Esketamine, sold under the brand namesSpravato (fordepression) andKetanest (foranesthesia) among others,[10][12] is theS(+)enantiomer ofketamine.[5][13] It is adissociative hallucinogen drug used as ageneral anesthetic and as anantidepressant for treatment ofdepression. Esketamine is theactive enantiomer of ketamine in terms ofNMDA receptor antagonism and is morepotent thanracemic ketamine.[14]
It is specifically used as a therapy fortreatment-resistant depression (TRD) and formajor depressive disorder (MDD) with co-occurringsuicidal ideation orbehavior.[10][15] Itsefficacy for depression is modest and similar to that of other antidepressants.[16][10] Esketamine is not used byinfusion into a vein for depression as it is onlyFDA-approved in the form of anasal spray under direct medical supervision for this indication (the parent compound ketamine is most often administered intravenously).[10][5]
Adverse effects of esketamine includedissociation,dizziness,sedation,nausea,vomiting,vertigo,numbness,anxiety,lethargy,increased blood pressure, and feelings ofdrunkenness.[10] Less often, esketamine can causebladder problems.[10][17] Esketamine acts primarily as aNMDA receptor antagonist, but also has other actions.[5][13]
In the form ofracemic ketamine, esketamine was firstsynthesized in 1962 and introduced for medical use as an anesthetic in 1970.[18]Enantiopure esketamine was introduced for medical use as an anesthetic in 1997 and as an antidepressant in 2019.[5][10][19] It is used as an anesthetic in the European Union and as an antidepressant in the United States and Canada.[19][20][21] Due tomisuse liability as a dissociative hallucinogen, esketamine is acontrolled substance.[18][10]
Esketamine is used for similar indications as ketamine.[5] Such uses include induction of anesthesia in high-risk patients such as those withcirculatory shock, severebronchospasm, or as a supplement toregional anesthesia with incompletenerve blocks.[5]
In the US, esketamine (brand name Spravato) is a nasal sprayindicated, as monotherapy, or in conjunction with an oralantidepressant as a therapy fortreatment-resistant depression (TRD) as well asmajor depressive disorder (MDD) associated withsuicidal ideation orbehavior in adults.[10] In the clinical trials that led to approval of esketamine, treatment-resistant depression was defined as major depressive disorder with inadequate response to at least two different conventional antidepressants.[10] The nasal spray formulation of esketamine used for depression delivers two sprays containing a total of 28 mg esketamine and doses of 56 mg (2 devices) to 84 mg (3 devices) are used.[10] Due to concerns aboutsedation,dissociation, andmisuse, esketamine is available for treatment of depression only from certified providers through a restricted program under aRisk Evaluation and Mitigation Strategy (REMS) called Spravato REMS.[10]
Five clinical studies of esketamine for treatment-resistant depression (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 treatment-resistant depression was sought byJanssen 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 astatistically significant antidepressant effect of esketamine relative toplacebo.[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 theMontgomery–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 treatment-resistant depression 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]
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.[22][24] A difference of at least 6.5 points was originally suggested by the trial investigators to be a reasonable threshold for clinical significance.[24][22] 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.[27] 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 functionalunblinding caused by thepsychoactive effects of esketamine.[22][15][28] In other words, it is argued that the study was not truly adouble-blindcontrolled trial.[22][15]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%.[22][24][10] Deblinding andexpectancyconfounds are problems with studies ofhallucinogens 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]
Esketamine was approved for the treatment of major depressive disorder with co-occurring suicidal ideation or behavior on the basis of two short-term (4-week)phase 3 trials (ASPIRE-1 and -2) of esketamine nasal spray added to a conventional antidepressant.[10][15][32][31] The primary efficacy measure was reduction in MADRS total score after 24 hours following the first dose of esketamine.[10] In both trials, MADRS scores were significantly reduced with esketamine relative to placebo at 24 hours.[10] The mean MADRS scores at baseline were 39.4 to 41.3 in all groups and the MADRS reductions at 24 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.[10] The secondary efficacy measure in the trials was change inClinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) 24 hours after the first dose of esketamine.[10] The CGI-SS-r is a single-item scale with scores ranging from 0 to 6.[15] Esketamine was not significantly effective in reducing suicidality relative to placebo on this measure either at 24 hours or after 25 days.[10][31][15] At 24 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.[15] Hence, while efficacious in reducing depressive symptoms in people with depression and suicidality,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".[33][34][35] According to a 2018 review, ketamine showed more than double the antidepressanteffect size over placebo of conventional antidepressants in the treatment of depression based on the preliminary evidence available at the time (Cohen'sd = 1.3–1.7 for ketamine, Cohen'sd = 0.8 formidazolam (active placebo), and Cohen'sd = 0.53–0.81 for conventional antidepressants).[33] However, the efficacy of ketamine/esketamine for depression declined dramatically as studies became larger and more methodologically rigorous.[16][36] The effectiveness of esketamine for the indication of treatment-resistant depression is described as "modest" and is similar in magnitude to that of other antidepressants for treatment of major depressive disorder.[16] The comparative effectiveness of ketamine and esketamine in the treatment of depression has not been adequately characterized.[15] A January 2021meta-analysis reported that ketamine was similarly effective to esketamine in terms of antidepressant effect size (SMDTooltip standardized mean difference for depression score of –1.1 vs. –1.2) but more effective than esketamine in terms of response and remission rates (RRTooltip risk ratio = 3.01 vs. RR = 1.38 for response and RR = 3.70 vs. RR = 1.47 for remission).[37][15][38] A September 2021Cochrane review found that ketamine had an effect size (SMD) for depression at 24 hours of –0.87, with very low certainty, and that esketamine had an effect size (SMD) at 24 hours of –0.31, based on moderate-certainty evidence.[39] However, these meta-analyses have involved largely non-directly comparative studies with dissimilar research designs and patient populations.[37][15][38] Only a single clinical trial has directly compared ketamine and esketamine for depression as of May 2021.[40][15][41] This study reported similar antidepressant efficacy as well astolerability andpsychotomimetic effects between the two agents.[40][15][41] However, the study was small andunderpowered, and more research is still needed to better-characterize the comparative antidepressant effects of ketamine and esketamine.[40][15][41][37][38] Preliminary research suggests thatarketamine, theR(−)enantiomer of ketamine, may also have its own independent antidepressant effects and may contribute to the antidepressant efficacy ofracemic 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 treatment-resistant depression, 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 treatment-resistant depression 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 theNational Health Service (NHS) ofGreat 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 ofUS$32,400 per year when it launched in the United States in March 2019.[48] TheInstitute for Clinical and Economic Review (ICER), which evaluates cost effectiveness of drugs analogously to theNational 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 treatment-resistant depression by the FDA, followingolanzapine/fluoxetine (Symbyax) in 2009.[25][50] Other agents, like theatypical antipsychoticsaripiprazole (Abilify) andquetiapine (Seroquel), have been approved for use in theadjunctive therapy of major depressive disorder in people with a partial response to treatment.[25] In a meta-analysis conducted internally by the FDA during its evaluation of esketamine for treatment-resistant depression, the FDA reported astandardized mean difference (SMD) of esketamine for treatment-resistant depression of 0.28 using the threephase III short-term efficacy trials conducted by Janssen.[25] This was similar to an SMD of 0.26 for olanzapine/fluoxetine for treatment-resistant depression and lower than SMDs of 0.35 for aripiprazole and 0.40 for quetiapine as adjuncts for major depressive disorder.[25] These drugs are less expensive than esketamine and may serve as more affordable alternatives to it for depression with similar effectiveness.[25]
The most commonadverse effects of esketamine for depression (≥5% incidence) includedissociation,dizziness,sedation,nausea,vomiting,vertigo,numbness,anxiety,lethargy,increased blood pressure, and feelings ofdrunkenness.[10] Long-term abuse ofketamine has been associated withbladder disease.[10][17]
Esketamine is approximately twice as potent an anesthetic as racemic ketamine.[51]
In mice, the rapid antidepressant effect ofarketamine 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 inhibitsdopamine transporters eight times more than arketamine.[56] 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.[57][58] 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.[51][59] This is however in contradiction with arketamine being devoid ofpsychotomimetic side effects.[60]
Unlike arketamine, esketamine does not bind significantly tosigma receptors. Esketamine increasesglucose metabolism in thefrontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative orhallucinogenic 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]
Esketamine iseliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows the elimination of esketamine.[62] Thehalf-life of esketamine was found to be approximately 5 hours.[63] When administered intranasally, esketamine’sbioavailability is approximately 30–50%.[63]
Esketamine was introduced for medical use as an anesthetic inGermany 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.[64][65] Esketamine received abreakthrough designation from theFDATooltip Food and Drug Administration fortreatment-resistant depression (TRD) in 2013 andmajor depressive disorder (MDD) with accompanyingsuicidal ideation in 2016.[65][66] In November 2017, it completedphase IIIclinical trials fortreatment-resistant depression in the United States.[64][65]Johnson & Johnson filed aFood and Drug Administration (FDA)New Drug Application (NDA) for approval on 4 September 2018;[67] 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.[68]
Since the 1980s, closely associatedketamine has been used as aclub drug also known as "Special K" for itstrip-inducing side effects.[69][70]
Esketamine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name, whileesketamine hydrochloride is itsBANMTooltip British Approved Name, Modified.[20] It is also known asS(+)-ketamine,(S)-ketamine, or(–)-ketamine ((-)[+] ketamine), as well as by its developmental code nameJNJ-54135419.[20][65]
Esketamine is sold under the brand name Spravato for use as anantidepressant and the brand names Eskesia, Ketanest, Ketanest S, Ketanest-S, Keta-S for use as ananesthetic (veterinary), among others.[20]
Esketamine is aSchedule IIIcontrolled substance in the United States.[10]
Esketamine is a controlled drug In TheUnited Arab Emirates due to its potential for abuse, its use is only under strict medical supervision which is only available on government hospitals in the country, and its use only approved fortreatment-resistant depression registered under the trademark Spravato.[71]
A legitimate criticism, as it relates to interpreting the effect sizes reported with single or repeat-dose ketamine in treatment-resistant depression, 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.
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.
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].
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.
Ketamine has been hailed as the most important advance in the treatment of depression of the past 50 years.1
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.
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].
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 byJanssen Pharmaceutica, for the treatment of treatment-resistant depression.
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.
