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Treating Treatment-resistant Depression with Esketamine Nasal Spray When All Therapeutic Options Have Been Exhausted: Clinical Experience from a Spanish Cohort of Expanded Use

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Objective Treatment Resistant Depression (TRD) is commonly defined as the lack of response to two or more antidepressants with different mechanisms of action. Up to 30% of patients diagnosed with major depressive disorder might be considered to present TRD. The objective of this study was to assess the effectiveness and tolerability of esketamine in patients diagnosed with TRD, who were referred to our program after exhausting all available treatments. A secondary objective consisted in researching the relationship between response and previous use of electroconvulsive therapy. Methods A prospective, observational study was carried out in patients enrolled in the expanded use of esketamine in our center. They received esketamine prior to its marketing authorisation, for therapeutic purposes. Sixteen subjects were analyzed. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS). Patients were followed up to 4 months after the administration. Results Esketamine showed a rapid, robust effect in improving depressive symptoms, with no specific correlation between outcome and any demographic or clinical traits evaluated. No differences were found between patients that previously received Electroconvulsive Therapy, and those that didn’t. 10 out of 16 patients responded (> 50% change in baseline MADRS scores), but only five achieved remission (< 12 points in the global MADRS score). We provide some recommendations, based on clinical experience, to improve tolerability and adherence, and to manage adverse effects. Conclusion Results suggest that esketamine is a safe, effective and rapid-acting option for TRD. More studies are needed to properly assess predictors of response outcome.
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Original Article
https://doi.org/10.9758/cpn.23.1097 pISSN 1738-1088 / eISSN 2093-4327
Clinical Psychopharmacology and Neuroscience 2024;22(1):159-168 Copyright2024, Korean College of Neuropsychopharmacology
159
Received: May 24, 2023 / Revised: July 24, 2023
Accepted: August 1, 2023 / Published online: September 6, 2023
Address for correspondence: Óscar Soto-Angona
Department of Mental Health, Hospital Universitari Vall
dHebron, Passeig de la Vall dHebron, 119-129, Barcelona
08035, Spain
E-mail: oscar.soto@vhir.org
ORCID: https://orcid.org/0000-0003-0234-4280
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Treating Treatment-resistant Depression with Esketamine Nasal
Spray When All Therapeutic Options Have Been Exhausted: Clinical
Experience from a Spanish Cohort of Expanded Use
Júlia Vendrell-Serres1,2,3, Óscar Soto-Angona1,2,3, Amanda Rodríguez-Urrutia1,2,3,4, Benedetta Inzoli1,
Antonia López González1, Josep Antoni Ramos-Quiroga1,2,3,4
1Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
2Group of Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
3Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
4Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain
Objective: Treatment Resistant Depression (TRD) is commonly defined as the lack of response to two or more anti-
depressants with different mechanisms of action. Up to 30% of patients diagnosed with major depressive disorder might
be considered to present TRD. The objective of this study was to assess the effectiveness and tolerability of esketamine
in patients diagnosed with TRD, who were referred to our program after exhausting all available treatments. A secondary
objective consisted in researching the relationship between response and previous use of electroconvulsive therapy.
Methods: A prospective, observational study was carried out in patients enrolled in the expanded use of esketamine
in our center. They received esketamine prior to its marketing authorisation, for therapeutic purposes. Sixteen subjects
were analyzed. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS). Patients were
followed up to 4 months after the administration.
Results: Esketamine showed a rapid, robust effect in improving depressive symptoms, with no specific correlation be-
tween outcome and any demographic or clinical traits evaluated. No differences were found between patients that
previously received Electroconvulsive Therapy, and those that didnt. 10 out of 16 patients responded (50% change
in baseline MADRS scores), but only five achieved remission (12 points in the global MADRS score). We provide some
recommendations, based on clinical experience, to improve tolerability and adherence, and to manage adverse effects.
Conclusion: Results suggest that esketamine is a safe, effective and rapid-acting option for TRD. More studies are needed
to properly assess predictors of response outcome.
KEY WORDS: Esketamine; Depressive disorder, treatment-resistant; Prospective study; Compassionate use.
INTRODUCTION
Major depressive disorder (MDD) is a prevalent psychi-
atric condition characterized by depressed mood or anhe-
donia, along with at least four additional symptoms such
as cognitive and sleep disturbances or vegetative symp-
toms, for a minimum of 2 weeks (Diagnostic and Statistical
Manual of Mental Disorders 5th edition, DSM-5). MDD is
a significant contributor to global disease burden, impairs
functioning [1], and elevates the risk of comorbid con-
ditions such as diabetes mellitus, obesity, and functional
gastrointestinal diseases [2,3]. The mean annual preva-
lence of MDD in Europe is estimated to be 6.4% [4] and
4.73% in Spain [5]. Furthermore, individuals with MDD
are at a 20-fold increased risk of suicide compared to the
general population [6].
Despite the growing impact of this disorder, current
treatment options are suboptimal, with up to 30% of pa-
tients demonstrating inadequate response to first-line
treatments [7,8]. This has led to the concept of treatment
resistant depression (TRD). Although this term lacks a
160 J. Vendrell-Serres,
et al
.
consensus-based definition, most authors consider it the
failure to respond or achieve remission in patients treated
with at least two antidepressants of different mechanisms
of action [9]. While there is no established algorithm for
treating TRD, the most commonly used strategies involve
combining different classes of antidepressants, adding
other treatments such as lithium, or physical therapies
such as electroconvulsive therapy (ECT), repetitive mag-
netic transcranial stimulation, or deep brain stimulation.
However, none of these options is specifically indicated
for TRD, and evidence for their effectiveness is limited
[10].
Esketamine, the S-enantiomer of racemic ketamine, is a
novel antidepressant that acts as an antagonist of the N-
methyl-D-aspartate (NMDA) receptor expressed in gam-
ma-aminobutyric-acidergic inhibitory interneurons, en-
hancing glutamatergic neurotransmission. This mecha-
nism of action is thought to increase synaptogenesis and
modulate inflammation through mediators such as the in-
crease in the secretion of blood-derived neurotrophic fac-
tor (BDNF) [11]. It is administered as a nasal spray, with a
7-month dosing regimen that includes an induction phase
and a maintenance phase.
According to a solid body of evidence, esketamine seems
to be a rapid and effective treatmenfor TRD, although
there is still a lack of data regarding some relevant ques-
tions such as proper setting for administration, or long
term efficacy and safety [12]. Due to its recent marketing
approval, there is almost no clinical experience of its use
outside research settings, which also brings questions
about its proper implementation within healthcare sys-
tems and its performance in real-life and complex clinical
settings [13]. Moreover, in the case of esketamine, and
due to a number of reasons, most of the clinical trials as-
sessing esketamine for TRD involved the adjunct ini-
tiation of a conventional antidepressant, which involved a
serious risk of bias [14-16].
At our institution, prior to its marketing approval, ex-
panded access to esketamine was granted between
February 2020 and November 2022. The term expanded
accessrefers to the provision of an investigational prod-
uct for therapeutic purposes prior to receiving marketing
authorization. This type of access is usually considered for
patients with serious or life-threatening diseases or con-
ditions that lack alternative treatments or have exhausted
all available options. In the case of esketamine, the in-
clusion criteria included patients diagnosed with major
depressive disorder who failed to respond to at least two
oral antidepressants during the current episode, failed to
respond to at least one combination/potentiation strategy,
and declined or were unresponsive to at least one non-
pharmacological strategy, such as ECT. These criteria
were established by the Spanish Drug Agency, based on
clinical consensus regarding the severity and treatment-
resistance features of major depressive disorder.
Given the knowledge gaps described above, the main
purpose of this study was to shed light on the effective-
ness, tolerability and safety of esketamine in a real-world
environment, prospectively describing the evolution of all
the patients included in the expanded access program of
our institution.
Objective
The aim of this study was to characterize the population
receiving esketamine treatment in our Treatment Resistant
Depression Program. Specifically, we sought to evaluate
the response to the treatment. A secondary, exploratory
objective was to identify potential clinical markers of im-
provement in a real-world setting, where esketamine was
administered after previous treatment failures. Specifi-
cally, we aimed to explore the relationship between treat-
ment response and prior ECT use.
METHODS
Study Design
We conducted a descriptive prospective study of all pa-
tients with TRD who received esketamine as expanded
use between February 2020 and November 2022. Eligible
participants for expanded use were those diagnosed with
MDD according to the DSM-5 and fulfilled a number of
inclusion criteria, including failure to respond to two or
more oral antidepressants in the current episode, failure to
respond to at least one combination/potentiation strategy,
failure or refusal of one non-pharmacological strategy,
such as ECT, no access to any clinical trial for the same in-
dication or other expanded access program, and medical
stability. There was no need to perform any change on the
baseline treatment before starting treatment with esketamine.
Exclusion criteria included, among others, previous
lack of response to ketamine or esketamine, previous or
current diagnosis of bipolar disorder, psychotic disorder,
Clinical Experience with Esketamine 161
MDD with psychotic features or cognitive disability. Also,
active suicidal ideation in the last 6 months, or a suicide
attempt in the last 12 months, medical instability, a num-
ber of medical diagnosis such as epilepsy, hepatic cir-
rhosis, or relevant cardiac alterations, as well as preg-
nancy, and a baseline blood pressure higher than 140/90
(systolic/diastolic) millimeters of mercury were reason for
exclusion. Patients with a history of mild to severe sub-
stance use disorder were also excluded from the ex-
panded use program. These criteria were defined by the
Spanish Drug Agency in a clinical guideline for internal
use that is no publically available, but isrovided as a sup-
plement to this publicationr.
Recruitment occurred between January 2021 and June
2022, and patients received esketamine treatment at
doses ranging from 28 to 84 mg, depending on clinical re-
sponse and tolerability. Participants were referred for ex-
panded use from our Treatment Resistant Depression
Program, as well as from outpatient clinics. Standard
schedule was followed, implying a 4-week induction
phase, when treatment was administered twice weekly,
and a 6-month maintenance phase, during which the fre-
quency of administration varied from once a week to ev-
ery two weeks. Preparation visits took place before treat-
ment. During these visits, we focused on psychoeducation
about the expected effects during administration, as well
as teaching tools for support, such as mindful breathing or
therapeutic touch. Esketamine was administered in a qui-
et room, accompanied with music (with headphones),
and under the supervision of an expert nurse. A psychia-
trist was present at the beginning and end of the treatment,
and remained on call at all times.
Ethics Approval
This study was approved by the Ethics Committee of
Vall dHebron Research Institute (PR(AG)110/2021). All
participants gave informed consent before participation
in the study.
Measurements
Depressive symptoms were assessed weekly during the
first month and monthly during the maintenance phase,
using the Spanish validated version of the Montgomery-
Asberg depression rating scale (MADRS) [17]. The MADRS
scale was administered before the administration of esket-
amine in the same dosing visit, to avoid biases due to pos-
sible impairments in response immediately following the
administration. The MADRS is a hetero-administered in-
strument designed to assess the severity of depression
symptoms in adults and the efficacy of antidepressant
treatment [18]. Generally accepted cut-points for the
MADRS are as follows: A score of 06 indicates a patient
free of depression; a score of 719 indicates mild depres-
sion, 2034 indicates moderate depression, and 3560
indicates severe depression [19].
In addition, we administered the Maudsley staging meth-
od (MSM) scale (Spanish version) [20] to assess treatment
resistance and compliance with inclusion criteria. The
MSM is a points-based staging model that incorporates
three factors: previous treatments, severity of illness, and
duration of current episode. A final score of 36 points
indicates mild resistance to treatment, 710 points in-
dicate moderate resistance to treatment, and 1115
points indicate severe resistance to treatment [21].
Treatment side effects were systematically assessed and
recorded in the patients medical record using leading
and open questions in every follow-up visit. Symptom re-
mission was defined as a MADRS score 12, and full re-
sponse was defined as 50% reduction in the baseline
MADRS score, following national guidelines on clinical
practice in MDD [22].
Statistical Analysis
A descriptive analysis was conducted to examine clin-
ical and demographic variables using means and standard
deviations for quantitative variables, while qualitative var-
iables were described in terms of counts and percentages.
To evaluate changes and evolution compared to base-
line, a repeated analysis of variance (ANOVA) analysis
and linear mixed-model were performed to assess the
evolution of MADRS scores through time. The influence
of each variable on MADRS scores was also tested by add-
ing them to the mixed model.
Finally, a KaplanMeyer survival analysis was used to
describe the time to achieve a 50% reduction of the
MADRS initial score (or full response), and the time to
achieve 12 points in the score (or remission).
All statistical analyses were performed using the STATA
15 version (StataCorp LLC).
162 J. Vendrell-Serres,
et al
.
RESULTS
Sixteen patients were included in the study, 9 of whom
were females (56.3%) and 7 males. The patients had an age
range of 27 to 71 years old, with a mean of 53.13 and a
standard deviation of 10.31. Table 1 displays the primary
demographic and clinical characteristics, comorbidities,
and treatment.
The mean time from the first diagnosis of depression
was 20.81 years (standard deviation [SD] = 11.41). Ac-
cording to MSM scores, no patient had mild TRD, while
50% had moderate TRD, and 50% had severe TRD, with
a mean score of 11 (SD = 1.86) indicating severe treat-
ment-resistant depression.
Regarding treatment with intranasal esketamine, 84 mg
(81.25%) was the most frequently used dose, and the tran-
sition from the 56 mg to 84 mg dose occurred between the
first and second week in all patients.
Pooled reported adverse events are shown in Table 2,
and all but one adverse event were mild and did not re-
quire treatment.
Included patients had a baseline mean MADRS score of
36.69 (SD = 4.44), indicating severe depression. The
mean score of MADRS was 26.67 (moderate depression)
at T1 (in the first 48 hours after the first administration) and
19.07 (mild depression) at T6 (one month after treat-
ment), reaching a mean of 16 at the end of the follow-up.
These results were statistically significant (
p
0.00001).
The pooled means evolution through time is shown in
Figure 1, where the MADRS level consistently fell until
T3, remaining stable through time after that moment.
A linear regression analysis was performed to assess the
effect of time on the evolution of the MADRS score, in-
dicating a significant global
p
value using the Wald test of
p
0.001 (Table 3). A random-effects model was used to
evaluate the association between MADRS score and dem-
ographic and clinical variables, and no significant associ-
ation was found. Furthermore, data for patients who had
received ECT was compared to those who had not, and no
significant differences were found between the two
groups.
A KaplanMayer survival test was conducted to eval-
uate the response and remission rate through time.
Figure 2 shows the Kaplan-Mayer survival test assessing
the time to achieve response (50% of the initial MADRS
score). After the induction phase (one month after the ini-
tial dose), 50.53% of patients had reached response.
Figure 3 displays the Kaplan-Mayer survival test assess-
ing the time to achieve remission (12 in the MADRS
score), where five patients (31.25%) achieved remission
at the end of the follow-up period.
DISCUSSION
The present study investigated the effectiveness and tol-
erability of nasal esketamine treatment in patients with
TRD. As far as we know, this is the study with the largest
number of patients with TRD treated with nasal esket-
amine in our country.
The results described in this study show that esket-
amine is a fast an effective treatment for TRD patients, al-
lowing for a consistent improvement in their MADRS
scores from a mean baseline of 36.69 (severe depression)
to a mean of 19.07 (moderate depression) after one month
of treatment, although the onset of response can already
be observed in the first 48 hours after the first admin-
istration (mean MADRS score 26.67). Most of the patients
maintained the improvement after two months, even
when the dose schedule was changed to once weekly, or
every two weeks, keeping a mean of 16 points in the
MADRS score after this period. However, it is relevant to
mention that a longer follow-up would be needed to as-
sess how this improvement evolves through time after the
discontinuation of the treatment, as esketamine is consid-
ered a short-term treatment that precisely aims at avoiding
chronicity.
The reported results are consistent with previous clin-
ical trials that show a response rate of 50.2% and a re-
mission rate of 35.8% in TRD patients [23], which is rele-
vant given that the criteria to access these trials involved
only the failure to respond to two or more antidepressants,
while all the participants in our sample tried at least 3 anti-
depressants, and were using an augmentation treatment.
It is also worthy of note that most of the patients en-
rolled in the study had been diagnosed a mean of 20 years
before they started treatment with esketamine and had
been treated with at least 3 different therapies without
responding. Six of them (37.5%) had also received ECT in
the same episode without improvement, but no sig-
nificant difference was found between this group of pa-
tients and the rest of the sample, who didnt receive ECT in
that episode, or refused to do so.
Clinical Experience with Esketamine 163
Table 1. Description of clinical and demographical variables
Variable Summary of statistical values
Age 16
53.13 ± 10.31
52.00 (49.00;61.00)
27.00/71.00
Sex Male 7 (43.8%)
Female 9 (56.3%)
Total 16 (100%)
BMI 16
27.68 ± 2.84
27.10 (25.85;30.50)
21.40/32.50
Years since diagnosis 16
20.81 ± 11.41
21.00 (15.50;30.00)
2.00/42.00
Single or recurrent episode Recurrent 14 (87.5%)
Single 2 (12.5%)
Total 16 (100%)
Psychiatric comorbidities No 12 (75%)
ADHD 1 (6.3%)
PTSD 1 (6.3%)
Mixed personality disorder 2 (12.5%)
Total 16 (100%)
Previous suicide attempts No 13 (81.3%)
Yes 3 (18.8%)
Total 16 (100%)
Duration of current episode Acute (12 months) 1 (6.3%)
Chronic (24 months) 10 (62.5%)
Sub-acute (1324 months) 5 (31.3%)
Total 16 (100%)
Symptom severity Severe without psychosis 14 (87.5%)
Moderate 2 (12.5%)
Total 16 (100%)
Treatment failures (AD) (34 AD) 5 (31.3%)
(56 AD) 5 (31.3%)
(710 AD) 4 (25%)
(10 AD) 2 (12.5%)
Total 16 (100%)
Augmentation Used 16 (100%)
Not used 0 (0%)
ECT Not used 10 (62.5%)
Used 6 (37.5%)
Total 16 (100%)
MSM score 16
11.00 ± 1.86
10.50 (9.00;13.00)
9.00/14.00
Main antidepressant SNRI 7 (43.8%)
SSRI 9 (56.3%)
Total 16 (100%)
Psychotherapy No 12 (75%)
Yes 4 (25%)
Total 16 (100%)
Values are presented as number only, mean ± standard deviation, median (P25;P75), minimum/maximum.
BMI, body mass index; ADHD, attention deficit hyperactivity disorder; PTSD, post-traumatic stress disorder; ECT, electroconvulsive therapy; MSM,
Maudsley staging method scale; AD, antidepressant; SNRI, serotonine and norepinephrine reuptake inhibitor; SSRI, selective serotonine reuptake
inhibitor.
164 J. Vendrell-Serres,
et al
.
Table 2. Summary of the reported adverse events
Adverse event Frequency, n (%) Severity Treatment required
Dissociation 6 (37.5) Mild None
Sleepiness 4 (25) Mild None
Blurry vision 1 (6.25) Mild None
Nausea 3 (18.75) Mild None
Paresthesia 1 (6.25) Mild None
Anxiety 2 (12.5) Mild None
HBP and headache 1 (6.25) Moderate Captopril 25 mg
Metallic taste 1 (6.25) Mild None
Frequency is pooled (some patients presented with more than one adverse events, while others presented with none).
HBP, high blood pressure.
Fig. 1. Evolution of MADRS scores through time.
T1 = baseline (pretreatment), T2 = 48 hours after treatment, T3 = 8 days
after treatment, T4 = 15 days after, T5 = 22 days after, T6 = 29 days
after, T7 = 2 months after, T8 = 3 months after, T9 = 4 months after.
MADRS, Montgomery-Asberg depression rating scale; CI, confidence
interval.
This data means that our sample included very severe
and difficult to treat depressive patients. The delay in diag-
nosis and treatment has been related to a lack of response
with conventional treatments [24], but the requirements
needed to access the expanded use program prevented
the inclusion of patients with a more recent diagnosis or
who had tried less treatments. Further studies should as-
sess if esketamine might be more efficacious in a more
naïvepopulation. Chronic, or long-term MDD, has been
associated with more mental and non-mental comorbid-
ities, worse clinical features [25] and higher mortality
[26]. An early access to this treatment might lead to a gain
in functionality, an economic save of resources, and a de-
crease in comorbidities and poorer prognosis. The fact
that we found no difference between patients that pre-
viously received ECT and those that didnt, could point to
the possibility of using esketamine, with a better profile of
adverse effects, before resolving to ECT. A recent clinical
trial showed ketamine to be non-inferior to ECT when
treating severe depression, which is in line with our find-
ings [27], taking also into account that esketamine has
been found to be non-inferior to ketamine [28].
The fact that our patients responded to esketamine
when they had failed to respond to other, more conven-
tional treatments, is also consistent with the novel mecha-
nisms of action through which esketamine is thought to
act, involving glutamatergic neurotransmission and mod-
ulation of inflammation [29].
In our study, we observed that esketamine was gen-
erally well tolerated among the patients enrolled. Notably,
no serious adverse events were reported during the study
period. However, we did observe a higher-than-expected
rate of dissociation, which was present in almost one third
of the patients, but no specific medical intervention was
required in any case. Of note, we did encounter one mod-
erate adverse event in our study, which involved hyper-
tension with a blood pressure reading of up to 180 mmHg
and headache. This adverse event was effectively man-
aged with the administration of captopril 25 mg, resulting
in full remission, with no recurrence during subsequent
administration sessions. The use of captopril instead of
benzodiazepines was motivated by the fact that benzo-
diazepines might hinder the therapeutic effect of ket-
amine and esketamine [30]. We did observe some tran-
sient increases in blood pressure that were not registered
as adverse events as they were mild (less than 10 mmHg),
transient and self-limited, and asymptomatic (no head-
ache, or any other symptom that can be caused by sudden
increases in blood pressure). These changes were mainly
observed 40 minutes after administration, as expected,
since the maximum plasmatic concentration of esket-
Clinical Experience with Esketamine 165
Table 3. Coefficients of each variable in a mixed model of time
Variable Coefficient Confidence interval
p
value
Sex 0.2612287 5.372666 to 4.850208 0.921
Suicide attempts (yes/no) 0.6285083 6.977684 to 5.720668 0.846
Symptoms severity 5.37205 13.19416 to 2.450063 0.178
ECT (yes/no) 1.7527 6.879572 to 3.374172 0.503
Main antidepressant 1.286003 6.31715 to 3.745145 0.616
Esketamine dose 0.9383852 7.897841 to 6.02107 0.792
Psychotherapy 4.842932 10.18356 to 0.4976959 0.076
Severity 1.6 14.44746 to 11.24746 0.807
Treatment discontinuation (yes) 1.6 14.44746 to 11.24746 0.807
Pharmacologic treatment 1.6 14.44746 to 11.24746 0.807
Age 0.1017835 0.3482411 to 0.1446741 0.418
BMI 0.240486 0.6696656 to 1.150638 0.605
Years since diagnosis 0.2334347 0.4417477 to 0.0251217 0.028
MSM score 0.2151012 1.183008 to 1.61321 0.763
ECT, electroconvulsive therapy; BMI, body mass index; MSM, Maudsley staging method scale.
Fig. 2. KaplanMayer survival test for response (50% of the initial
MADRS score).
MADRS, Montgomery-Asberg depression rating scale.
Fig. 3. KaplanMayer survival test for remission (12 in MADRS
score).
MADRS, Montgomery-Asberg depression rating scale.
amine is reached at this moment. Blood pressure was
measured before administering esketamine, and 15, 40,
and 90 minutes after administration. There was not any
case of observed elevation of blood pressure that lasted
between measure times.
We also observed that two patients discontinued treat-
ment before the end of the follow-up period due to a wor-
sening of depressive symptoms. During the administration
sessions, both patients presented with anxiety, which was
managed with non-pharmacological techniques such as
verbal support and therapeutic touch. These techniques
were effective in managing their symptoms, and no phar-
macological intervention was required. This adverse event
was not considered the reason for discontinuing treat-
ment, but might grant consideration as a possible proxy
for poor prognosis.
In our clinical experience, the administration of esket-
amine in a supportive environment, with trained clini-
cians that were able to manage acute distress, and the use
of music and minimization of sensory stimuli, were very
useful in improving tolerability and allowing the patient to
ease into the experience. Also, agreeing on a care plan,
166 J. Vendrell-Serres,
et al
.
especially during the induction phase, can increase safety
and reduce anxiety; this generally involves including a
significant person of the patient to pick them up after treat-
ment and to be available, as well as learning to identify
signs of distress and ways of coping with it.
None of the reported adverse effects was significantly
correlated with differences in the clinical outcomes. This
fact grants consideration, given the current debate be-
tween authors that consider esketamine and ketamine to
exert their effect only through their pharmacological ac-
tion, while others suggest that dissociation could be a
marker associated with improvement [31]. Our results,
showing no relationship between dissociation and im-
provement, are consistent with recent findings [32]. No
specific psychotherapy was combined with the treatment
in our patients, and we found no difference in improve-
ment between patients already receiving psychotherapy,
and those that didnt. Nonetheless, the different proposed
mechanisms of esketamine and ketamine, including the
altered states of consciousness that they can cause, and
the window of neuroplasticity that they seem to open,
could prove beneficial for a synergy with certain types of
psychotherapy [33]. We believe that further studies com-
paring the combination of esketamine with psychother-
apy, versus the sole use of esketamine, could shed light on
this question, and maybe allow for the development of
structured treatment programs that could enhance its ef-
fectiveness and prevent relapses. Also, recent studies
show that some clinical factors can predict the chances of
remission and response to treatment [34]. We suggest that
developing prospective studies testing possible endophe-
notypes and biomarkers of depression as well as a thor-
ough stratification based on these factors could contribute
to a better prediction of response to esketamine.
Although our results can shed some light onto real-life
experience on esketamine response in severe and com-
plex patients, the main limitation of our study rests in its
low sample size, which could have hindered the possi-
bility of finding relevant correlations that could inform
prognosis. In the case of the survival model, the number of
events are few, so the variability and the interval of the es-
timation is not precise; hence, conclusions in this regard
must be taken with care. Given its observational nature,
there was also no specific control for possible bias such as
confounding factors.
In conclusion, esketamine appears to be a promising
treatment for individuals with TRD, demonstrating fast
and effective results and good tolerance. However, fur-
ther studies are necessary to fully understand its potential,
such as longer-term follow-up periods and the assessment
of its combination with other pharmacological and psy-
chotherapeutic treatments. Additionally, incorporating
new endophenotypes, biomarkers, and a highly detailed
clinical phenotype based on novel discoveries related to
the etiologic pathways of depression would greatly im-
prove our knowledge of this novel treatment and aid in
better stratifying patients.
None.
Over the course of this investigation, Óscar Soto-
Angona was a recipient of a Río Hortega contract from the
Carlos III National Health Institute.
We thank and acknowledge Santiago Pérez Hoyos
(Vall dHebron Research Institute Biostatistics Unit) for
his expert supervision of the statistical results reported.
J.A.R.Q was on the speakersbureau and/or acted as a
consultant for Janssen-Cilag, Novartis, Shire, Takeda,
Bial, Shionogi, Sincrolab, Novartis, BMS, Medicine,
Rubió, Uriach, Technofarma, and Raffo in the last three
years. He also received travel awards (air tickets + hotel)
for taking part in psychiatric meetings from Janssen-Cilag,
Rubió, Shire, Takeda, Shionogi, Bial, and Medice. The
Department of Psychiatry chaired by him received unre-
stricted educational and research support from the follow-
ing companies in the last three years: Janssen- Cilag,
Shire, Oryzon, Roche, Psious, and Rubió.
A.R.U has received travel awards (air tickets + hotel) for
taking part in annual psychiatric meetings from Lundbeck
and has acted as a speaker at various training courses fi-
nanced by Organon, Janssen-Cilag, Lundbeck.
O.S.A has received travel awards (air tickets + hotel) for
taking part in annual psychiatric meetings from Lundbeck
and Janssen-Cilag. He also has acted as a speaker for
Lundbeck, and as a consultant for MAPS Foundation.
J.V.S has received travel awards (air tickets + hotel) for
taking part in annual psychiatric meetings from Lundbeck
and Janssen-Cilag and was on the speakersbureau and
Acknowledgments
Conflicts of Interest
Funding
Clinical Experience with Esketamine 167
acted as consultant for Janssen Cilag.
B.I. has no conflict of interest to report.
A.L.G. has no conflict of interest to report.
Conceptualization: Júlia Vendrell-Serres, Óscar Soto-
Angona, Amanda Rodríguez-Urrutia and Josep Antoni
Ramos-Quiroga designed the study and obtained the
ethics approval. Data acquisition: Júlia Vendrell-Serres,
Antonia López González and Óscar Soto-Angona gath-
ered the clinical data and collaborated in the creation of
the dataset used for the study. Formal analysis: Júlia
Vendrell-Serres, Amanda Rodríguez-Urrutia and Óscar
Soto-Angona performed the statistical analysis of the re-
sults obtained. Funding: no funding was provided or used
for the development of this publication. Supervision: Josep
Antoni Ramos-Quiroga supervised the development of
the study. Writing of original draft: Óscar Soto-Angona,
Benedetta Inzoli and Amanda Rodríguez-Urrutia con-
ducted the bibliographic search, and wrote the different
versions of the manuscript. Writing review & editing: All
authors provided key suggestions and contributed to the
discussion, proofreading and correction of the final ver-
sion of this work. All authors meet all four criteria for au-
thorship included in the ICMJE recommendations
Júlia Vendrell-Serreshttps://orcid.org/0000-0002-1333-7943
Óscar Soto-Angona https://orcid.org/0000-0003-0234-4280
Amanda Rodríguez-Urrutia
https://orcid.org/0000-0001-6882-205X
Benedetta Inzoli https://orcid.org/0000-0002-4745-6182
Antonia López González
https://orcid.org/0009-0004-2286-9994
Josep Antoni Ramos-Quiroga
https://orcid.org/0000-0003-1622-0350
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... There is growing evidence on the use of adjunctive treatment as a strategy for addressing inadequate response to ADT [7][8][9][10][11][12][13]. Research supports the adjunctive use of antidepressants with non-monoaminergic activity or atypical antipsychotics for patients not responding adequately to ADT [7][8][9][10][11][12][13]. Recently, esketamine, a substance with glutamatergic neuromodulatory properties, has exhibited positive outcomes in reducing depressive symptoms in re-al-world scenarios when used as an adjunct treatment [7,8]. ...
... There is growing evidence on the use of adjunctive treatment as a strategy for addressing inadequate response to ADT [7][8][9][10][11][12][13]. Research supports the adjunctive use of antidepressants with non-monoaminergic activity or atypical antipsychotics for patients not responding adequately to ADT [7][8][9][10][11][12][13]. Recently, esketamine, a substance with glutamatergic neuromodulatory properties, has exhibited positive outcomes in reducing depressive symptoms in re-al-world scenarios when used as an adjunct treatment [7,8]. ...
... There is growing evidence on the use of adjunctive treatment as a strategy for addressing inadequate response to ADT [7][8][9][10][11][12][13]. Research supports the adjunctive use of antidepressants with non-monoaminergic activity or atypical antipsychotics for patients not responding adequately to ADT [7][8][9][10][11][12][13]. Recently, esketamine, a substance with glutamatergic neuromodulatory properties, has exhibited positive outcomes in reducing depressive symptoms in re-al-world scenarios when used as an adjunct treatment [7,8]. Additionally, the adjunctive use aripiprazole, an atypical antipsychotic, has been demonstrated to be an effective intervention in patients with MDD who had inadequate responses to ADT [9]. ...
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Background: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. Methods: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. Results: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. Conclusions: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).
Article
Background: Major depressive disorder (MDD) is a leading cause of disability worldwide and most people do not achieve symptom remission. Treatment-resistant depression (TRD) is characterized by the failure of at least one adequate trial of a major class of antidepressant, with adequate time and dosage. We aimed to identify clinical predictors of depressive symptom remission and response 24 h and 7 days after racemic ketamine and esketamine infusions. Methods: A randomized, double-blind, active-controlled, non-inferiority trial using ketamine and esketamine in TRD. Individuals diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders version IV and fulfilling TRD criteria were recruited from March 2017 to June 2018. Participants received a single subanesthetic dose of ketamine (0.5 mg/kg) or esketamine (0.25 mg/kg) for 40 min. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and symptom remission was defined as a MADRS score ≤7 and response defined as ≥50% reduction in depressive symptom severity, 24 h and 7 days after the infusion. Clinical variables were selected based on previous clinical trials. Stepwise backward logistic regression was used, considering a confidence level of 95%. Results: 61 subjects were included: 39 (63.9%) were females with a mean age of 47.2 ± 14.9. Higher number of therapeutic failures (Odds Ratio (OR) = 0.677; 95% confidence interval (CI): 0.47-0.97) and higher severity of illness (OR = 0.912; 95% CI: 0.83-0.99) were associated with fewer remissions of depressive symptoms 7 days after intervention, and with fewer response in 24 h (OR = 0.583; 95% CI: 0,40; 0,84 and OR = 0.909; 95% CI: 0,83; 0,99, respectively). Conclusion: Number of treatment failures and severity of illness were predictors of fewer remissions and responses of depressive symptoms in this TRD population. Study of predictors of remission may contribute to better selection patients that may benefit from receiving ketamine.
Article
Depressive Disorders are the most common psychiatric diagnoses in the general population. To estimate the frequency, costs associated with Depressive Disorders in usual clinical practice, and in the whole Spanish population, a longitudinal, retrospective, observational study was carried out using data from the BIG-PAC database®. Study population: all patients aged ≥ 18 years with a diagnosis of a Depressive Disorder in 2015–2017. Prevalence was computed as the proportion of Depressive Disorder cases in the adult general population, and the incidence rate, as the number of new Depressive Disorder cases diagnosed per 1,000 person-years in the population using health services, during 2015–2017. We collected demographic variables, comorbidity, direct health costs, and indirect costs (temporary and permanent disability). Health costs related to Depressive Disorders were estimated according to the annual resource use rate (resource/patient/year). Indirect costs were calculated according to the human capital method. Using the study data and information from the Spanish National Institute of Statistics, we estimated the cost of Depressive Disorders corresponding to the Spanish adult population, including premature mortality. 69,217 Depressive Disorder patients aged ≥ 18 years who met the inclusion/exclusion criteria were studied (mean age: 56.8 years; female: 71.4%). Prevalence of Depressive Disorders in the general population was 4.73% (95% CI: 4.70–4.76%). Annual incidence rates (2015–2017) were 7.12, 7.35 and 8.02 per 1,000 person-years, respectively. Total costs observed in our Depressive Disorder patients were € 223.9 million (corresponding to a mean of € 3,235.3; mean/patient/year), of which, 18.4% were direct health care costs and 81.6%, non-health indirect costs (18% temporary occupational disability, 63.6% permanent disability). Considering also the cost of premature death, the mean cost per patient/year was € 3,402 and the estimated societal costs of Depressive Disorders in Spain were € 6,145 million. The prevalence and incidence of Depressive Disorders are consistent with other series reviewed. Resource use and total costs (especially non-health costs) were high.