Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review
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Ketamine and its enantiomer S-ketamine (esketamine) are promising candidates to produce a rapid-onset antidepressant effect in treatment-resistant depression. Ketamine causes continued blockade of the glutamate N-methyl-d-aspartate (NMDA) receptor, though this might not primarily mediate the antidepressant effect. Alternative hypotheses include selectivity for the NMDA receptor subtype containing the NMDA receptor subunit 2B (NR2B), inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase, increased expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrKB), and activation of the mammalian target of rapamycin (mTOR) signaling pathway, alongside other independent actions attributed to the ketamine metabolism to R-hydroxynorketamine (R-HNK). The enantiomer S-ketamine (esketamine) displays approximately fourfold greater affinity for the glutamate NMDA receptor in vitro than R-ketamine. Proof-of-concept single-dose and repeat-dose studies with intravenous ketamine show a significant antidepressant and probably antisuicidal effect in the short term, with response rates over 60% as early as 4.5 h after a single dose, with a sustained effect after 24 h, and over 40% after 7 days. This response can be further sustained over several weeks with repeated doses (two to three doses per week). Tolerability seems acceptable in the short term, with transient elevation of blood pressure and mild and transient dissociative and psychotomimetic effects. Intranasal esketamine has shown a comparable antidepressant effect, which has resulted in the US FDA granting the drug a “breakthrough therapy” designation, and theoretically it may offer an improved tolerability profile. However, major concerns remain regarding an effective protocol to maintain the clinical antidepressant effect of ketamine seen with acute administration and the safety of ketamine and esketamine in the long term, specifically related to potential neurocognitive and urologic toxicity, together with the potential induction of substance use disorders. Ketamine and esketamine are not currently approved treatments for depression, but the clinical use of ketamine is increasing in a variety of practice settings internationally.
All authors made a substantial contribution to the conception, writing and structure of the review article. The first draft of the manuscript was prepared by PM (clinical aspects) and JJM (pharmacological aspects). All authors proofread the manuscript.
Compliance with Ethical Standards
No sources of funding were used to conduct this study or prepare this manuscript.
Conflict of interest
Three of the six authors are principal investigators or subinvestigators on several Janssen-supported studies of esketamine for depression. PM is supported by Clinica Universidad de Navarra and has received research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health and Astrazeneca. Without any relevance to this work, PM declares that he is a clinical consultant for MedAvante-ProPhase and has received speaker honoraria from Scienta, AB-Biotics and Janssen. PM is the principal investigator at Clinica Universidad de Navarra of several studies supported by Janssen about the efficacy and safety of esketamine. JARQ is the principal investigator for Hospital Universitari Vall d’Hebron in several studies about the efficacy and safety of esketamine supported by Janssen-Cilag. ECS is cooperating as subinvestigator at Hospital Universitari Vall d’Hebron in several studies about the efficacy and safety of esketamine for the treatment of depression supported by Janssen-Cilag. LGR has been speaker and advisory board member for Janssen, Rovi, Servier, Lundbeck, Otsuka, Pfizer and Exeltis. RMS and JJM have no conflicts of interest.
- 1.Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry [Internet]. 2006;163:1905–17. Available from: http://psychiatryonline.org/doi/abs/10.1176/ajp.2006.163.11.1905.
- 2.Domino EF. Taming the ketamine tiger. 1965. Anesthesiology [Internet]. 2010;113:678–84. Available from: http://anesthesiology.pubs.asahq.org/Article.aspx?doi=10.1097/ALN.0b013e3181ed09a2.
- 3.Li L, Vlisides PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosci. [Internet]. 2016;10:612. Available from: http://journal.frontiersin.org/article/10.3389/fnhum.2016.00612/full.
- 4.Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry [Internet]. 2018;5:65–78. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2215036617302729.
- 5.Singh I, Morgan C, Curran V, Nutt D, Schlag A, McShane R. Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight. Lancet Psychiatry [Internet]. 2017;4:419–26. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2215036617301025.
- 6.Pomarol-Clotet E, Honey GD, Murray GK, Corlett PR, Absalom AR, Lee M, et al. Psychological effects of ketamine in healthy volunteers. Phenomenological study. Br J Psychiatry [Internet]. 2006;189:173–9. Available from: http://bjp.rcpsych.org/cgi/doi/10.1192/bjp.bp.105.015263.
- 7.Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry [Internet]. 2017; Available from: http://linkinghub.elsevier.com/retrieve/pii/S2215036617302729.
- 8.Lener MS, Kadriu B, Zarate CA. Ketamine and beyond: investigations into the potential of glutamatergic agents to treat depression. Drugs [Internet]. 2017;77:381–401. Available from: http://link.springer.com/10.1007/s40265-017-0702-8.
- 9.Muller J, Pentyala S, Dilger J, Pentyala S. Ketamine enantiomers in the rapid and sustained antidepressant effects. Ther Adv Psychopharmacol [Internet]. 2016;6:185–92. Available from: http://journals.sagepub.com/doi/10.1177/2045125316631267.
- 10.Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA, Charney DS. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annu Rev Pharmacol Toxicol [Internet]. 2014;54:119–39. Available from: http://www.annualreviews.org/doi/10.1146/annurev-pharmtox-011613-135950.
- 11.Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet [Internet]. 2016;55:1059–77. Available from: http://link.springer.com/10.1007/s40262-016-0383-6.
- 12.Fanta S, Kinnunen M, Backman JT, Kalso E. Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. Eur J Clin Pharmacol [Internet]. 2015;71:441–7. Available from: http://link.springer.com/10.1007/s00228-015-1826-y.
- 13.Andrade C. Ketamine for depression, 5: potential pharmacokinetic and pharmacodynamic drug interactions. J Clin Psychiatry [Internet]. Physicians Postgraduate Press, Inc.; 2017;78:e858–61. Available from: http://www.psychiatrist.com/JCP/article/Pages/2017/v78n07/17f11802.aspx.
- 14.Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L, et al. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors. Eur J Pharmacol [Internet]. 2013;698:228–34. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0014299912009545.
- 15.Zeilhofer HU, Swandulla D, Geisslinger G, Brune K. Differential effects of ketamine enantiomers on NMDA receptor currents in cultured neurons. Eur J Pharmacol [Internet]. 1992;213:155–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1386806.
- 16.Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-d-aspartate receptors. J Pharmacol Exp Ther [Internet]. 1992;260:1209–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1312163.
- 17.Yang C, Shirayama Y, Zhang J, Ren Q, Yao W, Ma M, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry [Internet]. 2015;5:e632. Available from: http://www.nature.com/doifinder/10.1038/tp.2015.136.
- 18.Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature [Internet]. 2016;533:481–6. Available from: http://www.nature.com/doifinder/10.1038/nature17998.
- 19.Zanos P, Moaddel R, Morris PJ, Wainer IW, Albuquerque EX, Thompson SM, et al. Reply to: Antidepressant Actions of Ketamine Versus Hydroxynorketamine. Biol Psychiatry [Internet]. 2017;81:e69–71. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322316328323.
- 20.Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry [Internet]. 2018;23:801–11. Available from: http://www.nature.com/doifinder/10.1038/mp.2017.255.
- 21.Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci [Internet]. 2007;27:11496–500. Available from: http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.2213-07.2007.
- 22.Lang E, Mallien AS, Vasilescu A-N, Hefter D, Luoni A, Riva MA, et al. Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets. Neurosci Biobehav Rev [Internet]. 2017; Available from: http://linkinghub.elsevier.com/retrieve/pii/S0149763417303226.
- 23.Chan SY, Matthews E, Burnet PWJ. ON or OFF?: modulating the N-methyl-d-aspartate receptor in major depression. Front Mol Neurosci [Internet]. 2016;9:169. Available from: http://journal.frontiersin.org/article/10.3389/fnmol.2016.00169/full.
- 24.Yang C, Ren Q, Qu Y, Zhang J-C, Ma M, Dong C, et al. Mechanistic target of rapamycin-independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry [Internet]. 2018;83:18–28. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322317316189.
- 25.Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs [Internet]. 2018; Available from: http://link.springer.com/10.1007/s40263-018-0492-x.
- 26.Williams NR, Schatzberg AF. NMDA antagonist treatment of depression. Curr Opin Neurobiol [Internet]. 2016;36:112–7. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0959438815001750.
- 27.Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry [Internet]. 2000;47:351–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10686270.
- 28.Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry [Internet]. 2006;63:856–64. Available from: http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archpsyc.63.8.856.
- 29.Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol [Internet]. 2010;13:71–82. Available from: https://academic.oup.com/ijnp/article-lookup/doi/10.1017/S1461145709000169.
- 30.Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology [Internet]. 2012;37338:1526–33. Available from: http://www.nature.com/doifinder/10.1038/npp.2011.338.
- 31.Murrough JW, Iosifescu D V, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry [Internet]. 2013;170:1134–42. Available from: http://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2013.13030392.
- 32.Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al. Antidepressant drug effects and depression severity. JAMA [Internet]. 2010;303:47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20051569.
- 33.Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, Aan Het Rot M, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry [Internet]. 2013;74:250–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322312005574.
- 34.Shiroma PR, Johns B, Kuskowski M, Wels J, Thuras P, Albott CS, et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J Affect Disord [Internet]. 2014;155:123–9. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0165032713007787.
- 35.Rasmussen KG, Lineberry TW, Galardy CW, Kung S, Lapid MI, Palmer BA, et al. Serial infusions of low-dose ketamine for major depression. J Psychopharmacol [Internet]. 2013;27:444–50. Available from: http://journals.sagepub.com/doi/10.1177/0269881113478283.
- 36.Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry [Internet]. 2016;173:816–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27056608.
- 37.Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry [Internet]. 2009;66:522–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322309005198.
- 38.Grunebaum MF, Galfalvy HC, Choo T-H, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry [Internet]. 2017;appi.ajp.2017.1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29202655.
- 39.Vande Voort JL, Ballard ED, Luckenbaugh DA, Bernert RA, Richards EM, Niciu MJ, et al. Antisuicidal response following ketamine infusion is associated with decreased nighttime wakefulness in major depressive disorder and bipolar disorder. J Clin Psychiatry [Internet]. 2016; Available from: http://www.ncbi.nlm.nih.gov/pubmed/27929610.
- 40.Price RB, Mathew SJ. Does ketamine have anti-suicidal properties? Current status and future directions. CNS Drugs [Internet]. 2015;29:181–8. Available from: http://link.springer.com/10.1007/s40263-015-0232-4.
- 41.Wan L-B, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry [Internet]. 2015;76:247–52. Available from: http://www.psychiatrist.com/jcp/article/pages/2015/v76n03/v76n0302.aspx.
- 42.Persson J, Hasselström J, Maurset A, Oye I, Svensson JO, Almqvist O, et al. Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity. Eur J Clin Pharmacol [Internet]. 2002;57:869–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11936706.
- 43.Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G, et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry [Internet]. 2016;80:424–31. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322315009142.
- 44.Correia-Melo FS, Argolo FC, Araújo-de-Freitas L, Leal GC, Kapczinski F, Lacerda AL, et al. Rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review. Neuropsychiatr Dis Treat [Internet]. 2017;13:1627–32. Available from: https://www.dovepress.com/rapid-infusion-of-esketamine-for-unipolar-and-bipolar-depression-a-ret-peer-reviewed-article-NDT.
- 45.Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos [Internet]. John Wiley & Sons, Ltd.; 2003;24:37–43. Available from: http://doi.wiley.com/10.1002/bdd.336.
- 46.Lapidus KAB, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry [Internet]. 2014;76:970–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322314002273.
- 47.Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression. JAMA Psychiatry [Internet]. 2017; Available from: http://www.ncbi.nlm.nih.gov/pubmed/29282469,
- 48.van de Loo AJAE, Bervoets AC, Mooren L, Bouwmeester NH, Garssen J, Zuiker R, et al. The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study. Psychopharmacology (Berl). [Internet]. 2017;234:3175–83. Available from: http://link.springer.com/10.1007/s00213-017-4706-6.
- 49.Ionescu DF, Papakostas GI. Experimental medication treatment approaches for depression. Transl Psychiatry [Internet]. Nature Publishing Group; 2017;7:e1068. Available from: http://www.nature.com/doifinder/10.1038/tp.2017.33.
- 50.FDA. FDA breakthrough therapy designation [Internet]. [cited 2018 Jan 1]. Available from: https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm.
- 51.Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med [Internet]. 2016;22:238–49. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26937618.
- 52.Carlson PJ, Diazgranados N, Nugent AC, Ibrahim L, Luckenbaugh DA, Brutsche N, et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study. Biol Psychiatry [Internet]. 2013;73:1213–21. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322313001534.
- 53.Ionescu DF, Felicione JM, Gosai A, Cusin C, Shin P, Shapero BG, et al. Ketamine-associated brain changes. Harv Rev Psychiatry [Internet]. 2018;1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29465479.
- 54.Morgan CJA, Curran HV, Independent scientific committee on drugs. Ketamine use: a review. Addiction [Internet]. 2012;107:27–38. Available from: http://doi.wiley.com/10.1111/j.1360-0443.2011.03576.x.
- 55.Mathew SJ, Shah A, Lapidus K, Clark C, Jarun N, Ostermeyer B, et al. Ketamine for treatment-resistant unipolar depression. CNS Drugs [Internet]. 2012;26:189–204. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22303887.
- 56.Ajub E, Lacerda ALT. Efficacy of esketamine in the treatment of depression with psychotic features: a case series. Biol Psychiatry [Internet]. 2017; Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322317316815.
- 57.Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry [Internet]. 2017;74:399. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28249076.