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European Archives of Psychiatry and Clinical Neuroscience

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01-04-2021 | Antidepressant Drugs | Invited Review

Esketamine: a glimmer of hope in treatment-resistant depression

Authors: Upinder Kaur, Bhairav Kumar Pathak, Amit Singh, Sankha Shubhra Chakrabarti

Published in: European Archives of Psychiatry and Clinical Neuroscience | Issue 3/2021

Abstract

The motive of this article is to review the pharmacological and clinical aspects of esketamine (ESK), an NMDA-receptor antagonist approved recently by the FDA for treatment-resistant depression (TRD). PubMed/Medline database was searched using keywords ‘esketamine’ and ‘depression’, ‘S-ketamine’ and ‘depression’, and ‘NMDA antagonist’ and ‘depression’. Individual trials were searched from ClinicalTrials.gov. We included English-language articles evaluating pharmacokinetics and pharmacodynamics of intranasal (IN) esketamine, along with clinical trial data related to its efficacy and safety in patients diagnosed with TRD. Compared to placebo, IN esketamine causes significant and rapid improvement in depression. Dizziness, vertigo, headache, increase in blood pressure are some of its common adverse effects. With the growing number of patients of TRD, additional effective and safe treatment is the need of the hour. Esketamine appears to be an effective therapy when combined with oral antidepressants in patients with TRD. It is of special value due to the rapid onset of its action. Long-term clinical studies are, however, needed to ascertain its safety profile.

World Health Organization (2017) Depression and other common mental disorders. Inst Health Natl 1:1–22

Stassen HH, Angst J (1998) Delayed onset of action of antidepressants. CNS Drugs 9(3):177–184

Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA (2016) The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom 85(5):270–288PubMed

Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC et al (2018) Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression. JAMA Psychiatry 75(2):139PubMed

Morrison RL, Fedgchin M, Singh J, Van Gerven J, Zuiker R, Lim KS et al (2018) Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. Psychopharmacology 235(4):1107–1119PubMedPubMedCentral

Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P et al (2018) 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 175(7):620–630PubMed

Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P et al (2019) Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. https://doi.org/10.1093/ijnp/pyz039CrossRefPubMedPubMedCentral

Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P et al (2019) Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry 176(6):428–438PubMed

Ochs-Ross R, Daly EJ, Zhang Y, Lane R, Lim P, Foster K et al (2018) Efficacy and safety of intranasal esketamine plus an oral antidepressant in elderly patients with treatment-resistant depression. Biol Psychiatry 83(9):S391

10.

Bahr R, Lopez A, Rey JA (2019) Intranasal esketamine (SpravatoTM) for use in treatment-resistant depression in conjunction with an oral antidepressant. Pharm Ther 44(6):340–375

11.

Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X et al (2019) Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 76(9):893–990PubMedPubMedCentral

12.

Wajs E, Aluisio L, Morrison R et al. Long-term safety of esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: phase 3, open-label, safety and efficacy study (SUSTAIN-2). In: American Society of Clinical Psychopharmacology Annual Meeting; Miami, Florida. 2018.

13.

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354PubMed

14.

Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al (2006) A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864PubMed

15.

Corriger A, Pickering G (2019) Ketamine and depression: a narrative review. Drug Des Dev Ther 13:3051–3067

16.

Rosenblat JD, Carvalho AF, Li M, Lee Y, Subramanieapillai M, McIntyre RS (2019) Oral ketamine for depression: a systematic review. J Clin Psychiatry 80:3

17.

Mathisen LC, Skjelbred P, Skoglund LA, Oye I (1995) Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain 61(2):215–220PubMed

18.

Oye I, Paulsen O, Maurset A (1992) Effects of ketamine on sensory perception: evidence for a role of N-methyl-d-aspartate receptors. J Pharmacol Exp Ther 260(3):1209–1213PubMed

19.

Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (1997) Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol 7(1):25–38PubMed

20.

Hashimoto K (2019) Rapid-acting antidepressant ketamine, its metabolites and other candidates: a historical overview and future perspective. Psychiatry Clin Neurosci 73(10):613–627PubMedPubMedCentral

21.

Chang L, Zhang K, Pu Y, Qu Y, Wang S-M, Xiong Z et al (2019) Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacol Biochem Behav 181:53–59PubMed

22.

Correia-Melo FS, Leal GC, Carvalho MS, Jesus-Nunes AP, Ferreira CBN, Vieira F et al (2018) Comparative study of esketamine and racemic ketamine in treatment-resistant depression: protocol for a non-inferiority clinical trial. Medicine (Baltimore) 97(38):e12414

23.

Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M (1996) Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 77(2):203–207PubMed

24.

Cohen ML, Chan SL, Way WL, Trevor AJ (1973) Distribution in the brain and metabolism of ketamine in the rat after intravenous administration. Anesthesiology 39(4):370–376PubMed

25.

White PF, Schüttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ (1985) Comparative pharmacology of the ketamine isomers. Br J Anaesth 57(2):197–203PubMed

26.

Geisslinger G, Hering W, Kamp HD, Vollmers KO (1995) Pharmacokinetics of ketamine enantiomers. Br J Anaesth 75(4):506–507PubMed

27.

Grant IS, Nimmo WS, McNicol LR, Clements JA (1983) Ketamine disposition in children and adults. Br J Anaesth 55(11):1107–1111PubMed

28.

Mion G, Villevieille T (2013) Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther 19(6):370–380PubMedPubMedCentral

29.

Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P et al (2018) Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev 70(3):621–660PubMedPubMedCentral

30.

Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM (1997) Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 333(1):99–104PubMed

31.

Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L et al (2013) Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors. Eur J Pharmacol 698(1–3):228–234PubMed

32.

Zhang J-C, Li S-X, Hashimoto K (2014) R(−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol Biochem Behav 116:137–141PubMed

33.

Yang C, Kobayashi S, Nakao K, Dong C, Han M, Qu Y et al (2018) AMPA receptor activation-independent antidepressant actions of ketamine metabolite (S)-norketamine. Biol Psychiatry 84(8):591–600PubMed

34.

Castrén E, Antila H (2017) Neuronal plasticity and neurotrophic factors in drug responses. Mol Psychiatry 22(8):1085–1095PubMedPubMedCentral

35.

Denk MC, Rewerts C, Holsboer F, Erhardt-Lehmann A, Turck CW (2011) Monitoring ketamine treatment response in a depressed patient via peripheral mammalian target of rapamycin activation. Am J Psychiatry 168(7):751–752PubMed

36.

Yang C, Zhou Z, Gao Z, Shi J, Yang J-J (2013) Acute increases in plasma mammalian target of rapamycin, glycogen synthase kinase-3β, and eukaryotic elongation factor 2 phosphorylation after ketamine treatment in three depressed patients. Biol Psychiatry 73(12):e35–e36PubMed

37.

Abdallah CG, Averill LA, Gueorguieva R, Goktas S, Purohit P, Ranganathan M, et al. Rapamycin, an immunosuppressant and mTORC1 inhibitor, triples the antidepressant response rate of ketamine at 2 weeks following treatment: a double-blind, placebo-controlled, cross-over, randomized clinical trial. bioRxiv. 2018;500959.

38.

Pham TH, Gardier AM (2019) Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacol Ther 199:58–90PubMed

39.

Hashimoto K, Yang C (2019) Is (S)-norketamine an alternative antidepressant for esketamine? Eur Arch Psychiatry Clin Neurosci 269(7):867–868PubMed

40.

Shirayama Y, Hashimoto K (2018) Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine. Int J Neuropsychopharmacol 21(1):84–88PubMed

41.

Yang C, Qu Y, Abe M, Nozawa D, Chaki S, Hashimoto K (2017) (R)-Ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine. Biol Psychiatry 82(5):e43–e44PubMed

42.

Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI et al (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533(7604):481–486PubMedPubMedCentral

43.

Pham TH, Defaix C, Xu X, Deng S-X, Fabresse N, Alvarez J-C et al (2018) Common neurotransmission recruited in (R, S)-ketamine and (2R,6R)-hydroxynorketamine-induced sustained antidepressant-like effects. Biol Psychiatry 84(1):e3–6PubMed

44.

Zhu W, Ding Z, Zhang Y, Shi J, Hashimoto K, Lu L (2016) Risks associated with misuse of ketamine as a rapid-acting antidepressant. Neurosci Bull 32(6):557–564PubMedPubMedCentral

45.

Morgan CJA, Riccelli M, Maitland CH, Curran HV (2004) Long-term effects of ketamine: evidence for a persisting impairment of source memory in recreational users. Drug Alcohol Depend 75(3):301–308PubMed

46.

Tsai YC, Kuo H-C (2015) Ketamine cystitis: Its urological impact and management. Urol Sci 26(3):153–157

47.

Ho CCK, Pezhman H, Praveen S, Goh EH, Lee BC, Zulkifli MZ et al (2010) Ketamine-associated ulcerative cystitis: a case report and literature review. Malays J Med Sci 17(2):61–65PubMedPubMedCentral

48.

United States Food and Drug Administration. United States Food and Drug Administration approved labelling-Spravato. Accessed 8 Sept 2019, pp 1–41. 2019

49.

Szymkowicz SM, Finnegan N, Dale RM (2013) A 12-month naturalistic observation of three patients receiving repeat intravenous ketamine infusions for their treatment-resistant depression. J Affect Disord 147(1–3):416–420PubMed

50.

Pretto G, Westphal GA, Silva E (2014) Clonidine for reduction of hemodynamic and psychological effects of S+ ketamine anesthesia for dressing changes in patients with major burns: an RCT. Burns 40(7):1300–1307PubMed

51.

Cesarovic N, Jirkof P, Rettich A, Nicholls F, Arras M (2012) Combining sevoflurane anesthesia with fentanyl-midazolam or S-ketamine in laboratory mice. J Am Assoc Lab Anim Sci 51(2):209–218PubMedPubMedCentral

52.

Adams HA (1997) S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation. Anaesthesist 46(12):1081–1087PubMed

53.

Noppers I, Olofsen E, Niesters M, Aarts L, Mooren R, Dahan A et al (2011) Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration. Anesthesiology 114(6):1435–1445PubMed

54.

Ashraf MW, Peltoniemi MA, Olkkola KT, Neuvonen PJ, Saari TI (2018) Semimechanistic population pharmacokinetic model to predict the drug-drug interaction between S-ketamine and ticlopidine in healthy human volunteers. CPT Pharmacom Syst Pharmacol 7(10):687–697

55.

Peltoniemi MA, Saari TI, Hagelberg NM, Reponen P, Turpeinen M, Laine K et al (2011) Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. Clin Pharmacol Ther 90(2):296–302PubMed

56.

Hagelberg NM, Peltoniemi MA, Saari TI, Kurkinen KJ, Laine K, Neuvonen PJ et al (2010) Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine. Eur J Pain 14(6):625–629PubMed

57.

Peltoniemi MA, Saari TI, Hagelberg NM, Laine K, Neuvonen PJ, Olkkola KT (2012) St John’s wort greatly decreases the plasma concentrations of oral S-ketamine. Fundam Clin Pharmacol 26(6):743–750PubMed

58.

Li C-T, Yang K-C, Lin W-C (2019) Glutamatergic dysfunction and glutamatergic compounds for major psychiatric disorders: evidence from clinical neuroimaging studies. Front Psychiatry 2019:9

Title: Esketamine: a glimmer of hope in treatment-resistant depression
Authors: Upinder Kaur
Bhairav Kumar Pathak
Amit Singh
Sankha Shubhra Chakrabarti
Publication date: 01-04-2021
Publisher: Springer Berlin Heidelberg
Keywords: Antidepressant Drugs
Mood Disorders
Affective Disorder
Antidepressant Drugs
Esketamine
Esketamin
Ketamine
Published in: European Archives of Psychiatry and Clinical Neuroscience / Issue 3/2021
Print ISSN: 0940-1334
Electronic ISSN: 1433-8491
DOI: https://doi.org/10.1007/s00406-019-01084-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Esketamine: a glimmer of hope in treatment-resistant depression

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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