Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: https://www.tandfonline.com/loi/iern20

Esketamine for treatment resistant depression

Jennifer Swainson, Rejish K Thomas, Shaina Archer, Carson Chrenek, Glen

Baker, Serdar Dursun, Mary-Anne MacKay, Larry J. Klassen, Pratap Chokka &
Michael L Demas

To cite this article: Jennifer Swainson, Rejish K Thomas, Shaina Archer, Carson Chrenek, Glen
Baker, Serdar Dursun, Mary-Anne MacKay, Larry J. Klassen, Pratap Chokka & Michael L Demas
(2019): Esketamine for treatment resistant depression, Expert Review of Neurotherapeutics, DOI:
10.1080/14737175.2019.1640604

To link to this article: https://doi.org/10.1080/14737175.2019.1640604

Accepted author version posted online: 08

Jul 2019.

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Publisher: Taylor & Francis

Journal: Expert Review of Neurotherapeutics

DOI: 10.1080/14737175.2019.1640604
Esketamine for treatment resistant depression
Jennifer Swainson1*, Rejish K Thomas1, Shaina Archer1, Carson Chrenek1, Glen

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Baker1, Serdar Dursun1, Mary-Anne MacKay1, Larry J. Klassen2, Pratap Chokka1,

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Michael L Demas1

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1. Department of Psychiatry, University of Alberta, Edmonton, AB, Canada

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2. Department of Psychiatry, Eden Mental Health Center, Winkler, MB, Canada
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*Corresponding author:

Jennifer Swainson,
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Address: University of Alberta, 3rd floor Cabrini Center, 16940 87 Avenue, Edmonton,
AB, Canada
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Telephone: 780-735-2594

Fax: 780-735-2595
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Email: [email protected]
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Abstract

Introduction: Treatment Resistant Depression (TRD) is a common and burdensome

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condition with poor outcomes and few treatment options. Esketamine is the S-
enantiomer of ketamine and has recently been FDA approved in the United States for
treating depression that has failed to respond to trials of two or more antidepressants.

Areas covered: This review will briefly discuss current treatment options for TRD, then
review esketamine. Relevant literature was identified through online database
searches, and clinical trial data were provided by Janssen Pharmaceuticals.
Pharmacology, including kinetics and dynamics, is discussed, 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
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

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option offering new hope for TRD.

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Keywords: esketamine, treatment resistant depression, ketamine, glutamate, nmda
receptor

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Article highlights

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• TRD carries a large burden of illness
• Currently available treatments have limited efficacy and/or a lengthy time to
response
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• 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
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risk evaluation and mitigation strategy (REMS) for distribution and use, as well as
potential limitations in 3rd party coverage, access to this treatment may prove
limited for patients
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• 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 burdensome illness
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• Other agents targeting the glutamate system may prove novel

antidepressants/adjuncts and offer promise within the field of psychiatry
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• Given the strong data from animal studies suggesting that R-ketamine 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, esketamine and
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R-ketamine will be important.

1. Introduction
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 antidepressant 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 psychiatric and

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medical comorbidities [3]. As each trial of a traditional antidepressant takes several

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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 adjunctive
medications or combination strategies, which carry increased risk of side effects. The

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generally accepted definition of TRD in the literature is a failure to respond to 2 or more
antidepressants. One problem with this definition, however, is that it fails to address

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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 available treatments has led to a
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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 focusing on serotonin, noradrenaline
and dopamine systems, recent interest has focused on targeting the glutamate system.
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Glutamatergic agents have offered promise of a rapid antidepressant 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
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for use of esketamine as a treatment for TRD, and discuss future directions, including
the authors’ opinion as to where this drug may fit in the field of psychiatry moving
forward.
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2. Overview of current treatment options for TRD

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2.1 Standard pharmacotherapy

Currently, treatment guidelines for depression guide clinicians to either switch or

combine antidepressants, or to use adjunctive medications such as antipsychotics,
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stimulants, or mood stabilizers when remission is not achieved with an antidepressant

[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, neurostimulation offers an alternate

treatment option. Electroconvulsive therapy (ECT) has long been considered the gold
standard treatment for TRD, with an estimated 71% efficacy. While efficacy is
promising at 71% [7], use of ECT is limited by the need for general anesthesia, hospital
resources, potential for side-effects and stigma [7,8]. Deep Brain Stimulation (DBS) and
Vagal Nerve stimulation (VNS), are other neurostimulation techniques, both of which
carry limitations of requiring surgery and increased latency of response compared to
traditional antidepressants [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 low availability

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of treatment [12–15].

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2.3 Intravenous ketamine
Ketamine is considered a novel antidepressant, acting primarily as a non-selective and

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non-competitive antagonist at glutamate N-methyl-D-aspartate (NMDA) receptors by
binding to the allosteric phencyclidine (PCP) site within the ionotropic channel pore

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[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].
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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 forty minutes. IV ketamine produced
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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
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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].
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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
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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 treatment in terms of long term safety and efficacy, or to guide
frequency and duration of treatment. One retrospective case series of patients with
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URD who had exhausted other treatment options suggested that ongoing maintenance
treatments with IV ketamine may be of benefit in sustaining response in this population,
although potential risks and benefits 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 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 experience has found IN ketamine to be
well tolerated, suggesting this could be a viable treatment option for some patients [26].

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2.5 Esketamine

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In response to the positive results combined with the challenges 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 glutamate receptor

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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
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directions and implications for the field of psychiatry.

3. Esketamine
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3.1. Chemistry
Esketamine is the S(+) enantiomer of ketamine (Figure 1), an arylcyclohexylamine
derivative. Numerous drugs used in psychiatry have one or more chiral centers (center
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of asymmetry), resulting 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 may reside primarily in one enantiomer,
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and the two enantiomers may influence each other’s pharmacokinetics [28,29].

3.2 Pharmacology
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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
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[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 comparisons 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 hypotheses of ketamine. In the
disinhibition hypothesis, subanaesthetic doses of ketamine have a preferential affinity
for NMDA receptors on gamma-aminobutyric acid (GABA)-secreting inhibitory
interneurons, resulting in pyramidal cell disinhibition and an increase in glutamate
release and extracellular glutamate concentration [46]. This presynaptic pyramidal
neuron excitatory effect preferentially activates α-amino-3-hydroxy-5-methylisoxazole-4-

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propionic acid (AMPA) receptors. The blockade of NMDA receptors and enhanced

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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

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regions that seems to be responsible for the antidepressant effect of ketamine [47,48].

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In the second hypothesis, ketamine directly inhibits extra-synaptic NMDA receptors
containing GluN2B subunits on pyramidal neurons. Basal cortical activity activates
these receptors by extracellular ambient concentrations of glutamate. Direct inhibition
by ketamine is thought to disrupt the basal activation of pyramidal neurons, resulting in
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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 rapamycin, an immunosuppressant drug
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and inhibitor of mTORC1, markedly increases the antidepressant response rate with
ketamine, raising questions as to the role of TORC1 in ketamine’s action [49].
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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
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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 suggested that this metabolite is not necessary for antidepressant activity
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(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)
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receptors, monoaminergic receptors 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]
suggested 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 mode of administration.
While intravenous administration provides most predictable dosing with 100%
bioavailability, alternate routes of administration include IN, sublingual, oral,
intramuscular and rectal preparations Zhang and Hashimoto [42] have included a table
[acknowledged to be from 52] comparing the pharmacokinetic properties of racemic
ketamine in humans after various routes of administration; bioavailability of IN ketamine
was reported to vary from 8-45%. Intranasally administered esketamine is absorbed
quickly through the rich vascular bed within the IN cavity, reaching maximum plasma

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concentration (Tmax) within 10-14 minutes of administration [57]. Mean absolute

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bioavailability of IN esketamine is equal to that of ketamine [52]. Unlike orally
administered esketamine and racemic ketamine formulations, IN esketamine is not
subject to extensive hepatic first-pass metabolism [58,59]. Plasma protein binding of IN

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esketamine is 27% [60] and it is extensively distributed throughout perfused tissues in
the body. Yanagihara et al. compared plasma concentrations of ketamine in healthy

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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].
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Esketamine undergoes rapid and extensive metabolism by hepatic cytochrome P450
(CYP) liver enzyme CYP2B6 and CYP3A4 systems through N-demethylation to the
active metabolite S-norketamine. S-norketamine is then further metabolized by CYP-
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dependent pathways to metabolites such as S-5-hydroxynorketamine (HNK) and S-5,6-
dehydronorketamine (DHNK) which are further metabolized by glucuronidation [61]. It
has been proposed that S-norketamine may also be a useful antidepressant with fewer
adverse effects than esketamine [see [43] for review). Esketamine has a faster
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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 hour period following
administration.
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3.5. Intranasal drug delivery system

IN esketamine HCl (SpravatoTM) is supplied in a single-use nasal spray device

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containing 200 µl of vehicle solution (2 sprays), with each device delivering a total of 28
mg (14 mg of esketamine base per 100µl of spray) [63]. The device has an indicator
system that informs the user of when the device is full (2 green dots), one spray
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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 hours 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 minutes 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

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Janssen pharmaceuticals has now conducted a series of studies of esketamine for TRD

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involving patients with nonpsychotic, unipolar depression with a history of failure of
greater than two previous antidepressant treatments. Studies will be summarized

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below, but for further detail please refer to tables 1 and 2.

4.1.1. Phase 2 studies

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The SYNAPSE 1 study was a fixed dose trial giving patients 14mg, 28mg, 56mg and 84
mg of IN esketamine or IN saline placebo. Treatments were given on days 1 and 4.
The study yielded statistically significant and clinically meaningful improvement at all
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doses aside from 14mg, and there appeared to be a dose response relationship. It was
also found that doses of 56mg and 84mg produced plasma levels equivalent to IV
ketamine dosing of esketamine 0.2mg/kg, which was previously shown to have
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antidepressant efficacy [64]. A second phase 2 study (SUI2001) looked at reduction of
depressive symptoms and suicidality in acutely depressed patients presenting to the
emergency room. Primary endpoint was mean change from baseline MADRS and this
was significant at 4 hours post esketamine dose, and at 2 and 81 days post esketamine
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dose, but not at 25 days [65].

4.1.2 Phase 3 studies

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The phase 3 efficacy studies for IN esketamine have been named the TRANSFORM
studies. TRANSFORM 1 investigated fixed doses of 56mg and 84mg esketamine
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versus placebo for antidepressant effect [66]. Both treatment arms involved a 56mg
initial dose on day 1, then on day 4 patients either continued 56mg or were increased to
84 mg, which was continued twice weekly for a month. All 3 arms included the initiation
of a new oral antidepressant two weeks prior to initiation of the study. The study’s
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primary endpoint of reduction in Montgomery-Asberg Depression Rating Scale

(MADRS) did not reach statistical significance (p=0.088 for the 84mg 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 significant 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 56mg to 84mg 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 therapeutics 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 84mg. 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

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placebo group. Remission rate was 52.0% in the esketamine group, compared to

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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].

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TRANSFORM 3 followed a similar study to TRANSFORM 2, with flexible dosing,
however the population was elderly patients without neurocognitive issues and a higher

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level of treatment resistance was allowed. This study included patients who had failed
up to 8 antidepressant trials compared to the maximum of 5 previous antidepressant
trials allowed in TRANSFORM 1 and 2. This trial did not meet the primary endpoint of
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change from baseline MADRS at 4 weeks statistically by a narrow margin. Secondary
endpoints of response and remission rates were 27.0% versus 13.3% and 17.5%
versus 6.7%, respectively for intervention versus control arms, demonstrating clinical
significance [70].
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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 endpoint, and it has
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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.
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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
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had either responded or remitted with esketamine through 16 weeks of treatment. Total
duration of treatment and examination 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.
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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, 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 end of study. Remission rates increased from 47.2% after the one 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.

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Two other efficacy studies are currently in the recruitment phase. NCT02918318

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involves Japanese sites and is proposed 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

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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 esketamine

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will be added on for further efficacy. They will be studying fixed dosing of 28mg versus
56mg versus 84mg versus saline placebo in a 4-arm RCT design. NCT03434041 is a
phase 3 trial with sites in the United States and China, with similar design, sample size
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and primary outcome measure to TRANSFORM 2.

There currently are no head to head comparison studies of IN racemic ketamine to IN

esketamine. To date, protocol for one small non-inferiority study [75] comparing single
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infusions of IV ketamine and IV esketamine has been published but results are not yet
reported in the peer reviewed literature. Large comparison studies of multiple dosing of
IV racemic ketamine versus IV esketamine would be of future interest.
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5. Safety and tolerability

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5.1 Common adverse effects

Seven studies have reported on the safety profile of IN esketamine

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([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
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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 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 side effects of ketamine treatments for depression and, similar to
esketamine, 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

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events reported in patients during treatment with esketamine included hip fracture,

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significant blood pressure elevation, ventricular extrasystoles, hypothermia, lacunar
stroke, partial seizure, syncope, anxiety, agitation, aggression, sedation, disorientation,
and suicidal ideation. Although these adverse events were reported, it was not clear that

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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)

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experienced serious adverse effects that were deemed related to IN esketamine.
These included anxiety, delusional content, delirium, suicidal ideation and a suicide
attempt. an
A total of 6 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
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MADRS scores, and the patient who died after 20 days was experiencing 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 esketamine
[77] aptly points out that high relapse rates have been demonstrated on discontinuation
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of esketamine, and cautions that protracted withdrawal from the drug, rather than
exposure to the drug itself, may have played a role. Other deaths included a motorcycle
accident 26 hours after receiving esketamine, and the other two were in elderly patients
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with metabolic 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.
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5.3 Specific side effects of concern

5.3.1. Hypertension
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Transient hypertension has been noted frequently, with peak blood pressure elevation
at approximately 40 minutes following administration, with blood pressure typically
returning to baseline within two hours. Mean systolic increase was 7-9 mm Hg and
diastolic was 4-6mm 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-
31.4% across studies, and attenuated over time with repeated treatments [74].
Comparatively, 24% of patients reported feeling “strange or unreal” within 120 minutes
of racemic IV ketamine infusion [78]. A previous study on IN ketamine found mild
increases in dissociation and psychotic symptoms, but did not comment on frequency of
occurrence [24], and a subsequent IN ketamine trial was aborted early due to severity of
dissociative side effects [25]. Authors attributed this difference to variations in nasal
vasculature and anatomy, differences in the device, formulation, and individual
variability. As such, it is difficult to determine whether intranasally administered

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esketamine is better tolerated than IN ketamine.

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5.3.3. Sedation
Sedation has been noted as a common side effect. In the general adult population it

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tends to peak at 30 minutes post dose and is resolved by 60 minutes. Latest time to
resolve was noted to be 210 minutes. Interestingly, sedation in the geriatric population

us
was less severe and resolved sooner. Two subjects in all studies experienced loss of
consciousness – in one subject this occurred once and they were transferred to the
emergency room. The other subject experienced this on five different visits, lasting 15-
35 minutes. The FDA report noted that “experience of previous visits cannot accurately
an
predict future onset, peak, resolution time, or severity, and this has implications for
monitoring and labeling” [79].

5.3.4. Driving
M
Given the nature of the common adverse effects, including transient dissociative
symptoms, dizziness, vertigo, and somnolence, 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 84mg of IN esketamine were not impaired on a driving
ed

safety test administered 8 hours 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
pt

time window to allow safe driving performance would be helpful.

5.3.5. Urinary symptoms

ce

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 racemic
ketamine or esketamine. In a long term study, three cases of nephritis occurred during
Ac

one year of esketamine treatment, 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 multiple domains including attention, visual and working memory, and
executive functioning. This study demonstrated acute transient impairment in cognition.
Significant impairment was noted 40 minutes after administration, but completely
dissipated by 2 hours post treatment [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 therapeutically to treat depression,
it has been suggested ketamine actually improves cognition, likely owing to

t
improvement of depressive symptoms with treatment [87]. The long term cognitive

ip
impacts of racemic ketamine, as well as esketamine, remain unclear.

5.3.7. Abuse/addictive potential

cr
Serious concerns relate to the addictive potential of esketamine. Ketamine itself is a
well-known substance of abuse, though the recent FDA report on esketamine cites

us
ketamine abuse as being relatively uncommon with a lifetime prevalence 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 polydrug users equally rated “Drug Liking”
an
when comparing experiences 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,
M
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
ed

be important in considering addictive potential. Certainly, as esketamine is used in real

world settings, close monitoring and evaluation of its addictive potential, and possibility
of harm will be crucial to monitor.
pt

5.3.8. Special populations

ce

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
Ac

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

t
ip
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

cr
remain unclear. Esketamine data have filled gaps missing in the ketamine literature.
To date, 3/5 studies on IN esketamine met all endpoints with positive results, while the
other two failed to meet endpoint but showed a favorable trend towards benefit. The

us
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 conducted on
an
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,
M
which are not currently available for ketamine itself. To date, data regarding potential
concerns with urinary and cognitive toxicity are reassuring. As esketamine is used in
the real world, more data will be required regarding addictive potential and real world
efficacy, as well as optimal duration of treatment.
ed

8. Expert opinion

Esketamine provides an exciting and novel treatment option for TRD. Given that trials
pt

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 advantage over the metabolic
ce

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
Ac

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 neurostimulation treatments may lead to patient preference for
esketamine as an alternative.

This treatment is unique in that it causes varying acute psychological side effects, so
patients must be given proper psychoeducation 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

t
same standard of care would be advised for esketamine treatments, so as to minimize

ip
any risk of psychological harm.

Esketamine should not be positioned as a panacea for resistant depression, but as

cr
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

us
options. Clinically the adverse effects of esketamine should be weighed against
alleviating of the burden of depression. While a promising 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
an
and benefits of both continuing and stopping the treatment. This evaluation should take
into account factors such as individual response, preference, tolerability, addictive
potential, and other treatment options.
M

8.2. Practitioner considerations

The role of glutamatergic agents to treat depression has heralded very exciting
ed

treatment options for clinicians, but there exists controversy, even among psychiatrists
regarding the use of ketamine in depression. The 2017 UK consensus statement on
ketamine 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,
pt

include informed consent, and incorporate collection of data from a mood monitoring
program [91]. The American Psychiatric Association’s position statement on use of
ketamine points to lack of long term data and provides many judicious suggestions for
ce

patient monitoring [92]. It would be wise for any clinician prescribing esketamine to also
review and implement the suggestions detailed there [92]. The Canadian Mood and
Anxiety Disorder Network (CANMAT) has placed IV ketamine as a 3rd line adjunctive
treatment for depression in its 2018 Bipolar Disorder Treatment guidelines [93], but the
Ac

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
2 or more antidepressants will support clinicians in offering a rapid acting
antidepressant to less treatment resistant populations, and may decrease 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 enantiomer (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 esketamine, 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 84mg group was analyzed before the 56 mg
dose, and it failed to separate from placebo. As such, the 56 mg dose could not

t
officially be analyzed, but did separate from placebo in “exploratory analysis”. It was

ip
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 sixty-five plus population also
failed to meet its primary endpoint. Nevertheless, it should be noted that the enrolled

cr
patients for these studies were severely ill and it is encouraging that there is positive
short term and one year data with esketamine for this population.

us
At this time, future comparative trials with other adjunct treatments for depression such
as atypical antipsychotics are needed. Finally, comparative trials with different
formulations, and delivery systems with esketamine and racemic ketamine could
an
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 addictive potential. Physicians prescribing esketamine
must diligently monitor patients for adverse effects and patient response to facilitate
M
weighing risk/benefit of treatment for each patient.

8.3. Societal considerations

ed

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.
pt

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
ce

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
Ac

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 therapeutic option due to practical obstacles in
ability 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 stimulants or benzodiazepines.
 8.4. Long term view
The FDA approval of esketamine brings forth a novel treatment option for treatment
resistant depression. Due to multiple 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 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

t
TRD indication, it seems likely that more 3rd party payers may cover the cost, though it

ip
will prove more costly than ketamine itself.

Interestingly, while it is well known that racemic ketamine has antidepressant properties,

cr
IN esketamine has been studied by Janssen only as an adjunct, accompanied by a
change in antidepressant. Antidepressants themselves carry long term side effects

us
including weight gain and sexual dysfunction. As esketamine begins to be prescribed
by psychiatrists, it seems likely that clinical experience may be gained using esketamine
as monotherapy, particularly in the subset of patients who have tried nearly every class
of antidepressant with no or limited benefit. Further research including Phase IV
an
clinical trials should be completed for determination of long term effects of IN
esketamine, which can lead future therapeutic directions.
M
The first approval of a rapid acting antidepressant is an exciting development and is
likely to be followed by 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
ed

of action of ketamine and esketamine and can guide targeted drug development.

Funding
pt

This paper was not funded.

Declaration of interests
ce

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
Ac

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 speaker’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 affiliations or
financial involvement with any organization or entity with a financial interest in or conflict
with the subject matter or materials discussed 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 manuscript have no other relevant

t
financial relationships or otherwise to disclose.

ip
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cr
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 Table 1 - Completed PHASE II Intranasal Esketamine trials

Study ID Trial Comparator Population Sample Phase Primary outcome and References

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Design size results

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NCT01998958 RCT, 5 Esketamine MDD, 108 II Change from [64]
SYNAPSE 1 arm failed •2 baseline MADRS at
14mg vs. AD (at

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Fixed 1 week; 14mg had a
Phase 2 28mg vs. least one in
dosing current negative result. All
Acute 56mg vs. other doses yielded
episode),
84mg vs.

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phase IDS-C30 positive results with
placebo •34 a dose-response
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SUI2001 RCT, 2 84 mg MDD with 66 II Mean change from [65]

Arm, esketamine suicidal baseline MADRS at
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fixed vs placebo ideation 4 hours post dose on
Dose day 1; yielded
positive results.
ed

Table 2 - Phase III – Completed Intranasal esketamine trials

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Study ID Trial Design Comparator Population Sample Phase Primary References

size outcome and
results
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NCT02417064 RCT, 3 arm Esketamine MDD, failed 346 III Change from [66]
TRANSFORM 1 Fixed dosing 56mg + AD 5•AD•1 and baseline
Acute phase vs. no ECT in
MADRS at 4
Phase 3 Esketamine current
84mg + AD episode weeks; not
Ac

vs. Placebo + IDS-C30 significant.

AD •34
Response and
remission rates
better with 56
mg and 84 mg,
not significant
but described as
clinically
 meaningful

NCT02418585 RCT, 2 arm Esketamine MDD, failed 227 III Change from [69]
TRANSFORM 2 Flexible dosing +AD vs. 5•AD•1 and baseline
Placebo +AD no ECT in
Acute phase MADRS at 4
Phase 3 current
episode weeks: positive
IDS-C30 results
•34
NCT02422186 RCT, 2 arm Esketamine MDD, 139 III Change from [70]

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TRANSFORM 3 Flexible dosing +AD vs. Elderly baseline in
Acute phase Placebo +AD MDD failed

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MADRS at 4
Phase 3 8•AD•1 and
no ECT in weeks: did not
current meet statistical

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episode significance in
No MCI primary
IDS-C30 endpoint

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•31
NCT02493868 RCT, 4 arm Maintenance MDD, in 718 III Time to relapse [73]
SUSTAIN 1 Optimization phase: remission, in patients with
Esketamine failed 5•AD
phase for all remission (up to
Phase 3
arms: AD +
weekly dosing •1 and
an 104 weeks):
vs. no ECT in
esketamine esketamine current remitters and
Flexible dosing biweekly episode, responders on
Maintenance dosing vs. response to both weekly and
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phase switch to esketamine biweekly
placebo and MADRS •28
maintenance
weekly dosing at original
vs. switch to screening with esketamine
placebo and had a lower risk
ed

biweekly of relapse
dosing compared to
placebo
pt

NCT02497287 Open label AD + MDD, failed 802 III Safety outcomes [74]
SUSTAIN 2 Single group, Esketamine •2 AD in at the end of 56
2x/wk for a current
Flexible dosing weeks: 6.9%
Phase 3 month, then episode,
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in induction once weekly MADRS •22 patients had

Maintenance for a month serious TEAE.
phase and then No clinical
flexible to meaningful
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weekly or changes to
biweekly for
cognition. No
44 weeks and
one month cases of cystitis.
follow up No major
without withdrawal
esketamine symptoms.
 t
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Table 3. Intranasal esketamine trials in progress
Study ID Trial Design Comparator Population Sample Phase Primary

us
size outcome
NCT02782104 Open label None MDD, patients 1150 III Safety
enter from outcome up to
Induction: 4 ~5 years and 3
SUSTAIN-3
weeks of
other
an
months.
2x/week esketamine
Flexible dosing studies
M
Maintenance: 4
weeks of
weekly dosing
and then dosed
ed

weekly or
biweekly based
on CGI-S
weekly dosing
pt

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

NCT02918318 RCT, 4-arm Esketamine MDD, AD 183 II Change from

Add on to AD 28mg vs. response in baseline
Only Japanese after response to MADRS at 4
56mg vs. current
AD documented weeks
sites 84mg vs. episode,
Acute phase
placebo MADRS •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.

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TABLE 4 – Common Side Effects of Intranasal Esketamine Treatments From Seven Studies

Adverse Effect Frequency

Dizziness 20.4-39.0%
an
Nausea 16.0-37.1%
Dissociation 11.1-31.4%
Headache 12.5-31.4%
M
Dysgeusia 5.6-31.4%
Vertigo 11.1-26.1%
Somnolence 11.4-21.1%
ed

Paresthesia 5.6-17.1%
Vomiting 6.6-20.0%
Oral hypoesthesia 6.9-13.2%
pt

Increased blood pressure 6.6-12.5%

Anxiety 2.8-17.1%
Hypoesthesia 5.6-13.3%
ce
Ac
 t
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Figure 1. Molecular structure of ketamine – chiral center marked with *

cr
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an
M
ed
pt
ce
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