Research

JAMA Psychiatry | Original Investigation

Efficacy and Safety of Intranasal Esketamine Adjunctive
to Oral Antidepressant Therapy
in Treatment-Resistant Depression
A Randomized Clinical Trial
Ella J. Daly, MD; Jaskaran B. Singh, MD; Maggie Fedgchin, PharmD; Kimberly Cooper, MS; Pilar Lim, PhD; Richard C. Shelton, MD; Michael E. Thase, MD;
Andrew Winokur, MD, PhD; Luc Van Nueten, MD; Husseini Manji, MD, FRCPC; Wayne C. Drevets, MD
Editorial page 123
IMPORTANCE Approximately one-third of patients with major depressive disorder (MDD) do

Supplemental content

not respond to available antidepressants.
OBJECTIVE To assess the efficacy, safety, and dose-response of intranasal esketaminehydrochloride in patients with treatment-resistant depression (TRD).
DESIGN, SETTING, AND PARTICIPANTS This phase 2, double-blind, doubly randomized,
delayed-start, placebo-controlled study was conducted in multiple outpatient referral centersfrom January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2)double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label
treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six
adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more
antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both
double-blind periods. Intent-to-treat analysis was used in evaluation of the findings.
INTERVENTIONS In period 1, participants were randomized (3:1:1:1) to placebo (n = 33),

esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28
placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants
continued their existing antidepressant treatment during the study. During the open-label phase,
dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks.
MAIN OUTCOMES AND MEASURES The primary efficacy end point was change from baseline today 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.
RESULTS Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were
included in the efficacy and safety analyses. Change (least squares mean [SE] difference vsplacebo) in MADRS total score (both periods combined) in all 3 esketamine groups was
superior to placebo (esketamine 28 mg: −4.2 [2.09], P = .02; 56 mg: −6.3 [2.07], P = .001; 84
mg: −9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001).
Improvement in depressive symptoms appeared to be sustained (−7.2 [1.84]) despite reduced
dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants
during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during
the open-label phase had adverse events that led to study discontinuation (1 event each ofsyncope, headache, dissociative syndrome, and ectopic pregnancy).
CONCLUSIONS AND RELEVANCE In this first clinical study to date of intranasal esketamine for
TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist
for more than 2 months with a lower dosing frequency. Results support further investigationin larger trials.
TRIAL REGISTRATION clinicaltrials.gov identifier: NCT01998958
JAMA Psychiatry. 2018;75(2):139-148. doi:10.1001/jamapsychiatry.2017.3739
Published online December 27, 2017.

Author Affiliations: Author
affiliations are listed at the end of thisarticle.
Corresponding Author: Ella J. Daly,
MD, Department of Neuroscience,
Janssen Research & Development,
LLC, 1125 Trenton-Harbourton Rd,
Titusville, NJ 08560 (edaly2@its.jnj.com).

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Research Original Investigation

Efficacy and Safety of Intranasal Esketamine in Depression

Major depressive disorder (MDD) is a common and disabling illness, with a lifetime prevalence of approximately 20% in the United States.1,2 Major depressive disorder impairs socio-occupational functioning3 andincreases suicide risk,4 adverse sequelae of other common comorbid medical conditions (eg, cardiovascular disease, type2 diabetes, and obesity), and mortality.5-9 Limitations of currently available antidepressant therapies include delayed onset of efficacy and low remission rates after multiple coursesof pharmacotherapy.10
Research on mood disorder pathophysiology implicatedabnormalities in glutamatergic transmission, along with synaptic and dendritic atrophy, in neural circuits that modulateemotional behavior.11 Several studies have shown antidepressant efficacy with the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine.12-17 One limitation of ketamine fortreating depression is that it may require intravenous administration, reducing its applicability in outpatient settings.
Esketamine, the S-enantiomer of ketamine, has a higher
affinity for the NMDA receptor than the R-enantiomer18 andis being developed as an intranasal formulation for therapy intreatment-resistant depression (TRD). Rapid onset of antidepressant effects has been observed following intravenous administration of esketamine.19 We report findings from a studyof intranasal esketamine, assessing its efficacy and safety compared with placebo in individuals with TRD.

Key Points
Question Is intranasal esketamine hydrochloride an efficacious
treatment option for patients with treatment-resistantdepression?
Findings In this randomized, double-blind clinical trial of 67 adults
with treatment-resistant depression, significant improvement ofdepressive symptoms, assessed by the Montgomery-Åsberg
Depression Rating Scale total score, was observed after 1 weekwith intranasal esketamine, 28 to 84 mg administered twice
weekly, with a significant ascending dose-response relationship.
Improvement appeared to be sustained with reduced dosing
frequency for up to 9 weeks.
Meaning Results of this first clinical trial of intranasal esketamine
for treatment-resistant depression support study in larger trials.

independent ethics committee (Belgium: Ethisch Comité O.L.
Vrouwenziekenhuis) approved the study protocol and amendments. The study was conducted in accordance with ethicalprinciples that have their origin in the Declaration of Helsinki,24
consistent with Good Clinical Practices and applicable regulatory requirements. All individuals provided written informed consent before participating in the study. Financial
compensation was provided.

Design

Methods
Population
The study enrolled medically stable (based on physical examination, medical history, vital signs, and 12-lead electrocardiogram performed at screening) adults (aged 20-64 years)
with a diagnosis of MDD, according to the DSM-IV-TR.20
All participants had TRD, defined as inadequate response
to 2 or more antidepressants (assessed by Massachusetts Gene r a l Ho s p it a l A nt i d e p r e s s a nt T r e at m e nt Re s p o n s e
Questionnaire21), with at least 1 inadequate response in the current depression episode. Otherwise, an antidepressant failure from a prior episode was acceptable. All participants continued the antidepressants they were receiving at study entry
during the trial. At screening and before the dose on day 1, eligible participants had a score of 34 or more on the 30-item, clinician-rated Inventory of Depressive Symptomatology,22,23 corresponding to moderate to severe depression. Key exclusion
criteria included recent or current suicidal ideation with intent to act, suicidal behavior, or homicidal ideation or intent,
diagnosis of bipolar or related disorders, intellectual disability, psychotic disorder, MDD with psychosis, posttraumaticstress disorder, obsessive-compulsive disorder, substance/
alcohol use disorders in the past year, and recent use of cannabis (more inclusion/exclusion criteria reported in the eAppendix in Supplement 1).
Independent review boards (United States: Sterling Institutional Review Board, University of Pennsylvania Institutional Review Board, Hartford Healthcare Institutional Review Board, and Western Institutional Review Board) and an
140

This phase 2, 2-panel, double-blind, doubly randomized,
delayed-start,25-28 placebo-controlled study (a variant of sequential parallel comparison design27-36) was conducted fromJanuary 28, 2014, to September 25, 2015. In panel A, reported
herein, 14 study sites (13 in the United States, 1 in Belgium) enrolled participants. The study protocol is available in
Supplement 2.
The study consisted of 4 phases: (1) screening; (2) doubleblind treatment (days 1-15), composed of two 1-week periods(period 1, period 2); (3) optional open-label treatment (days 1574) with tapering of intranasal dosing frequency; and (4) posttreatment follow-up (8 weeks). Based on prior studies of ketamine in which efficacy was reported after 1 to 2 doses, theduration of each period in the double-blind phase was 1 week,during which time it was expected that efficacy could beachieved. This design allowed evaluation of the dose(s) needed
to proceed to evaluation in phase 3. The purpose of the openlabel, flexible-dose phase was to evaluate the effect of lessfrequent dosing on sustaining efficacy.
At the beginning of double-blind period 1, eligible participants were randomized (3:1:1:1) to intranasal placebo or
esketamine 28, 56, or 84 mg, twice weekly (days 1 and 4)
based on the first of 2 computer-generated randomization
schedules (period 1 and period 2). Randomization was balanced by using randomly permuted blocks and stratified bystudy center. At the end of period 1, those randomized toplacebo who had moderate to severe symptoms (assessedby the 16-item Quick Inventory of Depressive
Symptomatology-Self Report23,37 [QIDS-SR16] total score:moderate, 11-16; severe, >16) were rerandomized (1:1:1:1) tointranasal esketamine 28, 56, or 84 mg or placebo twice

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Efficacy and Safety of Intranasal Esketamine in Depression

weekly (days 8 and 11); those having mild or no symptoms
continued placebo. To maintain the blinding, all participants completed an identical process before entry into
period 2, whether or not they were rerandomized. Regardless of response in the double-blind phase, all participants
were eligible to enter the optional open-label phase. Esketamine, 56 mg, was administered on the first day of the
open-label phase (study day 15); subsequent doses could be
adjusted (range, 28-84 mg) based on the investigator’s clinical judgment, with administration twice weekly for the first
2 weeks, weekly for the next 3 weeks, then every 2 weeks
thereafter.

Study Drug and Administration
Study drug was provided in a disposable nasal spray device
containing 200 μL of solution (ie, 2 sprays). Each device
delivered either esketamine hydrochloride, 16.14 (14 mg of
esketamine base) per 100-μL spray or placebo. To maintainblinding, the placebo solution (intranasal solution of water
for injection) had a bittering agent (denatonium benzoate)
added to simulate the taste of esketamine intranasal solution. As described above, the antidepressant that participants had been receiving immediately before study entry
was continued unchanged.
On each dosing day during the double-blind phase, participants self-administered 1 spray of study drug (esketamineor placebo) into each nostril at 3 points, each separated by 5
minutes. In the open-label phase, depending on the dose selected, participants self-administered 1 spray of esketamine into
each nostril at 1, 2, or 3 points (corresponding to 28, 56, or 84
mg, respectively), each separated by 5 minutes.

Efficacy Assessments
Efficacy was assessed with the Montgomery-Åsberg Depression Rating Scale 38,39 (MADRS) on days 1 (predose and 2hours postdose), 2, 8 (predose), 9, and 15, using the MADRS
structured interview guide.39
Overall illness severity was assessed on the Clinical Global
Impression of Severity scale.40 Participants assessed their severity of anxiety on the Generalized Anxiety Disorder 7-item
scale41 (eTables 1 and 2 in Supplement 1).

Safety Assessments
Adverse events were monitored throughout the study. Other
safety assessments (ie, laboratory tests, vital signs, physicalexamination) were performed at prespecified time points. Vital signs, the Clinician Administered Dissociative States Scale(CADSS),42 and the 4-item positive symptom subscale from theBrief Psychiatric Rating Scale43 were assessed predose, at 40
minutes, and 2 hours postdose.

Statistical Analysis
Efficacy data were analyzed in intent-to-treat analysis sets foreach period and phase. The intent-to-treat analysis sets included all participants who received at least 1 dose of study
medication during that period or phase and had baseline andat least 1 postbaseline MADRS total score within that periodor phase. Safety data were analyzed in period 1, period 2,
jamapsychiatry.com

Original Investigation Researchdouble-blind, and open-label data sets for all participants receiving at least 1 dose of study medication.
Efficacy End Points and Analyses
The primary efficacy end point—change from baseline (predose, day 1 in each period) to end point (day 8 in each period)in MADRS total score—was analyzed using the analysis of covariance model. For period 1, the model included treatment
and country as factors and baseline MADRS total score as a covariate. For period 2, the model included treatment and country as factors, period 2 baseline QIDS-SR16 score (moderate orsevere), and period 2 baseline MADRS total score as a continuous covariate.
Given the consistency between periods 1 and 2 results,25
esketamine dose groups were compared with placebo using a
combined test on the weighted test statistics for each period
in the double-blind treatment phase. A dose-response analysis on the primary efficacy end point was performed using data
combined from both periods. The multiple comparison procedure modeling methodology was performed.39,44
Sample Size Determination
Sample size was determined based on the following differences between intranasal esketamine and placebo for meanchange from baseline in MADRS total score: 9-point treatment difference was assumed for period 1 (day 8), 7-point treatment difference for period 2 (day 15) was assumed for individuals with a moderate QIDS-SR16 score, and 9-point treatment
difference for period 2 (day 15) was assumed for individuals
with a severe QIDS-SR16 score.
Based on the results of an intravenous esketamine study,19
it was estimated that 40% of placebo-receiving participants
would have a moderate QIDS-SR16 score and 55% would havea severe QIDS-SR16 score at the end of period 1 (day 8 predose). Additional assumptions for the sample size calculation included SD of 10, 92.5% power for the combined data fromday 8 and day 15,45 overall 1-sided significance level of .05, and
5% dropout rate for period 1. It was calculated that this panelof the doubly randomized, outcome-based design required 60
individuals to be randomly assigned to treatment on day 1 ina 3:1:1:1 ratio (30 in the placebo group and 10 per intranasal esketamine dose group). Statistical analysis was performed using
SAS, version 9.2 (SAS Institute Inc).

Results
Participants
A total of 126 individuals were screened, 67 of whom met theeligibility criteria and were randomized (38 women, mean [SD]age, 44.7 [10.0] years). Of 33 participants randomized to placebo in period 1, 28 (85%) had a QIDS-SR16 score of 11 or higher
at the end of period 1 and thus were randomly reassigned to
esketamine or placebo in period 2 (Figure 1). Most randomized participants (63 of 67 [94%]) completed period 1 and the
2-week double-blind phase (ie, periods 1 and 2 combined, 60
of 67 [90%], hereafter termed completers). Of these completers, 57 entered the open-label phase, with 51 (89%) sub(Reprinted) JAMA Psychiatry February 2018 Volume 75, Number 2© 2017 American Medical Association. All rights reserved.

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Research Original Investigation

Efficacy and Safety of Intranasal Esketamine in Depression

Figure 1. Disposition of Participants

59 Screen failuresa
13 MDD deemed invalid based on SAFER criteria interview
10 Withdrew informed consent
6 Unwilling or unable to adhere to the protocol prohibitions or restrictions
5 Laboratory values out of reference range
4 Exclusionary comorbid psychiatric disorder
4 Using prohibited medications
4 Exclusionary ECG findings
3 Suicidal or homicidal ideation with intent
3 Significant primary sleep disorder
3 Did not meet the definition of TRD
17 Other reasons (12 reasons, 1 or 2 participants each)

Screening phase–28 to –1 d

126 Screened

6 Placebo

8 Esketamine
28 mg

9 Esketamine
56 mg

11 Esketamine 28 mg
4 QIDS-SR16 <11

Double-blind phase: period 1
Double-blind phase: period 2

33 Placebo
28 QIDS-SR16 ≥11

1 to 8 d
8 to 15 d

67 Eligible participants with TRD

1 Withdrawn
1 Other

5 Esketamine
84 mg

11 Esketamine 56 mg

3 Withdrawn
1 AE
1 Lack ofefficacy
1 WBP

4 Placebo

8 Esketamine
28 mg

12 Esketamine 84 mg

1 Withdrawn
1 Other

11 Esketamine
56 mg

12 Esketamine
84 mg

2 Withdrawn
1 AE
1 WBP

1 Withdrawn
1 AE

Open-label phase

15 to 74 d

3 Elected not to participate
in OL phase

57 Optional OL treatment

Follow-up phase

74 to 130 d

16 Withdrawn
1 AE
3 Lack of efficacy
1 Lost to follow-up
5 WBP
6 Other

60 Follow-upb

Seven participants started the follow-up phase earlier than day 74, having
received 2 weeks of study drug during the open-label phase of the study. AE
indicates adverse event; ECG, electrocardiogram; MDD, major depressive
disorder; OL, open-label; QIDS-SR16, 16-item Quick Inventory of Depressive
Symptoms–Self-Report; SAFER, State vs Trait, Assessibility, Face Validity,
Ecological Validity, Rule of Three Ps; TRD, treatment-resistant depression; WBP,

sequently entering the follow-up phase, 41 (80%) of whomcompleted the week 8 follow-up visit.
142

withdrawal by participant.
aParticipants could have multiple reasons for being a screen failure.

b

Participants entered the follow-up phase if they did not choose to withdraw
from the study.

The treatment groups were similar with respect to demographic and baseline clinical characteristics (eTable 3 in

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Efficacy and Safety of Intranasal Esketamine in Depression

Supplement 1). Forty-three (64%) participants reported only
1 antidepressant treatment failure in the current episode (inaddition to 1 in prior episodes), 15 (22%) had 2 treatment failures, and 9 (13%) reported 3 or more antidepressant failures.
Twenty-six (39%) participants reported use of atypical antipsychotics as an adjunctive treatment of MDD before study entry.

Efficacy
The mean MADRS total score decreased from baseline to day
8 in period 1 and from day 8 to day 15 in period 2 in all groups,
with greater improvement in all esketamine dose groups compared with placebo (least squares mean difference ranging from−5.0 to −10.5 in period 1 and from −3.1 to −6.9 in period 2)(Table 1). Change from baseline in the MADRS total score wasstatistically significantly greater in all 3 esketamine groups thanin the placebo group after 1 week of treatment; the ascending
dose-response relationship also was significant. Response was
rapid in onset (Figure 2; eFigure 1 in Supplement 1) and appeared to increase over time during repeated dosing, as evidenced by a decrease in the mean MADRS total score during
the open-label phase (mean [SE] change from open-label baseline to day 74, −7.2 [1.84]). In addition, improvement in mean
MADRS ratings persisted over the 8-week follow-up phase(without additional esketamine doses) in participants who remained in the study (Figure 3).
For completers who received 2 weeks of the same treatment in the double-blind phase, the mean decrease in the
MADRS total score was greater in each esketamine dose groupcompared with placebo at day 15, with the magnitude of decrease directly related to dose (treatment differences relative
to placebo of −12.5, −8.3, and −6.0 for esketamine 84 mg, 56
mg, and 28 mg, respectively). Efficacy appeared to be better
sustained between drug administrations with the 2 higher
doses (Figure 1).
Among those who received the same treatment for both
periods and completed the double-blind phase, the proportion of responders (defined as ≥50% improvement from baseline in MADRS total score) in each esketamine dose group wasnumerically higher than in the placebo group at the period 2
end point (28 mg: 38% [3 of 8], 56 mg: 36% [4 of 11], 84 mg:
50% [5 of 10], and placebo: 10% [1 of 10]). A similar trend forremission (defined as MADRS total score ≤10) was observed
across groups. Among completers who received the same treatment in both periods, more participants who received the 2higher esketamine doses compared with placebo achieved remission after 2 weeks of treatment (13% [1 of 8], 27% [3 of 11],and 40% [4 of 10] in the 28-mg, 56-mg, and 84-mg groups, respectively, and 10% [1 of 10], in the placebo group). Response
and remission rates at the end of the open-label and follow-up phases are presented by type of treatment in the doubleblind and open-label phases in Table 2.

SafetyThree of 56 (5%) esketamine-treated participants during the
double-blind phase (compared with none receiving placebo)and 1 of 57 (2%) during the open-label phase had adverse events
leading to discontinuation of the study drug (1 event each of
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Original Investigation Research

syncope, headache, dissociative syndrome, and ectopic pregnancy). During the double-blind phase, the 3 most common
treatment-emergent adverse events observed among esketamine-treated participants were dizziness, headache, and dissociative symptoms; the frequency of each was more than
2-fold higher for esketamine than for placebo (eTable 4 in
Supplement 1). A dose-response trend was noted for dizziness and nausea, but not for other adverse events. The typeand frequency of adverse events reported in the open-labelphase were similar to those in the double-blind phase; events
reported for more than 10% of 57 open-label participants included dizziness (22 [39%]), dysgeusia (13 [23%]), nausea (9[16%]), headache (8 [14%]), and sedation (6 [11%]). Overall, 14of 57 (25%) participants reported transient dissociative symptoms. Most adverse events occurring on dosing days were transient and either mild or moderate in severity. No death was reported.
Most of the esketamine-treated participants manifested
transient elevations in blood pressure (maximum mean change:
systolic, 19.0 mm Hg; diastolic, 10.3 mm Hg) and heart rate
(maximum mean change: 9.4 bpm) on dosing days. Maximum blood pressure values were observed in most cases at 10
or 40 minutes after the dose (systolic: 199 mm Hg; diastolic:115 mm Hg); elevated values typically returned to the value observed before dosing by 2 hours after the dose (eFigures 2 and3 in Supplement 1). A dose effect was not observed for heartrate, although the greatest mean increases from baseline during both periods were observed in the 84-mg esketamine group.
Perceptual changes and/or dissociative symptoms, as measured by the CADSS, began shortly after the start of intranasal
dosing, peaked at approximately 30 to 40 minutes, and resolved by 2 hours (eFigure 4 in Supplement 1). Perceptualchanges/dissociative symptoms attenuated in all dose groups
with repeated dosing. No participant manifested symptoms
suggestive of psychosis based on the Brief Psychiatric Rating
Scale positive assessment.

Discussion
We observed a significant and clinically meaningful treatment effect (vs placebo) with 28-mg, 56-mg, and 84-mg dosesof esketamine, as evidenced by change in the MADRS total
score, with a significant relationship between esketamine doseand antidepressant response observed after 1 week of treatment. Duration of efficacy appeared to be shorter with the
28-mg dose administered twice weekly. Results from the openlabel phase suggest that improvement in depressive symptoms can be sustained with lower frequency (weekly or every
2 weeks) of esketamine administration. The size of the medication-placebo difference was substantial from baseline to 1
week and was larger than the mean difference from placebo
seen at 6 to 8 weeks in antidepressant studies in the US Foodand Drug Administration database.46 The majority of participants maintained improvement over the 2-month follow-up
phase.
The 56- and 84-mg intranasal doses of esketamine produce plasma esketamine levels that are in the pharmacoki(Reprinted) JAMA Psychiatry February 2018 Volume 75, Number 2© 2017 American Medical Association. All rights reserved.

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Efficacy and Safety of Intranasal Esketamine in Depression

Table 1. MADRS Total Score: Change From Baseline to 2 Hours, 24 Hours, and Period End Point
Variablea
Period 1

PlaceboEsketamine 28 mg

Esketamine 56 mg

Esketamine 84 mg

No.

33

11

11

12

MADRS total score at baseline, mean (SD)35.0 (5.18)

31.3 (3.80)

33.2 (6.26)

35.0 (4.22)−9.7 (1.76)−16.4 (2.76)−14.3 (2.70)−17.6 (2.60)−6.7 (3.03)−4.6 (2.96)−7.9 (2.84)

.02

.06

.003

Change at 2 h
LS mean change (SE)LS mean difference from placebo (SE)P value
Responders, No. (%)

6 (18)

6 (55)

4 (36)

7 (58)

Remitters, No. (%)

1 (3)3 (27)

2 (18)

3 (25)−14.8 (2.80)−15.7 (2.74)−16.4 (2.64)−9.1 (3.08)−10.0 (3.00)−10.7 (2.88)

.002

<.001

<.001

Change at 24 h
LS mean change (SE)−5.7 (1.79)

LS mean difference from placebo (SE)P value
Responders, No. (%)

1 (3)4 (36)

3 (27.3)

5 (42)

Remitters, No. (%)

0

4 (36)

2 (18)

3 (25)−4.9 (1.74)−9.8 (2.72)−12.4 (2.66)−15.3 (2.56)−5.0 (2.99)−7.6 (2.91)−10.5 (2.79)

.05

.006

<.001

Change at study period end point
LS mean change (SE)LS mean difference from placebo (SE)P value
Responders, No. (%)

2 (6)

1 (9)

2 (18)

5 (42)

Remitters, No. (%)

1 (3)

1 (9)

1 (9)

3 (25)

Period 2b
No.

6

8

9

5

MADRS total score at baseline, mean (SD)29.3 (5.79)

31.3 (7.09)

34.9 (6.13)

30.4 (4.67)−6.8 (3.74)−10.3 (3.18)−11.7 (3.22)−11.6 (3.44)−3.5 (3.82)−4 (3.92)−4.9 (4.36)

.18

.11

.14

Change at 2 h
LS mean change (SE)LS mean difference from placebo (SE)P value
Responders, No. (%)

1 (17)

1 (13)

2 (22)

2 (40)

Remitters, No. (%)

1 (17)

1 (13)02 (40)−4.1 (4.09)−8.9 (3.48)−10.2 (3.52)−11.6 (3.76)−4.8 (4.18)−6.1 (4.29)−7.5 (4.77)

.13

.09

.07

Change at 24 h
LS mean change (SE)LS mean difference from placebo (SE)P value
Responders, No. (%)

00

1 (11)

2 (40)

Remitters, No. (%)

0

0

0

1 (20)−4.5 (2.92)−7.6 (2.49)−8.9 (2.51)−11.4 (2.68)−3.1 (2.99)−4.4 (3.06)−6.9 (3.41)

.15

.08

.03

Change at study period end point
LS mean change (SE)LS mean difference from placebo (SE)P value
Responders, No. (%)

0

1 (13)0

1 (20)

Remitters, No. (%)

0

1 (13)0

1 (20)

Periods 1 and 2 Combined
Mean difference from placebo (SE)−4.2 (2.09)−6.3 (2.07)−9.0 (2.13)

90% CI for mean difference vs placebo−7.67 to −0.79−9.71 to −2.88−12.53 to −5.52

Combined period test statistic

−2.02

−3.04

4.24

.02

.001

<.001

P value
Abbreviations: LS, least squares; MADRS, Montgomery-Åsberg Depression
Rating Scale.

b

Period 1 (days 1-8) and period 2 (days 8-15) are discussed in the Design section

The study samples reported for period 2 include only the placebo
nonresponsive participants rerandomized following period 1.

netic range achieved by intravenous administration of esketamine, 0.2 mg/kg, which produced a similar clinical outcome
as reported for intravenous ketamine, 0.5 mg/kg (consistent
with higher affinity for NMDA receptors compared witharketamine47).19

In what we believe to be the first study of intranasal esketamine for TRD, efficacy and safety were compared with placebo using a double-blind, doubly randomized, delayed-startdesign.25 This design allowed for a smaller sample size to assess efficacy, dose-response, and safety than a standard par-a144of the Methods and shown in the vertical axis of Figure 1.

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Efficacy and Safety of Intranasal Esketamine in Depression

Original Investigation Research

Figure 2. Mean Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score Over Time in Double-Blind Phase
A Period 1

B

Period 2
PlaceboEsketamine 28 mg

10

Mean Change in MADRS Total Score

Mean Change in MADRS Total Score

10
5
0
–5
–10
–15
–20
–25

Esketamine 56 mg
Esketamine 84 mg

5
0
–5
–10
–15
–20
–25

BL

1(2H)

2

3

4

5

6

7

8

BL

1(2H)

2

3

4

Days
No. of participants
PlaceboEsketamine 28 mg
Esketamine 56 mg
Esketamine 84 mg

33
11
11
12

5

6

7

8

Days

33
11
11
12

No. of participants
PlaceboEsketamine 28 mg
Esketamine 56 mg
Esketamine 84 mg

33
11
11
12

Changes shown in periods 1 (A) and 2 (B). Period 2 consisted only of participants
who had received placebo in period 1 and had moderate to severe symptoms(n = 28). Period 1 (days 1-8) and period 2 (days 8-15) are discussed in the Design

6
8
9
5

6
8
9
5

6
8
9
5

section of the Methods and shown in the vertical axis of Figure 1. BL indicatesbaseline; 2H, 2 hours post dose. Error bars indicate SE.

Figure 3. MADRS Total Score: Mean Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score From Baseline to Follow-up
End Point for Participants Who Entered the Open-Label Phase50

Period1

Period2Open-label

Follow-up

Mean MADRS Total Score

40

30

20

10

0
BL

15 18 22 25

32

39

46

60

74

1

2

Days
No. of participants 57

57 53 56 52

47

40

39

4

8

Weeks
35

34

49

46

44

41

Period 1 (days 1-8), period 2 (days 8-15), open-label period (days 15-74), and the follow-up period (days 74-130) are discussed in the Design section of the Methods
and shown in the vertical axis of Figure 1. BL indicates baseline; error bars, SE.

allel-group design, while preserving a low chance of type 2 error to avoid missing the efficacy signal. The key aim of thedesign was to include only placebo-receiving participants fromperiod 1 who required treatment in period 2 and to rerandomize them to receive 1 of 3 intranasal esketamine doses or intranasal placebo. At the end of the trial, efficacy data from bothrandomizations (day 1 and day 8) were combined in an integrated analysis. Given the rerandomized placebo, nonresponders were expected to have a lower placebo response; thisapproach was used to mitigate high placebo responses observed in psychiatric clinical trials.25 The consistency in results obtained from the period 1 and period 2 samples supjamapsychiatry.com

ports their combination using weights as discussed by Chi
et al,25 although caution is required in interpretation due tothe small sample size.
In general, the esketamine doses evaluated in this study (28,56, and 84 mg) appeared to be safe, with no new or unexpectedsafety concerns observed. Overall, transient increases in bloodpressure after the dose, particularly increases in systolic bloodpressure, support an increase in cardiac output as the underlying mechanism, consistent with previous reports for ketamine.15
Analysis of perceptual change symptoms (measured by CADSS
assessment) suggests that onset begins shortly after initiation of
esketamine and resolution occurs by 2 hours after administra(Reprinted) JAMA Psychiatry February 2018 Volume 75, Number 2© 2017 American Medical Association. All rights reserved.

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Research Original Investigation

Efficacy and Safety of Intranasal Esketamine in Depression

Table 2. Response and Remission Rates for Participants Who Completed the OL and Follow-up Phasesa

Variable

Placebo/Placebo/OL Esketamine(n = 10)b

Esketamine/
Placebo/Esketamine/OL Esketamine Esketamine/OL Esketamine Total(n = 27)(n = 57)(n = 20)

6

10

18

6 (100)5 (50)

11 (61)22 (65)

7

12

22

41

5 (71)

3 (25)

15 (68)23 (56)

Response Ratec
OL end point, day 74, No.
≥50% Improvement, No. (%)
Week 8 (follow-up), No.
≥50% Improvement, No. (%)

34

Remission Ratec
OL end point, day 74, No.

6

10

18

34

No, No. (%)

4 (67)

6 (60)

13 (72)23 (68)

Yes, No. (%)

2 (33)

4 (40)

5 (28)

11 (32)

7

12

22

41

No, No. (%)

3 (43)

9 (75)

12 (55)24 (59)Yes, No. (%)

4 (57)

3 (25)

10 (46)17 (42)

Week 8 (follow-up), No.

number of participants per a visit as denominator; percentage change
calculated based on period 1 baseline.

Abbreviation: OL, open-label.
a

The follow-up phase includes data from 7 participants enrolled under theoriginal version of the protocol in which participants received 2 weeks of study
drug during the OL phase of the study and data from 50 participants enrolled
under a protocol amendment in which participants received up to 9 weeks ofstudy drug during the OL phase of the study. Percentages calculated with thetion. These symptoms were dose dependent and attenuated withrepeated administration. In contrast, antidepressant efficacy did
not attenuate across administrations.

Limitations
Generalizability of the study findings is limited by the small
sample size and enrollment criteria that excluded individuals
with a history of psychotic symptoms, substance/alcohol use disorders, recent use of cannabis, or significant medical comorbidities. Also excluded were individuals having current suicidal ideation with intent—a group that was evaluated in a separate
study.48 Difficulty blinding esketamine, despite adding a bittering agent to placebo to mimic the taste of esketamine, is anotherlimitation.

Esketamine was given as esketamine hydrochloride.

c

Response: Montgomery-Åsberg Depression Rating Scale (MADRS) total scoreⱖ50%; remission: MADRS total score ⱕ10.

Conclusions
Intranasal esketamine administered at doses of 28, 56, and84 mg appeared to be efficacious in treating TRD. There wasevidence of robust and durable efficacy in the double-blind
treatment phase (56 and 84 mg). Improvement in depressive symptoms persisted over the open-label phase, despite
reduced dosing frequency, and for up to 2 months after cessation of esketamine dosing. Results support further investigation of intranasal efficacy of esketamine for the treatment of TRD in larger trials. A phase 3 study evaluating thenecessary frequency of dosing and duration of effect isunder way.49

Farmington, Connecticut (Winokur); Department of
Neuroscience, Janssen Research & Development,
Beerse, Belgium (Van Nueten).

ARTICLE INFORMATION
Accepted for Publication: October 16, 2017.
Published Online: December 27, 2017.
doi:10.1001/jamapsychiatry.2017.3739
Open Access: This article is published under the JNOA license and is free to read on the day of
publication.
Author Affiliations: Department of Neuroscience,
Janssen Research & Development LLC, Titusville,
New Jersey (Daly, Fedgchin, Manji, Drevets);
Department of Neuroscience, Janssen Research &Development LLC, San Diego, California (Singh);
Department of Neuroscience, Janssen Research &Development LLC, Spring House, Pennsylvania(Cooper); Department of Quantitative Sciences,
Janssen Research & Development LLC, Titusville,
New Jersey (Lim); Department of Psychiatry,
University of Alabama School of Medicine,
Birmingham (Shelton); Department of Psychiatry,
Perelman School of Medicine, University ofPennsylvania, Philadelphia (Thase); Institute of
Living, Hartford, Connecticut (Winokur);
Department of Psychiatry, UConn Health,146bAuthor Contributions: Drs Daly and Singhcontributed equally to the study, had full access to
all the data in the study, and take responsibility for
integrity of the data and the accuracy of the data
analysis.
Study concept and design: Daly, Singh, Fedgchin,Lim, Shelton, Thase, Van Nueten, Drevets.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Daly, Singh, Lim,
Shelton, Drevets.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Singh, Cooper, Lim.
Obtained funding: Singh, Van Nueten, Drevets.
Administrative, technical, or material support:
Singh, Fedgchin, Shelton, Winokur, Manji.
Study supervision: Singh, Van Nueten, Manji,
Drevets.
Conflict of Interest Disclosures: Drs Daly, Singh,
Fedgchin, Cooper, Lim, Van Nueten, Manji, andDrevets are employees of Janssen Research &Development, LLC and hold company stock/stock
options. Dr Manji holds a patent, which is assigned
to Icahn School of Medicine at Mount Sinai, Yale
University, and the National Institutes of Health; nofinancial benefit was received from this patent. Drs
Shelton, Thase, and Winokur report no conflicts.
Funding/Support: This study was funded by
Janssen Research & Development, LLC.
Role of the Funder/Sponsor: Employees of thesponsor were involved in design and conduct of thestudy; collection, management, analysis, andinterpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Meeting Presentations: The study was presented
at the 54th Annual Meeting of the American Collegeof Neuropsychopharmacology; December 6, 2015;
Hollywood, Florida; American Society of ClinicalPsychopharmacology 2015 Annual Meeting; June22, 2015; Miami, Florida; and Society of BiologicalPsychiatry 71st Annual Meeting; May 12, 2016;
Atlanta, Georgia.

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Efficacy and Safety of Intranasal Esketamine in Depression

Additional Contributions: Sandra Norris, PharmD(Norris Communications Group LLC), provided
medical writing assistance and was compensatedfor her time by Janssen Research & Development
LLC. Ellen Baum, PhD (Janssen Research &Development, LLC), provided additional editorial
support. We thank the study participants and theinvestigators for their participation in this study:
Belgium: Geert DeBruecker, MD; United States:
California: David Walling, PhD; Florida: Mary
Stedman, MD; Georgia: Robert Riesenberg, MD;
Illinois: Mark Lerman MD; John Sonneberg PhD;
Maryland: Robert Litman, MD; New York: Maha
Ahmad, MD; Ronald Brenner, MD; Pennsylvania:
Paul Gross, MD; and, Tennessee: Valerie Arnold,
MD. There was no financial compensation.
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