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Esketamine: a glimmer of hope in treatment-resistant depression

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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.

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References

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

    Google Scholar 

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

    CAS  Google Scholar 

  3. 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):270–288

    PubMed  Google Scholar 

  4. 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):139

    PubMed  Google Scholar 

  5. 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):1107–1119

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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):620–630

    PubMed  Google Scholar 

  7. 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/pyz039

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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):428–438

    PubMed  Google Scholar 

  9. 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

    Google Scholar 

  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

    Google Scholar 

  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):893–990

    PubMed  PubMed Central  Google Scholar 

  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):351–354

    CAS  PubMed  Google Scholar 

  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):856–864

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  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

    Google Scholar 

  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):215–220

    CAS  PubMed  Google Scholar 

  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):1209–1213

    CAS  PubMed  Google Scholar 

  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):25–38

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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 181:53–59

    CAS  PubMed  Google Scholar 

  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

    CAS  Google Scholar 

  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):203–207

    CAS  PubMed  Google Scholar 

  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):370–376

    CAS  PubMed  Google Scholar 

  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):197–203

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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):621–660

    CAS  PubMed  PubMed Central  Google Scholar 

  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):99–104

    CAS  PubMed  Google Scholar 

  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):228–234

    CAS  PubMed  Google Scholar 

  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 116:137–141

    CAS  PubMed  Google Scholar 

  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):591–600

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  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):751–752

    PubMed  Google Scholar 

  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–e36

    CAS  PubMed  Google Scholar 

  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 199:58–90

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  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):84–88

    CAS  PubMed  Google Scholar 

  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–e44

    CAS  PubMed  Google Scholar 

  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):481–486

    CAS  PubMed  PubMed Central  Google Scholar 

  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):e3–6

    CAS  PubMed  Google Scholar 

  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):557–564

    CAS  PubMed  PubMed Central  Google Scholar 

  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):301–308

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  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):61–65

    PubMed  PubMed Central  Google Scholar 

  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):416–420

    CAS  PubMed  Google Scholar 

  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):1300–1307

    PubMed  Google Scholar 

  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):209–218

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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):1435–1445

    CAS  PubMed  Google Scholar 

  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

    CAS  Google Scholar 

  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):296–302

    CAS  PubMed  Google Scholar 

  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):625–629

    CAS  PubMed  Google Scholar 

  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):743–750

    CAS  PubMed  Google Scholar 

  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

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India

    Upinder Kaur, Bhairav Kumar Pathak & Amit Singh

  2. Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India

    Sankha Shubhra Chakrabarti

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  1. Upinder Kaur
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  2. Bhairav Kumar Pathak
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  3. Amit Singh
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Correspondence to Sankha Shubhra Chakrabarti.

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Kaur, U., Pathak, B.K., Singh, A. et al. Esketamine: a glimmer of hope in treatment-resistant depression . Eur Arch Psychiatry Clin Neurosci 271, 417–429 (2021). https://doi.org/10.1007/s00406-019-01084-z

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