Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Esketamine: Difference between pages

{{Short description|Medication}}

{{Use dmy dates|date=November 2023}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Verifiedfields = verified

| Watchedfields = verified

| verifiedrevid = 461095357

| image = Esketamine2DCSD.svg

| width = 150

| image2 = S-ketamine-from-HCl-xtal-3D-balls.png

| width2 = 175

<!-- Clinical data -->

| pronounce =

| tradename = Spravato, Ketanest, others

| Drugs.com = {{drugs.com|monograph|esketamine-hydrochloride}}

| MedlinePlus = a619017

| licence_EU = yes

| DailyMedID = Esketamine

| licence_US = Esketamine

| pregnancy_AU = B3

| pregnancy_AU_comment = <ref name="Spravato APM summary" /><ref name="AusPAR: Esketamine hydrochloride" /><ref>{{cite web | title=Updates to the Prescribing Medicines in Pregnancy database | website=Therapeutic Goods Administration (TGA) | date=12 May 2022 | url=https://www.tga.gov.au/resources/resource/guidance/updates-prescribing-medicines-pregnancy-database | access-date=13 May 2022}}</ref>

| pregnancy_category =

| addiction_liability = Moderate<ref name="pmid35509224">{{cite journal | vauthors = Orsolini L, Salvi V, Volpe U | title = Craving and addictive potential of esketamine as side effects? | journal = Expert Opinion on Drug Safety | volume = 21 | issue = 6 | pages = 803–812 | date = June 2022 | pmid = 35509224 | doi = 10.1080/14740338.2022.2071422 }}</ref>

| routes_of_administration = [[Intranasal]], [[Intravenous infusion]]<ref name="HimmelseherPfenninger2008" />

| class = [[NMDA receptor antagonists]]; [[Antidepressant]]s; [[General anesthetics]]; [[Dissociative hallucinogen]]s; [[Analgesic]]s

| ATC_prefix = N01

| ATC_suffix = AX14

| ATC_supplemental = {{ATC|N06|AX27}}

<!-- Legal status -->

| legal_AU = S8

| legal_AU_comment = <ref name="Spravato APM summary">{{cite web | title=Spravato | website=Therapeutic Goods Administration (TGA) | date=17 March 2021 | url=https://www.tga.gov.au/apm-summary/spravato | access-date=8 September 2021}}</ref><ref name="AusPAR: Esketamine hydrochloride">{{cite web | title=AusPAR: Esketamine hydrochloride | website=Therapeutic Goods Administration (TGA) | date=24 May 2021 | url=https://www.tga.gov.au/auspar/auspar-esketamine-hydrochloride | access-date=8 September 2021}}</ref>

| legal_BR = B1

| legal_BR_comment = <ref>{{cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Regulatory Decision Summary - Spravato - | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?linkID=RDS00738 | access-date=5 June 2022}}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = <ref>{{cite web | title=Spravato 28 mg nasal spray, solution - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/10977/smpc | access-date=24 November 2020}}</ref><ref>{{cite web | title=Vesierra 25 mg/ml solution for injection/infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=21 February 2020 | url=https://www.medicines.org.uk/emc/product/9413/smpc | access-date=24 November 2020 | archive-date=21 April 2021 | archive-url=https://web.archive.org/web/20210421011315/https://www.medicines.org.uk/emc/product/9413/smpc | url-status=dead }}</ref>

| legal_US = Schedule III

| legal_US_comment = <ref name="Spravato FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Spravato EPAR">{{cite web | title=Spravato EPAR | website=[[European Medicines Agency]] (EMA) | date=16 October 2019 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/spravato | access-date=24 November 2020}}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability =

| protein_bound =

| metabolism =

| metabolites =

| onset =

| elimination_half-life =

| duration_of_action =

| excretion =

<!-- Identifiers -->

| index2_label = HCl

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 33643-46-8

| CAS_number2_Ref = {{cascite|correct|CAS}}

| CAS_number2 = 33643-47-9

| PubChem = 182137

| IUPHAR_ligand = 9152

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01221

| DrugBank2_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank2 = DBSALT002086

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 158414

| ChemSpiderID2_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID2 = 26332012

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 50LFG02TXD

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = L8P1H35P2Z

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D07283

| KEGG2_Ref = {{keggcite|correct|kegg}}

| KEGG2 = D10627

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 60799

| ChEBI2_Ref = {{ebicite|correct|EBI}}

| ChEBI2 = 60800

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 395091

| ChEMBL2_Ref = {{ebicite|correct|EBI}}

| ChEMBL2 = 2364609

| NIAID_ChemDB =

| PDB_ligand = JC9

| synonyms = (''S'')-Ketamine; ''S''(+)-Ketamine; JNJ-54135419

<!-- Chemical and physical data -->

| IUPAC_name = (''S'')-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone

| C = 13

| H = 16

| Cl = 1

| N = 1

| O = 1

| SMILES = CN[C@]1(c2ccccc2Cl)CCCCC1=O

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = YQEZLKZALYSWHR-ZDUSSCGKSA-N

<!-- Definition and medical uses -->

'''Esketamine''', sold under the brand names '''Spravato''' (for [[depression (mood)|depression]]) and '''Ketanest''' (for [[anesthesia]]) among others,<ref name="Spravato FDA label">{{cite web | title=Spravato- esketamine hydrochloride solution | website=DailyMed | date=6 August 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d81a6a79-a74a-44b7-822c-0dfa3036eaed | access-date=26 September 2020}}</ref><ref>{{Cite web |title=Esketamin - Anwendung, Wirkung, Nebenwirkungen {{!}} Gelbe Liste |url=https://www.gelbe-liste.de/wirkstoffe/Esketamin_45078 |access-date=2024-03-19 |website=Gelbe Liste Online |language=de}}</ref> is the ''S''(+) [[enantiomer]] of [[ketamine]].<ref name="HimmelseherPfenninger2008">{{cite journal |vauthors=Himmelseher S, Pfenninger E |date=December 1998 |title=[The clinical use of S-(+)-ketamine--a determination of its place] |journal=Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie |language=de |volume=33 |issue=12 |pages=764–70 |doi=10.1055/s-2007-994851 |pmid=9893910 |s2cid=259981872}}</ref><ref name="pmid33155503" /> It is a [[dissociative hallucinogen]] drug used as a [[general anesthetic]] and as an [[antidepressant]] for treatment of [[depression (mood)|depression]]. Esketamine is the [[biological activity|active]] enantiomer of ketamine in terms of NMDA receptor antagonism and is more [[potency (pharmacology)|potent]] than racemic ketamine.<ref name="pmid9806706">{{cite journal | vauthors = Kohrs R, Durieux ME | title = Ketamine: teaching an old drug new tricks | journal = Anesthesia and Analgesia | volume = 87 | issue = 5 | pages = 1186–1193 | date = November 1998 | pmid = 9806706 | doi = 10.1213/00000539-199811000-00039 | doi-access = free }}</ref>

It is specifically used as a therapy for [[treatment-resistant depression]] (TRD) and for [[major depressive disorder]] (MDD) with co-occurring [[suicidal ideation]] or [[Suicide|behavior]].<ref name="Spravato FDA label" /><ref name="pmid33726522" /> Its [[efficacy]] for depression is modest and similar to that of other antidepressants.<ref name="pmid34421147" /><ref name="Spravato FDA label" /> Esketamine is not used by [[Intravenous therapy|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]].<ref name="Spravato FDA label" /><ref name="HimmelseherPfenninger2008" />

<!-- Side effects and mechanism -->

[[Adverse effect]]s of esketamine include [[dissociative drug|dissociation]], [[dizziness]], [[sedation]], [[nausea]], [[vomiting]], [[vertigo]], [[hypoesthesia|numbness]], [[anxiety]], [[lethargy]], [[hypertension|increased blood pressure]], and [[drunkenness|feelings of drunkenness]].<ref name="Spravato FDA label" /> Less often, esketamine can cause [[urotoxicity|bladder problems]].<ref name="Spravato FDA label" /><ref name="pmid33484298">{{cite journal| vauthors = Ng J, Lui LM, Rosenblat JD, Teopiz KM, Lipsitz O, Cha DS, Xiong J, Nasri F, Lee Y, Kratiuk K, Rodrigues NB, Gill H, Subramaniapillai M, Mansur RB, Ho R, Cao B, McIntyre RS | title = Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment | journal = Psychopharmacology (Berl) | volume = 238 | issue = 4 | pages = 917–926 | date = April 2021 | pmid = 33484298 | doi = 10.1007/s00213-021-05767-1 | s2cid = 231688343 | url = }}</ref> Esketamine acts primarily as a [[NMDA receptor antagonist|''N''-methyl-<small>D</small>-aspartate (NMDA) receptor antagonist]] but also has other actions.<ref name="HimmelseherPfenninger2008" /><ref name="pmid33155503">{{cite journal | vauthors = Jelen LA, Young AH, Stone JM | title = Ketamine: A tale of two enantiomers | journal = J Psychopharmacol | volume = 35 | issue = 2 | pages = 109–123 | date = February 2021 | pmid = 33155503 | pmc = 7859674 | doi = 10.1177/0269881120959644 | url = }}</ref>

<!-- History, society, and culture -->

In the form of [[racemate|racemic]] ketamine, esketamine was first [[chemical synthesis|synthesized]] in 1962 and introduced for medical use as an anesthetic in 1970.<ref name="pmid28418641">{{cite journal | vauthors = Tyler MW, Yourish HB, Ionescu DF, Haggarty SJ | title = Classics in Chemical Neuroscience: Ketamine | journal = ACS Chem Neurosci | volume = 8 | issue = 6 | pages = 1122–1134 | date = June 2017 | pmid = 28418641 | doi = 10.1021/acschemneuro.7b00074 | url = }}</ref> [[Enantiopure]] esketamine was introduced for medical use as an anesthetic in 1997 and as an antidepressant in 2019.<ref name="HimmelseherPfenninger2008" /><ref name="Spravato FDA label" /><ref name="FDA PR" /> It is used as an anesthetic in the European Union and as an antidepressant in the United States and Canada.<ref name="FDA PR" /><ref name="Drugs.com" /><ref name="pmid33174760">{{cite journal|vauthors=Swainson J, McGirr A, Blier P, Brietzke E, Richard-Devantoy S, Ravindran N, Blier J, Beaulieu S, Frey BN, Kennedy SH, McIntyre RS, Milev RV, Parikh SV, Schaffer A, Taylor VH, Tourjman V, van Ameringen M, Yatham LN, Ravindran AV, Lam RW |title=The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur |journal=Can J Psychiatry |pages=113–125 |date=November 2020 |volume=66 |issue=2 |pmid=33174760 |doi=10.1177/0706743720970860 |pmc=7918868 }}</ref> Due to [[misuse liability]] as a dissociative hallucinogen, esketamine is a [[controlled substance]].<ref name="pmid28418641" /><ref name="Spravato FDA label" />

==Medical uses==

===Anesthesia===

Esketamine is used for similar indications as ketamine.<ref name="HimmelseherPfenninger2008" /> Such uses include induction of anesthesia in high-risk patients such as those with [[Shock (circulatory)|circulatory shock]], severe [[bronchospasm]], or as a supplement to [[regional anesthesia]] with incomplete [[nerve block]]s.<ref name="HimmelseherPfenninger2008" />

===Depression===

Esketamine is approved under the brand name Spravato in the form of a [[nasal spray]] added to a conventional [[antidepressant]] as a therapy for [[treatment-resistant depression]] (TRD) as well as [[major depressive disorder]] (MDD) associated with [[suicidal ideation]] or [[suicidal behavior|behavior]] in adults in the United States.<ref name="Spravato FDA label" /> In the clinical trials that led to approval of esketamine, TRD was defined as MDD with inadequate response to at least two different conventional antidepressants.<ref name="Spravato FDA label" /> The nasal spray formulation of esketamine used for depression delivers two sprays containing a total of 28&nbsp;mg esketamine and doses of 56&nbsp;mg (2 devices) to 84&nbsp;mg (3 devices) are used.<ref name="Spravato FDA label" /> The recommended dosage of Spravato is 56&nbsp;mg on day 1, 56 or 84&nbsp;mg twice per week during weeks 1 to 4, 56 or 84&nbsp;mg once per week during weeks 5 to 8, and 56 or 84&nbsp;mg every 2&nbsp;weeks or once weekly during week 9 and thereafter.<ref name="Spravato FDA label" /> Dosing is individualized to the least frequent dosing necessary to maintain response or remission.<ref name="Spravato FDA label" /> Spravato is administered under the supervision of a healthcare provider and patients are monitored for at least 2&nbsp;hours during each treatment session.<ref name="Spravato FDA label" /> Due to concerns about [[sedation]], [[dissociative drug|dissociation]], and [[drug misuse|misuse]], esketamine is available for treatment of depression only from certified providers through a restricted program under a [[Risk Evaluation and Mitigation Strategy]] (REMS) called Spravato REMS.<ref name="Spravato FDA label" />

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]].<ref name="pmid32456714">{{cite journal | vauthors = Horowitz MA, Moncrieff J | title = Are we repeating mistakes of the past? A review of the evidence for esketamine | journal = Br J Psychiatry | volume = 219| issue = 5| pages = 614–617 | date = May 2020 | pmid = 32456714 | doi = 10.1192/bjp.2020.89 | s2cid = 218910799 | doi-access=free}}</ref><ref name="pmid34447651" /> Of these five studies, three were short-term (4-week) efficacy studies (the TRANSFORM studies).<ref name="pmid32456714" /><ref name="pmid31841104">{{cite journal | vauthors = Gastaldon C, Papola D, Ostuzzi G, Barbui C | title = Esketamine for treatment resistant depression: a trick of smoke and mirrors? | journal = Epidemiol Psychiatr Sci | volume = 29 | issue = | pages = e79 | date = December 2019 | pmid = 31841104 | pmc = 8061126 | doi = 10.1017/S2045796019000751 | url = }}</ref><ref name="pmid34447651" /> Two of these three studies (TRANSFORM-1 and -3) did not find a [[statistical significance|statistically significant]] antidepressant effect of esketamine relative to [[placebo]].<ref name="pmid32456714" /><ref name="pmid31841104" /><ref name="pmid34421147">{{cite journal | vauthors = Khan A, Mar KF, Brown WA | title = Consistently Modest Antidepressant Effects in Clinical Trials: the Role of Regulatory Requirements | journal = Psychopharmacol Bull | volume = 51 | issue = 3 | pages = 79–108 | date = June 2021 | pmid = 34421147 | doi = | pmc = 8374926 | url = | quote = Even drugs with novel mechanisms of action such as the esketamine nasal spray show the same effect size and look nearly identical to other antidepressants when evaluated in the regulatory context (42% symptom reduction with placebo, 54% with drug, effect size 0.29). However, it must be taken under consideration that this trial was unique from the others in that it was an adjunctive study of esketamine nasal spray in treatment resistant patients. It is worth noting that two shortterm trials conducted for regulatory approval of esketamine but not included in the label did not reach statistical significance (P = 0.058 and P = 0.088).28 Independent analysis of these esketamine trial data submitted to the FDA show that despite expectations from smallscale preliminary studies, esketamine performs modestly in patients with treatment resistant depression in the context of large, regulatory trials.29 These authors also raised concerns about the potential lack of specificity of drug effects and the risk of side effects demonstrated in these trials. [...] False negatives are well-known risks of small sized studies. However, it is equally important to note that if we do not enroll adequate sample sizes we will continue run the serious risk of getting an inflated false positive resulting in an overestimate of treatment effects that is not replicable (as was the case with many of the earlier regulatory trials, which tended to have small sample sizes).25 This is especially pertinent for early pilot studies of investigational antidepressants (phase I and II trials), which are not always subject to the same regulatory statutes of later stage trials. This phenomenon is illustrated by the dramatic decline of treatment effect sizes seen with esketamine over the course of development (from small pilot studies to large regulatory trials). Although regulatory agencies allow for more lenient methods for exploratory purposes, this method may yield misleading conclusions because these small trials are invariably under-powered. Specifically, these exploratory trials may end up with an erroneously low placebo response and thus a falsely inflated estimate of effect size.46 This possibility is under appreciated by many investigators but should be strongly considered given the persistence of modest effect sizes in regulatory trials of antidepressants.}}</ref><ref name="pmid34447651" /> 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&nbsp;weeks of treatment (''P'' = 0.020).<ref name="pmid32456714" /><ref name="pmid31841104" /><ref name="Spravato FDA label" /><ref name="pmid34447651" /> 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.<ref name="pmid32456714" /><ref name="pmid31841104" /><ref name="Spravato FDA label" /> The total change in score after 4&nbsp;weeks was –19.8 points in the esketamine group and –15.8 points in the placebo group.<ref name="pmid32456714" /><ref name="Spravato FDA label" /> 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.<ref name="pmid34421147" /><ref name="Spravato FDA label" /> 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.<ref name="pmid32456714" /><ref name="Spravato FDA label" /><ref name="pmid31680014">{{cite journal | vauthors = Turner EH | title = Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval | journal = Lancet Psychiatry | volume = 6 | issue = 12 | pages = 977–979 | date = December 2019 | pmid = 31680014 | doi = 10.1016/S2215-0366(19)30394-3 | s2cid = 207889274 | url = }}</ref> 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&nbsp;weeks of treatment.<ref name="pmid34447651" />

[[File:Short-term antidepressant efficacy of esketamine versus placebo added to an existing oral antidepressant in people with depression.png|thumb|left|400px|Short-term antidepressant efficacy (as measured by change in MADRS total score from baseline over 4&nbsp;weeks) with esketamine nasal spray (56 or 84&nbsp;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.<ref name="Spravato FDA label" /><ref name="TouchstoneTMS">{{cite web|url=https://touchstonetms.com/spravato-clinical-studies/|title = SPRAVATO™ Clinical Studies &#124; Touchstone TMS|date = 13 January 2020}}</ref> In two other short-term efficacy trials, esketamine was not superior to placebo.<ref name="pmid32456714" /><ref name="pmid31841104" /><ref name="pmid34447651" />]]

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.<ref name="pmid32456714" /><ref name="pmid31841104" /> A difference of at least 6.5 points was originally suggested by the trial investigators to be a reasonable threshold for clinical significance.<ref name="pmid31841104" /><ref name="pmid32456714" /> In other literature, MADRS reductions have been interpreted as "very much improved" corresponding to 27–28 points, "much improved" to 16–17 points, and "minimally improved" to 7–9 points.<ref name="Paketci2021">{{cite journal | vauthors = Paketci S | title = Interpretation of the Montgomery-Åsberg Depression Rating Scale (MADRS) | journal = The British Journal of Psychiatry | volume = 219 | issue = 5 | pages = 620–621 | date = November 2021 | pmid = 35048825 | doi = 10.1192/bjp.2021.162 | s2cid = 244118803 | doi-access = free | eissn = 1472-1465 }}</ref> It has additionally been argued that the small advantage in scores with esketamine may have been related to an enhanced placebo response in the esketamine group due to functional [[unblinding]] caused by the [[psychoactive]] effects of esketamine.<ref name="pmid32456714" /><ref name="pmid33726522" /><ref name="pmid33353946">{{cite journal | vauthors = Ballard ED, Zarate CA | title = The role of dissociation in ketamine's antidepressant effects | journal = Nat Commun | volume = 11 | issue = 1 | pages = 6431 | date = December 2020 | pmid = 33353946 | pmc = 7755908 | doi = 10.1038/s41467-020-20190-4 | bibcode = 2020NatCo..11.6431B | url = }}</ref> In other words, it is argued that the study was not truly a [[double-blind]] [[controlled trial]].<ref name="pmid32456714" /><ref name="pmid33726522">{{cite journal| vauthors = McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, Brietzke E, Dodd S, Gorwood P, Ho R, Iosifescu DV, Lopez Jaramillo C, Kasper S, Kratiuk K, Lee JG, Lee Y, Lui LM, Mansur RB, Papakostas GI, Subramaniapillai M, Thase M, Vieta E, Young AH, Zarate CA, Stahl S | title = Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation | journal = Am J Psychiatry | volume = 178 | issue = 5 | pages = 383–399 | date = May 2021 | pmid = 33726522 | doi = 10.1176/appi.ajp.2020.20081251 | pmc = 9635017 | s2cid = 232262694 | url = | quote = A legitimate criticism, as it relates to interpreting the effect sizes reported with single or repeat-dose ketamine in TRD, is the possibility that nonspecific effects such as functional unblinding (e.g., by patients experiencing dissociation or euphoric responses) and expectancymayinadvertentlyinflate the efficacy of ketamine (51, 52). [...] Given the absence of an adequately designed head-to-head trial, the relative efficacies of intranasal esketamine and intravenous racemic ketamine are not known (65). [...] A recent meta-analysis comparing intranasal and intravenous ketamine formulations was unable to identify a significant difference between formulations as well as routes of delivery in efficacy at 24 hours, 7 days, and 28 days (17). A separate meta-analysis concluded that intravenous ketamine may be superior in efficacy and have lower dropout rates (66). However, it is difficult to draw definitive conclusions from these analyses given the heterogeneity across component studies.}}</ref> [[Dissociative|Dissociation]] was experienced as a side effect by a majority of participants who received esketamine (61–75% with esketamine and 5–12% with placebo; ~7-fold difference) and "severe" dissociation was experienced by 25%.<ref name="pmid32456714" /><ref name="pmid31841104" /><ref name="Spravato FDA label" /> Deblinding and [[subject-expectancy effect|expectancy]] [[confounding variable|confounds]] are problems with studies of [[hallucinogen]]s for psychiatric indications in general.<ref name="pmid34038314">{{cite journal | vauthors = Muthukumaraswamy SD, Forsyth A, Lumley T | title = Blinding and expectancy confounds in psychedelic randomized controlled trials | journal = Expert Rev Clin Pharmacol | volume = 14 | issue = 9 | pages = 1133–1152 | date = September 2021 | pmid = 34038314 | doi = 10.1080/17512433.2021.1933434 | s2cid = 235215630 | url = }}</ref><ref name="pmid34227438">{{cite journal | vauthors = Schenberg EE | title = Who is blind in psychedelic research? Letter to the editor regarding: blinding and expectancy confounds in psychedelic randomized controlled trials | journal = Expert Rev Clin Pharmacol | volume = 14 | issue = 10 | pages = 1317–1319 | date = October 2021 | pmid = 34227438 | doi = 10.1080/17512433.2021.1951473 | s2cid = 235746214 | url = }}</ref> 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.<ref name="pmid32456714" /><ref name="pmid31841104" /> 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.<ref name="pmid31841104" /> 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).<ref name="Spravato FDA label" /><ref name="pmid31841104" /><ref name="pmid34447651">{{cite journal | vauthors = Sapkota A, Khurshid H, Qureshi IA, Jahan N, Went TR, Sultan W, Alfonso M | title = Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review | journal = Cureus | volume = 13 | issue = 8 | pages = e17352 | date = August 2021 | pmid = 34447651 | pmc = 8381465 | doi = 10.7759/cureus.17352 | doi-access = free | url = }}</ref>

[[File:Short-term antidepressant efficacy of esketamine versus placebo added to an existing oral antidepressant in people with depression and suicidality.png|thumb|right|400px|Short-term antidepressant efficacy (as measured by change in MADRS total score from baseline over 4&nbsp;weeks) with esketamine nasal spray (84&nbsp;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.<ref name="Spravato FDA label" /><ref name="pmid34412104" /> Findings were similar in the other positive short-term efficacy trial.<ref name="Spravato FDA label" /><ref name="pmid34412104" />]]

Esketamine was approved for the treatment of MDD with co-occurring suicidal ideation or behavior on the basis of two short-term (4-week) [[Phases of clinical research#Phase III|phase 3]] trials (ASPIRE-1 and -2) of esketamine nasal spray added to a conventional antidepressant.<ref name="Spravato FDA label" /><ref name="pmid33726522" /><ref name="pmid34502248">{{cite journal | vauthors = Capuzzi E, Caldiroli A, Capellazzi M, Tagliabue I, Marcatili M, Colmegna F, Clerici M, Buoli M, Dakanalis A | title = Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review | journal = Int J Mol Sci | volume = 22 | issue = 17 | date = August 2021 | page = 9338 | pmid = 34502248 | pmc = 8430977 | doi = 10.3390/ijms22179338 | url = | doi-access = free }}</ref><ref name="pmid34412104">{{cite journal | vauthors = Canuso CM, Ionescu DF, Li X, Qiu X, Lane R, Turkoz I, Nash AI, Lopena TJ, Fu DJ | title = Esketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior | journal = J Clin Psychopharmacol | volume = 41 | issue = 5 | pages = 516–524 | date = 2021 | pmid = 34412104 | pmc = 8407443 | doi = 10.1097/JCP.0000000000001465 | url = }}</ref> The primary efficacy measure was reduction in MADRS total score after 24&nbsp;hours following the first dose of esketamine.<ref name="Spravato FDA label" /> In both trials, MADRS scores were significantly reduced with esketamine relative to placebo at 24&nbsp;hours.<ref name="Spravato FDA label" /> The mean MADRS scores at baseline were 39.4 to 41.3 in all groups and the MADRS reductions at 24&nbsp;hours were –15.9 and –16.0 with esketamine and –12.0 and –12.2 with placebo, resulting in mean differences between esketamine and placebo of –3.8 and –3.9.<ref name="Spravato FDA label" /> The secondary efficacy measure in the trials was change in [[Clinical Global Impression|Clinical Global Impression of Suicidal Severity - Revised]] (CGI-SS-r) 24&nbsp;hours after the first dose of esketamine.<ref name="Spravato FDA label" /> The CGI-SS-r is a single-item scale with scores ranging from 0 to 6.<ref name="pmid33726522" /> Esketamine was not significantly effective in reducing suicidality relative to placebo on this measure either at 24&nbsp;hours or after 25&nbsp;days.<ref name="Spravato FDA label" /><ref name="pmid34412104" /><ref name="pmid33726522" /> At 24&nbsp;hours, CGI-SS-r scores were changed by –1.5 with esketamine and –1.3 with placebo, giving a non-significant mean difference between esketamine and placebo of –0.20.<ref name="pmid33726522" /> Hence, while efficacious in reducing depressive symptoms in people with depression and suicidality, [[antisuicidal]] effects of esketamine in such individuals have not been demonstrated.<ref name="Spravato FDA label" /><ref name="pmid33726522" />

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".<ref name="pmid29736744">{{cite journal | vauthors = Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sánchez E, Gutiérrez-Rojas L, Meana JJ | title = Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review | journal = CNS Drugs | volume = 32| issue = 5| pages = 411–420| date = May 2018 | pmid = 29736744 | doi = 10.1007/s40263-018-0519-3 | s2cid = 13679905 | url = | quote = In brief, these studies (Table 1) have globally assessed responses to a single dose of intravenous ketamine in 166 patients with TDR with multiple treatment failures, including electroconvulsive therapy (ECT). The findings provide evidence of improvement in depressive symptoms within hours, with a response rate > 60% in the first 4.5 and 24 h, and > 40% after 7 days, with a big effect size in comparison with placebo (Cohen's d 1.3–1.7) or active placebo (midazolam, d = 0.8). These figures, though preliminary, contrast with the average effect size of conventional antidepressants (Cohen's d 0.53–0.81 in patients with intense symptoms) [32] and their response latency (about 4–7 weeks) [1].}}</ref><ref name="pmid32401866">{{cite journal | vauthors = Lacerda AL | title = Esketamine/ketamine for treatment-resistant depression | journal = Braz J Psychiatry | volume = 42 | issue = 6 | pages = 579–580 | date = 2020 | pmid = 32401866 | pmc = 7678896 | doi = 10.1590/1516-4446-2020-0996| quote = Some authors have described the discovery of rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine as the most important advance in the field of psychiatry in the past half century.}}</ref><ref name="pmid28395988">{{cite journal | vauthors = Singh I, Morgan C, Curran V, Nutt D, Schlag A, McShane R | title = Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight | journal = Lancet Psychiatry | volume = 4 | issue = 5 | pages = 419–426 | date = May 2017 | pmid = 28395988 | doi = 10.1016/S2215-0366(17)30102-5 | hdl = 10871/30208 | s2cid = 28186580 | quote = Ketamine has been hailed as the most important advance in the treatment of depression of the past 50 years.1| hdl-access = free }}</ref> According to a 2018 review, ketamine showed more than double the antidepressant [[effect size]] over placebo of conventional antidepressants in the treatment of depression based on the preliminary evidence available at the time ([[Cohen's d|Cohen's ''d'']] = 1.3–1.7 for ketamine, Cohen's ''d'' = 0.8 for [[midazolam]] ([[active placebo]]), and Cohen's ''d'' = 0.53–0.81 for conventional antidepressants).<ref name="pmid29736744" /> However, the efficacy of ketamine/esketamine for depression declined dramatically as studies became larger and more methodologically rigorous.<ref name="pmid34421147" /><ref name="pmid35665948">{{cite journal | vauthors = Moore TJ, Alami A, Alexander GC, Mattison DR | title = Safety and effectiveness of NMDA receptor antagonists for depression: A multidisciplinary review | journal = Pharmacotherapy | volume = 42 | issue = 7 | pages = 567–579 | date = July 2022 | pmid = 35665948 | doi = 10.1002/phar.2707 | pmc = 9540857 | s2cid = 249434988 | url = | quote = The promising results seen in the small, single-infusion, single-center trials of racemic ketamine were generally not replicated in the larger, multi-site trials of esketamine nasal spray. The esketamine trials were also subject to FDA site inspections, data integrity checks, and other forms of independent scrutiny.}}</ref> The effectiveness of esketamine for the indication of TRD is described as "modest" and is similar in magnitude to that of other antidepressants for treatment of MDD.<ref name="pmid34421147" /> The comparative effectiveness of ketamine and esketamine in the treatment of depression has not been adequately characterized.<ref name="pmid33726522" /> A January 2021 [[meta-analysis]] reported that ketamine was similarly effective to esketamine in terms of antidepressant effect size ({{Abbrlink|SMD|standardized mean difference}} for depression score of –1.1 vs. –1.2) but more effective than esketamine in terms of response and remission rates ({{Abbrlink|RR|risk ratio}} = 3.01 vs. RR = 1.38 for response and RR = 3.70 vs. RR = 1.47 for remission).<ref name="pmid33022440" /><ref name="pmid33726522" /><ref name="pmid33571795" /> A September 2021 [[Cochrane review]] found that ketamine had an effect size (SMD) for depression at 24{{nbsp}}hours of –0.87, with very low certainty, and that esketamine had an effect size (SMD) at 24{{nbsp}}hours of –0.31, based on moderate-certainty evidence.<ref name="pmid34510411">{{cite journal | vauthors = Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A | title = Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder | journal = Cochrane Database Syst Rev | volume = 9 | issue = 11| pages = CD011612 | date = September 2021 | pmid = 34510411 | doi = 10.1002/14651858.CD011612.pub3 | pmc = 8434915 | url = }}</ref> However, these meta-analyses have involved largely non-directly comparative studies with dissimilar research designs and patient populations.<ref name="pmid33022440" /><ref name="pmid33726522" /><ref name="pmid33571795" /> Only a single clinical trial has directly compared ketamine and esketamine for depression as of May 2021.<ref name="pmid33904154">{{cite journal | vauthors = Henter ID, Park LT, Zarate CA | title = Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status | journal = CNS Drugs | volume = 35 | issue = 5 | pages = 527–543 | date = May 2021 | pmid = 33904154 | pmc = 8201267 | doi = 10.1007/s40263-021-00816-x | url = | quote = To date, only one study has examined the differences between esketamine (0.25 mg/kg) and (R,S)-ketamine (0.5 mg/kg); though underpowered, it found no differences in efficacy, tolerability, or psychotomimetic profile between the two agents [67]. A recent meta-analysis suggests the need to compare these two agents head-to-head [68].}}</ref><ref name="pmid33726522" /><ref name="pmid31786030">{{cite journal | vauthors = Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, Caliman-Fontes AT, Echegaray MV, Bandeira ID, Silva SS, Cavalcanti DE, Araújo-de-Freitas L, Sarin LM, Tuena MA, Nakahira C, Sampaio AS, Del-Porto JA, Turecki G, Loo C, Lacerda AL, Quarantini LC | title = Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study | journal = J Affect Disord | volume = 264 | issue = | pages = 527–534 | date = March 2020 | pmid = 31786030 | doi = 10.1016/j.jad.2019.11.086 | s2cid = 208535227 | url = }}</ref> This study reported similar antidepressant efficacy as well as [[tolerability]] and [[psychotomimetic]] effects between the two agents.<ref name="pmid33904154" /><ref name="pmid33726522" /><ref name="pmid31786030" /> However, the study was small and [[statistical power|underpowered]], and more research is still needed to better-characterize the comparative antidepressant effects of ketamine and esketamine.<ref name="pmid33904154" /><ref name="pmid33726522" /><ref name="pmid31786030" /><ref name="pmid33022440">{{cite journal | vauthors = Bahji A, Vazquez GH, Zarate CA | title = Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis | journal = J Affect Disord | volume = 278 | issue = | pages = 542–555 | date = January 2021 | pmid = 33022440 | doi = 10.1016/j.jad.2020.09.071 | pmc = 7704936 | url = }}</ref><ref name="pmid33571795">{{cite journal | vauthors = Drevets WC, Popova V, Daly EJ, Borentain S, Lane R, Cepeda MS, Mathews M, Manji HK, Canuso CM | title = Comments to Drs. Bahji, Vazquez, and Zarate | journal = J Affect Disord | volume = 283 | issue = | pages = 262–264 | date = March 2021 | pmid = 33571795 | doi = 10.1016/j.jad.2021.01.046 | s2cid = 231899423 | url = | doi-access = free }}</ref> Preliminary research suggests that [[arketamine]], the ''R''(−) [[enantiomer]] of ketamine, may also have its own independent antidepressant effects and may contribute to the antidepressant efficacy of [[racemate|racemic]] ketamine, but more research likewise is needed to evaluate this possibility.<ref name="pmid32224141">{{cite journal | vauthors = Hashimoto K | title = Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine | journal = Biochem Pharmacol | volume = 177 | issue = | pages = 113935 | date = July 2020 | pmid = 32224141 | doi = 10.1016/j.bcp.2020.113935 | s2cid = 214732428 | url = | doi-access = free }}</ref><ref name="pmid33963284">{{cite journal | vauthors = Wei Y, Chang L, Hashimoto K | title = Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | journal = Mol Psychiatry | volume = 27| issue = 1| pages = 559–573| date = May 2021 | pmid = 33963284 | doi = 10.1038/s41380-021-01121-1 | pmc = 8960399 | s2cid = 233875775 | url = }}</ref>

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.<ref name="urlBloomberg">{{cite news |url=https://www.bloomberg.com/news/articles/2019-02-12/first-big-depression-advance-since-prozac-nears-fda-approval | vauthors = Koons C, Edney A |title=First Big Depression Advance Since Prozac Nears FDA Approval. |work= [[Bloomberg News]] |date=12 February 2019 |access-date=12 February 2019}}</ref><ref name="Belluz 2019">{{cite web | vauthors = Belluz J | title=Why a ketamine-like drug is being used to treat depression | website=Vox | date=6 March 2019 | url=https://www.vox.com/2019/3/6/18253041/ketamine-johnson-johnson-spravato | access-date=27 November 2021}}</ref> 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.<ref name="urlwww.fda.gov">{{cite web | author = Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee |url= https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM630970.pdf |title= FDA Briefing Document | quote = 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. | publisher = [[Food and Drug Administration]] |date=12 February 2019 |access-date=12 February 2019}}</ref> The approval of esketamine for TRD by the FDA was controversial due to limited and mixed evidence of efficacy and safety.<ref name="Belluz 2019" /><ref name="pmid31841104" /><ref name="pmid32456714" /><ref name="pmid31680014" /> In January 2020, esketamine was rejected by the [[National Health Service]] (NHS) of [[Great Britain]].<ref name="BBC2020">{{cite web|url=https://www.bbc.com/news/health-51279176|title=Anti-depressant spray not recommended on NHS|date=28 January 2020|website=BBC News}}</ref> The NHS questioned the benefits of the medication for depression and claimed that it was too expensive.<ref name="BBC2020" /> People who have been already using esketamine were allowed to complete treatment if their doctors considered this necessary.<ref name="BBC2020" />

Spravato debuted to a cost of treatment of {{US$|32,400}} per year when it launched in the United States in March 2019.<ref name="Blankenship 2019">{{cite web | vauthors = Blankenship K | title=J&J scores Spravato trial win in high-risk depression. Will doctors and payers buy in? | website=FiercePharma | date=10 September 2019 | url=https://www.fiercepharma.com/pharma/j-j-scores-spravato-trial-win-high-risk-depression-will-doctors-and-payers-buy | access-date=27 November 2021 | quote = Pricing, though, may still be an issue. In early May, the Institute for Clinical and Economic Review (ICER) declined to recommend Spravato for use at its steep list price of $32,400 per year. The U.S. cost watchdog said J&J would need to cut the sticker price between 25% and 52% to be considered cost-effective.}}</ref> 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.<ref name="Blankenship 2019" /><ref name="NICE2022">{{cite web | url=https://www.nice.org.uk/guidance/ta854/chapter/1-Recommendations | title=1 Recommendations &#124; Esketamine nasal spray for treatment-resistant depression &#124; Guidance &#124; NICE | date=14 December 2022 }}</ref>

Esketamine is the second drug to be approved for TRD by the FDA, following [[olanzapine/fluoxetine]] (Symbyax) in 2009.<ref name="pmid31680014" /><ref name="pmid33647726">{{cite journal | vauthors = Sanders B, Brula AQ | title = Intranasal esketamine: From origins to future implications in treatment-resistant depression | journal = J Psychiatr Res | volume = 137 | issue = | pages = 29–35 | date = May 2021 | pmid = 33647726 | doi = 10.1016/j.jpsychires.2021.02.020 | s2cid = 232088383 | url = }}</ref> Other agents, like the [[atypical antipsychotic]]s [[aripiprazole]] (Abilify) and [[quetiapine]] (Seroquel), have been approved for use in the [[adjunct therapy|adjunctive therapy]] of MDD in people with a partial response to treatment.<ref name="pmid31680014" /> In a meta-analysis conducted internally by the FDA during its evaluation of esketamine for TRD, the FDA reported a [[standardized mean difference]] (SMD) of esketamine for TRD of 0.28 using the three [[Phases of clinical research#Phase III|phase 3]] short-term efficacy trials conducted by Janssen.<ref name="pmid31680014" /> 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.<ref name="pmid31680014" /> These drugs are less expensive than esketamine and may serve as more affordable alternatives to it for depression with similar effectiveness.<ref name="pmid31680014" />

==Adverse effects==

{{Main | Ketamine#Adverse effects}}

The most common [[adverse effect]]s of esketamine for depression (≥5% incidence) include [[dissociative drug|dissociation]], [[dizziness]], [[sedation]], [[nausea]], [[vomiting]], [[vertigo]], [[hypoesthesia|numbness]], [[anxiety]], [[lethargy]], [[hypertension|increased blood pressure]], and [[drunkenness|feelings of drunkenness]].<ref name="Spravato FDA label" /> Long-term use of esketamine has been associated with [[bladder disease]].<ref name="Spravato FDA label" /><ref name="pmid33484298" />

==Pharmacology==

{{See also|Ketamine#Pharmacology}}

===Pharmacodynamics===

Esketamine is approximately twice as potent an anesthetic as racemic ketamine.<ref name="pmid9893910">{{cite journal | vauthors = Himmelseher S, Pfenninger E | title = [The clinical use of S-(+)-ketamine--a determination of its place] | language = de | journal = Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie | volume = 33 | issue = 12 | pages = 764–70 | date = December 1998 | pmid = 9893910 | doi = 10.1055/s-2007-994851 | s2cid = 259981872 }}</ref>

In mice, the rapid antidepressant effect of [[arketamine]] was greater and lasted longer than that of esketamine.<ref name="pmid24316345">{{cite journal | vauthors = Zhang JC, Li SX, Hashimoto K | title = R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine | journal = Pharmacology, Biochemistry, and Behavior | volume = 116 | pages = 137–41 | date = January 2014 | pmid = 24316345 | doi = 10.1016/j.pbb.2013.11.033 | s2cid = 140205448 }}</ref> The usefulness of arketamine over esketamine has been supported by other researchers.<ref name="pmid27354907">{{cite journal | vauthors = Muller J, Pentyala S, Dilger J, Pentyala S | title = Ketamine enantiomers in the rapid and sustained antidepressant effects | journal = Therapeutic Advances in Psychopharmacology | volume = 6 | issue = 3 | pages = 185–92 | date = June 2016 | pmid = 27354907 | pmc = 4910398 | doi = 10.1177/2045125316631267 }}</ref><ref name="pmid27646666">{{cite journal | vauthors = Hashimoto K | title = Ketamine's antidepressant action: beyond NMDA receptor inhibition | journal = Expert Opinion on Therapeutic Targets | volume = 20 | issue = 11 | pages = 1389–1392 | date = November 2016 | pmid = 27646666 | doi = 10.1080/14728222.2016.1238899 | s2cid = 1244143 }}</ref><ref name="pmid27488193">{{cite journal | vauthors = Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, Ma M, Chen QX, Hashimoto K | title = Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression | journal = Psychopharmacology | volume = 233 | issue = 19–20 | pages = 3647–57 | date = October 2016 | pmid = 27488193 | pmc = 5021744 | doi = 10.1007/s00213-016-4399-2 }}</ref>

Esketamine inhibits [[dopamine transporter]]s eight times more than arketamine.<ref name="pmid10553955">{{cite journal | vauthors = Nishimura M, Sato K | title = Ketamine stereoselectively inhibits rat dopamine transporter | journal = Neuroscience Letters | volume = 274 | issue = 2 | pages = 131–4 | date = October 1999 | pmid = 10553955 | doi = 10.1016/s0304-3940(99)00688-6 | s2cid = 10307361 }}</ref> 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.<ref name="pmid1443509">{{cite journal | vauthors = Doenicke A, Kugler J, Mayer M, Angster R, Hoffmann P | title = [Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings] | language = de | journal = Der Anaesthesist | volume = 41 | issue = 10 | pages = 610–8 | date = October 1992 | pmid = 1443509 }}</ref><ref name="pmid7840417">{{cite journal | vauthors = Pfenninger E, Baier C, Claus S, Hege G | title = [Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses] | language = de | journal = Der Anaesthesist | volume = 43 | issue = Suppl 2 | pages = S68-75 | date = November 1994 | pmid = 7840417 }}</ref> 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.<ref name="pmid9893910" /><ref name="pmid9088882" /> This is however in contradiction with arketamine being devoid of [[psychotomimetic]] side effects.<ref name="pmid26327690">{{cite journal | vauthors = Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K | title = R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects | journal = Translational Psychiatry | volume = 5 | issue = 9 | pages = e632 | date = September 2015 | pmid = 26327690 | pmc = 5068814 | doi = 10.1038/tp.2015.136 }}</ref>

Unlike arketamine, esketamine does not bind significantly to [[sigma receptor]]s. Esketamine increases [[glucose]] metabolism in the [[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.<ref name="pmid9088882">{{cite journal | vauthors = Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J | title = Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET) | journal = European Neuropsychopharmacology | volume = 7 | issue = 1 | pages = 25–38 | date = February 1997 | pmid = 9088882 | doi = 10.1016/s0924-977x(96)00042-9 | s2cid = 26861697 }}</ref> However, another study found no difference between racemic ketamine and esketamine on the patient's level of vigilance.<ref name="pmid1443509" /> Interpretation of this finding is complicated by the fact that racemic ketamine is 50% esketamine.<ref>{{cite web| vauthors = Pezeshkian M |date=15 February 2021 |title= The Nuances of Ketamine's Neurochemistry |url= https://psychedelicreview.com/the-nuances-of-ketamines-neurochemistry/|access-date=16 February 2021 |website=Psychedelic Science Review|language=en-US}}</ref>

===Pharmacokinetics===

Esketamine is [[elimination (pharmacology)|eliminated]] from the human body more quickly than arketamine (''R''(–)-ketamine) or racemic ketamine, although arketamine slows the elimination of esketamine.<ref name="pmid11719729">{{cite journal | vauthors = Ihmsen H, Geisslinger G, Schüttler J | title = Stereoselective pharmacokinetics of ketamine: R(–)-ketamine inhibits the elimination of S(+)-ketamine | journal = Clinical Pharmacology and Therapeutics | volume = 70 | issue = 5 | pages = 431–8 | date = November 2001 | pmid = 11719729 | doi = 10.1016/S0009-9236(01)06321-4 | s2cid = 20431267 }}</ref>

==History==

Esketamine was introduced for medical use as an anesthetic in [[Germany]] in 1997, and was subsequently marketed in other countries.<ref name="HimmelseherPfenninger2008" /><ref name="Drugs.com" /> In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such.<ref name="pmid28598698">{{cite journal | vauthors = Rakesh G, Pae CU, Masand PS | title = Beyond serotonin: newer antidepressants in the future | journal = Expert Review of Neurotherapeutics | volume = 17 | issue = 8 | pages = 777–790 | date = August 2017 | pmid = 28598698 | doi = 10.1080/14737175.2017.1341310 | s2cid = 205823807 }}</ref><ref name="AdisInsight" /> Esketamine received a [[breakthrough therapy|breakthrough designation]] from the {{abbrlink|FDA|Food and Drug Administration}} for [[treatment-resistant depression]] (TRD) in 2013 and [[major depressive disorder]] (MDD) with accompanying [[suicidal ideation]] in 2016.<ref name="AdisInsight" /><ref name="pmid28194724">{{cite journal | vauthors = Lener MS, Kadriu B, Zarate CA | title = Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression | journal = Drugs | volume = 77 | issue = 4 | pages = 381–401 | date = March 2017 | pmid = 28194724 | pmc = 5342919 | doi = 10.1007/s40265-017-0702-8 | url = }}</ref> In November 2017, it completed [[Phases of clinical research#Phase III|phase III]] [[clinical trial]]s for [[treatment-resistant depression]] in the United States.<ref name="pmid28598698" /><ref name="AdisInsight">{{cite web | title = Esketamine - Johnson & Johnson - AdisInsight | url = http://adisinsight.springer.com/drugs/800037644 | access-date = 7 November 2017}}</ref> [[Johnson & Johnson]] filed a [[Food and Drug Administration]] (FDA) [[New Drug Application]] (NDA) for approval on 4 September 2018;<ref name="Press Release">{{cite web | url=https://www.janssen.com/janssen-submits-esketamine-nasal-spray-new-drug-application-us-fda-treatment-resistant-depression | title=Janssen Submits Esketamine Nasal Spray New Drug Application to U.S. FDA for Treatment-Resistant Depression | publisher=Janssen Pharmaceuticals, Inc. | access-date=12 February 2019 | archive-date=14 August 2020 | archive-url=https://web.archive.org/web/20200814221643/https://www.janssen.com/janssen-submits-esketamine-nasal-spray-new-drug-application-us-fda-treatment-resistant-depression | url-status=dead }}</ref> 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.<ref name="FDA PR">{{cite press release |url= https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified |title=FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=6 March 2019}}</ref> 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.<ref>{{cite news | title=FDA Approves A Nasal Spray To Treat Patients Who Are Suicidal | newspaper=NPR.org | date=4 August 2020 | url=https://www.npr.org/2020/08/04/899060885/fda-approves-a-nasal-spray-to-treat-patients-who-are-suicidal | access-date=27 September 2020}}</ref>

Since the 1980s, closely associated [[ketamine]] has been used as a [[club drug]] also known as "Special K" for its [[Psychedelic experience|trip]]-inducing side effects.<ref>{{cite magazine| vauthors = Marsa L |date=January 2020|title=A Paradigm Shift for Depression Treatment|magazine=[[Discover (magazine)|Discover]]|publisher=[[Kalmbach Media]]}}</ref><ref>{{cite magazine| vauthors = Hoffer L |date=7 March 2019|title=The FDA Approved a Ketamine-Like Nasal Spray for Hard-to-Treat Depression|url=https://www.vice.com/en_au/article/9kp8ny/what-is-esketamine-fda-approves-nasal-spray-for-depression|magazine=Vice|access-date=11 February 2020}}</ref>

==Society and culture==

===Names===

''Esketamine'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}, while ''esketamine hydrochloride'' is its {{abbrlink|BANM|British Approved Name, Modified}}.<ref name="Drugs.com">{{cite web | url=https://www.drugs.com/international/esketamine.html | title=Esketamine |publisher = Drugs.com|date=25 October 2022|accessdate=14 September 2023 }}</ref> It is also known as ''S(+)-ketamine'', ''(''S'')-ketamine'', or ''(–)-ketamine'' (''(-)[+] ketamine''), as well as by its developmental code name ''JNJ-54135419''.<ref name="Drugs.com" /><ref name="AdisInsight" />

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 medicine|veterinary]]), among others.<ref name="Drugs.com" />

===Legal status===

Esketamine is a [[Controlled Substances Act#Schedule III controlled substances|Schedule III]] [[controlled substance]] in the United States.<ref name="Spravato FDA label" />

==References==

{{Reflist}}

{{General anesthetics}}

{{Hallucinogens}}

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