ARTICLES

Efficacy and Safety of Flexibly Dosed Esketamine

Nasal Spray Combined With a Newly Initiated Oral
Antidepressant in Treatment-Resistant Depression:
A Randomized Double-Blind Active-Controlled Study
Vanina Popova, M.D., Ella J. Daly, M.D., Madhukar Trivedi, M.D., Kimberly Cooper, M.S., Rosanne Lane, M.A.S., Pilar Lim, Ph.D.,
Christine Mazzucco, M.Sc., David Hough, M.D., Michael E. Thase, M.D., Richard C. Shelton, M.D., Patricio Molero, M.D., Ph.D.,
Eduard Vieta, M.D., Ph.D., Malek Bajbouj, M.D., Husseini Manji, M.D., Wayne C. Drevets, M.D., Jaskaran B. Singh, M.D.

Objective: About one-third of patients with depression fail to plus antidepressant was significantly greater than with an-
achieve remission despite treatment with multiple antide- tidepressant plus placebo at day 28 (difference of least
pressants. This study compared the efficacy and safety of square means=24.0, SE=1.69, 95% CI=27.31, 20.64); like-
switching patients with treatment-resistant depression from wise, clinically meaningful improvement was observed in the
an ineffective antidepressant to flexibly dosed esketamine esketamine plus antidepressant arm at earlier time points.
nasal spray plus a newly initiated antidepressant or to a newly The five most common adverse events (dissociation, nausea,
initiated antidepressant (active comparator) plus placebo vertigo, dysgeusia, and dizziness) all were observed more
nasal spray. frequently in the esketamine plus antidepressant arm than in
the antidepressant plus placebo arm; 7% and 0.9% of patients
Methods: This was a phase 3, double-blind, active-controlled, in the respective treatment groups discontinued study drug
multicenter study conducted at 39 outpatient referral centers. because of an adverse event. Adverse events in the eske-
The study enrolled adults with moderate to severe non- tamine plus antidepressant arm generally appeared shortly
psychotic depression and a history of nonresponse to at least after dosing and resolved by 1.5 hours after dosing.
two antidepressants in the current episode, with one antide-
pressant assessed prospectively. Confirmed nonresponders Conclusions: Current treatment options for treatment-
were randomly assigned to treatment with esketamine nasal resistant depression have considerable limitations in terms
spray (56 or 84 mg twice weekly) and an antidepressant or of efficacy and patient acceptability. Esketamine is expected
antidepressant and placebo nasal spray. The primary efficacy to address an unmet medical need in this population through
endpoint, change from baseline to day 28 in Montgomery- its novel mechanism of action and rapid onset of antide-
Åsberg Depression Rating Scale (MADRS) score, was assessed pressant efficacy. The study supports the efficacy and safety
by a mixed-effects model using repeated measures. of esketamine nasal spray as a rapidly acting antidepressant
for patients with treatment-resistant depression.
Results: Of 435 patients screened, 227 underwent ran-
domization and 197 completed the 28-day double-blind
treatment phase. Change in MADRS score with esketamine AJP in Advance (doi: 10.1176/appi.ajp.2019.19020172)

Major depressive disorder is the leading cause of disability symptomatic and at risk of suicidal behavior and self-harm
worldwide in terms of total years lost due to disability and is (3). There is a need to develop novel treatments that provide
associated with excess mortality (1). About 30% of patients rapid relief of depressive symptoms, especially in patients
with major depression fail to achieve remission despite with treatment-resistant depression.
treatment with multiple antidepressants and are considered Research on mood disorder pathophysiology has impli-
to have treatment-resistant depression (2). In patients who cated abnormalities in glutamatergic transmission, along
respond to antidepressants, the time to onset of effect is with disrupted function and structure in neural circuits in-
typically several weeks, during which time patients remain volved in mood regulation (4), findings that led to further

See related features: Commentary by Dr. Schatzberg (p. 422) and CME course (p. 491)

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ESKETAMINE NASAL SPRAY IN TREATMENT-RESISTANT DEPRESSION

investigation of glutamatergic N-methyl-D-aspartate (NMDA) blood level for specific tricyclic antidepressants), which was
receptor modulators in treating depression (5, 6). Ketamine (an continued prospectively for another 4 weeks during the
NMDA receptor antagonist) affects fast excitatory glutamate screening/prospective observational phase, providing a total
transmission, increases release of brain-derived neurotrophic duration of at least 6 weeks of the prospective antidepressant.
factor, and stimulates synaptogenesis (7). Early clinical evi- To determine patient eligibility, an independent clinical
dence suggested a potential role of ketamine in the treatment reviewer (a psychiatrist or psychologist) confirmed the ade-
of depression, with mood-elevating effects observed in chal- quacy of the prospective antidepressant medication and eval-
lenge studies (8). Intravenous ketamine administered at sub- uated the patient’s ratings on the Montgomery-Åsberg
anesthetic doses was found to exhibit robust and rapid onset Depression Rating Scale (MADRS) (14), the Mini International
of efficacy in patients with treatment-resistant depression (9). Neuropsychiatric Interview (15), the MGH Antidepressant
Esketamine, the S-enantiomer of ketamine racemate, with Treatment Response Questionnaire, the Columbia-Suicide
a higher affinity for the NMDA receptor than the R-enantiomer, Severity Rating Scale (C-SSRS) (16), the Inventory of Depressive
was recently approved by the U.S. Food and Drug Administration Symptomatology–Clinician Rating (IDS-C) (17), and the Clinical
for treatment-resistant depression in adults. In phase 2 studies, Global Impressions severity scale (CGI-S) (18) at screening, as
esketamine nasal spray demonstrated rapid onset and persistent well as medical history and concomitant therapies.
efficacy in patients with treatment-resistant depression as well Patients who had not responded to the prospective anti-
as in depressed patients at imminent risk for suicide (10–12). depressant treatment by the end of the screening phase (non-
Here we report findings from a phase 3 study comparing the response was defined as #25% improvement in MADRS score
efficacy and safety of switching adult patients with treatment- from week 1 to week 4 and a MADRS score $28 at weeks 2 and
resistant depression from a prior antidepressant to which 4) entered the 4-week double-blind treatment phase, at which
they had not responded, to flexibly dosed esketamine nasal time they discontinued all current antidepressant treatments
spray and a newly initiated oral antidepressant or to a newly and were randomly assigned to the intranasal treatment com-
initiated oral antidepressant plus placebo nasal spray. bined with a newly initiated oral antidepressant.

Study Population
METHODS
To be eligible, participants had to be between 18 and 64 years
Institutional review boards (in the United States) or in- of age; have either single-episode ($2 years) or recurrent
dependent ethics committees (in Europe) at the various study major depressive disorder (per DSM-5 criteria) without
sites approved the study protocol and amendments. The study psychotic features, confirmed by the Mini International
was conducted in accordance with the ethical principles of the Neuropsychiatric Interview; have a score $34 on the IDS-C,
Declaration of Helsinki, Good Clinical Practices, and applica- consistent with moderate to severe depression; and meet the
ble regulatory requirements. All patients provided written in- study definition of treatment-resistant depression, which was
formed consent before participating in the study. nonresponse to an adequate trial (dosage, duration, and ad-
herence) of at least two antidepressants in the current epi-
Study Design sode (of which one was observed prospectively). Patients
This was a phase 3 randomized, double-blind, active- also had to be medically stable (those on thyroid hormones
controlled, multicenter study conducted between August had received a stable dosage for $3 months) and able to
2015 and November 2017 at six sites in the Czech Republic, self-administer intranasal medication.
nine in Germany, seven in Poland, seven in Spain, and 10 Key exclusion criteria were current or recent (past 6
in the United States. months) homicidal ideation/intent or suicidal ideation with
The study consisted of three phases: 1) a 4-week screening intent to act or suicidal behavior within the past year; di-
and prospective observation phase during which treatment agnosis of psychotic disorder, major depressive disorder with
response to the current ongoing oral antidepressants was psychotic features, bipolar or related disorders, borderline,
assessed; 2) a 4-week treatment phase during which par- antisocial, histrionic, or narcissistic personality disorder,
ticipants received a new oral antidepressant combined with obsessive-compulsive disorder (current), intellectual dis-
either esketamine nasal spray or placebo nasal spray; and 3) a ability, autism spectrum disorder; uncontrolled hyperten-
posttreatment follow-up phase of up to 24 weeks. At study sion; seizures; a recent history (past 6 months) of moderate or
entry, participants had documented (retrospectively) non- severe substance use disorder (including a lifetime history of
response (#25% improvement) to one to five antidepressants ketamine use disorder); and positive urine test results for
(based on the Massachusetts General Hospital [MGH] An- specified drugs of abuse (cannabinoids, barbiturates, meth-
tidepressant Treatment Response Questionnaire [13]) in the adone, opioids, cocaine, phencyclidine, and amphetamine/
current depressive episode and were currently receiving methamphetamine). A urine drug screen with adequate
a different oral antidepressant, to which they had been ad- assay sensitivity and specificity for ketamine and derivatives
herent (,4 missed days of treatment based on the Patient was not available and therefore was not performed. Patients
Adherence Questionnaire) for at least the previous 2 weeks at who had previously shown nonresponse to esketamine or
or above the minimum therapeutic dosage (or therapeutic ketamine, nonresponse to the oral antidepressant options for

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this study (detailed below), or nonresponse to electrocon- considering that the selected antidepressant was one with
vulsive therapy were excluded. Participants were required to which the patient had not previously experienced non-
use adequate contraception during the study. A full list of the response (in the current depressive episode) or been intol-
inclusion and exclusion criteria is presented in the online erant to (lifetime), and was available in the participating
supplement. country.
Dosing of the oral antidepressant followed a fixed titration
Randomization and Blinding schedule (presented in Table S4 in the online supplement).
A computer-generated randomization schedule was used
to randomly assign eligible patients in a 1:1 ratio to receive Efficacy Assessments
double-blind treatment with either esketamine (56 mg or Because esketamine exhibits transient dissociative effects
84 mg) nasal spray (hereafter referred to as esketamine) or that are difficult to blind, possibly biasing the site staff su-
placebo nasal spray (hereafter referred to as placebo), ad- pervising the dosing, all MADRS assessments (used for the
ministered twice weekly, each combined with a newly ini- primary endpoint, the first key secondary endpoint, and
tiated open-label oral antidepressant administered daily. calculation of response and remission rates) were performed
Randomization was balanced by using randomly permuted by independent, remote (by telephone) raters who were blind
blocks and was stratified by country and by class of oral an- to the protocol details, including study visit, the patient’s
tidepressant (serotonin-norepinephrine reuptake inhibitor clinical status, and side effects during the trial.
[SNRI] or selective serotonin reuptake inhibitor [SSRI]). Patients rated the impact of the study treatments on
Patients, investigators, site personnel, those assessing out- socio-occupational disability using the Sheehan Disability
comes, and those analyzing the data were blind to treatment Scale (19), on depressive symptoms using the 9-item Patient
assignment. Health Questionnaire (PHQ-9) (20), on severity of anxi-
ety using the 7-item Generalized Anxiety Disorder scale
Intranasal Study Drug and Administration (21), and on overall health outcome using the EuroQol-5
Both intranasal study drugs (esketamine and placebo) were dimension-5 level (EQ-5D-5L [22]; results reported in the
provided in disposable nasal spray devices with identical online supplement) at baseline and on days 15 (except the
appearance and packaging. Each device contained 200 mL of Generalized Anxiety Disorder scale) and 28. Investigators
solution and delivered two sprays of either esketamine (for rated change in severity of depressive illness using the
a total dose of 28 mg per device) or placebo. To maintain CGI-S.
blinding, a bittering agent was added to the intranasal placebo
to simulate the taste of the esketamine solution, and three Safety Assessments
devices were administered to all patients at all sessions; in the Adverse events and other safety assessments (hematology
esketamine plus antidepressant arm, a total dose of 56 mg and serum chemistry, urinalysis, physical examination,
was delivered by use of two active devices and one placebo electrocardiogram, C-SSRS) were monitored throughout the
device, and a total dose of 84 mg was delivered by use of three study. Vital signs, the Clinician-Administered Dissociative
active devices (see Table S2 in the online supplement). States Scale (CADSS) (23), and the 4-item positive symptom
All participants received training and practiced using the subscale of the Brief Psychiatric Rating Scale (BPRS) (24)
intranasal device before the first administration. Participants were assessed at baseline and at all dosing visits (before
self-administered intranasal study drug at the clinical site dosing and at 40 minutes, 1 hour [vital signs only], and 1.5
under the direct supervision of the investigator. hours after dosing). Investigators were provided guidance on
For improved tolerability, esketamine was started on day blood pressure monitoring on intranasal treatment days (see
1 at 56 mg (see Table S3 in the online supplement), with the the online supplement). Investigators were also instructed on
possibility, per the investigator’s clinical judgment based on being watchful of requests for an increase in intranasal study
efficacy and tolerability, of increasing the dose to 84 mg or drug dose and/or dosing frequency, which may indicate early
remaining at 56 mg on days 4, 8, 11, or 15 (after which the dose signs of abuse or addiction.
remained stable). The Modified Observer’s Assessment of Alertness/
Sedation scale (scored from 0 [no response to painful stimuli]
Newly Initiated Oral Antidepressant to 5 [readily responds to name spoken in normal tone]) was
The open-label oral antidepressant initiated with the in- used to assess the level of postdose sedation every 15 minutes
tranasal study drug was selected by the investigator from two from before dosing to 1.5 hours after dosing.
different drug classes: an SSRI (escitalopram or sertraline) or Investigators assessed patients’ clinical status and dis-
an SNRI (duloxetine or venlafaxine extended release), pro- charge readiness (based on their overall clinical status, in-
vided by the sponsor. The investigator chose one of the four cluding sedation, blood pressure, and other adverse events)
options (representing the most commonly used standard- using a scale developed for the program—the Clinical Global
of-care antidepressants) based on review of the patient’s Assessment of Discharge Readiness—1 hour and 1.5 hours
MGH Antidepressant Treatment Response Questionnaire and after dosing (the earliest discharge time point), and every
relevant prior antidepressant medication information, and 15 minutes thereafter until ready for discharge.

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ESKETAMINE NASAL SPRAY IN TREATMENT-RESISTANT DEPRESSION

Local nasal tolerability was assessed by nasal examination using the respective baseline score for the instrument as a
and a self-report nasal symptom questionnaire (results are covariate.
reported in the online supplement). Other secondary efficacy endpoints included the propor-
The Physician Withdrawal Checklist (25) was adminis- tions of responders ($50% reduction from baseline MADRS
tered to assess for potential withdrawal symptoms after score) and patients in remission (defined as a MADRS
cessation of esketamine treatment. Cognitive testing was score #12) at the end of the 4-week double-blind treatment
performed to assess for potential impact on cognition; these phase, change in CGI-S score, and anxiety symptoms (based
data will be addressed in separate publications. on the Generalized Anxiety Disorder scale) and health-
related quality of life and health status (based on the
Statistical Analysis EQ-5D-5L).
Data were analyzed based on analysis sets that included all In a post hoc analysis of response and remission rates, the
randomized patients who received at least one dose of in- number needed to treat (NNT) was estimated by taking the
tranasal study medication and one dose of oral antidepressant reciprocal of the risk difference. Change in Generalized
medication for the efficacy analyses, and at least one dose of Anxiety Disorder scale score was analyzed based on last-
either medication for the safety analyses. observation-carried-forward data using an analysis of co-
Statistical tests were conducted at a two-sided signifi- variance (ANCOVA) model, with country and antidepressant
cance level of 0.05. Analyses were performed using SAS, class as factors and baseline score as the covariate. The others
version 9.2. were summarized descriptively.

Efficacy endpoints and analyses. The primary efficacy end- Sample size determination. The sample size planned for this
point, change in MADRS score from baseline (day 1) to study was calculated assuming a treatment difference for the
endpoint (day 28), was analyzed using a mixed-effects model double-blind treatment phase of 6.5 points in MADRS score
using repeated measures (MMRM). The model included between the esketamine plus antidepressant group and the
baseline MADRS score as a covariate, and treatment, country, antidepressant plus placebo group and a standard deviation
oral antidepressant class (SNRI or SSRI), day, and day-by- of 12, based on the results of a phase 2 study of esketamine
treatment interaction as fixed effects, and a random patient nasal spray for treatment-resistant depression (11) and cli-
effect. A delta adjustment tipping point sensitivity analysis nical judgment, a two-sided significance level of 0.05, and
was performed to evaluate the robustness of the MMRM a dropout rate of 25%. Randomization of 98 individuals to
analysis to increasing deviations from the missing-at-random each treatment group was required to achieve 90% power.
assumption (results are presented in the online supplement).
Subgroup analyses were conducted according to the MMRM
RESULTS
model used for the primary endpoint, including age, sex,
baseline severity, antidepressant class, number of previous Of 435 patients screened, nine (randomized at one site in
treatment failures, functional impairment, and region. Poland) were excluded from all analyses because of Good
A serial gatekeeping (fixed sequence) approach was ap- Clinical Practices violations (sensitivity analyses including
plied to adjust for multiplicity and to strongly control type this site confirmed no impact on the overall conclusions of the
I error across the primary and the three key secondary ef- study), 227 underwent randomization to treatment; of these,
ficacy endpoints—namely, onset of clinical response by day 2, three did not receive any study drug and one did not receive a
change in Sheehan Disability Scale score, and change in PHQ- dose of oral study antidepressant. Thus, the data set for the
9 score. These three key secondary endpoints were analyzed efficacy analyses included 223 patients (114 in the esketamine
sequentially and considered significant at the two-sided plus antidepressant group and 109 the antidepressant plus
0.05 level only if the endpoint individually and previous placebo group). Most randomized patients (197/227, 86.8%)
endpoints in the hierarchy, including the primary endpoint, completed the 28-day double-blind treatment phase (see
were significant at the two-sided 0.05 level. Figure S1 in the online supplement).
The first key secondary efficacy endpoint compared the The treatment groups were similar with respect to de-
proportion of participants with onset of clinical response mographic and baseline clinical characteristics (Table 1).
(defined as a $50% reduction in MADRS score by day All patients in the esketamine plus antidepressant arm,
2 maintained to the end of the double-blind treatment phase with one exception (who received 42 mg because of a
with one excursion—i.e., a $25% reduction relative to technical issue with the device), self-administered 56 mg
baseline MADRS was allowed on day 8, 15, or 22) using a esketamine on day 1 of the double-blind treatment phase. On
Cochran-Mantel-Haenszel chi-square test adjusting for coun- day 4, just over half the patients in the esketamine plus an-
try and antidepressant class. tidepressant arm (58 of 107; 54.2%) remained at the 56 mg
The second and third key secondary efficacy endpoints— dose, and the remaining patients (49 of 107; 45.8%) were
change from baseline to week 4 in Sheehan Disability Scale increased to the 84 mg dose. Two-thirds (66.7%) of the pa-
and PHQ-9 scores, respectively—were analyzed using the tients were on the 84 mg dose at the end of the 4-week
MMRM model described for the primary efficacy analysis but treatment period. No patient requests to increase the

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TABLE 1. Baseline characteristics of participants in a randomized controlled trial of esketamine nasal spray for treatment-resistant
depression
Esketamine Plus Antidepressant
Characteristic Antidepressant (N=114) Plus Placebo (N=109)
Mean SD Mean SD
Age (years) 44.9 12.58 46.4 11.14
Age at diagnosis of major depression (years) 32.1 12.53 35.3 13.04
Duration of current episode (weeks) 111.4 124.28 118.0 187.37
Montgomery-Åsberg Depression Rating Scale score 37.0 5.69 37.3 5.66
Body mass index (calculated as kg/m2) 27.5 5.84 28.6 6.24
N % N %
Sex
Male 39 34.2 46 42.2
Female 75 65.8 63 57.8
Race
Asian 1 0.9 1 0.9
Black or African American 6 5.3 5 4.6
White 106 93.0 102 93.6
Multiple 1 0.9 1 0.9
Employment statusa
Any type of employment 68 59.6 63 57.8
Any type of unemployment 34 29.8 35 32.1
Other 12 10.5 11 10.1
Country
Czech Republic 30 26.3 28 25.7
Germany 10 8.8 10 9.2
Poland 20 17.5 18 16.5
Spain 9 7.9 9 8.3
United States 45 39.5 44 40.4
Number of previous antidepressant medicationsb
1 or 2 78 68.4 72 66.1
$3 36 31.6 37 39.9
Class of antidepressant
Serotonin-norepinephrine reuptake inhibitor 77 67.5 75 68.8
Selective serotonin reuptake inhibitor 37 32.5 34 31.2
Antidepressant
Duloxetine 60 52.6 61 56.0
Escitalopram 21 18.4 17 15.6
Sertraline 16 14.0 16 14.7
Venlafaxine extended-release 17 14.9 15 13.8
a
Any type of employment includes any category containing “employed,” sheltered work, housewife or dependent husband, and student; any type of unem-
ployment includes any category containing “unemployed”; “other” includes retired and no information available.
b
Number of previous antidepressant medications indicates antidepressants taken for at least 6 weeks with nonresponse (defined as #25% improvement) during
the current episode in addition to one prospective antidepressant.

esketamine dose or dosing frequency were reported in the 20.85) 24 hours after dosing (i.e., at the day 2 visit), 22.9 (95%
study. CI=25.17, 20.59) at day 8, 22.0 (95% CI=24.78, 0.82) at day
The mean MADRS score decreased from baseline to day 15, 23.8 (95% CI=26.87, 20.65) at day 22, and, as noted
28, with greater improvement observed among those in the above, 24.0 (95% CI=27.31, 20.64) at day 28 (p=0.020)
esketamine plus antidepressant arm as compared with the (Figure 1).
antidepressant plus placebo arm (difference of least square Subgroup analyses on the primary endpoint generally
means=24.0, SE=1.69, 95% CI=27.31, 20.64; p=0.020) showed consistent benefit favoring esketamine in subgroups,
(Table 2). The effect size for change in MADRS score from including age, sex, region, baseline severity, number of pre-
baseline to day 28 was 0.30. A scatterplot of individual patient vious treatment failures, functional impairment, and class
data displaying MADRS score at baseline compared with day of oral antidepressant (SNRIs and SSRIs) (Figure 2).
28 is provided in Figure S2 in the online supplement. In the hierarchical testing of the key secondary endpoints,
Response was rapid in onset and increased over time dur- the proportion of patients with a $50% decrease in MADRS
ing repeated dosing, with least square mean between-group score by day 2 (24 hours after a single dose) who also
differences, favoring esketamine, of 23.3 (95% CI=25.75, maintained this magnitude of reduction to day 28 (the first

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ESKETAMINE NASAL SPRAY IN TREATMENT-RESISTANT DEPRESSION

TABLE 2. Change in Montgomery-Åsberg Depression Rating FIGURE 1. Least square mean change in Montgomery-Åsberg
Scale (MADRS) score from baseline to day 28 in the double-blind Depression Rating Scale (MADRS) score over time in the double-
phase of a randomized controlled trial of esketamine nasal spray blind treatment phase of a randomized controlled trial of
for treatment-resistant depressiona esketamine nasal spray for treatment-resistant depressiona
Esketamine Antidepressant 0 Esketamine plus antidepressant
Plus Antidepressant Plus Placebo
Antidepressant plus placebo

Least Square Mean Change (±SE) in MADRS Score

Baseline
N 114 109
Mean and SD 37.0 5.69 37.3 5.66 –5

Change from baseline

to day 28
N 101b 100b –10
Mean and SD –21.4 12.32 –17.0 13.88
c
MMRM analysis
Difference of LS –4.0 1.69
meansd and SE –15
95% CI on difference –7.31, –0.64
2-sided p value 0.020
a
MADRS score ranges from 0 to 60; a higher score indicates a more severe
–20
condition. Negative change in score indicates improvement. Negative dif-
ference favors esketamine.
b
A total of 196 patients completed the double-blind phase and had a day
28 assessment, and five patients discontinued the study but provided a day
–25 *
28 MADRS assessment, resulting in 201 patients included in the analysis. Base- Day 2 Day 8 Day 15 Day 22 Day 28
c
Mixed model for repeated measures (MMRM) analysis with change from line (24 hrs)
baseline as the response variable and the fixed-effect model terms for
treatment (esketamine plus antidepressant, antidepressant plus placebo), Esketamine plus antidepressant (N)
day, country, class of antidepressant (serotonin-norepinephrine reuptake 114 109 109 107 103 101
inhibitor or selective serotonin reuptake inhibitor), and treatment-by-day Antidepressant plus placebo (N)
interaction, and baseline value as a covariate. LS=least squares. 109 102 105 102 104 100
d
Esketamine plus antidepressant minus antidepressant plus placebo. a
Data are from a mixed model for repeated measures (observed cases)
with change from baseline as the response variable and the fixed-effect
model terms for treatment (esketamine plus antidepressant, antide-
key secondary endpoint) was higher for the esketamine plus pressant plus placebo), day, country, class of antidepressant (serotonin-
antidepressant arm compared with the antidepressant plus norepinephrine reuptake inhibitor or selective serotonin reuptake
inhibitor), and treatment-by-day interaction and with baseline value
placebo arm (nine of 114 patients [7.9%] compared with five of as a covariate. Negative change in MADRS score indicates improve-
109 patients [4.6%]), although the difference was not sig- ment. The difference at day 28 was statistically significant.
nificant (p=0.321) (see Table S5 in the online supplement). *p50.020.

Early response ($50% decrease in MADRS score by day 2)

was observed in 18 of 109 patients in the esketamine plus between patients using concomitant benzodiazepines com-
antidepressant arm (16.5%), compared with 11 of 102 patients pared with those not using benzodiazepines.
in the comparator arm (10.8%). Given the lack of statistical Both treatment groups had a decrease in mean score on
significance on the first endpoint, analyses of the other two the Generalized Anxiety Disorder scale from baseline to the
key secondary endpoints could not be formally evaluated. double-blind treatment phase endpoint (27.9 [SD=6.12] from
Nevertheless, the results for change from baseline to day 28 in 13.2 at baseline in the esketamine plus antidepressant arm,
patient-reported Sheehan Disability Scale and PHQ-9 scores and 26.8 [SD=5.75] from 13.1 at baseline in the antidepres-
numerically favored the esketamine plus antidepressant arm sant plus placebo arm (difference of least square means=
over the comparator arm (difference of least square means of 21.0, 95% CI=22.35, 0.28).
24.0 [95% CI=26.28, 21.64] and 22.4 [95% CI=24.18, 20.69], Median CGI-S scores improved from baseline to end-
respectively; see Table S5 in the online supplement). point of the double-blind treatment phase in both groups,
In post hoc analyses, the proportion of patients who at a with a median change from baseline of 22.0 (range=25 to 1;
given time point were responders and in remission in both interquartile range=2) in the esketamine plus antidepressant
treatment groups generally increased over time during arm and 22.0 (range=25 to 1; interquartile range=3) in the
the double-blind treatment phase, with 70 of 101 patients antidepressant plus placebo arm (see Table S6 in the online
(69.3%) in the esketamine plus antidepressant arm and 52 of supplement). The ANCOVA analysis based on the ranks of
100 patients (52.0%) in the antidepressant plus placebo arm change showed a numerical difference favoring the esketa-
being responders at day 28 (odds ratio=2.4, 95% credible mine arm over the comparator arm, with an odds ratio of 2.8
interval=1.30, 4.54). The NNT for response was 6. At day 28, (95% credible interval=1.14, 7.68), suggesting that the odds of
53 of 101 (52.5%) and 31 of 100 (31.0%) patients in the re- an improved CGI-S score at endpoint for patients in the
spective treatment groups were in remission, with an NNT esketamine arm were 2.8 times the odds for patients in the
of 5 for remission. No notable differences were observed comparator arm.

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FIGURE 2. Forest plot of treatment differences on change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline
to day 28 in the double-blind treatment phase of a randomized controlled trial of esketamine nasal spray for treatment-resistant
depressiona
Esketamine Plus Antidepressant Plus
Characteristic LS Mean Difference (95% CI) Antidepressant (N) Placebo (N)
Overall 101 100
Sex
Male 33 41
Female 68 59
Age group
18–44 years 47 35
45–64 years 54 65
Region
Europe 61 62
North America 40 38
Baseline MADRS total score
≤Median 61 49
>Median 40 51
Number of previous treatment failures
<3 69 66
≥3 32 34
Sheehan Disability Scale rating
Moderate (12–19) 14 14
Marked (20–26) 52 43
Extreme (27–30) 31 37
Class of antidepressant study medication
SNRI 70 69
SSRI 31 31
–30 –20 –10 0 10 20 30
Favors esketamine Favors antidepressant
plus antidepressant plus placebo
a
Data are differences of least square (LS) means (95% CI) from a mixed model for repeated measures, by subgroup. Subgroups of #15 patients or
considered confounded on data review are not presented. Number of previous treatment failures refers to number of antidepressants taken with
nonresponse in addition to one prospective antidepressant. SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake
inhibitor.

During the double-blind treatment phase, the five most double-blind treatment phase (approximately 28 hours after
common treatment-emergent adverse events observed an esketamine dose) and subsequently died on day 55, 40 days
among patients in the esketamine plus antidepressant arm after the last dose of esketamine (additional information is
were dizziness, dissociation, dysgeusia, vertigo, and nausea provided in the online supplement). The investigator con-
(incidences ranging from 20.9% to 26.1%); the incidence of sidered the events as doubtfully related to esketamine or
each was two to 10 times lower in the antidepressant plus to antidepressant. No other deaths or nonfatal study drug–
placebo arm (Table 3). Most adverse events were of mild or related serious adverse events were reported.
moderate severity and were transient, with onset shortly af- Nine patients experienced one or more adverse events
ter dosing and resolution by 1.5 hours after dosing, while leading to discontinuation of intranasal study drug during
patients were in the clinic. A total of 57.4% [66/115] and the double-blind treatment phase, eight (of 115, 7.0%) in the
10.1% [11/109] of patients in the esketamine and comparator esketamine plus antidepressant arm (single events of anxiety,
arms, respectively, had a score #4 (moderate or greater se- depression, depressive symptoms, panic attack, drug intol-
dation) on the Modified Observer’s Assessment of Alertness/ erance, feeling drunk, dizziness, headache, vertigo, nausea,
Sedation at any postdose time during the double-blind road traffic accident, and multiple injuries) and one (of 109,
treatment phase. Generally, for patients who experienced 0.9%) in the antidepressant plus placebo arm (generalized
sedation, this symptom started around 15 minutes into dos- rash).
ing and peaked at 30 to 45 minutes after dosing, and symp- Transient blood pressure increases occurred after each
toms of sedation spontaneously resolved by 1 to 1.5 hours dose of esketamine; the maximum value was reached at 40
after dosing. Sedation was not associated with hypoxemia. minutes after dosing in most cases and typically returned to
One patient in the esketamine plus antidepressant arm or near the predose range by 1.5–2 hours after dosing (see
experienced multiple injuries in a road traffic (motorbike) Figure S3 in the online supplement). The maximum across
accident (reported as serious adverse events) on day 16 of the dosing days of the mean maximum increase in systolic blood

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ESKETAMINE NASAL SPRAY IN TREATMENT-RESISTANT DEPRESSION

pressure from before dosing at any postdose time point was TABLE 3. Most frequently reported adverse events in the
+11.6 mmHg in the esketamine plus antidepressant arm and double-blind treatment phase of a randomized controlled trial
of esketamine nasal spray for treatment-resistant depressiona
+5.0 mmHg in the antidepressant plus placebo arm, and in
diastolic blood pressure was +8.1 and +4.5 mmHg for the Esketamine Plus Antidepressant
Antidepressant Plus Placebo
respective treatment groups. (N=114) (N=109)
No clinically significant change in ECG was observed
Adverse Event N % N %
during the study.
The percentage of patients reporting suicidal ideation Dissociation 30 26.1 4 3.7
Nausea 30 26.1 7 6.4
(C-SSRS scores of 1 [wish to be dead], 2 [nonspecific active Vertigo 30 26.1 3 2.8
suicidal thoughts], or 3 [active suicidal ideation with any Dysgeusia 28 24.3 13 11.9
methods, not plan, without intent to act]) decreased from Dizziness 24 20.9 5 4.6
baseline to the endpoint in both treatment groups (see Figure Headache 23 20.0 19 17.4
S4 in the online supplement). In both treatment groups, the Somnolence 15 13.0 7 6.4
Blurred vision 14 12.2 3 2.8
maximum score reported on the C-SSRS during the double- Paresthesia 13 11.3 1 0.9
blind treatment phase was 3. Six of 112 (5.4%) patients in the Anxiety 12 10.4 5 4.6
esketamine plus antidepressant arm and seven of 109 (6.4%) Increased blood pressure 11 9.6 0 0.0
patients in antidepressant plus placebo arm had treatment- Insomnia 11 9.6 5 4.6
emergent postbaseline suicidal ideation. No patients in Vomiting 11 9.6 2 1.8
Diarrhea 10 8.7 10 9.2
either treatment group had treatment-emergent suicidal Dry mouth 9 7.8 3 2.8
behavior. Feeling drunk 9 7.8 1 0.9
Present-state dissociative symptoms and transient per- Oral hypoesthesia 9 7.8 1 0.9
ceptual effects measured by the CADSS (see Figure S5 in the Oral paresthesia 9 7.8 1 0.9
online supplement) began shortly after the start of esketa- Throat irritation 9 7.8 5 4.6
Postural dizziness 8 7.0 1 0.9
mine dosing, peaked at 40 minutes, generally resolved by 1.5 Hypoesthesia 8 7.0 1 0.9
hours, and attenuated with repeated dosing (the mean change Nasal discomfort 8 7.0 2 1.8
in CADSS score from before dosing to 40 minutes after dosing Fatigue 5 4.3 6 5.5
decreased from 7.8 [SE=0.84] on day 1 to 3.5 [SE=0.55] on day a
The table lists adverse events with an incidence $5% in either treatment
25). No symptoms or adverse events of psychosis were re- group, listed in decreasing order based on incidence within the esketamine
ported. The number needed to harm for dissociation was 5 for plus antidepressant group, and in alphabetical order for events with the
same incidence.
the esketamine plus antidepressant arm compared with the
antidepressant plus placebo arm. The proportion of responders
treatment with esketamine nasal spray. There were no re-
at day 28 was comparable for patients who experienced dis-
ports of drug abuse or cravings during the follow-up phase.
sociation (maximum CADSS score .4 on day 1) and those who
did not (maximum CADSS score #4 on day 1), with response
DISCUSSION
rates of 68.5% and 70.2%, respectively.
On each intranasal treatment day, approximately half In this study, patients with treatment-resistant depression
($44.3%) of the patients in the esketamine plus antidepressant achieved clinically meaningful and statistically significant
arm and $92.0% of those in antidepressant plus placebo arm improvement (based on change in MADRS score after
were considered ready for discharge (based on overall clinical 28 days) in depressive symptoms after being switched to
status, including sedation, blood pressure, and other adverse esketamine nasal spray plus a newly initiated oral antide-
events) by 1 hour after dosing, based on the Clinical Global pressant, with a group treatment difference of 24.0 against
Assessment of Discharge Readiness, and more than 90% in an active comparator—a newly initiated antidepressant plus
each treatment group by 1.5 hours after dosing (93.2% and intranasal placebo.
98.9% for the esketamine and comparator arms, respectively). While the hypothesized between-group difference of
All patients were ready for discharge by 3 hours. 26.5 was not reached, this large treatment difference had
Changes in withdrawal symptoms assessed by the Phy- been based on previously conducted phase 2 esketamine
sician Withdrawal Checklist after cessation of esketamine treatment-resistant depression studies (10, 11) and not on any
were consistent with observed changes in symptoms of de- threshold for defining a clinically meaningful improvement;
pression and anxiety. The most frequently reported ($25%) the observed 24.0 difference exceeded minimum clinically
new or worsened symptoms among patients in the eske- important difference thresholds reported in the literature
tamine plus antidepressant arm were fatigue-lethargy/lack (26, 27). The between-group difference in this study is similar
of energy, weakness, dysphoric mood/depression, loss of to that on the same primary outcome observed in two other
appetite, and restlessness/agitation, and for patients in the phase 3 short-term studies of esketamine for treatment-
antidepressant plus placebo arm, insomnia, irritability, and resistant depression—a fixed-dose study in the same age
dysphoric mood/depression. No clear evidence of with- group (56 mg: 24.1; 84 mg: 23.2] (28) and a study of
drawal was observed at either 1 or 2 weeks after cessation of patients $65 years old (23.6) (29) conducted at the same

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time, although statistical significance was not achieved in with our phase 2 work, and the higher response and remission
those two studies. Of note, the mean MADRS treatment dif- rates observed for the oral antidepressant plus placebo group:
ferences for adjunctive brexipiprazole (30), quetiapine (31), 1) use of a newly initiated antidepressant (to which the pa-
or aripiprazole (32) in major depression and for combina- tients had not shown a previous nonresponse) in the com-
tion treatment with olanzapine/fluoxetine (33) in treatment- parator arm (i.e., not a true placebo control), a design element
resistant depression range from 21.94 to 23.17. that would increase expectation of response in the active
The number of patients meeting the full criterion for onset comparator arm; 2) high frequency of patient interaction with
of clinical response by day 2 with persistence to day 28, a clinic staff because of the need for twice-weekly visits; 3) use
metric not evaluated in previous antidepressant drug or of a nasal spray delivery system, leading to patients’ expec-
ketamine trials, was lower than anticipated. Factors poten- tation of “something novel”; 4) high patient expectation of
tially contributing to this finding were 1) the strict criteria benefit as a result of the portrayal in the media of ketamine as a
used, which included onset and sustained response through new treatment option for depression; and 5) nocebo response
the entire 4-week treatment period and excluded patients (i.e., adverse effect following an “inert” treatment), as noted
who had any fluctuation in scores early in the treatment, a by an increase in CADSS scores after placebo nasal spray
finding commonly seen over the course of treatment in de- administration to which a bittering agent was added for
pression; and 2) the use of independent, remote MADRS blinding.
raters, which may have reduced the sensitivity of detecting The odds ratio of 2.4 for response at day 28 in the
the onset of clinical response by day 2, as remote raters did esketamine plus oral antidepressant group was higher
not know individual patients and their baseline character- compared with odds ratios reported in a recent systematic
istics, could only assess reported symptoms on the structured review of antidepressant efficacy (34). The NNT for the
interview, and could not take into account any of the signs esketamine plus oral antidepressant arm was 6 for response
of improvement of depression. and 5 for remission. The only medication approved for the
Earlier studies of esketamine in patients with treatment- treatment of treatment-resistant depression is olanzapine
resistant depression (10, 11) and major depression at immi- plus fluoxetine, which has an NNT of 8 for response and 13
nent risk for suicide (12), which demonstrated greater for remission (35). NNT for response and remission provide
magnitude of early response, applied a less stringent defi- clinical perspective for an effect size of 0.3 on the primary
nition for response onset and employed site-based raters for endpoint.
efficacy evaluation. Analyses of dissociation/perceptual change symptoms
Although the endpoint for onset of clinical response was (assessed by the CADSS) and sedation (assessed by the
not statistically significant, the difference in least square Modified Observer’s Assessment of Alertness/Sedation)
mean MADRS score between treatment groups at day suggest onset shortly after esketamine administration, with
2 (24 hours after a single dose) was 23.3 points, which is resolution generally by 1.5 hours after dosing, and evidence
considered a clinically meaningful treatment difference of attenuation of dissociation after repeated administra-
(26, 27) suggesting rapid onset of antidepressant efficacy. tions, unlike esketamine’s antidepressant efficacy, which was
Moreover, the mean difference between the active and sustained. The magnitude of postdose blood pressure in-
control arms observed at day 2 generally persisted through creases was lower compared with the previous phase 2 study
day 28 (Figure 1). of esketamine nasal spray (11), possibly because of the risk-
Based on the predefined testing sequence, the other two mitigation blood pressure guidelines initiated in phase
key secondary endpoints (change in Sheehan Disability Scale 3 studies (see the online supplement). Most patients were
and PHQ-9 scores) could not be formally evaluated. However, ready for discharge by 1.5 hours after dosing, with the latest
in post hoc analyses, the results from both patient-reported discharge readiness time point reported at 3 hours.
outcomes showed consistency with the primary clinician- Because this trial was a flexible-dose study, dose-response
based outcome result (see Figure S6 in the online sup- relationships were not evaluated. The trial aimed to assess the
plement), providing supportive evidence from patients’ short-term efficacy and safety of esketamine, and therefore it
perspective of improvement in mood and function after does not inform on maintenance of effect and long-term
4 weeks of treatment. safety, which are being evaluated in other studies (36, 37).
The response and remission rates seen in the antide- In this trial, esketamine efficacy was evaluated when
pressant plus placebo arm were higher than those reported combined with a newly initiated antidepressant. To further
in the Sequenced Treatment Alternatives to Relieve Depres- inform clinical practice, trials of monotherapy or of eske-
sion trial for step 3 (response rate, 16.8%; remission rate, tamine augmentation to an ongoing antidepressant may be
13.7%) and in the olanzapine-fluoxetine study (33) (response considered in the future.
and remission rates, respectively, of 40.4% and 27.3% for Some limitations of the study design merit comment. The
olanzapine/fluoxetine combination, 29.6% and 16.7% for generalizability of the study findings may be limited by the
fluoxetine, and 25.9% and 14.7% for olanzapine). A number of exclusion of patients with significant psychiatric or medical
factors may have contributed to the smaller than anticipated comorbidities or substance dependence, non-treatment-
effect size finding, the lower treatment difference compared resistant forms of major depression, prior nonresponse to

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ESKETAMINE NASAL SPRAY IN TREATMENT-RESISTANT DEPRESSION

ketamine or esketamine in the current episode, and imminent Pharmaceutical Research and Development, Lilly Research Laboratories,
risk of suicide (studied in a separate program) as well as a low Lundbeck Research USA, Medscape, Merck, Mitsubishi Pharma, MSI
Methylation Sciences, Navitor, One Carbon Therapeutics, Otsuka America
proportion of nonwhite patients. While eventual efficacy bias
Pharmaceutical, Oxford Pharmagenesis, Pamlab, Pfizer, Sage Thera-
was mitigated by using independent remote MADRS raters, it peutics, and Takeda Global Research; he has received royalties from
is possible that the specific adverse event profile of eske- Janssen Research and Development; he has received research support
tamine affected the blind for the study patients. Although from the Agency for Healthcare Research and Quality, the Cancer Pre-
patients were not specifically asked whether they believed vention and Research Institute of Texas, Janssen Research and Devel-
opment, Johnson & Johnson, the National Center for Advancing
they had received drug or placebo, it is noteworthy that the
Translational Sciences, the National Institute of Diabetes and Digestive
dissociation ratings (CADSS scores) increased in the control and Kidney Diseases, NIDA, NIMH, and the Patient-Centered Outcomes
group who received placebo nasal spray, providing evidence Research Institute; he has author agreements from Janssen Asia Pacific
of adequate blinding and supporting expectation of benefit as and Oxford University Press; and he has received editorial compensation
one of the contributing factors of the higher than anticipated from Engage Health Media, Healthcare Global Village, and Oxford Uni-
versity Press. Dr. Thase has served as a consultant or independent con-
placebo response observed in the control group.
tractor to Acadia, Akili, Alkermes, Allergan (Forest, Naurex), AstraZeneca,
In summary, despite the unexpected high response to the Axsome, Cerecor, Eli Lilly, Fabre-Kramer, Gerson Lehrman Group,
oral antidepressant plus placebo comparator, results of the Guidepoint Global, Lundbeck, Johnson & Johnson, MedAvante, Merck,
study consistently showed a clinically relevant, favorable Moksha8, Nestlé (Pamlab), Neuralstem, Novartis, Otsuka, Pfizer, Shire,
improvement in depressive symptoms with esketamine (ei- Sage, Sunovion, and Takeda; he has received grant or research support
from Acadia, the Agency for Healthcare Research and Quality, Alkermes,
ther 56 mg or 84 mg) nasal spray plus a newly initiated an-
Allergan (Forest), AssureRx Health, Avanir, Axsome, Intracellular, Janssen
tidepressant as assessed by change in MADRS score after Pharmaceuticals, Johnson & Johnson (including for the present study),
28 days in adult patients with treatment-resistant depres- NIMH, Otsuka, the Patient-Centered Outcomes Research Institute, and
sion and clinically meaningful benefit 24 hours after the first Takeda; he has received royalties from the American Psychiatric Foun-
dose. Moreover, administration of esketamine in this sample dation, Guilford Publications, Herald House, and W.W. Norton & Com-
pany; his spouse is employed by Peloton Advantage, which does business
appeared safe and tolerated.
with a number of pharmaceutical companies. Dr. Shelton has served as a
consultant to Acadia Pharmaceuticals, Allergan, Cerecor, Janssen Phar-
AUTHOR AND ARTICLE INFORMATION maceutica, MSI Methylation Sciences, Naurex, and Takeda Pharmaceu-
Janssen Research and Development, Beerse, Belgium (Popova); Janssen ticals; he has received grant support from Acadia Pharmaceuticals, the
Research and Development, Titusville, N.J. (Daly, Lane, Lim, Hough, Manji, Agency for Healthcare Research and Quality, Alkermes, Allergan, Avanir
Drevets); the Department of Psychiatry, University of Texas Southwestern Pharmaceuticals, Cerecor, Genomind, Intracellular Therapies, Janssen
Medical Center, Dallas (Trivedi); Janssen Research and Development, Pharmaceutica, Myriad Genetics, Navitor Pharmaceuticals, NeuroRx,
Spring House, Pa. (Cooper); Janssen Canada, Toronto (Mazzucco); the NIMH, Novartis, Otsuka Pharmaceuticals, the Patient-Centered Out-
Department of Psychiatry, Perelman School of Medicine, University of comes Research Institute, Sage Therapeutics, and Takeda Pharmaceu-
Pennsylvania, Philadelphia (Thase); the Department of Psychiatry, Uni- ticals. Dr. Molero is supported by Clínica Universidad de Navarra and has
versity of Alabama School of Medicine, Birmingham (Shelton); Clínica received research grants from the Ministry of Education (Spain), the
Universidad de Navarra, Pamplona, Spain (Molero); Institute of Neuro- Government of Navarra (Spain), the Spanish Foundation of Psychiatry and
science, University of Barcelona, Hospital Clinic, IDIBAPS, CIBERSAM, Mental Health, and AstraZeneca; he is a clinical consultant for MedAvante-
Barcelona, Spain (Vieta); Charité Universitätsmedizin Berlin, Berlin ProPhase and has received lecture honoraria from or has been a con-
(Bajbouj); Janssen Research and Development, San Diego (Singh). sultant for AB-Biotics, Janssen, Novumed, Roland Berger, and Scienta. Dr.
Send correspondence to Dr. Popova (vpopova@its.jnj.com). Vieta has received grants from and/or served as consultant, adviser, or
CME speaker for AB-Biotics, Allergan, Angelini, AstraZeneca, the Brain
Drs. Popova and Daly are joint first authors, and Drs. Drevets and Singh
and Behavior Foundation, Bristol-Myers Squibb, Dainippon Sumitomo,
are joint senior authors.
Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, the
The data sharing policy of Janssen Pharmaceutical Companies of Johnson Generalitat de Catalunya (2014 SGR 398), GlaxoSmithKline, Janssen,
& Johnson is available at https://www.janssen.com/clinical-trials/trans- Lundbeck, Otsuka, Pfizer, Roche, Sage, Sanofi-Aventis, Servier, the Sev-
parency. Requests for access to the study data can be submitted through enth European Framework Programme (ENBREC), Shire, the Spanish
Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. Ministry of Science and Innovation, the Stanley Medical Research Institute,
Supported by Janssen Research and Development, Titusville, N.J. Sunovion, and Takeda. Dr. Bajbouj has received research grants from the
Deutsche Forschungsgemeinschaft, the German Federal Ministry for
The authors acknowledge Sandra Norris, Pharm.D., of the Norris Com-
Education and Research, and the Germany Ministry of Health; he has
munications Group, for medical writing assistance and Ellen Baum, Ph.D.,
served as a consultant on or advisory boards for Parexel, Janssen, and
of Janssen Global Services, for additional editorial support. The authors
Johnson & Johnson; and he has received lecture support from Servier. Dr.
also thank the study patients and the investigators (listed in online sup-
Manji is named on a patent, which is assigned to Icahn School of Medicine
plement) for their participation in this study.
at Mount Sinai, Yale University, and NIH; no financial benefit was received
ClinicalTrials.gov identifier: NCT02418585. from this patent.
Dr. Popova, Dr. Daly, Ms. Cooper, Ms. Lane, Dr. Lim, Ms. Mazzucco, Dr. Received February 15, 2019; revisions received March 13 and March 26,
Hough, Dr. Manji, Dr. Drevets, and Dr. Singh are employees of Janssen 2019; accepted March 28, 2019.
Research and Development and hold company equity. Dr. Trivedi has
consulted for or served on advisory boards of AcademyHealth, Acadia
Pharmaceuticals, Akili Interactive, Alkermes, Allergan Pharmaceuticals,
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