EXPERT REVIEW OF NEUROTHERAPEUTICS

https://doi.org/10.1080/14737175.2019.1640604

DRUG PROFILE

Esketamine for treatment resistant depression

Jennifer Swainsona,b, Rejish K Thomasa,c, Shaina Archera, Carson Chreneka,b, Mary-Anne MacKaya, Glen Bakera,
Serdar Dursuna,c, Larry J. Klassend, Pratap Chokkaa,c and Michael L Demasa,c
a
Department of Psychiatry, University of Alberta, Edmonton, AB, Canada; bMisericordia Community Hospital, Edmonton, AB, Canada; cGrey Nuns
Community Hospital, Edmonton, AB, Canada; dEden Mental Health Center, Winkler, MB, Canada

ABSTRACT ARTICLE HISTORY

Introduction: Treatment Resistant Depression (TRD) is a common and burdensome condition with poor Received 11 April 2019
outcomes and few treatment options. Esketamine is the S-enantiomer of ketamine and has recently Accepted 3 July 2019
been FDA approved in the United States for treating depression that has failed to respond to trials of KEYWORDS
two or more antidepressants. Esketamine; treatment
Areas covered: This review will briefly discuss current treatment options for TRD, then review esketa- resistant depression;
mine. Relevant literature was identified through online database searches, and clinical trial data were ketamine; glutamate; nmda
provided by Janssen Pharmaceuticals. Pharmacology, including kinetics and dynamics, is discussed, receptor
then clinical data regarding efficacy and safety for esketamine from Phase 2–3 trials are reviewed.
Expert opinion: In the expert opinion, the authors discuss multiple factors including patient, physician,
and social factors that will influence the use of esketamine. While the efficacy of esketamine compared
to off-label use of racemic ketamine remains unclear, both esketamine’s approval for use in TRD and
longer-term safety data may position it preferentially above racemic ketamine, although factors such as
cost and monitoring requirements may limit its use. While questions remain regarding duration and
frequency of treatment, as well as addictive potential, esketamine is a novel treatment option offering
new hope for TRD.

1. Introduction focusing on serotonin, noradrenaline and dopamine systems,

1.1. The problem of treatment-resistant depression
(TRD)
Major depressive disorder (MDD) is a common disease with a
lifetime prevalence of 9.9% [1]. It terms of total disability-adjusted
life years (DALYs), MDD represents the most disabling disease in
the Americas [2]. The Sequenced Alternatives to Relieve
Depression (STAR*D) report revealed that despite many antide-
pressant trials, a large portion of patients develop TRD and
patients who require more treatment steps to reach remission
carry a greater burden of depressive illness as well as more psy-
chiatric and medical comorbidities [3]. As each trial of a traditional
antidepressant takes several weeks to be considered adequate,
patients suffer the burden of this illness for long periods of time.
Similarly, partial response may lead to polypharmacy with adjunc-
tive medications or combination strategies, which carry an
increased risk of side effects. The generally accepted definition of
TRD in the literature is a failure to respond to 2 or more antide-
pressants. One problem with this definition, however, is that it fails
to address real-world considerations such as patients who partially
respond and those who have tried adjunctive strategies [4].
High levels of treatment resistance even with currently avail-
able treatments have led to a call for alternate antidepressant
strategies that could offer a rapid response with a better long-
term side effect profile. While traditional antidepressants have
focused on monoamine systems, with various mechanisms
recent interest has focused on targeting the glutamate system.
Glutamatergic agents have offered the promise of a rapid anti-
depressant response via a novel mechanism. One of these agents
is esketamine, which is the S-enantiomer of the parent drug
ketamine. This paper will briefly review current TRD treatment
options, then focus on esketamine in terms of its properties and
pharmacology, review evidence for use of esketamine as a treat-
ment for TRD, and discuss future directions, including the
authors’ opinion as to where this drug may fit in the field of
psychiatry moving forward.
2. Overview of current treatment options for TRD
2.1. Standard pharmacotherapy
Currently, treatment guidelines for depression guide clinicians
to either switch or combine antidepressants, or to use adjunc-
tive medications such as antipsychotics, stimulants, or mood
stabilizers when remission is not achieved with an antidepres-
sant [5,6]. As even these strategies are unsuccessful with a
subset of patients, novel treatment options are desirable.
2.2. Neurostimulation
When traditional antidepressants fail to offer relief, neurostimu-
lation offers an alternate treatment option. Electroconvulsive
therapy (ECT) has long been considered the gold standard

CONTACT Jennifer Swainson jns1@ualberta.ca 3rd floor Cabrini Center, 16940 87 Avenue, Edmonton, AB, Canada
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 J. SWAINSON ET AL.
Article highlights
● TRD carries a large burden of illness.
● Currently available treatments have limited efficacy and/or a lengthy
time to response.
● The addition of esketamine intranasally to a new antidepressant
increases rates of response and remission in TRD.
● IN esketamine will offer a new adjunctive treatment option for
patients who fail to respond to trials of two or more antidepressants,
but due to its requirement of a risk evaluation and mitigation
strategy (REMS) for distribution and use, as well as potential limita-
tions in third party coverage, access to this treatment may prove
limited for patients.
● IN esketamine appears to be safe, and well tolerated in the short
term, but longer-term studies are required, particularly to look at
urinary and cognitive side effects, and to evaluate addictive potential.
● IN esketamine may offer patients relief from an otherwise burden-
some illness.
● Other agents targeting the glutamate system may prove novel anti-
depressants/adjuncts and offer promise within the field of psychiatry.
● Given the strong data from animal studies suggesting that R-keta-
mine is a good antidepressant with a better adverse effect profile
than esketamine, clinical studies on R-ketamine as an antidepressant
are warranted.
● Future head-to-head clinical comparisons of racemic ketamine, eske-
tamine and R-ketamine will be important.
treatment for TRD, with an estimated 71% efficacy. While effi-
cacy is promising at 71% [7], use of ECT is limited by the need for
general anesthesia, hospital resources, the potential for side-
effects and stigma [7,8]. Deep Brain Stimulation (DBS) and
Vagal Nerve stimulation (VNS), are other neurostimulation tech-
niques, both of which carry limitations of requiring surgery and
increased latency of response compared to traditional antide-
pressants [9–11] Repetitive transcranial magnetic stimulation
(rTMS) is a non-invasive neuromodulation option that does not
require general anesthesia. It does, however, require a patient to
attend 20–30 treatment sessions over the course of several
weeks. The frequency of appointments for the treatment itself
may serve as a barrier to the most ill depressed patients. Clinical
use is also limited by the low availability of treatment [12–15].
2.3. Intravenous ketamine
Ketamine is considered a novel antidepressant, acting primarily
as a non-selective and non-competitive antagonist at glutamate
N-methyl-D-aspartate (NMDA) receptors by binding to the allos-
teric phencyclidine (PCP) site within the ionotropic channel pore
[16,17]. NMDA receptor antagonism is believed to be the most
important molecular target underlying the antidepressant effect
of ketamine, but this remains under investigation and other
mechanisms of action have been hypothesized [18].
In 2000, Berman et al. reported on the first randomized
controlled clinical trial of IV ketamine on nine depressed
patients after a two-week medication washout period [19].
Patients were randomized to receive two IV infusions over a
week of either a saline solution or a 0.5mg/kg ketamine HCl
solution over 40 min. IV ketamine produced a rapid and robust
antidepressant response. The effects were transient, however,
with relapse over one to two weeks. There are few multi-dose
studies with IV ketamine. The largest open-label trial treated
24 TRD patients with six IV ketamine doses in a twelve-day
period and found a response rate of 70.8% [20]. IV ketamine
has subsequently been demonstrated to have a large effect
size and response rate in even severe TRD, both in research
and clinical settings [21,22].
While response rate has been reported as 40–90% in
patients with TRD [21] and 44% in patients with ultra-resistant
depression (URD) [23], the time to depressive relapse averages
18 days after the last infusion [20]. URD has been defined as a
failure of over five antidepressants ± ECT [22]. At this time,
there are no robust data to support ongoing ketamine treat-
ment in terms of long-term safety and efficacy, or to guide
frequency and duration of treatment. One retrospective case
series of patients with URD who had exhausted other treat-
ment options suggested that ongoing maintenance treat-
ments with IV ketamine may be of benefit in sustaining
response in this population, although potential risks and ben-
efits should be considered on an individual basis [23].
2.4. Intranasal ketamine
The intranasal (IN) delivery of racemic ketamine was first studied
in an RCT of 18 patients with TRD in 2014. The treatment was
tolerable and demonstrated positive results, with a 44%
response rate [24]. Interestingly, this response rate coincides
with that seen in the use of IV ketamine with URD patients in
real-world clinical settings [22,24]. A more recent randomized
controlled trial of IN racemic ketamine was aborted early due to
extremely poor tolerability of the treatment, suggesting this
would not be a viable treatment option moving forward.
Patients in this study experienced extreme side effects that
prevented several patients from continuing to self-administer
the nasal sprays of the drug [25]. However, other clinical experi-
ence has found IN ketamine to be well tolerated, suggesting this
could be a viable treatment option for some patients [26].
2.5. Esketamine
In response to the positive results combined with the chal-
lenges of ketamine treatments for TRD, IN esketamine has
been studied with hopes of offering another treatment option.
Esketamine (the S enantiomer of ketamine) is a NMDA gluta-
mate receptor antagonist that has been demonstrated to
produce rapid antidepressant and anti-suicidal efficacy that is
sustained well beyond its half-life [27]. This review will focus
on chemical properties of esketamine, clinical data and safety
data, and explore future directions and implications for the
field of psychiatry.
3. Esketamine
3.1. Chemistry
Esketamine is the S(+) enantiomer of ketamine (Figure 1), an
arylcyclohexylamine derivative. Numerous drugs used in psychia-
try have one or more chiral centers (center of asymmetry), result-
ing in the existence of stereoisomers termed enantiomers (non-
superimposable mirror images). Though these two enantiomers
make up one molecule, each may differ significantly with regard to
pharmacokinetics and pharmacodynamics. Pharmacologic activity

Figure 1. Molecular structure of ketamine – chiral center marked with *.
may reside primarily in one enantiomer, and the two enantiomers
may influence each other’s pharmacokinetics [28,29].
3.2. Pharmacology
Esketamine is a more potent NMDA receptor antagonist than
its enantiomer R-ketamine and it has higher analgesic potency
than both R-ketamine and the racemic ketamine [29–32].
There is considerable disagreement in the literature about
the degree of adverse effects such as dissociation, psychoses,
and cognitive effects with esketamine [29–45]and readers are
referred especially to two comprehensive review articles on
this matter [30,40]; it should be remembered that some of the
studies reported were at anesthetic doses. There are now
numerous animal studies that report R-ketamine has a rapid
onset of antidepressant effects and a better side effect profile
than esketamine [35–43]. Large head-to-head clinical compar-
isons of esketamine with R-ketamine and racemic ketamine
have not yet been reported, but several researchers have
commented on the importance of doing so [e.g. 35,40,42] .
3.3. Pharmacodynamics
There are two neuronal NMDA receptor binding site hypoth-
eses of ketamine. In the disinhibition hypothesis, subanaes-
thetic doses of ketamine have a preferential affinity for NMDA
receptors on gamma-aminobutyric acid (GABA)-secreting inhi-
bitory interneurons, resulting in pyramidal cell disinhibition
and an increase in glutamate release and extracellular gluta-
mate concentration [46]. This presynaptic pyramidal neuron
excitatory effect preferentially activates α-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid (AMPA) receptors. The block-
ade of NMDA receptors and enhanced activation of AMPA
receptors then drive neurotropic effects such as the release
of brain-derived neurotrophic factor (BDNF) and activation of
downstream trophic signaling cascades. This leads to dendritic
sprouting and synaptogenesis in corticolimbic brain regions
that seems to be responsible for the antidepressant effect of
ketamine [47,48].
In the second hypothesis, ketamine directly inhibits extra-
synaptic NMDA receptors containing GluN2B subunits on pyrami-
dal neurons. Basal cortical activity activates these receptors by
extracellular ambient concentrations of glutamate. Direct inhibi-
tion by ketamine is thought to disrupt the basal activation of
pyramidal neurons, resulting in a GluN2B-dependent mechanism
involving eukaryotic elongation factor (eEF2) dephosphorylation,
an increase in BDNF translation and activation of homeostatic
mTOR synaptic plasticity, also in a protein-synthesis dependent
manner [18]. Interestingly, it has recently been reported that rapa-
mycin, an immunosuppressant drug and inhibitor of mTORC1,
EXPERT REVIEW OF NEUROTHERAPEUTICS 3
markedly increases the antidepressant response rate with keta-
mine, raising questions as to the role of TORC1 in ketamine’s
action [49].
Specific metabolites of ketamine have also been studied for
their antidepressant behavioral effects in animal models [50–53].
The active metabolite of ketamine (2R,6R)-hydroxynorketamine
(HNK) has been reported to exert antidepressant-like effects
without side-effect behaviors in mice and apparently targets
receptor binding sites other than NMDA receptors that currently
remain unknown [50]. However, more recent reports have sug-
gested that this metabolite is not necessary for the antidepres-
sant activity (reviewed in [42,51]). Further safety and efficacy
clinical trials are required to translate these findings to the clinical
condition of depression in humans.
Additional cellular targets of ketamine include binding to
opioid (mu, delta, and kappa) receptors, monoaminergic recep-
tors and transporters, and muscarinic and nicotinic cholinergic
receptors [52–54]. Interestingly, it has been suggested that
ketamine’s antidepressant effect, but not its dissociative effect,
may depend on activation of the opioid system [53]. However,
based on animal experiments, Zhang and Hashimoto [55] sug-
gested that the opioid system may not play a role in ketamine’s
antidepressant effects. Voltage-gated sodium channels and L
and T-type voltage-dependent calcium channels have also
been suggested to be involved in the therapeutic benefit of
ketamine [56]; for a review see [40].
3.4. Pharmacokinetics and metabolism
Bioavailability of ketamine, and thus esketamine, differs with the
mode of administration. While intravenous administration pro-
vides most predictable dosing with 100% bioavailability, alter-
nate routes of administration include IN, sublingual, oral,
intramuscular and rectal preparations Zhang and Hashimoto
[42] have included a table [acknowledged to be from 52] com-
paring the pharmacokinetic properties of racemic ketamine in
humans after various routes of administration; bioavailability of
IN ketamine was reported to vary from 8% to 45%. Intranasally
administered esketamine is absorbed quickly through the rich
vascular bed within the IN cavity, reaching maximum plasma
concentration (Tmax) within 10–14 min of administration [57].
Mean absolute bioavailability of IN esketamine is equal to that of
ketamine [52]. Unlike orally administered esketamine and race-
mic ketamine formulations, IN esketamine is not subject to
extensive hepatic first-pass metabolism [58,59]. Plasma protein
binding of IN esketamine is 27% [60] and it is extensively dis-
tributed throughout perfused tissues in the body. Yanagihara et
al. compared plasma concentrations of ketamine in healthy
Japanese volunteers after various routes of administration and
found that bioavailability after IN administration (45%) was
higher than after administration by oral tablet, sublingual tablet
or suppository (20%, 30%, and 30%, respectively) [57].
Esketamine undergoes rapid and extensive metabolism by
hepatic cytochrome P450 (CYP) liver enzyme CYP2B6 and
CYP3A4 systems through N-demethylation to the active metabo-
lite S-norketamine. S-norketamine is then further metabolized by
CYP-dependent pathways to metabolites such as S-5-hydroxynor-
ketamine (HNK) and S-5,6-dehydronorketamine (DHNK) which are
further metabolized by glucuronidation [61]. It has been proposed
4 J. SWAINSON ET AL.
that S-norketamine may also be a useful antidepressant with
fewer adverse effects than esketamine (see [43] for review).
Esketamine has a faster systemic clearance when it is administered
alone as opposed to a racemic mixture [62], with a rapid decline in
plasma concentration within the initial 2–4-h period following
administration.
3.5. Intranasal drug delivery system
IN esketamine HCl (SpravatoTM) is supplied in a single-use nasal
spray device containing 200 µl of vehicle solution (2 sprays),
with each device delivering a total of 28 mg (14 mg of esketa-
mine base per 100 µl of spray) [63]. The device has an indicator
system that informs the user of when the device is full (2 green
dots), one spray remaining (one green dot) and when the
device is empty (no green dots, 28 mg delivered). Esketamine
is only available through a restricted distribution system where
certified administration sites are equipped to monitor and
observe the patient for at least 2 h following dosing for safety
purposes.
Before esketamine administration, the patient is instructed
to blow their nose (only before the first device is administered)
and then assisted to recline their head to 45° (semi-reclined
position) during administration to contain the medication
within the nasal cavity. For each spray, the device tip is inserted
straight into the nostril until the nose rest touches the skin. The
patient closes the opposite nostril and is instructed to breathe
in while pushing the plunger up until it completely stops.
Sniffing gently after administration is encouraged to maintain
the medication inside the nose. It is recommended to wait 5
min between each device (28 mg) application and to keep the
patient in a semi-reclined position for improved tolerability.
4. Clinical efficacy
4.1. Intranasal esketamine studies
Janssen pharmaceuticals have now conducted a series of stu-
dies of esketamine for TRD involving patients with nonpsycho-
tic, unipolar depression with a history of failure of greater than
two previous antidepressant treatments. Studies will be sum-
marized below, but for further detail please refer to Tables 1
and 2.
4.1.1. Phase 2 studies
The SYNAPSE 1 study was a fixed dose trial giving patients 14, 28,
56, and 84 mg of IN esketamine or IN saline placebo. Treatments
were given on days 1 and 4. The study yielded statistically sig-
nificant and clinically meaningful improvement at all doses aside
from 14 mg, and there appeared to be a dose-response
Table 1. Completed PHASE II intranasal esketamine trials.
Study ID Trial Design Comparator Population
NCT01998958 RCT, 5 arm Fixed Esketamine 14mg MDD, failed ≥2 AD
SYNAPSE 1 dosing Acute phase vs. 28mg vs. (at least one in
Phase 2 56mg vs. 84mg current episode),
vs. placebo IDS-C30 ≥ 34
SUI2001 RCT, 2 Arm, fixed Dose 84 mg esketamine MDD with suicidal
vs placebo ideation
relationship. It was also found that doses of 56 mg and 84 mg
produced plasma levels equivalent to IV ketamine dosing of eske-
tamine 0.2mg/kg, which was previously shown to have antide-
pressant efficacy [64]. A second phase 2 study (SUI2001) looked at
the reduction of depressive symptoms and suicidality in acutely
depressed patients presenting to the emergency room. The pri-
mary endpoint was mean change from baseline MADRS and this
was significant at 4-h post esketamine dose, and at 2 and 81 days
post esketamine dose, but not at 25 days [65].
4.1.2. Phase 3 studies
The phase 3 efficacy studies for IN esketamine have been
named the TRANSFORM studies. TRANSFORM 1 investigated
fixed doses of 56 mg and 84 mg esketamine versus placebo
for antidepressant effect [66]. Both treatment arms involved a
56 mg initial dose on day 1, then on day 4 patients either
continued 56 mg or were increased to 84 mg, which was
continued twice weekly for a month. All three arms included
the initiation of a new oral antidepressant two weeks prior to
initiation of the study. The study’s primary endpoint of reduc-
tion in Montgomery-Asberg Depression Rating Scale (MADRS)
did not reach statistical significance (p = 0.088 for the 84 mg
arm), but results were stated to be clinically significant based
on the change seen in subjects and not compared to placebo,
which is a difficult assertion without statistical significance
[67,68]. The study also yielded response rates over 50% for
both treatments arms – which was felt to be clinically signifi-
cant but again did not separate statistically from placebo.
Authors noted three times the number of study dropouts
with the highest dose, suggesting the dose increase of 56
mg to 84 mg from Day 1 to Day 4 may have been too fast
for some patients [66]. The sample size (315) may have been
too small considering a higher than predicted placebo
response, which may have been a result of frequent therapeu-
tics contacts during the study.
TRANSFORM 2 had a similar study design, but with flexible
dosing of IN esketamine. Over the span of a month, two-thirds
of the intervention arm reached the maximum dose allowed
of 84 mg. This study did meet primary outcomes with clinical
and statistically significant results. Response rate was 69.3% in
the treatment arm vs 52.5% in the placebo group. Remission
rate was 52.0% in the esketamine group, compared to 31.0%
in the placebo group. With a smaller sample size than
TRANSFORM 1, it was thought that the change to the flexible
dosing strategy in this study may have been a factor in leading
to a statistically significant positive trial [66,69].
TRANSFORM 3 followed a similar study to TRANSFORM 2,
with flexible dosing, however the population was elderly
patients without neurocognitive issues and a higher level of
Sample
size Phase Primary outcome and results References
108 II Change from baseline MADRS at 1 week; [64]
14mg had a negative result. All other doses
yielded positive results with a dose-
response relationship
66 II Mean change from baseline MADRS at 4 hours [65]
post dose on day 1; yielded positive results.
Table 2. Phase III – completed intranasal esketamine trials.
Sample
Study ID Trial Design Comparator Population size Phase Primary outcome and results References
NCT02417064 RCT, 3 arm Fixed dosing Esketamine 56mg + AD vs. Esketamine 84mg + AD vs. MDD, failed 5≥ AD≥1 and no 346 III Change from baseline MADRS at 4 weeks; not [66]
TRANSFORM 1 Acute phase Placebo + AD ECT in current episode IDS- significant.
Phase 3 C30 ≥34 Response and remission rates better with 56
mg and 84 mg, not significant but
described as clinically meaningful
NCT02417064 RCT, 3 arm Fixed dosing Esketamine 56mg + AD vs. Esketamine 84mg + AD vs. MDD, failed 5≥ AD≥1 and no 346 III Change from baseline MADRS at 4 weeks; not [66]
TRANSFORM 1 Acute phase Placebo + AD ECT in current episode IDS- significant.
Phase 3 C30 ≥34 Response and remission rates better with 56
mg and 84 mg, not significant but
described as clinically meaningful
NCT02418585 RCT, 2 arm Flexible dosing Esketamine +AD vs. Placebo +AD MDD, failed 5≥ AD≥1 and no 227 III Change from baseline MADRS at 4 weeks: [69]
TRANSFORM 2 Acute phase ECT in current episode IDS- positive results
Phase 3 C30 ≥34
NCT02422186 RCT, 2 arm Flexible dosing Esketamine +AD vs. Placebo +AD MDD, Elderly MDD failed 8≥ 139 III Change from baseline in MADRS at 4 weeks: [70]
TRANSFORM 3 Acute phase AD≥1 and no ECT in current did not meet statistical significance in
Phase 3 episode No MCI IDS-C30 primary endpoint
≥31
NCT02493868 RCT, 4 arm Optimization phase Maintenance phase: Esketamine weekly dosing vs. MDD, in remission, failed 5≥ 718 III Time to relapse in patients with remission (up [73]
SUSTAIN 1 for all arms: AD + esketamine biweekly dosing vs. switch to placebo AD ≥1 and no ECT in to 104 weeks): remitters and responders on
Phase 3 esketamine Flexible dosing and weekly dosing vs. switch to placebo and current episode, response both weekly and biweekly maintenance
Maintenance phase biweekly dosing to esketamine MADRS ≥28 with esketamine had a lower risk of relapse
at original screening compared to placebo

EXPERT REVIEW OF NEUROTHERAPEUTICS

NCT02497287 Open label Single group, AD + Esketamine 2x/wk for a month, then once MDD, failed ≥2 AD in current 802 III Safety outcomes at the end of 56 weeks: 6.9% [74]
SUSTAIN 2 Flexible dosing in induction weekly for a month and then flexible to weekly or episode, MADRS ≥22 patients had serious TEAE. No clinical
Phase 3 Maintenance phase biweekly for 44 weeks and one month follow up meaningful changes to cognition. No cases
without esketamine of cystitis. No major withdrawal symptoms.

5
6 J. SWAINSON ET AL.

Table 3. Intranasal esketamine trials in progress.

Sample
Study ID Trial Design Comparator Population size Phase Primary outcome
NCT02782104 Open label None MDD, patients enter from 1150 III Safety outcome up to
SUSTAIN-3 Induction: 4 weeks of 2x/week other esketamine ~5 years and 3
Flexible dosing studies months.
Maintenance: 4 weeks of weekly
dosing and then dosed weekly
or biweekly based on CGI-S
weekly dosing

NCT03434041 RCT, 2-arm plus initiation of new Esketamine + AD vs. MDD, failed 5≥ AD≥1 and 234 III Change from baseline
Includes US and Chinese sites oral antidepressant Flexible Placebo + AD no ECT in current MADRS at 4 weeks
dosing Acute phase episode,
MADRS ≥28

NCT02918318 RCT, 4-arm Add on to AD after Esketamine 28mg vs. MDD, AD response in 183 II Change from baseline
Only Japanese sites response to AD documented 56mg vs. 84mg vs. current episode, MADRS MADRS at 4 weeks
Acute phase placebo ≥28 at screening.
TRD not defined
Abbreviations: AD = oral antidepressant; IDS-C30 = Inventory of Depressive Symptoms-Clinician rated, 30-item total score; MADRS = Montgomery–Åsberg
Depression Rating Scale total score; RCT = randomized controlled trial; CGI-S = Clinical Global Impression-Severity scale total score; ECT = electroconvulsive
therapy; MCI = mild cognitive impairment; TEAE = treatment emergent adverse event.
Note: All studies excluded psychosis. AD used in trials were new ADs started 2 weeks prior to the trial.

treatment resistance was allowed. This study included patients
who had failed up to eight antidepressant trials compared to
the maximum of five previous antidepressant trials allowed in
TRANSFORM 1 and 2. This trial did not meet the primary
endpoint of change from baseline MADRS at 4 weeks statisti-
cally by a narrow margin. Secondary endpoints of response
and remission rates were 27.0% versus 13.3% and 17.5% ver-
sus 6.7%, respectively, for intervention versus control arms,
demonstrating clinical significance [70].
It is notable that patients in the TRANSFORM 1 and 3
studies had an average longer period of illness in the current
depressive episode, compared to TRANSFORM 2. This may be
important because only TRANSFORM 2 met its primary end-
point, and it has been established that a longer duration of
illness is a poor prognostic factor in the management of
unipolar MDD [71,72]. TRANSFORM 1 and 3 may have been
treating a more chronically ill population.
Maintenance treatment studies for IN esketamine have
been completed and named SUSTAIN 1 and 2. SUSTAIN 1
was a large study (n = 708) that followed patients that had
either responded or remitted with esketamine through 16
weeks of treatment. Total duration of treatment and examina-
tion went up to 88 weeks. In this study, both weekly and every
second week maintenance dosing with esketamine had a
lower risk of relapse compared to placebos administered
weekly or every second week. Determination of weekly vs
every second-week maintenance was made on the basis of
‘severity of depressive symptoms’, suggesting more ill patients
received weekly maintenance. As this was not randomized, the
efficacy of weekly vs every second-week maintenance cannot
be compared in this study [73].
SUSTAIN 2 was an open-label design following patients on
maintenance therapy that responded to IN esketamine for up
to one year. In this study, 802 patients were followed who
were responders to an initial trial of a new oral antidepressant
two weeks prior to the study initiation and then IN esketamine
flexibly dosed, twice a week for a month. These patients were
then treated with weekly IN esketamine for a month and then
flexibly dosed to a frequency of weekly or biweekly for 44
weeks, followed by a one month follow up period. The primary
outcomes were safety outcomes which will be commented on
later in this review. In terms of efficacy, 76.5% of patients
remained responders at the end of study. Remission rates
increased from 47.2% after the 1-month induction phase to
58.2% by the end of this trial [74]. This is an interesting finding
in that it suggests the possibility that some individuals may
benefit further with longer-term, cumulative treatment.
Table 3 summarizes studies ongoing. SUSTAIN 3 is a 5
year study to evaluate long term safety of esketamine.
Two other efficacy studies are currently in the recruitment
phase. NCT02918318 involves Japanese sites and is pro-
posed to be a phase 2 trial with 183 patients with the
primary outcome of change in baseline MADRS at 4
weeks. This will build on SYNAPSE 1, which was a phase
2 study with a primary outcome with an endpoint of 1
week. It is also unique in that the inclusion criteria limit
the sample to patients that have already had a response
to an oral antidepressant in the acute phase and IN eske-
tamine will be added on for further efficacy. They will be
studying fixed dosing of 28 mg versus 56 mg versus 84
mg versus saline placebo in a 4-arm RCT design.
NCT03434041 is a phase 3 trial with sites in the United
States and China, with a similar design, sample size and
primary outcome measure to TRANSFORM 2.
There currently are no head-to-head comparison stu-
dies of IN racemic ketamine to IN esketamine. To date, a
protocol for one small non-inferiority study [75] compar-
ing single infusions of IV ketamine and IV esketamine have
been published but results are not yet reported in the
peer-reviewed literature. Large comparison studies of mul-
tiple dosing of IV racemic ketamine versus IV esketamine
would be of future interest.

5. Safety and tolerability
5.1. Common adverse effects
Seven studies have reported on the safety profile of IN eske-
tamine ([64,66,69,70,73,74]) . Common adverse effects have
been summarized in Table 4. Across studies, these adverse
effects tend to be of mild to moderate severity, and typically
occur during and immediately after treatment, with resolution
also occurring the same day. The longest study of side effects
and tolerability (SUSTAIN 2) followed 802 patients receiving
esketamine treatment for one year [74] and noted that nearly
all patients (90.1%) did experience at least one adverse effect
during the course of the study.
These reported acute side effects are similar to those
reported for racemic ketamine, but is it is difficult to compare
the frequency of occurrence as reports of ketamine side
effects in the literature tend not to be systematically collected
[75]. A recent systematic review [76] looked at the side effects
of ketamine treatments for depression and, similar to esketa-
mine, found that transient acute side effects were common.
The most common ketamine side effects included headache,
dizziness, dissociation, blurred vision, transient hypertension,
and anxiety (the most common psychiatric side effect). The
authors point out that there is currently insufficient data in the
literature to comment on side effects with repeated dosing or
with long-term treatment with ketamine.
5.2. Serious adverse events
Across all esketamine studies, serious treatment emergent
adverse effects occurred in less than 5% of the population
receiving IN esketamine [64,66,69,70,73,74]. Adverse events
reported in patients during treatment with esketamine
included hip fracture, significant blood pressure elevation,
ventricular extrasystoles, hypothermia, lacunar stroke, partial
seizure, syncope, anxiety, agitation, aggression, sedation, dis-
orientation, and suicidal ideation. Although these adverse
events were reported, it was not clear that any of the adverse
events were directly related to receiving the drug. Throughout
one year of maintenance esketamine treatment [74], five
patients (0.6% of sample) experienced serious adverse effects
that were deemed related to IN esketamine. These included
anxiety, delusional content, delirium, suicidal ideation, and a
suicide attempt.
Table 4. Common side effects of intranasal esketamine treatments from seven
studies.
Adverse Effect Frequency
Dizziness 20.4–39.0%
Nausea 16.0–37.1%
Dissociation 11.1–31.4%
Headache 12.5–31.4%
Dysgeusia 5.6–31.4%
Vertigo 11.1–26.1%
Somnolence 11.4–21.1%
Paresthesia 5.6–17.1%
Vomiting 6.6–20.0%
Oral hypoesthesia 6.9–13.2%
Increased blood pressure 6.6–12.5%
Anxiety 2.8–17.1%
Hypoesthesia 5.6–13.3%
EXPERT REVIEW OF NEUROTHERAPEUTICS 7
A total of six deaths have been reported as of January 2019
in Janssen’s esketamine clinical program, all of which have
occurred in patients receiving esketamine. Three of these
were due to suicide, and they occurred 4, 12, and 20 days
after the last dose of esketamine. Patients who died after 4
and 12 days had been improving based on their MADRS
scores, and the patient who died after 20 days was experien-
cing a worsening of symptoms. Due to lack of consistency, the
FDA report on esketamine indicates it is difficult to attribute
suicides to the drug, however a recent commentary on eske-
tamine [77] aptly points out that high relapse rates have been
demonstrated on discontinuation of esketamine, and cautions
that protracted withdrawal from the drug, rather than expo-
sure to the drug itself, may have played a role. Other deaths
included a motorcycle accident 26 h after receiving esketa-
mine, and the other two were in elderly patients with meta-
bolic comorbidities, one experiencing sudden death and the
other a myocardial infarction. These were not felt to be related
to esketamine as all vitals had been stable during treatments.
5.3. Specific side effects of concern
5.3.1. Hypertension
Transient hypertension has been noted frequently, with peak
blood pressure elevation at approximately 40 min following
administration, with blood pressure typically returning to
baseline within 2 h. Mean systolic increase was 7–9 mm Hg
and diastolic was 4–6 mm Hg. However, a subset of patients
(8–17%) may have a more clinically significant blood pressure
increase, in the realm of 40 mm Hg systolic and/or 25 mm Hg
diastolic [63]
5.3.2. Dissociation
As noted in Table 4, rates of dissociation with esketamine
treatment varied from 11.1% to 31.4% across studies, and
attenuated over time with repeated treatments [74].
Comparatively, 24% of patients reported feeling ‘strange or
unreal’ within 120 min of racemic IV ketamine infusion [78]. A
previous study on IN ketamine found mild increases in disso-
ciation and psychotic symptoms, but did not comment on the
frequency of occurrence [24], and a subsequent IN ketamine
trial was aborted early due to the severity of dissociative side
effects [25]. Authors attributed this difference to variations in
nasal vasculature and anatomy, differences in the device, for-
mulation, and individual variability. As such, it is difficult to
determine whether intranasally administered esketamine is
better tolerated than IN ketamine.
5.3.3. Sedation
Sedation has been noted as a common side effect. In the
general adult population, it tends to peak at 30-min post
dose and is resolved by 60 min. Latest time to resolve was
noted to be 210 min. Interestingly, sedation in the geriatric
population was less severe and resolved sooner. Two subjects
in all studies experienced loss of consciousness – in one sub-
ject this occurred once and they were transferred to the
emergency room. The other subject experienced this on five
different visits, lasting 15–35 min. The FDA report noted that
8 J. SWAINSON ET AL.
‘experience of previous visits cannot accurately predict future
onset, peak, resolution time, or severity, and this has implica-
tions for monitoring and labeling’ [79].
5.3.4. Driving
Given the nature of the common adverse effects, including
transient dissociative symptoms, dizziness, vertigo, and somno-
lence, the impact of esketamine on the ability to safely operate a
motor vehicle is an important clinical question. One study found
that individuals who had received 84 mg of IN esketamine were
not impaired on a driving safety test administered 8 h later [80].
The product monograph for esketamine advises patients not to
drive until the day following esketamine treatment, after a restful
night’s sleep. Given the short half-life of esketamine, further
studies to elucidate the time window to allow safe driving per-
formance would be helpful.
5.3.5. Urinary symptoms
A ketamine-induced uropathy or ulcerative cystitis has been
previously reported in chronic ketamine abusers [81–84].
However, there is no clear evidence that an equivalent risk is
present in patients utilizing therapeutic doses of either race-
mic ketamine or esketamine. In a long-term study, three cases
of nephritis occurred during one year of esketamine treat-
ment, but all cases resolved without clinical sequelae and
whilst continuing esketamine treatment. There were no
reported cases of interstitial or ulcerative cystitis [74]. Further
research on the long term risks of esketamine on the lower
urinary tract will be of importance.
5.3.6. Cognition
In one study specifically evaluating cognitive function, healthy
participants received esketamine, and cognition was evaluated
using Cogstate®, a computerized test battery evaluating multi-
ple domains including attention, visual and working memory,
and executive functioning. This study demonstrated acute
transient impairment in cognition. Significant impairment
was noted 40 min after administration, but completely dissi-
pated by 2-h posttreatment [85]. Esketamine studies that have
evaluated cognitive measures as part of safety and tolerability
have found that cognition (including measures of spatial
memory, executive function, and processing speed) has either
remained stable or improved after treatment for up to 1 year
[76,77]. However, cognition remains an area worth further
study and monitoring, as cognitive impairment has been
noted in chronic ketamine abusers [86]. When used therapeu-
tically to treat depression, it has been suggested ketamine
actually improves cognition, likely owing to the improvement
of depressive symptoms with treatment [87]. The long-term
cognitive impacts of racemic ketamine, as well as esketamine,
remain unclear.
5.3.7. Abuse/addictive potential
Serious concerns relate to the addictive potential of esketa-
mine. Ketamine itself is a well-known substance of abuse,
though the recent FDA report on esketamine cites ketamine
abuse as being relatively uncommon with a lifetime preva-
lence of 1.2% [79]. To date, there are no published data on the
risk of abuse or misuse for either racemic ketamine or
esketamine, when used therapeutically in the treatment of
depression. Unpublished data from Janssen found that poly-
drug users equally rated ‘Drug Liking’ when comparing experi-
ences with therapeutic doses of IV ketamine and IN
esketamine, both of which were higher than placebo [88]. It
has been suggested that there is a theoretical risk for patients
to develop tolerance, dependence, craving, and withdrawal
related to esketamine usage [89]. In one review of several
substances of abuse, ketamine was identified as having a
relatively high ‘harm score’, similar to substances such as
alcohol and benzodiazepines [90]. Although it is known that
naltrexone blocks the antidepressant effects of ketamine, it is
unclear whether this is due to binding to mu opioid receptors
or ketamine-mediated release of endogenous opioids [54],
which may be important in considering addictive potential.
Certainly, as esketamine is used in real-world settings, close
monitoring and evaluation of its addictive potential, and the
possibility of harm will be crucial to monitor.
5.3.8. Special populations
Safety and efficacy of IN esketamine have not been studied in
special populations such as in pregnancy, breastfeeding, or for
use in patients under the age of 18.
6. Regulatory affairs
IN esketamine HCl, marketed by Janssen Pharmaceuticals as
Spravato, was approved for use in conjunction with an oral
antidepressant on 5 March 2019 by FDA of the United States
of America for the treatment of depression resistant to prior
antidepressant medication treatments. The application for
approval was given Fast Track and Breakthrough Therapy
designations. Ketamine, including its enantiomer esketamine,
does not have an approved indication for Major Depressive
Disorder or Suicidality at present in other countries. However,
in Canada, esketamine is being reviewed under the Priority
Review Policy of Health Canada, which fast tracks the review of
the compound by the agency. Janssen also has a current
Marketing Authorization Application for the European Union
for esketamine.
7. Conclusion
There is a need in psychiatry for novel treatment options for
TRD. Some of the current options include neurostimulation
and adjunct medications, both of which can carry burdensome
adverse effects. New antidepressants targeting the glutamate
system offer promise as rapid antidepressants with a novel
mechanism. The entrance of esketamine into the field of
psychiatry comes on the heels of early excitement from initial
studies on racemic ketamine, which have been short term in
nature. It has been clear that ketamine has antidepressant
properties, but long-term safety and dosing remain unclear.
Esketamine data have filled gaps missing in the ketamine
literature. To date, 3/5 studies on IN esketamine met all end-
points with positive results, while the other two failed to meet
endpoint but showed a favorable trend towards benefit. The
failure to meet endpoint in these studies may have been a
reflection of study design (fixed vs flexible dosing), power, and

high placebo response of an IN treatment. Similarly, it should
be noted that esketamine studies have generally been con-
ducted on more severely depressed patients than would be
typical in phase 3 studies for FDA approved antidepressants
and adjunctive treatment medications for depression [79]
Tolerability and safety data appear promising, with data now
extending up to a year, which are not currently available for
ketamine itself. To date, data regarding potential concerns
with urinary and cognitive toxicity are reassuring. As esketa-
mine is used in the real world, more data will be required
regarding addictive potential and real-world efficacy, as well
as the optimal duration of treatment.
8. Expert opinion
Esketamine provides an exciting and novel treatment option for
TRD. Given that trials were conducted in severely depressed
patients, esketamine may be an alternative or even provide
greater efficacy than currently available adjunctive medications.
The transient nature of esketamine side effects may confer an
advantage over the metabolic and extrapyramidal side effects
that may be associated with atypical antipsychotics commonly
used as treatment adjuncts. This commentary section will
address esketamine, its use, and role from the perspective of
the patient, practitioner, society and long -term implications.
8.1. Patient considerations
Esketamine provides TRD patients an option that has been
FDA approved and eliminates the uncertainty associated with
racemic ketamine used in some clinical settings. Although
access and cost may play a role for some patients, the efficacy
data from esketamine trials provide hope for the difficult to
treat patients with depression. Stigma associated with neuro-
stimulation treatments may lead to patient preference for
esketamine as an alternative.
This treatment is unique in that it causes varying acute psy-
chological side effects, so patients must be given proper psy-
choeducation prior to treatment and supportive care during
treatment. While ketamine has been used to treat depression
in a number of settings, by a number of medical specialties, our
clinical experience is that patients both require and benefit from
mental health support during ketamine treatments, and the
same standard of care would be advised for esketamine treat-
ments, so as to minimize any risk of psychological harm.
Esketamine should not be positioned as a panacea for
resistant depression, but as potentially a very good option
for short-term treatment with favorable outcomes for up to
one year. Short-term side effects tend to be of a transient
nature, likely improving acceptability of side effect burden
for patients compared to other adjunctive medication options.
Clinically the adverse effects of esketamine should be weighed
against alleviating of the burden of depression. While a pro-
mising agent, esketamine dosing and side effects in the long
term remain unknown. Beyond one year, ongoing use of
esketamine should be considered on a case by case basis,
considering potential risks and benefits of both continuing
and stopping the treatment. This evaluation should take into
EXPERT REVIEW OF NEUROTHERAPEUTICS 9
account factors such as individual response, preference, toler-
ability, addictive potential, and other treatment options.
8.2. Practitioner considerations
The role of glutamatergic agents to treat depression has heralded
very exciting treatment options for clinicians, but there exists
controversy, even among psychiatrists regarding the use of keta-
mine in depression. The 2017 UK consensus statement on keta-
mine for depression suggests that it be used only as part of
research studies, but that use outside formal studies should be
supported by a second psychiatrist opinion, include informed
consent, and incorporate a collection of data from a mood mon-
itoring program [91]. The American Psychiatric Association’s posi-
tion statement on the use of ketamine points to lack of long-term
data and provides many judicious suggestions for patient mon-
itoring [92]. It would be wise for any clinician prescribing esketa-
mine to also review and implement the suggestions detailed there
[92]. The Canadian Mood and Anxiety Disorder Network
(CANMAT) has placed IV ketamine as a third line adjunctive treat-
ment for depression in its 2018 Bipolar Disorder Treatment guide-
lines [93], but the 2016 Depression treatment guidelines still list
ketamine as an ‘experimental’ treatment [6], which has limited its
use. Regulatory approval of esketamine for TRD with failure of two
or more antidepressants will support clinicians in offering a rapid-
acting antidepressant to less treatment-resistant populations, and
may decrease the overall burden of illness if a glutamatergic agent
is used earlier in the course of illness. Efficacy and tolerability of
esketamine compared to racemic ketamine remains uncertain. To
date, there is discrepancy across the literature as to which enan-
tiomer (R or S) offers the best antidepressant effect and most
tolerability.
There has been a spectrum of overpromising efficacy and at
times underdelivering in some of the clinical trials. Nevertheless,
a body of literature now exists to support ongoing use of eske-
tamine, whereas ketamine studies have tended to focus only on
single infusions or a series of 6–8 treatments. ‘Maintenance’
treatment data for racemic ketamine is limited to trials lasting
only several weeks, or retrospective case reports. The esketamine
trials met primary endpoint objectives in three trials, but failed to
achieve primary endpoint in two others. There may be several
reasons for this. First, in the TRANSFORM 1 acute dose trial, the 84
mg group was analyzed before the 56 mg dose, and it failed to
separate from placebo. As such, the 56 mg dose could not
officially be analyzed, but did separate from placebo in ‘explora-
tory analysis’. It was noted that the patients receiving 84 mg were
likely more ill than the 56 mg group. Similarly, the TRANSFORM 3
study looking at the age 65 plus population also failed to meet its
primary endpoint. Nevertheless, it should be noted that the
enrolled patients for these studies were severely ill and it is
encouraging that there is positive short term and 1-year data
with esketamine for this population.
At this time, future comparative trials with other adjunct treat-
ments for depression such as atypical antipsychotics are needed.
Finally, comparative trials with different formulations, and delivery
systems with esketamine and racemic ketamine could provide
some clarity in achieving much more precision in patient-focused
treatments. Further, Phase 4 trials should be conducted to gather
longer-term data to address safety, efficacy, tolerability, and
10 J. SWAINSON ET AL.
addictive potential. Physicians prescribing esketamine must dili-
gently monitor patients for adverse effects and patient response to
facilitate weighing the risk/benefit of treatment for each patient.
8.3. Societal considerations
Although the evidence for the role of ketamine for treating
depression is growing, there is still considerable misunderstanding
from a societal perspective on its therapeutic role. Direction of
acceptability seems likely to be dictated by societal cues. There has
been extensive media and social media coverage of ketamine/
esketamine due to their novel antidepressant nature offering
rapid relief of suffering, combined with controversy as substances
of potential abuse. The FDA has taken a cautionary approach and
has made esketamine available through its restricted distribution
system, Risk Evaluation Management System, ‘REMS’. The FDA has
also stated that esketamine ‘must be administered in a certified
medical office where the health-care provider can monitor the
patient’. This restricted distribution, while put in place as a societal
protection, may limit practitioners from choosing this as a ther-
apeutic option due to practical obstacles inability to administer
treatments in the health-care setting. The REMS for esketamine
may also create a new standard of care, frowning heavily on
prescription of take-home ketamine in any form. While concerns
for diversion and abuse are not to be taken lightly, the addictive
potential of ketamine or esketamine could be considered similar
to other commonly used psychiatric medications such as stimu-
lants or benzodiazepines.
8.4. Long-term view
The FDA approval of esketamine brings forth a novel treat-
ment option for treatment-resistant depression. Due to multi-
ple influences outlined previously involving patient, physician
and societal factors, there will be many issues at play in
determining where IN esketamine itself will eventually settle
within the psychiatric practice. Various formulations of racemic
ketamine have been used off label for some time to treat
depression, but this treatment has been limited in availability
within public health-care systems, or limited to those who can
cover the cost in private settings. With esketamine approved
for the TRD indication, it seems likely that more third party
payers may cover the cost, though it will prove more costly
than ketamine itself.
Interestingly, while it is well known that racemic ketamine has
antidepressant properties, IN esketamine has been studied by
Janssen only as an adjunct, accompanied by a change in anti-
depressant. Antidepressants themselves carry long-term side
effects including weight gain and sexual dysfunction. As esketa-
mine begins to be prescribed by psychiatrists, it seems likely that
clinical experience may be gained using esketamine as mono-
therapy, particularly in the subset of patients who have tried
nearly every class of antidepressant with no or limited benefit.
Further research including Phase IV clinical trials should be com-
pleted for determination of long-term effects of IN esketamine,
which can lead future therapeutic directions.
The first approval of a rapid-acting antidepressant is an
exciting development and is likely to be followed by the
development of other glutamatergic agents. Due to limitations
with IN delivery, it seems likely that there will be a push for an
oral agent that acts on the glutamate system. Future studies
may bring more understanding as to mechanisms of action of
ketamine and esketamine and can guide targeted drug
development.
Funding
This paper was not funded.
Declaration of interest
J Swainson has received speaking honoraria from Otsuka and Lundbeck
and has acted on advisory boards for Otsuka, Lundbeck, and Janssen. R
Thomas, S Dursun and M Demas have acted on advisory boards for
Janssen. C Chrenek has received speaking honoraria from Otsuka and
has acted on advisory boards for Otsuka, Lundbeck, and Janssen. LJ
Klassen has received research grants and speaker’s honoraria from and
has acted on an advisory board for Shire. They have also received speak-
er’s honoraria from and acted on advisory boards for Janssen, Lundbeck,
Otsuka, Pfizer, Purdue, and Sunovion. They have also acted on an advisory
board for Allergan and received speaker’s honoraria from CPA and The
Canadian ADHD Resource Alliance. P Chokka received speaker’s honoraria
and acted on advisory boards for Allergan, Lundbeck, Janssen, Purdue,
Sunovion, and Shire. They have also received research grants from
Lundbeck, Janssen, and Shire. The authors have no other relevant affilia-
tions or financial involvement with any organization or entity with a
financial interest in or conflict with the subject matter or materials dis-
cussed in this manuscript apart from those disclosed.
Reviewer disclosures
A peer reviewer on this manuscript in an inventor holding a patent of R-
ketamine in the treatment of depression. Peer reviewers on this manu-
script have no other relevant financial relationships or otherwise to
disclose.
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