Esketamine

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Esketamine
Clinical data
Trade namesSpravato, Ketanest, others
Other names(S)-Ketamine; S(+)-Ketamine; JNJ-54135419
AHFS/Drugs.comMonograph
MedlinePlusa619017
License data
Pregnancy
category
Dissociative hallucinogens; Analgesics
ATC code
Legal status
Legal status
Identifiers
  • (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone
JSmol)
  • CN[C@]1(c2ccccc2Cl)CCCCC1=O
  • InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3/t13-/m0/s1 ☒N
  • Key:YQEZLKZALYSWHR-ZDUSSCGKSA-N ☒N
  (verify)

Esketamine, sold under the brand names Spravato (for

general anesthetic and as an antidepressant for treatment of depression. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.[14]

It is specifically used as a therapy for treatment-resistant depression (TRD) and for major depressive disorder (MDD) with co-occurring suicidal ideation or behavior.[10][15] Its efficacy for depression is modest and similar to that of other antidepressants.[16][10] Esketamine is not used by infusion into a vein for anesthesia as it is only FDA approved for depression in the form of an intranasal spray (the parent compound Ketamine is most often administered intravenously) and under direct medical supervision as a nasal spray.[10][5]

bladder problems.[10][17] Esketamine acts primarily as a N-methyl-D-aspartate (NMDA) receptor antagonist but also has other actions.[5][13]

In the form of

misuse liability as a dissociative hallucinogen, esketamine is a controlled substance.[18][10]

Medical uses

Anesthesia

Esketamine is used for similar indications as ketamine.

regional anesthesia with incomplete nerve blocks.[5]

Depression

Esketamine is approved under the brand name Spravato in the form of a

Risk Evaluation and Mitigation Strategy (REMS) called Spravato REMS.[10]

Five clinical studies of esketamine for TRD (TRANSFORM-1, -2, and -3, and SUSTAIN-1 and -2) were submitted to and evaluated by the FDA when approval of esketamine for treatment of TRD was sought by Janssen Pharmaceuticals.[22][23] Of these five studies, three were short-term (4-week) efficacy studies (the TRANSFORM studies).[22][24][23] Two of these three studies (TRANSFORM-1 and -3) did not find a statistically significant antidepressant effect of esketamine relative to placebo.[22][24][16][23] In the one positive short-term efficacy study (TRANSFORM-2), there was a 4.0-point difference between esketamine and placebo on the Montgomery–Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment (P = 0.020).[22][24][10][23] This scale ranges from 0 to 60 and the average score of the participants at the start of the study was about 37.0 in both the esketamine and placebo groups.[22][24][10] The total change in score after 4 weeks was –19.8 points in the esketamine group and –15.8 points in the placebo group.[22][10] This corresponded to a percentage change in MADRS score from baseline of –53.5% with esketamine and –42.4% with placebo (a difference and reduction of depression score of –11.1% potentially attributable to the pharmacological action of esketamine) in these patient samples.[16][10] Placebo showed 80.0% of the antidepressant effect of esketamine for TRD in this study and hence approximately 20.0% of the antidepressant response was attributable to esketamine.[22][10][25] In the two negative short-term efficacy trials that did not reach statistical significance (TRANSFORM-1 and -3), the differences in MADRS reductions between esketamine and placebo were –3.2 (P = 0.088) and –3.6 (P = 0.059) after 4 weeks of treatment.[23]

Short-term antidepressant efficacy (as measured by change in MADRS total score from baseline over 4 weeks) with esketamine nasal spray (56 or 84 mg) added to an existing oral antidepressant (n = 114) versus placebo nasal spray added to an existing oral antidepressant (n = 109) in people with treatment-resistant depression in the single positive efficacy trial.[10][26] In two other short-term efficacy trials, esketamine was not superior to placebo.[22][24][23]

The 4.0-point additional reduction in MADRS score with esketamine over placebo in the single positive efficacy trial corresponds to less than "minimal improvement" and has been criticized as being below the threshold for clinically meaningful change.

confounds are problems with studies of hallucinogens for psychiatric indications in general.[29][30] The FDA normally requires at least two positive short-term efficacy studies for approval of antidepressants, but this requirement was loosened for esketamine and a relapse-prevention trial was allowed to fill the place of the second efficacy trial instead.[22][24] This is the first time that the FDA is known to have made such an exception and the decision has been criticized as lowering regulatory standards.[24] In the relapse-prevention trial (SUSTAIN-2), the rate of depression relapse was significantly lower with esketamine continued than with it discontinued and replaced with placebo in esketamine-treated stable responders and remitters (51% rate reduction in remitters and 70% reduction in responders).[10][24][23]

Short-term antidepressant efficacy (as measured by change in MADRS total score from baseline over 4 weeks) with esketamine nasal spray (84 mg twice weekly) added to an existing oral antidepressant (n = 177–225) versus placebo nasal spray added to an existing oral antidepressant (n = 175–225) in people with major depressive disorder and suicidality in one of the two positive efficacy trials.[10][31] Findings were similar in the other positive short-term efficacy trial.[10][31]

Esketamine was approved for the treatment of MDD with co-occurring suicidal ideation or behavior on the basis of two short-term (4-week)

antisuicidal effects of esketamine in such individuals have not been demonstrated.[10][15]

Expectations were initially very high for ketamine and esketamine for treatment of depression based on early small-scale clinical studies, with discovery of the rapid and ostensibly robust antidepressant effects of ketamine described by some authors as "the most important advance in the field of psychiatry in the past half century".

racemic ketamine, but more research likewise is needed to evaluate this possibility.[42][43]

In February 2019, an outside panel of experts recommended in a 14–2 vote that the FDA approve the nasal spray version of esketamine for TRD, provided that it be given in a clinical setting, with people remaining on site for at least two hours after.[44][45] 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.[46] The approval of esketamine for TRD by the FDA was controversial due to limited and mixed evidence of efficacy and safety.[45][24][22][25] In January 2020, esketamine was rejected by the National Health Service (NHS) of Great Britain.[47] The NHS questioned the benefits of the medication for depression and claimed that it was too expensive.[47] People who have been already using esketamine were allowed to complete treatment if their doctors considered this necessary.[47]

Spravato debuted to a cost of treatment of US$32,400 per year when it launched in the United States in March 2019.[48] The Institute for Clinical and Economic Review (ICER), which evaluates cost effectiveness of drugs analogously to the National Institute for Health and Care Excellence (NICE) in the United Kingdom, declined to recommend esketamine for depression due to its steep cost and modest efficacy, deeming it not sufficiently cost-effective.[48][49]

Esketamine is the second drug to be approved for TRD by the FDA, following

standardized mean difference (SMD) of esketamine for TRD of 0.28 using the three phase 3 short-term efficacy trials conducted by Janssen.[25] This was similar to an SMD of 0.26 for olanzapine/fluoxetine for TRD and lower than SMDs of 0.35 for aripiprazole and 0.40 for quetiapine as adjuncts for MDD.[25] These drugs are less expensive than esketamine and may serve as more affordable alternatives to it for depression with similar effectiveness.[25]

Adverse effects

Main article: Ketamine § Adverse effects

The most common

bladder disease.[10][17]

Pharmacology

See also: Ketamine § Pharmacology

Pharmacodynamics

Esketamine is approximately twice as potent an anesthetic as racemic ketamine.[51]

In mice, the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine.[52] The usefulness of arketamine over esketamine has been supported by other researchers.[53][54][55]

Esketamine inhibits

psychotomimetic side effects.[60]

Unlike arketamine, esketamine does not bind significantly to

hallucinogenic effect while arketamine is reportedly more relaxing.[59] However, another study found no difference between racemic ketamine and esketamine on the patient's level of vigilance.[57] Interpretation of this finding is complicated by the fact that racemic ketamine is 50% esketamine.[61]

Pharmacokinetics

Esketamine is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows the elimination of esketamine.[62]

History

Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries.[5][20] In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such.[63][64] Esketamine received a breakthrough designation from the FDATooltip Food and Drug Administration for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016.[64][65] In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States.[63][64] Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on 4 September 2018;[66] 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.[19] 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.[67]

Since the 1980s, closely associated ketamine has been used as a club drug also known as "Special K" for its trip-inducing side effects.[68][69]

Society and culture

Names

Esketamine is the

BANMTooltip British Approved Name, Modified.[20] It is also known as S(+)-ketamine, (S)-ketamine, or (–)-ketamine ((-)[+] ketamine), as well as by its developmental code name JNJ-54135419.[20][64]

Esketamine is sold under the brand name Spravato for use as an antidepressant and the brand names Eskesia, Ketanest, Ketanest S, Ketanest-S, Keta-S for use as an anesthetic (veterinary), among others.[20]

Legal status

Esketamine is a Schedule III controlled substance in the United States.[10]

References

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