CNS Drugs

https://doi.org/10.1007/s40263-018-0519-3

REVIEW ARTICLE

Antidepressant Efficacy and Tolerability of Ketamine

and Esketamine: A Critical Review
P. Molero1 • J. A. Ramos-Quiroga2,3 • R. Martin-Santos4 • E. Calvo-Sánchez2,3 •

L. Gutiérrez-Rojas5 • J. J. Meana6,7

Ó Springer International Publishing AG, part of Springer Nature 2018

Abstract Ketamine and its enantiomer S-ketamine (es- metabolism to R-hydroxynorketamine (R-HNK). The
ketamine) are promising candidates to produce a rapid- enantiomer S-ketamine (esketamine) displays approxi-
onset antidepressant effect in treatment-resistant mately fourfold greater affinity for the glutamate NMDA
depression. Ketamine causes continued blockade of the receptor in vitro than R-ketamine. Proof-of-concept
glutamate N-methyl-D-aspartate (NMDA) receptor, single-dose and repeat-dose studies with intravenous
though this might not primarily mediate the antidepres- ketamine show a significant antidepressant and probably
sant effect. Alternative hypotheses include selectivity for antisuicidal effect in the short term, with response rates
the NMDA receptor subtype containing the NMDA over 60% as early as 4.5 h after a single dose, with a
receptor subunit 2B (NR2B), inhibition of the phospho- sustained effect after 24 h, and over 40% after 7 days.
rylation of the eukaryotic elongation factor 2 (eEF2) This response can be further sustained over several
kinase, increased expression of brain-derived neu- weeks with repeated doses (two to three doses per week).
rotrophic factor (BDNF) and tropomyosin receptor Tolerability seems acceptable in the short term, with
kinase B (TrKB), and activation of the mammalian target transient elevation of blood pressure and mild and tran-
of rapamycin (mTOR) signaling pathway, alongside sient dissociative and psychotomimetic effects. Intrana-
other independent actions attributed to the ketamine sal esketamine has shown a comparable antidepressant
effect, which has resulted in the US FDA granting the
& P. Molero
drug a ‘‘breakthrough therapy’’ designation, and theo-
pmolero@unav.es retically it may offer an improved tolerability profile.
However, major concerns remain regarding an effective
1
Department of Psychiatry, Instituto de Investigación Sanitaria protocol to maintain the clinical antidepressant effect of
de Navarra (IdiSNA), University Clinic of Navarra, 31008
Pamplona, Spain
ketamine seen with acute administration and the safety
2
of ketamine and esketamine in the long term, specifically
Department of Psychiatry, Hospital Universitari Vall
d’Hebron, CIBERSAM, Barcelona, Catalonia, Spain
related to potential neurocognitive and urologic toxicity,
3
together with the potential induction of substance use
Department of Psychiatry and Forensic Medicine, Universitat
Autònoma de Barcelona, Barcelona, Catalonia, Spain
disorders. Ketamine and esketamine are not currently
4
approved treatments for depression, but the clinical use
Department of Psychiatry and Psychology, Hospital Clinic,
IDIBAPS, CIBERSAM, Institute of Neuroscience, University
of ketamine is increasing in a variety of practice settings
of Barcelona, Barcelona, Spain internationally.
5
Psychiatry and Neurosciences Research Group (CTS-549),
Institute of Neurosciences, University of Granada, Granada,
Spain
6
Department of Pharmacology, University of the Basque
Country, UPV/EHU, CIBERSAM, Leioa, Bizkaia, Spain
7
Biocruces Health Research Institute, Barakaldo, Bizkaia,
Spain

Key Points
Ketamine and esketamine are promising candidates
to produce a rapid-onset antidepressant effect in
treatment-resistant depression.
Antidepressant effects of ketamine may be mediated
by a range of mechanisms beyond unspecific N-
methyl-D-aspartate (NMDA) receptor antagonism,
including the selective antagonism of NMDA
receptor subtypes containing the NMDA receptor
subunit 2B (NR2B), inhibition of the
phosphorylation of the eukaryotic elongation factor 2
(eEF2) kinase, increased expression of brain-derived
neurotrophic factor (BDNF) and tropomyosin
receptor kinase B (TrKB), and activation of the
mammalian target of rapamycin (mTOR) signaling
pathway, alongside other independent actions
attributed to the ketamine metabolite
R-hydroxynorketamine (R-HNK). Esketamine has a
higher affinity for the NMDA receptors than
ketamine, resulting in the S-enantiomer being about
two to four times as potent as the R-enantiomer.
In clinical proof-of-concept studies, ketamine and
esketamine showed a rapid, significant
antidepressant effect and probable antisuicidal effect
that was transient when limited to a single
administration.
Major concerns remain regarding both the evidence
for efficacious strategies to maintain an
antidepressant effect and the safety of the long-term
use of ketamine or esketamine.
1 Introduction
The treatment of major depressive disorder (MDD) and
bipolar depression has classically targeted modulation of
monoamine neurotransmission systems. Blockade of
noradrenaline, dopamine and/or serotonin reuptake by
acting on their selective transporters (NET, DAT and
SERT, respectively) and inhibition of monoamine break-
down by the monoamine oxidase enzyme are the most
established mechanisms of pharmacological action for
antidepressant drugs. Typically, current antidepressants
require several weeks to promote clinical response. This
reflects that the mechanism of therapeutic activity differs,
and probably is more complex, than the simple
P. Molero et al.
pharmacological inhibition of reuptake or monoamine
oxidase activities. The most recent large real-world effec-
tiveness trials indicated that only one-third of patients had
achieved remission by the end of 12 weeks of antidepres-
sant drug therapy and that the remission rate approached
70% after four sequential pharmacological treatments [1].
Therefore, improvement of remission rates and shortening
of the latency period before onset of drug action remain
unmet clinical needs in MDD treatment.
In recent years, ketamine has become a promising can-
didate to produce a rapid-onset antidepressant effect in
MDD, including treatment-resistant depression (TRD). We
provide a critical overview of ketamine clinical pharma-
cology, the controversy around its mechanism of action and
clinical experience in TRD and discuss the clinical
potential of the S-ketamine enantiomer esketamine in
MDD.
2 Clinical Pharmacology of Ketamine
Ketamine was developed in the 1960s as a short-acting
analog of phencyclidine to be used as an anesthetic drug
with less emergence delirium [2]. Dissociative anesthesia
was the term selected for a state where patients appear
awake, do not respond to sensory inputs but do preserve
spontaneous respiratory activity. Standard initial doses for
anesthesia are in the ranges of 1–4.5 and 6.5–13 mg/kg via
intravenous and intramuscular routes, respectively, with
further repeated infusions of half the initial dose for
anesthesia maintenance. Ketamine can also induce a pro-
found analgesia and sustained sedation at lower doses.
Analgesia and sedation are achieved at intravenous doses
of 0.2–0.8 mg/kg, and infusion at 0.5 mg/kg/h provides
continuous effect [3]. In addition to anesthesia, analgesia
and sedative actions, ketamine induces central sympath-
omimetic effects leading to tachycardia, hypertension and
palpitations. Higher doses (20 mg/kg) can induce a direct
myocardial depressant effect.
Other neuropsychiatric side effects of ketamine in
anesthesia have been described, although the frequency and
severity are low [3]. In the treatment of depression, more
detailed side effects associated with ketamine have been
described [4] (see Sect. 4.4). The clinical condition termed
‘‘ketamine bladder’’ is described in daily recreational users
as an ulcerative cystitis characterized by frequent and
painful urination [5].
The psychoactive effects that maintain concerns about
ketamine use in clinical therapeutics have been evaluated
under experimental conditions and are described as a
feeling of intoxication, visual, auditory and somatosensory
perceptual distortions, referential thinking disorders and
negative symptoms [6]. Recreational users describe
Ketamine and Esketamine in Depression
dissociative symptoms with hallucinations and distortion of
time and space that—under long-term use conditions—can
reproduce persistent schizophrenia-like symptoms [3]. The
development of a compulsive pattern of ketamine use is a
potential harm reported by recreational users [7]. Tolerance
develops rapidly to ketamine, leading to the use of an
increased dose over time [5].
Parenteral intravenous or intramuscular administration
is the most used route for ketamine because of the limited
bioavailability from extensive first-pass metabolism. In
oral formulations, increasing the dose is a feasible method
to surmount the lower bioavailability but does pose the risk
of tolerability issues and erratic residual effects related to
active metabolites. This pharmacokinetic profile has led to
the development of more convenient routes than parenteral
administration, such as an intranasal formulation (8–45%
bioavailability) [3]. Ketamine is highly soluble in lipids,
which determines a distribution volume of 3 L/kg and
different half-life values between the acute (anesthesia) and
maintained (potential use for depression) conditions of
administration. Thus, intravenous ketamine at a standard
dose provides 5–10 min of surgical anesthesia, whereas
repeated sub-anesthetic doses of intravenous ketamine are
being delivered in clinical trials every 2–3 days with pro-
longed antidepressant effects (see Sect. 4.2). The existence
of active metabolites of ketamine with longer half-lives
than the mother compound also contributes to reduced
administration frequency. The dissociative effects of acute
ketamine administration resolve in approximately
80–120 min [8], but the analgesic effects last longer [9].
With oral administration, ketamine undergoes liver
metabolism mainly by cytochrome P450 (CYP)-3A4,
CYP2C9 and CYP2B6 to the active metabolite norke-
tamine, which retains one-third of the pharmacological
activity of ketamine with a plasma half-life of 12 h [10] or
less [11, 12]. Other metabolites of ketamine are dehy-
dronorketamine, hydroxyketamine and hydroxynorke-
tamine (HNK). The clinical relevance of potential
pharmacokinetic interactions between ketamine and other
antidepressant drugs has not been sufficiently evaluated,
but available data seem to suggest the absence of important
interactions [13].
Ketamine is a racemic mixture of different R- and S-
enantiomers. S-ketamine (esketamine) displays approxi-
mately fourfold greater affinity for the glutamate N-methyl-
D-aspartate (NMDA) receptor in vitro than R-ketamine
[14–16]. In human studies, esketamine has greater anal-
gesic and anesthetic activity with less psychotomimetic
effects than the racemic mixture and R-isomer [9]. There-
fore, emerging interest in the potential efficacy of ketamine
in MDD is focused on esketamine. In contrast, in animal
models of depression, R-ketamine shows higher and
longer-lasting antidepressant potency than esketamine [17].
More recently, it was proposed that the antidepressant
activity of ketamine could be related to the R-enantiomer
of the HNK metabolite [18]. According to this study, the
pharmacological activity of (2R,6R)-HNK did not seem to
be mediated by NMDA receptor blockade because HNK
neither binds to nor inhibits NMDA receptor function [18].
Despite the controversy, these findings need to be con-
firmed in the human brain and under clinical conditions.
Indeed, the ratio between the four R- and S-HNK enan-
tiomers could differ between normal and pathological
human brains and those of rodents. On the other hand,
evidence that esketamine provides better antidepressant
efficacy than racemic ketamine under controlled conditions
has not yet been provided. The superiority of esketamine
has been assumed from anesthetic and analgesic activity
but needs further demonstration [19]. Moreover, the pos-
sibility that different mechanisms of action could be
involved in obtaining anesthetic, analgesic, sedative and
antidepressant activity with ketamine remains debatable.
3 Mechanism of Action of Ketamine
The pharmacological and therapeutic mechanism of action
of ketamine has been debated [20]. Ketamine binds to the
channel pore on the glutamate NMDA receptor and causes
continued blockade. This functional antagonism of NMDA
receptors expressed by c-aminobutyric acid (GABA)
inhibitory neurons has been postulated as the mechanism
by which ketamine induces psychosis-like effects [21].
However, other NMDA-receptor antagonist drugs fail to
produce sustained antidepressant properties. Alternative
hypotheses have been proposed, wherein the NMDA
receptor subtype expressing the NMDA receptor subunit
2B (NR2B) seems to be the target for antidepressant
activity [22], which could explain the lack of activity and
neurotoxicity associated with non-selective NMDA recep-
tor antagonists. The NMDA receptor subtype containing
the NR2B subunit is mostly expressed at extrasynaptic sites
and seems to mediate the phosphorylation of the eukaryotic
elongation factor 2 (eEF2) kinase and subsequent sup-
pression of brain-derived neurotrophic factor (BDNF)
translation. The increased expression of BDNF and its
receptor tropomyosin receptor kinase B (TrKB) have been
related to the antidepressant activity of ketamine. BDNF
also activates the mammalian target of rapamycin (mTOR)
signaling pathway, a critical intracellular effect of keta-
mine administration [23]. This extrasynaptic NMDA
receptor-mediated signaling pathway activation clearly
differs from the neurochemical consequences of synaptic
NMDA receptor activation, where the NR2A is the pre-
dominant subunit [23]. Therefore, the NMDA receptor
subunit composition and anatomical location could

underlie the singular activity and therapeutic effects of
ketamine in MDD. More recently, separate intracellular
pathways involving mTOR and ERK have been proposed
for R-ketamine and S-ketamine, respectively [24]. Finally,
the possibility that the antidepressant activity of ketamine
might depend on R-HNK pharmacological activity at an
NMDA receptor-independent target has been also pre-
sented in animal models [18]. However, these exciting
preclinical findings await translation to human conditions
[25]. Alternative or complementary mechanisms of phar-
macological action have been suggested, such as an effect
of ketamine on mu opiate receptors and voltage channels
[3, 20, 26].
4 Clinical Experience in Treatment-Resistant
Depression (TRD)
4.1 Single-Dose, Proof-of-Concept Studies
with Ketamine
The first randomized, double-blinded clinical study
specifically designed to determine the antidepressant
effects of ketamine was published by Berman et al. [27] in
2000. A single dose of intravenous ketamine 0.5 mg/kg
monotherapy in seven patients with MDD yielded a sig-
nificantly greater reduction in depressive symptoms (as
measured with the Hamilton Depression Rating Scale
[HDRS]) than saline treatment after 72 h [27]. This work
revitalized the hypotheses of NMDA dysfunction in
depression and of the potential therapeutic effects of
NMDA antagonism. Six years later, Zarate et al. [28]
conducted a randomized, double-blind, placebo-controlled
crossover study to test the same single dose of intravenous
ketamine monotherapy in 18 patients with unipolar TRD.
Their results were similar: [ 70% response rate (change
of C 50% from baseline in HDRS) and almost 30%
remission rate to ketamine after 24 h. This response was
maintained for 1 week in 35% of patients [28]. These two
seminal studies laid the foundations of the clinical evidence
supporting the hypothesis of a putative antidepressant
effect from ketamine. Two important aspects of this
hypothesis have since been tested with the single-dose
methodology. The first was how to prolong the initial, rapid
antidepressant effect without resorting to a repeated dose of
ketamine, given the expected tolerability issues. Two pilot
studies addressed this matter with the proper methodology:
open-label, single-dose ketamine monotherapy followed by
randomization to riluzole (a glutamatergic modulator
already incorporated in clinical practice without major
tolerability issues) or placebo in patients with TRD
[29, 30]. Both studies confirmed the rapid, significant
improvement of depressive symptoms following a
P. Molero et al.
ketamine dose without an augmentation or prolongation
effect after administration of riluzole. The second,
involving an active placebo (midazolam) in a double-blind,
parallel-arm study with a larger sample (73 patients with
TRD), yielded a comparable response rate in terms of
Montgomery-Asberg Depression Rating Scale (MADRS)
reduction (64% with ketamine monotherapy vs. 28% with
midazolam) with evidence of a specific antidepressant
effect that differed from the nonspecific effect of an
anesthetic agent such as midazolam [31].
In brief, these studies (Table 1) have globally assessed
responses to a single dose of intravenous ketamine in 166
patients with TDR with multiple treatment failures,
including electroconvulsive therapy (ECT). The findings
provide evidence of improvement in depressive symptoms
within hours, with a response rate [ 60% in the first 4.5
and 24 h, and [ 40% after 7 days, with a big effect size in
comparison with placebo (Cohen’s d 1.3–1.7) or active
placebo (midazolam, d = 0.8). These figures, though pre-
liminary, contrast with the average effect size of conven-
tional antidepressants (Cohen’s d 0.53–0.81 in patients
with intense symptoms) [32] and their response latency
(about 4–7 weeks) [1].
4.2 Studies of Repeated Doses of Intravenous
Ketamine
With prior evidence that a different glutamatergic modu-
lator (riluzole) apparently did not confer augmentation or
prolongation effects to the single dose [29, 30], repeated
doses of intravenous ketamine monotherapy 0.5 mg/kg
were tested. An open-label study of three doses per week
over 12 days in 24 patients with TDR yielded a stable re-
sponse rate in terms of MADRS score reduction from day 1
to day 12, with a median time to relapse of 18 days [33].
Interestingly, the response after 4 h following the first dose
predicted the response at day 12, with a positive predictive
value (PPV) of 0.89. A similar scheme in a different series
of 12 patients yielded a response rate of 91.6% after six
doses and a comparable time to relapse (mean time of
16 days in six subjects, and five subjects with maintained
response after 28 days of follow-up) [34]. A briefer open-
label study of two doses per week of intravenous ketamine
0.5 mg/kg adjunctive with conventional antidepressants
until remission, with a total maximum of four doses, in ten
patients with TRD achieved a response rate of 80% and a
remission rate of 50%, with two patients sustaining the
remission status for 4 weeks after the last dose [35]. The
issue of the optimal dose frequency has been studied in a
double-blind, randomized, placebo-controlled trial evalu-
ating the efficacy of twice- and thrice-weekly repeated
doses of intravenous ketamine 0.5 mg/kg over 40 min for
up to 4 weeks, in a larger sample (67 patients with TRD).
Ketamine and Esketamine in Depression

Table 1 Summary and main results of the seminal, single-dose intravenous ketamine (0.5 mg/kg) studies in unmedicated patients with major
depressive disorder (DSM-IV criteria)
Study Sample Study design Efficacy Effect size (Cohen’s d) Conclusion/most significant results
measure

Berman 7 pts DB ran clinical trial of KET HDRS NR Pts experienced significant improvement of
et al. vs. PL depressive symptoms within 72 h after KET but
[27] not PL infusion
Zarate 18 pts DB ran clinical trial of KET HDRS 1.46 (95% CI 0.91–2.01) KET showed significant improvement of
et al. with vs. PL after 24 h; 0.68 (95% depression vs. PL. 71% response rate and 29%
[28] TRD CI 0.13–1.23) after 1 remission rate the day following KET infusion.
wk 35% of pts maintained response for at least 1 wk
Price et al. 26 pts OL trial of KET plus ran MADRS d = 2.11 (95% CI 24 h after a single infusion, MADRS-Suicidality
[37] with DB continuation trial of 1.25–2.97) item scores reduced by an average 2.08 points;
TRD RIL 100–200 mg/d or PL reductions were sustained for 12 days by
repeated-dose KET
Mathew 26 pts OL trial of KET plus ran MADRS d = 2.11 (95% CI 65% response rate 24 h after a single infusion.
et al. with DB continuation trial of 1.25–2.97) RIL did not prevent relapse
[29] TRD RIL 100–200 mg/d or PL
Ibrahim 42 pts DB, ran, parallel, PC trial of MADRS 1.02 (day 2); 0.46 (day 62% response rate 4–6 h after infusion. Average
et al. with KET vs. KET plus RIL 28) time to relapse: 13.2 days. RIL did not prevent
[30] TRD relapse
Murrough 73 pts Two-site DB ran clinical MADRS 0.81 MADRS score 7.95 points lower with KET vs.
et al. with trial of KET vs. active PL MID (95% CI 3.20–12.71) with response rates
[31] TRD (MID) assigned in 2:1 of 64 and 28%, respectively
ratio
CI confidence interval, DB double-blind, HDRS Hamilton Depression Rating Scale, KET ketamine, MADRS Montgomery-Asberg Depression
Rating Scale, MID midazolam, NR not reported, OL open label, PC placebo-controlled, PL placebo, pt(s) patient(s), ran randomized, RIL
riluzole, wk week

This study yielded response rates of 68.8% for twice-
weekly dosing and 53.8% for thrice-weekly dosing at day
15, without apparent significant differences in tolerability,
favoring the twice-weekly regimen to induce a robust and
maintained antidepressant effect with less patient and clinic
burden and costs [36].
induced reduction of nocturnal wakefulness has been sug-
gested as a possible mediator of a putative antisuicidal
effect [39]. Whether ketamine promotes a specific
antisuicidal effect and whether this effect is sustained in the
long term are yet to be determined, as are its neurobio-
logical underpinnings [40].

4.3 Possible Antisuicidal Effects with Ketamine 4.4 Tolerability of Ketamine

Aside from its antidepressant effects, intravenous ketamine
(0.5 mg/kg over 40 min) produced a significant reduction
in suicidality 24 h after the single dose (monotherapy) in
26 patients with TRD, measured as a reduction in both
suicidal cognition using the Implicit Association Test and
in the suicidality item of MADRS (mean reduction 2.08
points, with 81% of patients receiving a rating of 0 or 1
post-infusion). This effect was sustained for 12 days with
thrice-weekly repeated doses [37]. A recent midazolam-
controlled randomized clinical trial of adjunctive ketamine
in patients with MDD yielded a significant antisuicidal
response rate (proportion of patients experiencing a
reduction C 50% on the Scale of Suicide Ideation score) of
55% at 24 h after infusion; this effect was partially inde-
pendent of the antidepressant effect [38]. Ketamine-
Current published data on tolerability indicate that intra-
venous ketamine (0.5 mg/kg over 40 min) for the treatment
of MDD is safe and well tolerated in the short term. A
review of 205 doses in 97 patients [41] yielded an overall
attrition rate of 3.1% and a profile of common, non-vital-
risk-associated and reversible effects during the 4 h after
infusion (drowsiness, dizziness, poor coordination, blurred
vision, feeling strange or unreal). About 30% of patients
presented hemodynamic changes (transient increases in
pulse and mean blood pressure, with a mean systolic
increase of 19.6 ± 12.8 mmHg and a mean diastolic
increase of 13.4 ± 9.8 mmHg). In that review, ketamine
was associated with mild and reversible but significant
dissociative and psychotomimetic effects in the 40-min
evaluation. Four subjects (1.95%) discontinued infusions

because of adverse effects: two experienced elevated blood
pressure, up to 180/115 and 187/91 mmHg, respectively,
with normalization shortly after discontinuation; one
experienced increased anxiety; and another experienced
transient hypotension and bradycardia with venipuncture.
Side effects occurred in the first 2 h after infusion and had
generally resolved by the 4 and 24-h evaluations.
A lower infusion rate of the intravenous dose (100
instead of 40 min) showed improved tolerability, without
significant increases on the Brief Psychiatric Rating Scale
(BPRS) or Young Mania Rating Scale (YMRS), with
similar efficacy [35].
4.5 Clinical Studies with Esketamine: The
Intranasal Route
Esketamine has a higher affinity for the NMDA receptors
than ketamine, resulting in the S-enantiomer being about
two to four times as potent as the R-enantiomer [14–16]. It
has been suggested that intravenous ketamine 0.5 mg/kg is
comparable to esketamine 0.4 mg/kg, taking into account
both the higher potency of esketamine and its greater
clearance in the absence of R-ketamine [16, 42]. Eske-
tamine monotherapy was tested in 29 patients with TRD
randomly assigned to receive intravenous esketamine 0.20
or 0.40 mg/kg (over 40 min) or placebo [43]. Both doses
yielded similar response rates (67 and 64%, respectively),
comparable to the reported efficacy of intravenous keta-
mine. However, the tolerability profile was better with the
low dose (0.20 mg/kg), which might represent the optimal
risk/benefit ratio of intravenous esketamine for TRD. A
retrospective report found that 0.25 mg/kg (over 10 min in
conjunction with conventional antidepressants) yielded a
significant increase in mild/severe dissociative effects in 23
patients with TRD and four with bipolar depression [44].
Intravenous administration involves inherent difficulties
for both patients and clinicians. Oral administration results
in low bioavailability of around 20% [3, 45], whereas the
intranasal route offers a more acceptable bioavailability of
up to 45% [3, 45]. Results from a pilot trial of a single dose
of intranasal ketamine 50 mg in conjunction with con-
ventional antidepressants in 18 patients with MDD were
comparable to those with intravenous ketamine with min-
imal adverse effects [46]. Taking this evidence all together,
it seems plausible to anticipate that intranasal esketamine
may offer an efficacy outcome comparable to that with
intravenous ketamine, with an improved tolerability pro-
file. Indeed, a recent placebo-controlled randomized trial of
intranasal esketamine 28, 56 or 84 mg in conjunction with
oral antidepressant therapy in 67 patients with TRD
showed a dose-related, robust, rapid antidepressant effect
with 56 and 84 mg and a safety profile comparable to that
previously obtained with intravenous ketamine 0.5 mg/kg
P. Molero et al.
[47]. In this trial, reductions in dosing frequency from
twice weekly to weekly and to every 2 weeks showed a
sustained response up to 2 months after cessation of dos-
ing. Interestingly, another study found that a single dose of
intranasal esketamine 84 mg caused no significant
impairment in road-driving performance [48]. Further
clinical trials to prove this hypothesis of advantages of
intranasal esketamine over ketamine are needed.
The clinical evidence favoring an antidepressant effect
with intranasal esketamine has led the US FDA to grant
this drug a ‘‘breakthrough therapy’’ designation [49] (in-
tended to expedite the development and review of drugs for
serious or life-threatening conditions based on preliminary
clinical evidence [50]). Approval is expected if this evi-
dence is supported by completed and recruiting clinical
trials.
A search in ClinicalTrials.gov (on 25 January 2018)
identified 14 trials of esketamine in depression (13 intra-
nasal, one intravenous), of which six are still recruiting
(two in TRD, four in MDD), two are active but not
recruiting (both in TRD) and six are completed (four in
TRD, two in MDD). Of these, two are focused on the long-
term safety and efficacy of esketamine in TDR (one is still
active), four are focused on the rapid reduction of suicide
ideation in adult and pediatric patients with MDD, and one
is focused on the effects on on-road driving of single-dose
and repeated administration of esketamine. The results of
these trials will probably answer some of the unresolved
queries regarding the efficacy and safety of esketamine in
depressive disorder.
5 Unresolved Issues and Limitations
of the Current Evidence
Both the pharmacodynamics and the neurobiological
underpinnings of the antidepressant effects of ketamine/
esketamine remain largely unknown. Regarding the phar-
macodynamics, NMDA receptor antagonism leads to
induction of mTORC1 and ERK cellular pathways, con-
tributing to neuroplasticity and synaptogenesis through
indirect mechanisms, which may involve the release of
BDNF [51], but a definite molecular model that explains
the antidepressant action remains missing. Preliminary
evidence from a positron emission tomography (PET)
study in 20 patients with TRD showed decreased metabo-
lism in the right habenula and the extended medial and
orbital prefrontal networks in association with rapid
antidepressant response to ketamine [52]. A recent review
of the brain effect of ketamine measured in neuroimaging
studies implicated the subgenual anterior cingulate cortex,
among other brain areas, alongside a variety of hypothe-
sized mechanisms such as increased activity in reward
Ketamine and Esketamine in Depression
processing and emotional blunting and decreased ability to
self-monitor [53]. Limitations include the high hetero-
geneity in the selected studies (imaging procedure, limited
sample sizes, sex bias, time to antidepressant effect, use of
different regimens and doses of both racemic ketamine or
esketamine). Future research may address these limitations
to improve our knowledge of ketamine’s antidepressant
mechanisms of action.
Future studies should investigate several safety con-
cerns. A major concern involves the potential for neuro-
toxicity associated with long-term use of ketamine, leading
to neurocognitive impairment [54]. There is evidence of
cognitive impairment in recreational ketamine users, albeit
at much higher doses than used for TRD, and it is critical
this aspect be tested in long-term, prospective, controlled
studies [55]. Caution is also needed regarding the potential
for physical side effects as seen in frequent users of keta-
mine, such as ulcerative cystitis with concerns of an
increased risk of bladder cancer [54]. In addition, two other
main issues arise. On one hand, further studies are needed
to assess the tolerability profile of repeated doses of keta-
mine or esketamine in the long term, especially regarding
the systemic and cardiovascular response and dissociative
and psychotomimetic reactions. On the other hand, whether
this treatment may induce substance abuse in general
should be clarified, as should how to control the risk of
ketamine/esketamine abuse specifically by means of new
galenical forms.
The possibility of nasal injuries or olfactory dysfunction
associated with ketamine or esketamine administered via
this route in the long term has yet to be confirmed. Overall,
further clinical evidence to prove the putative advantages
of intranasal esketamine over ketamine are needed.
Further unresolved issues include whether repeated
doses of ketamine/esketamine in the longer term (i.e.
9–12 months) maintain a significant antidepressant effect
and, if so, whether psychotomimetic and dissociative
reactions are attenuated or aggravated. Possible strategies
to prolong the acute antidepressant effect of single-dose
ketamine (other than repeated doses) are needed after the
negative trials with riluzole. For instance, evidence
regarding the role of existing psychotropic drugs (e.g.,
lithium or other mood stabilizers—except lamotrigine,
which produced negative results as a post-ketamine
enhancer [29]) and new agents (such as different gluta-
matergic modulators) is needed. The anticipated response
to this treatment in patients with psychotic symptoms
(present in some forms of severe depression) remains
unclear because psychotic symptoms are a common
exclusion criterion in the proof-of-concept clinical trials.
However, a recent small case series provided preliminary
evidence of an acceptable safety and efficacy profile with
esketamine in the treatment of TRD with psychotic
symptoms [56]. As suggested by Murrough et al. [31],
future studies comparing the antidepressant effect of
ketamine/esketamine with that of established active com-
parators, such as ECT or antidepressant–antipsychotic
medication combinations, are also needed. Indeed, a
Patient-Centered Outcomes Research Institute (PCORI)-
funded comparative effectiveness clinical trial of ECT
versus ketamine for patients with TRD is currently ongoing
(ClinicalTrials.gov, NCT03113968).
Finally, an important aspect to consider in the global
evaluation of the efficacy and tolerability of ketamine and
esketamine as antidepressants is the inherent limitations of
a research area that has continued to evolve since the
seminal work by Berman et al. [27] in 2000. Given that
only 6 of the 14 trials of esketamine in depression listed on
ClinicalTrials.gov have been completed, the conclusions
presented herein might change considerably in the near
future. A considerable concern in the application of the
evidence reviewed herein to actual treatment for patients is
the lack of established consensus or clinical guidelines for
the use of ketamine in depression, as it remains an off-label
indication. However, of note, the American Psychiatric
Association (APA) Council of Research Task Force on
Novel Biomarkers and Treatments has published a con-
sensus statement on this topic with useful and detailed
recommendations on key aspects such as patient selection,
clinician experience and training, treatment setting, medi-
cation delivery, and follow-up and assessments [57].
6 Conclusions
Proof-of-concept single-dose and repeat-dose studies with
ketamine and esketamine show a significant antidepressant
and probably antisuicidal effect in the short term, with
response rates [ 60% as early as 4.5 h after a single dose,
with a sustained effect after 24 h, and [ 40% after 7 days.
This response can be further sustained over several weeks
with repeated doses (two to three doses per week). Toler-
ability seems acceptable in the short term, with transient
elevation of blood pressure and mild and transient disso-
ciative and psychotomimetic effects. Intranasal esketamine
theoretically might offer an improved tolerability profile.
However, major concerns remain in terms of establishing
an effective protocol to maintain the clinical antidepressant
effect of ketamine seen with acute administration while
managing long-term safety, specifically regarding the
potential for neurocognitive and urologic toxicity and the
induction of substance use disorders.
Author Contributions All authors made a substantial contribution to
the conception, writing and structure of the review article. The first

draft of the manuscript was prepared by PM (clinical aspects) and
JJM (pharmacological aspects). All authors proofread the manuscript.
Compliance with Ethical Standards
Funding No sources of funding were used to conduct this study or
prepare this manuscript.
Conflict of interest Three of the six authors are principal investi-
gators or subinvestigators on several Janssen-supported studies of
esketamine for depression. PM is supported by Clinica Universidad
de Navarra and has received research grants from the Ministry of
Education (Spain), the Government of Navarra (Spain), the Spanish
Foundation of Psychiatry and Mental Health and Astrazeneca.
Without any relevance to this work, PM declares that he is a clinical
consultant for MedAvante-ProPhase and has received speaker hono-
raria from Scienta, AB-Biotics and Janssen. PM is the principal
investigator at Clinica Universidad de Navarra of several studies
supported by Janssen about the efficacy and safety of esketamine.
JARQ is the principal investigator for Hospital Universitari Vall
d’Hebron in several studies about the efficacy and safety of eske-
tamine supported by Janssen-Cilag. ECS is cooperating as subinves-
tigator at Hospital Universitari Vall d’Hebron in several studies about
the efficacy and safety of esketamine for the treatment of depression
supported by Janssen-Cilag. LGR has been speaker and advisory
board member for Janssen, Rovi, Servier, Lundbeck, Otsuka, Pfizer
and Exeltis. RMS and JJM have no conflicts of interest.
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