonist. Neuropharmacology 1997; 36: 31-37
  • 8 Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 2018; 23: 801-811
  • 9 Berman R, Cappiello A, Anand A. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47: 351-354
  • 10 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: 856-864
  • 11 Murrough JW, Iosifescu DV, Chang LC. et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. Am J Psychiatry 2013; 170: 1134-1142
  • 12 Parsaik AK, Singh B, Khosh-Chashm D. et al. Efficacy of ketamine in bipolar depression: Systematic review and meta-analysis. J Psychiatr Pract 2015; 21: 427-435
  • 13 Lee EE, Della Selva MP, Liu A. et al. Ketamine as a novel treatment for major depressive disorder and bipolar depression: A systematic review and quantitative meta-analysis. Gen Hosp Psychiatry 2015; 37: 178-184
  • 14 Romeo B, Choucha W, Fossati P. et al. Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Res 2015; 230: 682-688
  • 15 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: 1459-1472
  • 16 Xu Y, Hackett M, Carter G. et al. Effects of low-dose and very low-dose ketamine among patients with major depression: A systematic review and meta-analysis. Int J Neuropsychopharmacol 2016; 19: 1-15
  • 17 Fond G, Loundou A, Rabu C. et al. Ketamine administration in depressive disorders: A systematic review and meta-analysis. Psychopharmacology (Berl) 2014; 231: 3663-3676
  • 18 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: 793-802
  • 19 Zarate Jr CA, Brutsche NE, Ibrahim L. et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled. Biol Psychiatry 2012; 71: 939-946
  • 20 Niciu MJ, Shovestul BJ, Jaso BA. et al. Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression. J Affect Disord 2018; 232: 310-315
  • 21 Aust S, Gärtner M, Basso L. et al. Anxiety during ketamine infusions is associated with negative treatment responses in major depressive disorder. Eur Neuropsychopharmacol 2019; 29: 529-538
  • 22 Brunovsky M, Horacek J, Palenicek T. et al. 05-qEEG predictors of response to antidepressive treatment with ketamine. Clin Neurophysiol 2018; 129: e8
  • 23 Cao Z, Lin C, Ding W. et al. Identifying ketamine responses in treatment-resistant depression using a wearable forehead EEG. IEEE Trans Biomed Eng 2019; 66: 1668-1679
  • 24 Costi S, Soleimani L, Glasgow A et al. Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: A randomized controlled trial. Neuropsychopharmacology 2019 Mar 11 [Epub ahead of print]
  • 25 Duncan WC, Selter J, Brutsche N. et al. Baseline delta sleep ratio predicts acute ketamine mood response in major depressive disorder. J Affect Disord 2013; 145: 115-119
  • 26 Chen MH, Lin WC, Wu HJ. et al. Antisuicidal effect, BDNF Val66Met polymorphism, and low-dose ketamine infusion: Reanalysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression (AKSTP-TRD). J Affect Disord 2019; 251: 162-169
  • 27 Freeman MP, Papakostas GI, Hoeppner B. et al. Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression. J Psychiatr Res 2019; 110: 166-171
  • 28 Price RB, Nock MK, Charney DS. et al. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009; 66: 522-526
  • 29 Wilkinson ST, Ballard ED, Bloch MH. et al. The effect of a single dose of intravenous ketamine on suicidal ideation: A systematic review and individual participant data meta-analysis. Am J Psychiatry 2018; 175: 150-158
  • 30 Canuso CM, Singh JB, Fedgchin M. et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: Results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry 2018; 175: 620-630
  • 31 Ren L, Deng J, Min S. et al. Ketamine in electroconvulsive therapy for depressive disorder: A systematic review and meta-analysis. J Psychiatr Res 2018; 104: 144-156
  • 32 Moghaddam B, Adams B, Verma A. et al. Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17: 2921-2927
  • 33 Mathew SJ, Wilkinson ST, Altinay M. et al. ELEctroconvulsive therapy (ECT) vs. ketamine in patients with treatment-resistant depression: The ELEKT-D study protocol. Contemp Clin Trials 2019; 77: 19-26
  • 34 Lapidus KAB, Levitch CF, Perez AM. et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014; 76: 970-976
  • 35 Daly EJ, Singh JB, Fedgchin M. et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression. JAMA Psychiatry 2018; 75: 139-148
  • 36 Cusin C, Hilton GQ, Nierenberg AA. et al. Long-term maintenance with intramuscular ketamine for treatment-resistant bipolar II depression. Am J Psychiatry 2012; 169: 868-869
  • 37 Loo CK, Gálvez V, O’Keefe E. et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatrica Scandinavica 2016; 134: 48-56
  • 38 Singh JB, Fedgchin M, Daly EJ. et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry 2016; 173: 816-826
  • 39 Singh JB, Fedgchin M, Daly E. et al. Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study. Biol Psychiatry 2016; 80: 424-431
  • 40 Fava M, Freeman MP, Flynn M et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 2018 Oct 3 [Epub ahead of print]
  • 41 Short B, Fong J, Galvez V. et al. Side-effects associated with ketamine use in depression: A systematic review. Lancet Psychiatry 2018; 5: 65-78
  • 42 Winstock AR, Mitcheson L, Gillatt DA. et al. The prevalence and natural history of urinary symptoms among recreational ketamine users. BJU Int 2012; 110: 1762-1766