Journal of Affective Disorders 348 (2024) 314–322

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

The rapid antidepressant effectiveness of repeated dose of intravenous

ketamine and intranasal esketamine: A post-hoc analysis of pooled
real-world data
Giacomo d'Andrea a, Mauro Pettorruso a, Giorgio Di Lorenzo b, c, Taeho Greg Rhee d, e, f,
Stefania Chiappini a, Rosalba Carullo a, Stefano Barlati g, h, Raffaella Zanardi i, j, Gianluca Rosso k,
Marco Di Nicola l, Ileana Andriola m, Matteo Marcatili n, Massimo Clerici n, o,
Bernardo Maria Dell'Osso p, Stefano L. Sensi a, Rodrigo B. Mansur q, r, Joshua D. Rosenblat q, r, s,
Giovanni Martinotti a, t, 1, Roger S. McIntyre q, r, s, *, 1
a
Department of Neurosciences, Imaging and Clinical Sciences, Università degli Studi G. D'Annunzio, Chieti, Italy
b
Chair of Psychiatry, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy
c
IRCCS Fondazione Santa Lucia, Rome, Italy
d
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
e
VA New England Mental Illness, Research, Education and Clinical Center (MIRECC), VA Connecticut Healthcare System, West Haven, CT, USA
f
Department of Public Health Sciences, School of Medicine, University of Connecticut, Farmington, CT, USA
g
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
h
Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, Brescia, Italy
i
Mood Disorder Unit, Department of Clinical Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
j
Department of Clinical Neurosciences, University Vita-Salute San Raffaele, Milan, Italy
k
Department of Neurosciences Rita Levi Montalcini, University of Torino, Turin, Italy
l
Department of Neurosciences, Section of Psychiatry, Università Cattolica del Sacro Cuore, Rome; Department of Psychiatry, Fondazione Policlinico Universitario
"Agostino Gemelli" IRCCS, Rome, Italy
m
Università degli Studi di Bari Aldo Moro, Italy
n
Department of Mental Health and Addiction, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
o
School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
p
Department of Biomedical and Clinical Sciences Luigi Sacco and Aldo Ravelli Center for Neurotechnology and Brain Therapeutic, University of Milan, Milano, Italy
q
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
r
Brain and Cognition Discovery Foundation, Toronto, ON, Canada
s
Braxia Health, Canadian Centre for Rapid Treatment Excellence (CRTCE), Mississauga, ON, Canada
t
Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10
9AB, UK

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: Intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) are effective in the acute
Intranasal esketamine treatment of Treatment-Resistant Depression (TRD). Studies comparing KET-IV and ESK-NS concerning their
Intravenous ketamine action, safety, and tolerability are currently lacking.
Treatment-resistant depression
Materials and methods: We combined patients' data from two unipolar TRD cohorts that received KET-IV (n =
TRD
Comparative study
171) at the Canadian Rapid Treatment Center of Excellence in Toronto, Canada, or ESK-NS (n = 140) at several
TRD clinics in Italy. The Quick Inventory for Depression Symptomatology-Self-Report-16/QIDS-SR16 in the KET-
IV group and Montgomery-Åsberg Depression Rating Scale/MADRS in the ESK-NS group measured depressive
symptoms at baseline (T0) and after the acute treatment phase (T1) (i.e., four infusions of KET-IV and eight
administrations of ESK-NS). As different scales were used, the primary outcome was to compare the improvement
in depression severity in the two cohorts by measuring effect sizes, response and remission rates. Finally, we
compare side effects and discontinuation rates.

* Corresponding author at: Brain and Cognition Discovery Foundation, Toronto, ON, Canada.
E-mail address: [email protected] (R.S. McIntyre).
1
These authors equally contributed as last authors.

https://doi.org/10.1016/j.jad.2023.12.038
Received 14 September 2023; Received in revised form 30 November 2023; Accepted 13 December 2023
Available online 23 December 2023
0165-0327/© 2024 Elsevier B.V. All rights reserved.
G. d'Andrea et al. Journal of Affective Disorders 348 (2024) 314–322

Results: At T1, KET-IV and ESK-NS significantly reduced depressive symptoms (respectively: QIDS-SR16 mean
reduction = 5.65, p < 0.001; MADRS mean reduction = 11.41, p = 0.025). KET-IV showed larger effect sizes
compared to ESK-NS (1.666 vs. 1.244). KET-IV had higher response rates (36 % vs. 25 %; p = 0.042) but not
superior remission rates (13 % vs. 12 %; p = 0.845) than ESK-NS at T1. Despite more reported side effects, KET-
IV did not cause more discontinuations for adverse events (4.6 % vs. 2.12 %; p = 0.228) than ESK-NS.
Conclusion: KET-IV showed a higher short-term antidepressant effect, whereas ESK-NS exhibited lower side ef­
fects. Both were generally well tolerated. Future head-to-head studies should consider the long-term efficacy of
these treatments.

1. Introduction 2022). Both KET-IV and ESK-NS have demonstrated their rapid antide­
pressant effects. ESK-NS has shown superior efficacy in reducing
Treatment-resistant Depression (TRD) is a severe and debilitating depressive symptoms within the first month of treatment, as supported
condition that imposes a significant disease burden and incurs sub­ by several RCTs (Fedgchin et al., 2019; Popova et al., 2019). Similarly,
stantial direct and indirect healthcare costs. It affects approximately KET-IV has shown greater antidepressant efficacy in both RCTs and real-
one-third of individuals diagnosed with Major Depressive Disorder world studies by the end of the acute phase of treatment, typically 3–4
(MDD) (Zhdanava et al., 2021). TRD is commonly defined as the absence weeks after initiation (McIntyre et al., 2020c; Phillips et al., 2019).
of response to two trials of antidepressant medications administered at Besides, the existing empirical data derived from investigations
adequate dosages and duration (at least 6–8 weeks) while ensuring pa­ comparing the effectiveness of ESK-NS and KET-IV remain relatively
tient compliance (Sforzini et al., 2022). Due to its high disease burden sparse, and the outcomes from meta-analytical examinations attempting
and the limitations of conventional therapies such as monoaminergic to match the antidepressant effect of these two treatments demonstrate
antidepressants, there is an increasing need to explore new, effective mixed results (Bahji et al., 2021; McIntyre et al., 2020a). Consensus
treatments for TRD (Shah et al., 2021). Recent research efforts have exists that both controlled and real-world evidence is needed to inform
focused mainly on Non-Invasive Brain Stimulation Techniques, such as the relative effectiveness of different routes of delivery of ketamine as
repetitive Transcranial Magnetic Stimulation(rTMS) (D'Andrea et al., well as different formulations (McIntyre et al., 2021).
2023b; Pettorruso et al., 2023a) and on glutamatergic agents, as The aim of the study herein is to evaluate and compare the real-world
demonstrated by multiple neuroimaging studies indicating that gluta­ effectiveness of repeat dose IV-racemic Ketamine and intranasal Esket­
matergic dysfunction plays a key element in mood disorders (Arnsten amine in a well-characterized cohort with mood disorders presenting
et al., 2023; Dean et al., 2021). with TRD. In addition, we separately evaluated the safety, tolerability,
Recently, ketamine and its S-enantiomer, esketamine, have emerged and overall effect on measures of suicidality.
as established acute treatments for adults with TRD. Numerous studies
have provided evidence of their strong efficacy in treating depression, 2. Materials and methods
leading to their recognition as evidence-based interventions for TRD
(McIntyre et al., 2021). Additionally, promising evidence supports their 2.1. Post-hoc study analysis and patient selection
use in treatment-resistant bipolar depression and mixed-features
symptoms (Martinotti et al., 2023; McIntyre et al., 2020b; Pettorruso The current study is a retrospective, post-hoc pooled analysis
et al., 2023b), in patients with comorbid substance use (Chiappini et al., encompassing data from two discrete cohorts of TRD subjects. The first
2023) and in older adults (d'Andrea et al., 2023a). While the exact cohort consists of subjects who underwent intravenous ketamine (KET-
mechanisms behind the antidepressant effects of ketamine are not yet IV) therapy at the Canadian Rapid Treatment Center of Excellence
fully understood, it is known to antagonize glutamatergic N-methyl-D- (CRTCE) in Mississauga, Ontario, Canada (McIntyre et al., 2020c). The
aspartate receptors (NMDAr) in the central nervous system (Zanos and second cohort includes subjects who received esketamine nasal spray
Gould, 2018). Moreover, emerging evidence suggests that ketamine's (ESK-NS) treatment as part of the REAL-ESK study (Martinotti et al.,
mechanisms extend beyond the glutamatergic system, involving cellular 2022) a multicentric real-world study that included different Italian TRD
excitability and complex second messenger pathways that result in centers.
varied neuroplastic and neurogenic responses (i.e., BDNF/mTOR path­ In the present analysis, we included a sub-sample of participants
ways and GFK3β phosphorylation) (D'Andrea et al., 2023c). Further­ from the two studies (for KET-IV n = 171, for ESK-NS n = 140), focusing
more, ketamine engages with multiple other neurotransmitter systems, solely on subjects primarily diagnosed with MDD. Subjects with a TRD in
notably including mu, delta, and kappa opioid receptors, and is pres­ the context of a Bipolar Disorder were excluded from the present anal­
ently employed as an analgesic for both acute and chronic pain man­ ysis. Additionally, to guarantee the proper matching of patients, we only
agement (Williams et al., 2018). include individuals with provided information about their age and
Despite ketamine demonstrating significant antidepressant effects in gender.
various studies, significant concerns regarding tolerability and the Given the discrepancy in the time-points evaluated across the two
implementation of intravenous administration (KET-IV) have limited its studies, we have considered two time-points for evaluation to maintain a
use in routine clinical practice and its approval by regulatory agencies (i. certain level of uniformity in the analysis. These are the baseline or pre-
e., U.S. Food and Drug Administration (FDA) and the European Medi­ treatment initiation (T0) and the one-month follow-up observation (T1),
cines Agency (EMA)) (Cohen et al., 2018; Smith-Apeldoorn et al., 2019). which corresponds to the post-treatment initiation visit in the KET-IV
In response to these limitations, clinicians and researchers have sought group (McIntyre et al., 2020c), and the conclusion of the treatment in­
alternative formulations and delivery systems for ketamine. Intranasal duction phase in the ESK-NS group (Martinotti et al., 2022).
esketamine (ESK-NS) has recently been approved by the FDA and EMA
as the first specific therapy for TRD (EMA, 2019; FDA, 2019), supported 2.1.1. KET-IV group
by several randomized controlled trials demonstrating its efficacy (Daly Data for the KET-IV group were obtained from patients treated at the
et al., 2018; Fedgchin et al., 2019; Wajs et al., 2020). ESK-NS appears to Canadian Rapid Treatment Center of Excellence (CRTCE) in Mis­
overcome the practical difficulties commonly associated with ketamine sissauga, Ontario, Canada. The CRTCE is an outpatient clinical and
infusion, and real-world studies have confirmed its effectiveness and research facility that provides KET-IV treatment for adults (i.e., ages
tolerability in clinical settings (Martinotti et al., 2022; Samalin et al., ≥18 years) with TRD as part of MDD. CRTCE eligibility for ketamine

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treatment, as well as best practices for the safe and appropriate delivery saline solution, and infused in 40 min. In cases where patients demon­
of ketamine, are in accordance with the Consensus Statement for the strated a suboptimal response after two infusions, they were offered a
American Psychiatric Association (APA) Council of Research Task Force dose optimization of 0.75 mg/kg for the subsequent two infusions. Dose
(Sanacora et al., 2017). All individuals must have had an insufficient optimization was not provided to patients who: a) exhibited a >20 %
response at two trials of different antidepressant classes, as reported in reduction in depression severity, b) could not tolerate the side effects at
consensus definitions for TRD (Sforzini et al., 2022). the initial dose, or c) opted to maintain the initial dose. The mean
Before the initial infusion, every patient undergoes an evaluation by number (±standard deviation) of ketamine infusions in the KET-IV
a CRTCE-affiliated psychiatrist to confirm the primary diagnosis of a group was 4 (±0.353).
mood disorder and provide psychoeducation concerning diagnosis and
treatment. Medical clearance must be granted to all patients before their 2.2.2. Esketamine administration
first infusion, ascertained by CRTCE staff anesthesiologists who assess Esketamine was dispensed in adherence to the guidelines set forth by
individuals for contraindicated unstable medical disorders related to the EMA (EMA, 2019). A starting dosage of 56 mg was delivered on day
KET-IV administration (e.g., malignant hypertension, supraventricular one (the dosage was modified to 28 mg for patients exceeding 65 years
tachycardia). KET-IV is typically administered as an adjunct to subop­ of age), and all ensuing dosage protocols were clinician-determined,
timal psychotropic medication regimens. The rationale for adjunctive contingent upon efficacy and patient tolerance. In cases where pa­
administration, in most instances, aims to increase patient acceptability, tients demonstrated a suboptimal response, they were offered a dose
enhance feasibility, and expedite ketamine treatment delivery (i.e., optimization of 84 mg for the subsequent administrations. Following
circumventing the necessity for medication washout syndrome/mitiga­ EMA directives, ESK-NS was administered bi-weekly.
tion). Patients prescribed an irreversible monoamine oxidase inhibitor
(MAOI) discontinued its use at least two weeks before ketamine 2.3. Sociodemographic data and psychometric assessment
administration. Naltrexone is not allowed during ketamine treatment,
and benzodiazepines must not be consumed within 12 h preceding The collection of sociodemographic data in this study involved the
intravenous ketamine administration. These restrictions were based on gathering of information related to various factors, including gender,
preliminary evidence suggesting that naltrexone and benzodiazepines age, treatment history for the current MDE, prior trials of antidepressant
may diminish ketamine's efficacy (Frye et al., 2015; Williams et al., medication, and the use of augmentation strategies (i.e., the combined
2018). Patients undergoing a medication taper or change for KET-IV use of mood stabilizers, or antipsychotics) and other therapeutic in­
treatment were closely monitored by their referring physician and the terventions employed for TRD (i.e., Transcranial Magnetic Stimulation,
CRTCE. To minimize the risk of drug-drug interactions from medications Electroconvulsive Therapy). Additionally, data were collected in case of
other than benzodiazepine, naltrexone, or MAOIs, patients were asked premature study withdrawal or clinically significant events, such as
to temporarily stop all other medications 6 h before infusion. These admission or discharge from inpatient care, symptom relapse, or MDE
medications could then be restarted 4 h after the infusion. This study remission.
was approved by a community Institutional Review Board and regis­ For the KET-IV group, depression severity was evaluated via the self-
tered on the clinicaltrials.gov website (https://clinicaltrials.gov/s reported Quick Inventory of Depressive Symptomatology with 16 items
tudy/NCT04209296). (QIDS-SR16).
On the other hand, in the ESK-NS cohort, the severity of depression
2.1.2. ESK-NS group was measured using the clinician-rated Montgomery-Åsberg Depression
Data for the ESK-NS group were obtained from the REAL-ESK study, Rating Scale (MADRS).
a multicentric, retrospective study that investigates the effectiveness of
ESK-NS in real-world TRD subjects recruited from several Italian TRD 2.4. Statistical analysis
centers. Centers involved are reported in previous studies (Martinotti
et al., 2022). Inclusion criteria were as follows: a) age over 18; b) current Statistical analyses were performed using SPSS 20.0 software (SPSS
TRD in the context of a MDD. TRD was defined as having a major Inc., Chicago, IL, USA) and JASP for Mac (JASP version: 0.16.4; JASP
depressive episode (MDE) undergoing at least two conventional anti­ Team, 2022). All tests were two-tailed, with a statistical significance
depressant trials at optimal dose and duration, without a clinical level set at p < 0.05. Continuous variables are expressed as mean ±
response (i.e., ≥50 % decrease of depressive symptoms from baseline) standard deviation (SD), while categorical variables are reported as
(Sforzini et al., 2022); c) following indication of ESK-NS Summary of average numbers and percentages. The student t-test was conducted to
Product Characteristics (SPCs) being in treatment with at least one SSRI assess changes in continuous variables, whereas the Pearson χ 2 test was
or SNRI antidepressant (EMA, 2019). performed for categorical variables. We used the Shapiro-Wilk test to
The only exclusion criterion was the presence of severe comorbidities assess the normality distribution of continuous variables. Parametric
contraindicating the administration of ESK-NS (myocardial infarction tests were used for continuous variables with normal distributions (i.e.
within six weeks before ESK-NS introduction, severe and untreated hy­ repeated measure ANCOVA), whereas non-parametric test was con­
pertension, aneurysmal vascular disease, hemorrhagic ictus) consid­ ducted in presence of non-normal distributions (Wilcoxon signed-rank
ering previous evidence on possible safety issues (EMA, 2019). test).
This study was approved by the local ethic committee of the Uni­ Given the presence of discrepancies between the two groups in terms
versità degli Studi di Brescia (Protocol number: NP5331), and the study of the psychometric scales used to assess depressive symptoms (i.e.,
protocol was published in the open-access journal of the Italian Society clinician-rated MADRS in the ESK-NS group vs. self-administered scale
of Psychiatry (D'Andrea et al., 2022). QIDS-SR16 in the KET-IV group), separate analyses were performed in
the two groups. The general linear model approach via repeated mea­
2.2. Study procedures sure ANCOVA (rm-ANCOVA) (within-factor: “time”; between-factors:
gender; covariates: age, number of failed antidepressant trials in the
2.2.1. Ketamine infusions current episode) was used to assess the variation across timepoints of
All patients were administered KET-IV following the best practice MADRS scores for the ESK-NS group, and of QIDS-SR16 scores for the
guidelines proposed by the American Psychiatric Association (Sanacora KET-IV group. The effect sizes of the two different analyses (Cohen's
et al., 2017). Upon approval from medical staff, patients initiated an d for rm-ANCOVA, Rank-Biserial Correlation for Wilcoxon signed-rank
acute treatment phase comprising four infusions over two weeks. The test) were compared to discern differences in the efficacy of the two
initial two infusions were administered at 0.5 mg/kg, diluted in a 0.9 % treatments.

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Response rates (i.e., a reduction of at least 50 % of the overall significantly higher in the KET-IV group compared to the ESK-NS group
MADRS score from baseline in the ESK-NS group and a reduction of at [respectively, n = 61/171 (36 %) vs. n = 35/140 (25 %); χ 21 = 4.127, p =
least 50 % in the QIDS-SR16) and remission rates (i.e., MADRS total 0.042]. On the other hand, there were no significant differences between
score < 10 for the ESK-NS group, QIDS-SR16 < 5 for the KET-IV group) the two groups regarding rates of remission at T1 [KET-IV: n = 22/171
were compared using a Pearson χ 2 test. Consequently, a binomial lo­ (13 %) vs. n = 17/140 (12 %); χ 21 = 0.38, p = 0.845].
gistic regression model was conducted to estimate the Exp(B) ratio and The logistic binary regression model confirmed the significance of
associated Confidence Intervals (CIs, 95 %) of random-effects (i.e., treatment type (i.e., KET-IV vs. ESK-NS) in determining the overall
gender, age) and fixed-effects (i.e., treatment type/ESK-NS vs. KET-IV) probability of response at T1 in favor of KET-IV [Exp(B) = 1.722 (95%CI
able to influence response and remission rates at T1. 1.048–2.830), p = 0.032]. Furthermore, age [Exp(B) = 1.007 (95%CI
0.987–1.027), p = 0.518], gender [Exp(B) = 1.139 (95%CI
2.5. Ethics 0.700–1.852), p = 0.601] and number of previous antidepressant trials
[Exp(B) = 1.164 (95%CI 0.929–1.458), p = 0.186] failed to be pre­
The study was conducted in line with the principles of the Declara­ dictors of the model.
tion of Helsinki (WMA, 2013). All personal data were treated confi­ A logistic binary regression model for remission indicated that at T1
dentially and anonymously. neither age [Exp(B) = 0.999 (95%CI 0.967–1.033), p = 0.972], treat­
ment type (i.e. KET-IV vs. ESK-NS) [Exp(B) = 1.357 (95%CI
3. Results 0.599–3.073), p = 0.464], gender [Exp(B) = 1.497 (95%CI
0.681–3.294), p = 0.316] or number of previous antidepressant trials
3.1. Sociodemographic and clinical characteristics [Exp(B) = 1.045 (95%CI 0.797–1.369), p = 0.752] are significant pre­
dictors of remission at T1.
The total sample included 311 TRD subjects, comprised of two sub-
groups: those who received KET-IV (n = 171) and those who under­ 3.3. Anti-suicidal action of KET-IV and ESK-NS
went treatment with ESK-NS (n = 140). Samples were matched based on
age and gender while concurrently ensuring the absence of statistically Since distribution for suicidal symptoms (i.e. MADRS item-10, QIDS-
significant disparities among groups in the quantity of unsuccessful SR16 item-12) across the two cohorts was found to be not normal
previous antidepressant trials (Table 1). In the KET-IV group, 106 of the (Shapiro-Wilk test; ps < 0.001) a Wilcoxon signed-rank test was used to
171 participants received a 0.5 mg/kg infusion, which was escalated to assess the effect of “time” on suicidal symptoms. Suicidal symptoms
0.75 mg/kg at the third infusion, while the remaining 65 subjects were reduced in both groups (KET-IV: W = 2.381, p < 0.001; ESK-NS: W
continued with a consistent 0.5 mg/kg infusion throughout the treat­ = 3451.5, p < 0.001) with similar effect sizes [KET-IV: Rank-Biserial
ment period. Regarding the ESK-NS group, 69 of the 140 participants Correlation = 0.916 (95%CI: 0.861–0.950); ESK-NS: Rank-Biserial
were administered 84 mg per treatment session, 66 received 56 mg, and Correlation = 0.934 (95%CI: 0.894–0.959)] (see Fig. 1, Table 2).
5 had the lowest dose of 28 mg.
3.4. Safety and tolerability between ESK-NS and KET-IV
3.2. Antidepressant effectiveness of ESK-NS and KET-IV
Compared to ESK-NS, the KET-IV group exhibited higher levels of
Since MADRS and QIDS-SR16 scores were found to be normal in both reported dissociative symptoms as treatment-emergent adverse events
the cohorts (Shapiro-Wilk test, QIDS-SR16: p = 0.171; MADRS: p = (TEAEs) [KET-IV n = 99/171 (57.5 %), ESK-NS: n = 48/140 (34 %); χ 22
0.331), a parametric test was used (rm-ANCOVA). In both groups, the = 10.327, p = 0.006), higher frequency of treatment-emergent hyper­
rm-ANCOVA showed a significant effect of “time” on depressive symp­ tension [KET-IV: n = 78/171 (45 %), ESK-NS: n = 13/140 (9.2 %); χ 21 =
toms when controlling for several baseline factors (between factor: 39.834, p < 0.001], more frequent dizziness after administration [KET-
gender; covariates: age, number of failed antidepressant trials in the IV: n = 51/171 (30 %), ESK-NS: n = 9/140 (6.3 %); χ 21 = 23.749, p <
current episode) [KET-IV: mean reduction:5.65 (95%CI:5.59–5.71) 0.001] and sedation [KET-IV: n = 86/171 (50 %), ESK-NS: n = 38/140
F1,143 = 22.428, p < 0.001; ESK-NS: mean reduction: 11.41 (95%CI: (27 %); χ 21 = 12.785, p < 0.001]. The frequency of other reported TEAEs
10.76–12.06), F1,126 = 5.146, p = 0.025] with KET-IV exhibiting larger did not differ between the two groups; other side effects were: vomiting
effect size [KET-IV: Cohen's d = 1.666 (95%CI: 1.367–1.859); ESK-NS:
[KET-IV: n = 2/171 (1.2 %), ESK-NS: n = 3/140 (2.12 %); χ 21 = 0.283, p
Cohen's d = 1.244(95%CI: 1.039–1.350)] (see Fig. 1, Table 2).
= 0.595], headache [KET-IV: n = 8/171 (4.6 %), ESK-NS: n = 6/140
Furthermore, as shown in Fig. 2, response rates at T1 were
(4.2 %); χ 21 = 0.000, p = 0.989]. All TEAEs exhibited a transient nature
and were associated with the administration of the pharmaceutical
Table 1
agent, with the majority of them resolving after the peak phase of drug
Sociodemographic and clinical characteristics of the two sample.
exposure. No case of abuse/misuse has been reported, and no case of
KET-IV (n ESK-NS (n ¼ Statistics p ketamine-induced uropathy was reported.
¼ 171) 140)
The rate of drop-outs due to adverse events was not significantly
Age 47.53 ± 49.37 ± − 1.341 0.181 different between groups [KET-IV: n = 26/171 (15.2 %), ESK-NS: n =
12.43 11.64
12/140 (8.5 %); χ 21 = 3.158, p = 0.066]. In both groups, most of the
Gender (M/F) 85/87 66/75 0.125 0.723
Number of antidepressant 2.73 ± 0.72 2.46 ± 0.70 1.538 0.125 dropouts are related to inefficacy [KET-IV: n = 17/171 (10 %), ESK-NS:
trials (n) n = 9/140 (6.3 %)]. Drop-outs for tolerability reasons [KET-IV: n = 8/
SSRI 1.43 ± 0.55 1.52 ± 0.501 − 1.360 0.175 171 (4.6 %), ESK-NS: 3/140 (2.12 %)] were not statistically different
SNRI 0.30 ± 0.35 ± 0.479 − 0.699 0.485
between the two groups (χ 21 = 1.450, p = 0.228).
0.466
TCAs 0.07 ± 0.08 ± − 0.239 0.812
0.300 0.0.280 4. Discussion
MAOIs 0.01 ± 0.01 ± 0.092 − 0.952 0.342
0.081 This is the largest study of real-world patients to compare ESK-NS
Other antidepressants 1.00 ± 1.48 0.54 ± 0.50 3.413 0.001
Occupation (employed/
and KET-IV antidepressant action in TRD subjects. In addition to
80/92 73/68 0.859 0.354 comparing outcomes between two distinct formulations and delivery
unemployed)
methods, patients were real-world patients receiving care in two

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G. d'Andrea et al. Journal of Affective Disorders 348 (2024) 314–322

Fig. 1. QIDS-SR16 and MADRS means score (A and B) and confidence intervals (vertical bars) in the ESK-NS and KET-IV groups at baseline (T0) and after
one month (T1). QIDS-SR16 item-12 and MADRS item-10 (suicidal ideation) means score (C and D) and confidence intervals (vertical bars) in the ESK-NS
and KET-IV groups at baseline (T0) and after one month (T1).

separate countries. Both interventions resulted in clinically meaningful

Table 2
improvement in depressive symptoms, as evidenced by the significance
Mean and standard deviation (SD) values of MADRS and QIDS-SR16 total scores
of the rm-ANCOVA models for both the KET-IV and the ESK-NS groups.
and suicidal ideation items (QIDS-SR16 item-12; MADRS item-10) in ESK-NS
and KET-IV groups at baseline/pre-treatment (T0), at the end of the treatment This is consistent with the current body of evidence, indicating that both
with KET-IV/first treatment month with ESK-NS (T1). treatments offer expedited intervention strategies for TRD, manifesting
significant alleviation of depressive symptoms within the first month
Protocol N Mean SD
(Fedgchin et al., 2019; McIntyre et al., 2020c; Popova et al., 2019).
QIDS-SR16 Total Score A comparison of the estimated effect sizes and response rates in­
T0 KET-IV 171 18.61 3.795
dicates that the overall magnitude of depressive symptom reduction was
T1 KET-IV 145 11.37 5.381
MADRS Total Score greater in KET-IV than in ESK-NS treated participants at T1 [effect sizes:
T0 ESK-NS 140 34.40 8.69 KET-IV: Cohen's d = 1.666; ESK-NS: Cohen's d = 1.244; response rates:
T1 ESK-NS 128 22.99 10.64 KET-IV: n = 61/171 (36 %) vs. ESK-NS: n = 35/140 (25 %)]. This finding
QIDS-SR16 item-12
is also confirmed by the regression model, which indicates a higher
T0 KET-IV 171 1.29 0.835
T1 KET-IV 157 0.75 0.837
probability for subjects treated with KET-IV to achieve a clinical
MADRS item-10 response compared to those treated with ESK-NS [Exp(B) = 1.722 (95%
T0 ESK-NS 140 2.17 1.542 CI 1.048–2.830), p = 0.032].
T1 ESK-NS 128 1.07 1.253 The observed discrepancy in response between KET-IV and ESK-NS
in our sample might indicate the faster onset of action from KET-IV.

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Fig. 2. Percentages of the response rates (≥50 % decrease of MADRS total score or QIDS-SR16) at T1 (left panel/A.) and remission rates (MADRS total score < 10 or
QIDS-SR16 < 5) at T1 (right panel/B.) in the KET-IV and ESK-NS protocol groups.

Concerning ESK-NS use in TRD, multiple real-world studies suggest that demonstrated a satisfactory safety profile, with no serious adverse
the incidence of late-responders (i.e., patients who don't exhibit a events reported in either group. TEAEs were all transient, subsiding
response within the first month but show a response in the following post-treatment administration. Nevertheless, ESK-NS presents a lower
months of treatment) is significant (Martinotti et al., 2022; Samalin incidence of TEAEs than KET-IV, with higher discontinuation rates
et al., 2022). Indeed, our results could not be interpreted as indicating a found in the KET-IV group compared to the ESK-NS group, respectively,
superior antidepressant efficacy of KET-IV compared to ESK-NS. 18 % vs. 8.5 %. However, discontinuations for heavy TEAEs were very
The more rapid antidepressant action of KET-IV compared to ESK-NS low in both groups (4.6 % vs. 2.12 %, respectively) and not significantly
is highly significant and may be due to various factors, including po­ different. Furthermore, no serious or life-threatening side effects were
tential differences in bioavailability. On the one hand, the intravenous reported, including ketamine-induced urological toxicity, which is
administration of ketamine ensures optimal bioavailability, reaching commonly considered a significant concern according to the existing
nearly 100 % (Zanos and Gould, 2018). On the other, the intranasal literature (Ng et al., 2021). This further corroborates the safety of both
formulation of esketamine appears to result in a lower bioavailability of treatments in naturalistic settings.
approximately 54 % (Perez-Ruixo et al., 2021). This could explain our Several methodological limitations affect how our data should be
finding of a more rapid action of intravenous ketamine. Furthermore, interpreted. Primarily, the inherent characteristics of the study (i.e.,
ketamine constitutes a racemic mixture encompassing both esketamine retrospective, real-world) pose a substantial limitation that may give rise
and arketamine enantiomers. Recent discoveries underscore the poten­ to notable selection biases. In contrast, this characteristic also presents a
tial significance of arketamine as a rapid-acting antidepressant, with significant benefit, as it exemplifies the circumstances typically
numerous preclinical and initial clinical investigations emphasizing its encountered in everyday clinical settings. Furthermore, in this study,
rapid efficacy (Chang et al., 2019; Rafało-Ulińska and Pałucha-Ponie­ achieving uniformity in time-points was challenging, particularly in
wiera, 2022; Zhang et al., 2022). Based on these observations, we could terms of comparing the interval between the psychometric evaluations
speculate that arketamine may represent the enantiomer responsible for at T1 and the last administration in the KET-IV and ESK-NS cohorts. This
ketamine's rapid antidepressant effects, thereby accounting for the dis­ inconsistency could be viewed as a notable limitation, stemming from
crepancies observed with esketamine. Nonetheless, this conjecture the study's design that involves comparing disparate samples from
warrants validation through extensive comparative studies. separate investigations. Nonetheless, the time-points chosen (T0, T1)
Indeed, TRD and depressive disorders are associated with a signifi­ maintain a certain level of consistency. They correspond to the initial
cantly higher risk of suicidal ideation and consequent attempts (Bergfeld baseline evaluation before starting the treatments in both groups (T0),
et al., 2018). Evidence exists about the ability of KET-IV and ESK-NS to and to the evaluations conducted approximately one-month post-treat­
rapidly reduce suicidal ideation (Ionescu et al., 2021; Jawad et al., 2022; ment beginning (T1), coinciding with the post-treatment initiation visit
McIntyre et al., 2020c). On this basis, FDA and EMA approved ESK-NS for the KET-IV group and the conclusion of the induction phase for the
also as rapid treatment in psychiatric emergencies like suicidal idea­ ESK-NS group (Martinotti et al., 2022; McIntyre et al., 2020c).
tion by both. Herein, we found a comparable effect size of KET-IV and Another significant limitation relates to the comparisons between the
ESK-NS in determining a reduction of suicidal ideation, as measured by ESK-NS and KET-IV cohorts, which originated from distinct study pro­
item-10 of MADRS for ESK-NS and item 12 for QIDS-SR16, which further tocols employing different assessment scales. Specifically, a self-
corroborates the role of glutamatergic compounds in rapidly alleviating administered scale was used for the KET-IV cohort (i.e., QIDS-SR16),
suicidal ideation. Notably, no patients reported amplification of pre- while a clinician-administered scale was utilized for the ESK-NS
existing suicidal ideation in both groups. cohort (i.e., MADRS). Existing evidence suggests that clinician-
Concerning safety and tolerability, both therapeutic interventions administered scales may be more sensitive in detecting changes in

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G. d'Andrea et al. Journal of Affective Disorders 348 (2024) 314–322

depressive symptoms than self-administered ones (Carhart-Harris et al., Giorgio Di Lorenzo: Methodology, Writing – review & editing. Taeho
2021), potentially influencing the results of our study. Nevertheless, by Greg Rhee: Writing – original draft, Writing – review & editing. Ste­
comparing effect sizes and employing a logistic binary regression model fania Chiappini: Writing – original draft, Writing – review & editing.
to estimate the impact of treatment type on response rates, this limita­ Rosalba Carullo: Data curation, Writing – original draft. Stefano
tion is mitigated, offering a robust measure for comparing effects. Barlati: Data curation, Investigation, Project administration. Raffaella
Additionally, several studies demonstrate the convergent validity of Zanardi: Data curation, Investigation, Project administration. Gianluca
MADRS and QIDS-SR psychometric scales in detecting depressive Rosso: Data curation, Investigation, Project administration. Marco Di
symptoms (Bernstein et al., 2010; Carmody et al., 2006; Liu et al., 2021), Nicola: Data curation, Investigation, Project administration. Ileana
thus reinforcing the robustness of this analysis. Andriola: Data curation, Investigation, Project administration. Matteo
Finally, a potential source of heterogeneity between the two samples Marcatili: Data curation, Investigation, Methodology. Massimo Cler­
in our study pertains the different recruitment settings. The KET-IV ici: Data curation, Investigation, Project administration. Bernardo
cohort comprises TRD patients recruited from private clinics where Maria Dell'Osso: Data curation, Investigation, Project administration.
intravenous ketamine is administered, whereas the ESK-NS cohort Stefano L. Sensi: Supervision, Writing – review & editing. Rodrigo B.
consists of patients from public outpatient clinics for TRD. However, the Mansur: Data curation, Investigation, Methodology, Writing – original
matching procedure applied to the KET-IV and ESK-NS groups ensured a draft. Joshua D. Rosenblat: Data curation, Methodology, Writing –
certain level of uniformity in age, gender, and the number of previous original draft. Giovanni Martinotti: Conceptualization, Methodology,
antidepressant trials. Furthermore, the definition of TRD used in both Supervision, Validation, Writing – review & editing. Roger S. McIntyre:
cohorts was consistent) (Sforzini et al., 2022), further emphasizing a Conceptualization, Data curation, Formal analysis, Supervision, Vali­
degree of homogeneity between the two samples. The utilization of a dation, Writing – review & editing.
consistent TRD definition is a strength, considering the absence of a
clear and unanimous definition for this condition and the extreme het­ Declaration of competing interest
erogeneity in the populations included (McIntyre et al., 2023).
Dr. Taeho Greg Rhee was supported in part by the National Institute
5. Conclusions on Aging (NIA) (#R21AG070666; R21AG078972), National Institute of
Mental Health (#R21MH117438), National Institute on Drug Abuse
Taken together, the outcomes of our study corroborate the efficacy of (#R21DA057540) and Institute for Collaboration on Health, Interven­
both KET-IV and ESK-NS in individuals suffering from TRD, including tion, and Policy (InCHIP) of the University of Connecticut. Dr. Rhee
those presenting with suicidal ideation. KET-IV manifests a notably su­ serves as a review committee member for Patient-Centered Outcomes
perior antidepressant effect relative to ESK-NS during short-term follow- Research Institute (PCORI) and Substance Abuse and Mental Health
up periods (e.g., one month). Nevertheless, ESK-NS demonstrates a Services Administration (SAMHSA) and has received honoraria pay­
lower incidence of TEAEs. It is incumbent upon future investigations to ments from PCORI and SAMHSA. Dr. Rhee has also served as a stake­
conduct prospective head-to-head comparisons of these two formula­ holder/consultant for PCORI and received consulting fees from PCORI.
tions, extending the comparative analyses to include long-term efficacy. Dr. Rhee serves as an advisory committee member for International
Our findings also pave the way for exploring new frontiers in the po­ Alliance of Mental Health Research Funders (IAMHRF). Dr. Rhee is
tential combination of these two formulations: employing KET-IV for currently a co-Editor-in-Chief of Mental Health Science and has received
acute treatment and ESK-NS for maintaining efficacy could merge the honorarium payments annually from the publisher, John Wiley & Sons,
rapid action of the former with the enhanced tolerability and manage­ Inc.
ability of the latter (d'Andrea et al., 2023d). Dr. Giorgio Di Lorenzo has been a speaker and/or a consultant for
Angelini, FB-Health, Janssen-Cilag, Livanova, Lundbeck, Neuraxpharm,
Author's contribution Otsuka, and Recordati.
Dr. Raffaella Zanardi has been a consultant/speaker for Baldacci
All persons who meet authorship criteria are listed as authors, and all and Italfarmaco.
authors certify that they have participated sufficiently in the work to Dr. Gianluca Rosso has been a speaker and/or consultant from
take public responsibility for the content, including participation in the Angelini, Janssen, Lundbeck, Otsuka, Viatris.
concept, design, analysis, writing, or revision of the manuscript. RSMcI Dr. Ileana Andriola was a speaker at Janssen sponsored conference.
and GM were the coordinators, respectively, of the CRTCE study Group Dr. Bernardo Maria Dell'Osso has received lecture honoraria from
and the REAL-ESK study Group. Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and
GdA, RSMcI, GM and MP conceptualized the hypothesis and the Livanova.
design of the present study. All the authors were responsible for the Dr. Rosenblat is the medical director of the Braxia Scientific Corp,
patient recruitment and the collection of clinical data. GdA and RC which provides ketamine and esketamine treatment for depression; he
performed the statistical analysis, carried out data interpretation and has received research grant support from the American Psychiatric As­
wrote the first draft of the manuscript. GM, MP, GDL, TGR, JdR, RBM, sociation, the American Society of Psychopharmacology, the Canadian
and RSMcI revised the manuscript and provided substantial comments. Cancer Society, the Canadian Psychiatric Association, the Joseph M.
All authors have contributed to, and have approved, the final West Family Memorial Fund, the Timeposters Fellowship, the University
manuscript. Health Network Centre for Mental Health, and the University of Toronto
and speaking, consultation, or research fees from Allergan, COMPASS,
Funding Janssen, Lundbeck, and Sunovion.
Dr. Giovanni Martinotti has been a consultant and/or a speaker
This research did not receive any specific grant from funding and/or has received research grants from Angelini, Doc Generici,
agencies in the public, commercial, or not-for-profit sectors. Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati.
Dr. Roger McIntyre has received research grant support from CIHR/
CRediT authorship contribution statement GACD/National Natural Science Foundation of China (NSFC) and the
Milken Institute; speaker/consultation fees from Lundbeck, Janssen,
Giacomo d'Andrea: Conceptualization, Data curation, Formal Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen,
analysis, Methodology, Writing – original draft. Mauro Pettorruso: Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Suno­
Data curation, Investigation, Methodology, Writing – review & editing. vion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-

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Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sci­ intravenous ketamine and intranasal esketamine for treatment-resistant depression.
Acta Psychiatr. Scand. 148 (4), 385–387. https://doi.org/10.1111/acps.13605.
ences. Dr. Roger McIntyre is the CEO of Braxia Scientific Corp.
Dean, R.L., Hurducas, C., Hawton, K., Spyridi, S., Cowen, P.J., Hollingsworth, S.,
The remaining authors declare that the research was conducted Marquardt, T., Barnes, A., Smith, R., McShane, R., Al, et., 2021. Ketamine and other
without any commercial or financial relationship that could be glutamate receptor modulators for depression in adults with unipolar major
construed as a potential conflict of interest. depressive disorder. Cochrane Database Syst. Rev. 9 https://doi.org/10.1002/
14651858.CD011612.pub3.
EMA, 2019. Spravato, Summary of Product Characteristics.
Acknowledgements FDA, 2019. Office of the Commissioner: FDA Approves New Nasal Spray Medication for
Treatment-resistant Depression; Available Only at a Certified Doctor’s Office or
Clinic.
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tributions to this manuscript. Blier, P., Fava, M., Liebowitz, M., Ravindran, A., Gaillard, R., Ameele, H.V.D.,
Preskorn, S., Manji, H., Hough, D., Drevets, W.C., Singh, J.B., 2019. Efficacy and
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