Esketamine

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Esketamine
Esketamine2DCSD.svg
S-ketamine-from-HCl-xtal-3D-balls.png
Clinical data
Trade namesSpravato, Ketanest, Vesierra, others
Other namesEsketamine hydrochloride; (S)-Ketamine; S(+)-Ketamine; JNJ-54135419
AHFS/Drugs.comMonograph
MedlinePlusa619017
License data
Pregnancy
category
Routes of
administration		Intranasal, Intravenous infusion[3]
Drug classNMDA receptor antagonists; Antidepressants; General anesthetics; Dissociative hallucinogens; Analgesics
ATC code
Legal status
Legal status
  • AU: S8 (Controlled drug) [1][2]
  • UK: POM (Prescription only) [4][5]
  • US: Schedule III [6]
  • EU: Rx-only [7]
  • In general: ℞ (Prescription only)
Identifiers
IUPAC name
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.242.065 Edit this at Wikidata
Chemical and physical data
FormulaC13H16ClNO
Molar mass237.73 g·mol−1
3D model (JSmol)
SMILES
InChI
  

Esketamine, sold under the brand name Spravato[6] among others,[8][9] is a medication used as a general anesthetic and for treatment-resistant depression.[6][3] Esketamine is used as a nasal spray or by injection into a vein.[6][3]

Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist.[3][10] It also acts to some extent as a dopamine reuptake inhibitor but, unlike ketamine, does not interact with the sigma receptors.[3] The compound is the S(+) enantiomer of ketamine, which is an anesthetic and dissociative similarly.[3] It is unknown whether its antidepressant action is superior, inferior or equal to racemic ketamine and its opposite enantiomer, arketamine, which are both being investigated for the treatment of depression.

Esketamine was introduced for medical use in 1997.[3] In 2019, it was approved for use with other antidepressants, for the treatment of depression in adults in the United States.[11] It is basically a chiral switch of (±)-ketamine. The switch has been done for the perceived therapeutic benefits viz. Increased potency and tolerance, faster recovery.[12]

In August 2020, it was approved by the U.S. Food and Drug Administration (FDA) with the added indication for the short-term treatment of suicidal thoughts.[13]

Medical uses[]

Anesthesia[]

Esketamine is a general anesthetic and is used for similar indications as ketamine.[3] Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.[3]

Depression[]

See also: List of investigational antidepressants

Similarly to ketamine, esketamine appears to be a rapid-acting antidepressant.[10][14] It received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016.[15][14] The medication was studied for use in combination with an antidepressant in people with TRD who had been unresponsive to treatment;[15][10][14] six phase III clinical trials for this indication were conducted in 2017.[15][10][14] It is available as a nasal spray.[15][10][14]

In February 2019, an outside panel of experts recommended that the FDA approve the nasal spray version of esketamine,[16] provided that it be given in a clinical setting, with people remaining on site for at least two hours after. The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after.[17]

In January 2020, esketamine was rejected by the National Health Service of Great Britain. NHS questioned the benefits and claimed that it was too expensive. People who have been already using the medication were allowed to complete treatment if their doctors consider this necessary.[18]

Side effects[]

Most common side effects when used in those with treatment resistant depression include dissociation, dizziness, nausea, sleepiness, anxiety, and increased blood pressure.[19]

Pharmacology[]

Esketamine is approximately twice as potent an anesthetic as racemic ketamine.[20] It is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows its elimination.[21]

A number of studies have suggested that esketamine has a more medically useful pharmacological action than arketamine or racemic ketamine[citation needed] but, in mice, that the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine.[22] The usefulness of arketamine over esketamine has been supported by other researchers.[23][24][25]

Esketamine inhibits dopamine transporters eight times more than arketamine.[26] This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients.[27][28] Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly.[20][29] This is however in contradiction with R-ketamine being devoid of psychotomimetic side effects.[30]

Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing.[29] However, another study found no difference between racemic and (S)-ketamine on the patient's level of vigilance.[27] Interpretation of this finding is complicated by the fact that racemic ketamine is 50% (S)-ketamine.[31]

History[]

Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries.[3][32] In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such.[10][15] In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States.[10][15] Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on 4 September 2018;[33] the application was endorsed by an FDA advisory panel on 12 February 2019, and on 5 March 2019, the FDA approved esketamine, in conjunction with an oral antidepressant, for the treatment of depression in adults.[11]

In the 1980s and '90s, closely associated ketamine was used as a club drug known as "Special K" for its trip-inducing side effects.[34][35]

Society and culture[]

Names[]

Esketamine is the generic name of the drug and its INN and BAN, while esketamine hydrochloride is its BANM.[32] It is also known as S(+)-ketamine, (S)-ketamine, or (–)-ketamine ((-)[+] ketamine) as well as by its developmental code name JNJ-54135419.[32][15]

Esketamine is marketed under the brand name Spravato for use as an antidepressant and the brand names Ketanest, Ketanest S, Ketanest-S, Keta-S for use as an anesthetic (veterinary), among others.[32]

Availability[]

Esketamine is marketed as an antidepressant in the United States;[11] and as an anesthetic in the European Union.[32]

Legal status[]

Esketamine is a Schedule III controlled substance in the United States.[6]

References[]

  1. ^ Jump up to: a b "Spravato". Therapeutic Goods Administration (TGA). 17 March 2021. Retrieved 8 September 2021.
  2. ^ Jump up to: a b "AusPAR: Esketamine hydrochloride". Therapeutic Goods Administration (TGA). 24 May 2021. Retrieved 8 September 2021.
  3. ^ Jump up to: a b c d e f g h i j Himmelseher S, Pfenninger E (December 1998). "[The clinical use of S-(+)-ketamine--a determination of its place]". Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie. 33 (12): 764–70. doi:10.1055/s-2007-994851. PMID 9893910.
  4. ^ "Spravato 28 mg nasal spray, solution - Summary of Product Characteristics (SmPC)". (emc). Retrieved 24 November 2020.
  5. ^ "Vesierra 25 mg/ml solution for injection/infusion - Summary of Product Characteristics (SmPC)". (emc). 21 February 2020. Retrieved 24 November 2020.
  6. ^ Jump up to: a b c d e "Spravato- esketamine hydrochloride solution". DailyMed. 6 August 2020. Retrieved 26 September 2020.
  7. ^ "Spravato EPAR". European Medicines Agency (EMA). 16 October 2019. Retrieved 24 November 2020.
  8. ^ "Text search results for esketamine: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August 2017.[dead link]
  9. ^ Brayfield A, ed. (9 January 2017). "Ketamine Hydrochloride". MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August 2017.[dead link]
  10. ^ Jump up to: a b c d e f g Rakesh G, Pae CU, Masand PS (August 2017). "Beyond serotonin: newer antidepressants in the future". Expert Review of Neurotherapeutics. 17 (8): 777–790. doi:10.1080/14737175.2017.1341310. PMID 28598698. S2CID 205823807.
  11. ^ Jump up to: a b c "FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic". U.S. Food and Drug Administration (FDA) (Press release). Retrieved 6 March 2019.
  12. ^ Kohrs, Rainer; Durieux, Marcel E. (1998). "Ketamine". Anesthesia & Analgesia. 87 (5): 1186–1193. doi:10.1213/00000539-199811000-00039. ISSN 0003-2999.
  13. ^ "FDA Approves A Nasal Spray To Treat Patients Who Are Suicidal". NPR. 4 August 2020. Retrieved 27 September 2020.
  14. ^ Jump up to: a b c d e Lener MS, Kadriu B, Zarate CA (March 2017). "Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression". Drugs. 77 (4): 381–401. doi:10.1007/s40265-017-0702-8. PMC 5342919. PMID 28194724.
  15. ^ Jump up to: a b c d e f g "Esketamine - Johnson & Johnson - AdisInsight". Retrieved 7 November 2017.
  16. ^ Koons C, Edney A (12 February 2019). "First Big Depression Advance Since Prozac Nears FDA Approval". Bloomberg News. Retrieved 12 February 2019.
  17. ^ Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee (12 February 2019). "FDA Briefing Document" (PDF). Food and Drug Administration. Retrieved 12 February 2019. Meeting, February 12, 2019. Agenda Topic: The committees will discuss the efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceutica, for the treatment of treatment-resistant depression.
  18. ^ "Anti-depressant spray not recommended on NHS". BBC News. 28 January 2020.
  19. ^ "Esketamine nasal spray" (PDF). U.S. Food and Drug Administration (FDA). Retrieved 21 October 2019.
  20. ^ Jump up to: a b Himmelseher S, Pfenninger E (December 1998). "[The clinical use of S-(+)-ketamine--a determination of its place]". Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie (in German). 33 (12): 764–70. doi:10.1055/s-2007-994851. PMID 9893910.
  21. ^ Ihmsen H, Geisslinger G, Schüttler J (November 2001). "Stereoselective pharmacokinetics of ketamine: R(–)-ketamine inhibits the elimination of S(+)-ketamine". Clinical Pharmacology and Therapeutics. 70 (5): 431–8. doi:10.1067/mcp.2001.119722. PMID 11719729.
  22. ^ Zhang JC, Li SX, Hashimoto K (January 2014). "R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine". Pharmacology, Biochemistry, and Behavior. 116: 137–41. doi:10.1016/j.pbb.2013.11.033. PMID 24316345. S2CID 140205448.
  23. ^ Muller J, Pentyala S, Dilger J, Pentyala S (June 2016). "Ketamine enantiomers in the rapid and sustained antidepressant effects". Therapeutic Advances in Psychopharmacology. 6 (3): 185–92. doi:10.1177/2045125316631267. PMC 4910398. PMID 27354907.
  24. ^ Hashimoto K (November 2016). "Ketamine's antidepressant action: beyond NMDA receptor inhibition". Expert Opinion on Therapeutic Targets. 20 (11): 1389–1392. doi:10.1080/14728222.2016.1238899. PMID 27646666. S2CID 1244143.
  25. ^ Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, Ma M, Chen QX, Hashimoto K (October 2016). "Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression". Psychopharmacology. 233 (19–20): 3647–57. doi:10.1007/s00213-016-4399-2. PMC 5021744. PMID 27488193.
  26. ^ Nishimura M, Sato K (October 1999). "Ketamine stereoselectively inhibits rat dopamine transporter". Neuroscience Letters. 274 (2): 131–4. doi:10.1016/s0304-3940(99)00688-6. PMID 10553955. S2CID 10307361.
  27. ^ Jump up to: a b Doenicke A, Kugler J, Mayer M, Angster R, Hoffmann P (October 1992). "[Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings]". Der Anaesthesist (in German). 41 (10): 610–8. PMID 1443509.
  28. ^ Pfenninger E, Baier C, Claus S, Hege G (November 1994). "[Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses]". Der Anaesthesist (in German). 43 Suppl 2: S68-75. PMID 7840417.
  29. ^ Jump up to: a b Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). "Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)". European Neuropsychopharmacology. 7 (1): 25–38. doi:10.1016/s0924-977x(96)00042-9. PMID 9088882. S2CID 26861697.
  30. ^ Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (September 2015). "R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects". Translational Psychiatry. 5 (9): e632. doi:10.1038/tp.2015.136. PMC 5068814. PMID 26327690.
  31. ^ Pezeshkian, Melody (15 February 2021). "The Nuances of Ketamine's Neurochemistry". Psychedelic Science Review. Retrieved 16 February 2021.
  32. ^ Jump up to: a b c d e "Esketamine". Drugs.com.
  33. ^ "Janssen Submits Esketamine Nasal Spray New Drug Application to U.S. FDA for Treatment-Resistant Depression". Janssen Pharmaceuticals, Inc.
  34. ^ Marsa, Linda (January 2020). "A Paradigm Shift for Depression Treatment". Discover. Kalmbach Media.
  35. ^ Hoffer, Lee (7 March 2019). "The FDA Approved a Ketamine-Like Nasal Spray for Hard-to-Treat Depression". Vice. Retrieved 11 February 2020.

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