Appraising esketamine nasal spray for the management of treatment-resistant depression in adults: Number needed to treat, number needed to harm, and likelihood to be helped or harmed

Journal of Affective Disorders 271 (2020) 228–238

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Research paper

Appraising esketamine nasal spray for the management of treatmentresistant depression in adults: Number needed to treat, number needed to harm, and likelihood to be helped or harmed

T

Leslie Citromea,⁎, Allitia DiBernardob, Jaskaran Singhc a

Department of Psychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY 10595, United States Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, United States c Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States b

ARTICLE INFO

ABSTRACT

Keywords: Esketamine nasal spray Number needed to treat (NNT) Number needed to harm (NNH) Treatment-resistant depression

Introduction: This post hoc study assessed the evidence-base for esketamine nasal spray for management of treatment-resistant depression (TRD) using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Methods: Data sources were four phase III randomized, double-blind studies including two positive studies (acute flexible-dose; maintenance) in patients with TRD. Key efficacy study outcomes: acute response (≥50% decrease from baseline on Montgomery–Asberg Depression Rating Scale [MADRS] total score), acute remission (MADRS scores ≤12). NNT, NNH were calculated for esketamine nasal spray+newly initiated oral antidepressant (esketamine+AD) vs. placebo+AD. Results: In the pivotal acute flexible-dose study, MADRS response (63.4% vs. 49.5%) and remission (48.2% vs. 30.3%) at 4 weeks resulted in NNT of 8 and 6 for esketamine+AD vs. placebo+AD. NNH values <10 included dissociation (26.1% vs. 3.7%), vertigo (26.1% vs. 2.8%), nausea (26.1% vs. 6.4%), dizziness (20.9% vs. 4.6%), and dysgeusia (24.3% vs. 11.9%). Discontinuation rates due to adverse events (AE) (7.0% vs. 0.9%) yielded NNH=17. LHH comparing MADRS remission vs. discontinuation due to AE was 17 vs. 6. Maintenance use of esketamine+AD demonstrated NNT values<10 for relapse and/or maintenance of remission. In maintenance study, discontinuation due to AE (2.6% vs. 2.1%) yielded NNH=178 (non-significant). Limitations: Only dichotomous outcomes were included. Conclusion: NNT<10 for efficacy outcomes suggests potential benefit of esketamine+AD for both acute and maintenance use. LHH was favorable: esketamine+AD was 3 times likely to result in acute remission vs. discontinuations due to AE.

1. Introduction Esketamine (S-enantiomer of ketamine) nasal spray was recently approved in the United States (US, March 2019) for the management of treatment-resistant depression (TRD) in adults, in conjunction with newlyinitiated oral antidepressant medication (Janssen Pharmaceuticals, Inc., 2019). Until 2019, FDA-approved combination treatments for major depressive disorder (MDD) have been limited to selected second-generation antipsychotics, namely aripiprazole, brexpiprazole, quetiapine, and the combination of olanzapine and fluoxetine (Citrome, 2010a, 2015), of which only the latter has been approved specifically for TRD (Eli Lilly and Company, 2018). MDD is one of the most common mental health disorders in the US, with a lifetime prevalence of about 16% (Kessler et al.,

⁎

2003) and is the number one cause of disability from a mental health disorder in the US and ranks as the number two cause of disability overall after lower back pain (U.S. Burden of Disease Collaborators, 2013), with lost workplace productivity due to both absenteeism and presenteeism, costing billions of dollars (Greenberg et al., 2015). Patients with MDD usually do not achieve remission with their first treatment trial, as evidenced in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (Rush et al., 2006a, Rush et al., 2006a), and often several treatment trials (switching and/or augmentation) are necessary. Clinical studies suggest that subanesthetic doses of intravenous ketamine are effective and rapid-acting in major depression, supporting its use in the rapid resolution of depressive symptoms, reduction of suicidality, and/or managing TRD (Zarate et al., 2006; Naughton et al.,

Correspondence to: 11 Medical Park Drive, Suite 106, Pomona, NY 10595, United States. E-mail address: [email protected] (L. Citrome).

https://doi.org/10.1016/j.jad.2020.03.106 Received 29 November 2019; Received in revised form 30 January 2020; Accepted 28 March 2020 Available online 03 April 2020 0165-0327/ © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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2014; DeWilde et al., 2015; McGirr et al., 2015; Singh et al., 2016; Grunebaum et al., 2018; Wilkinson et al., 2018; Bartoli et al., 2017; Feifel et al., 2017). Interest in this intervention is substantial, with 1150 publications in the past 5 years matching up with the text words ‘ketamine AND depression’ in a search (June 30, 2019) of PubMed (https://www.ncbi.nlm.nih.gov/pubmed/?term=ketamine ±AND±depression), and 202 studies registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/results?cond=&term=ketamine±depression). Esketamine possesses a 3–4-fold higher affinity for N-methylD-aspartate (NMDA) receptors than the R-ketamine enantiomer (arketamine) (Andrade, 2017). A major advantage of esketamine nasal spray over intravenous ketamine is ease of use as it is a non-invasive route of administration. Available in the published medical literature is a phase II study (Daly et al., 2018) and four phase III studies (Popova et al., 2019; Daly et al., 2019; Fedgchin et al., 2019; Och-Ross et al., 2020) of esketamine nasal spray combined with a newly-initiated oral antidepressant (esketamine+AD) compared with placebo nasal spray combined with a newly-initiated oral antidepressant (AD+placebo), in patients with TRD. The efficacy results of the two positive pivotal studies, an acute flexible dose study (Popova et al., 2019) and a maintenance study (Daly et al., 2019), as well as the phase II study (Daly et al., 2018), demonstrated statistical significance. The aim of the current analysis is to review the evidence-base for esketamine nasal spray for the management of TRD using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH), to better place this intervention into clinical perspective (Citrome, 2008, 2009, Citrome, 2010b; Citrome and Kantrowitz, 2008; Citrome and Ketter, 2013; Straus, 2002). NNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. Lower NNTs are evidenced when there are large differences between the interventions in question. For example, a NNT of 2 would be a very large effect size, as a difference is encountered after treating just 2 patients with one of the interventions vs. the other. A NNT of 100 would mean little difference between the two interventions, as it would take treating 100 patients to encounter a difference in outcome. NNH is used when referring to undesirable events. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. A rule of thumb is that single digit NNTs (<10) for efficacy measures suggest that the intervention has potentially useful advantages, and that double digit or higher NNHs (≥10) for adverse outcomes indicate that the intervention is potentially tolerable. Confidence intervals (CIs) can also be calculated, provided that actual numerators and denominators for the proportions are available. The ratio of NNH to NNT is called the LHH. In general, a LHH > 1 would mean the likelihood to be helped is greater than the likelihood to be harmed. For a LHH < 1, the reverse is true. Examples of this type of systematic appraisal for medications for MDD can be found elsewhere (Citrome, 2010a; Citrome 2015, 2016).

initiated oral antidepressant (placebo+AD, active comparator). In the acute studies, patients received esketamine+AD or placebo+AD for 4 weeks (oral AD administered daily, and nasal spray administered twiceweekly), and the primary outcome was change from baseline to the 4week endpoint on the Montgomery–Asberg Depression Rating Scale (MADRS) total score. In the randomized withdrawal maintenance study, patients received esketamine+AD or placebo+AD, with the nasal spray administered once-weekly or once-every-other-week based on depressive symptoms, and the primary outcome measure was timeto-relapse. 2.2. Data extracted 2.2.1. Efficacy Specific efficacy outcomes of clinical interest were assessed, as occurring during the double-blind period for the acute studies and at early termination (ET)/endpoint (LOCF) of the double-blind period for all studies. Denominator is the number of randomized patients who received at least one dose of study drug and had at least one post-baseline assessment on the efficacy outcome of interest. 2.2.1.1 Acute studies: Outcomes assessed were response or remission with esketamine, by dose, as defined by: (a) Response, ≥50% decrease from baseline on the MADRS total score; (b) Remission, MADRS total score ≤8, ≤10, and ≤12; (c) Remission, Clinical Global ImpressionSeverity (CGI-S) = 1 or 2 (Leucht et al., 2017). Also assessed were categorical shifts in MADRS severity from baseline to 4 Weeks, using the following definitions (Müller et al., 2000): 0–8—recovered; 9–17—mild depression; 18–34—moderate depression; ≥ 35—severe depression; as well as shifts in CGI-S by ≥ 2 points decrease from baseline. 2.2.1.2 Maintenance study: Outcomes assessed were relapse in patients with stable remission at randomization, relapse in patients with stable response at randomization, and remission in all patients as defined by MADRS total score ≤8, ≤10, ≤12, or CGI-S of 1 or 2, at endpoint. 2.2.2. Tolerability Assessed were specific tolerability and safety outcomes of clinical interest, occurring at any time during the double-blind period. Denominator is the number of all randomized patients who have received at least one dose of study drug. Discontinuation due to an AE was assessed. In the acute studies, spontaneously reported AEs were assessed by dose of esketamine and the threshold used for reporting was an incidence rate of ≥ 5% for esketamine (doses pooled in case of multiple esketamine treatment arms) and incidence greater than that observed with placebo. 2.3. Data analysis In this post hoc analysis, NNT for efficacy outcomes and NNH for tolerability outcomes, and the respective 95% CIs, are calculated for esketamine+AD vs. placebo+AD, individually for each study. Pooled results are also calculated for the acute studies. LHH is calculated to illustrate potential trade-offs for efficacy and tolerability outcomes, specifically response vs. the most commonly encountered AEs and for discontinuation because of an AE. In all instances, if the 95% CI includes “infinity” the result is considered not statistically significant at the p < 0.05 threshold. The terms “statistically significant” and “non-statistically significant” are used descriptively and not inferentially. The notation “ns” is used rather than showing the non-continuous 95% CIs generated when statistical significance is not achieved.

2. Methods 2.1. Data sources Four completed pivotal phase III double-blind active-controlled studies of esketamine nasal spray on TRD in adults were conducted by Janssen as part of the development of this intervention (Table 1). Three were similarly designed 4-week acute studies (one fixed-dose study and two flexibly dosed studies) and one was a randomized-withdrawal maintenance study. In these studies, patients with TRD were randomized to receive esketamine nasal spray plus a newly-initiated oral antidepressant (esketamine+AD) or placebo nasal spray plus a newly229

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Table 1 Pivotal phase III double-blind placebo-controlled studies of intranasal esketamine in adults with treatment-resistant depression included in this analysis. Study Title and Identifiers

Key Design Characteristics

Primary Outcome

Summary of Results

A randomized, double-blind, multicenter, active-controlled study to evaluate the efficacy, safety, and tolerability of fixed doses of intranasal esketamine plus an oral antidepressant in adult patients with treatment-resistant depression (TRANSFORM-1) NCT02417064, CR107146, ESKETINTRD3001, 2014-004584-20

Adults 18–64 years. Patients receive by self-administration intranasal ESK (56 mg on day 1, and then 84 mg fixed dose from day 4 onwards, or 56 mg fixed dose from day 1 onwards) or matching PBO, twice per week for 4 weeks. Patients simultaneously initiate a new, open-label oral AD (duloxetine, escitalopram, sertraline, or venlafaxine extended release) on day 1 to be continued for the duration of DB phase.

Change from Baseline to the 4-week endpoint in MADRS total score

Enrollment: 346 Study Start Date: 8/2015 Study Completion Date: 2/2018 Primary endpoint not met (p = 0.088). Using MMRM median estimate of the difference (95% CI) in MADRS total score between the intranasal ESK 84 mg + oral AD and the oral AD + intranasal PBO treatment groups was −3.2 (−6.88, 0.45); For intranasal ESK 56 mg + oral AD and the oral AD+ intranasal PBO treatment groups was −4.1 (−7.67, −0.49). ANCOVA estimate of the difference (95% CI) between the intranasal ESK 84 mg + oral AD and the oral AD + intranasal PBO treatment groups was −2.0 (−5.52; 1.42), and that of the intranasal ESK 56 mg + oral AD and the oral AD + intranasal PBO treatment groups was −4.1 (−7.53; −0.60).

A randomized, double-blind, multicenter, active-controlled study to evaluate the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus an oral antidepressant in adult patients with treatment-resistant depression (TRANSFORM-2) NCT02418585, CR107147, ESKETINTRD3002, 2014-004585-22

Adults 18–64 years. Patients selfadminister ESK or PBO intranasally twice per week for 4 weeks as a flexible dose regimen in the DB phase. All participants start at a dose of 56 mg on day 1. On day 4, the dose may be increased to 84 mg or remain at 56 mg per investigator's discretion. On day 8 and 11 the dose may be increased to 84 mg (from 56 mg), remain same, or be reduced to 56 mg (from 84 mg) per investigator's discretion. On day 15, a dose reduction from 84 mg to 56 mg is permitted, if required for tolerability; no dose increase permitted. After day 15, dose must remain stable (unchanged). In addition, participants will simultaneously initiate a new, openlabel oral AD (duloxetine, escitalopram, sertraline, or venlafaxine extended release) on day 1 that will be continued for the duration of DB phase

Change from Baseline to the 4-week endpoint in MADRS total score

Enrollment: 236 Study Start Date: 8/2015 Study Completion Date: 11/2017 Met the primary endpoint (p = 0.020). Change in MADRS total score from baseline to day 28 favored the intranasal ESK + oral AD group over the oral AD + intranasal PBO group. MMRM LSMD (SE) between intranasal ESK + oral AD and oral AD + intranasal PBO was −4.0 (1.69). The difference between treatment groups was statistically significant (one-sided p = 0.010). ANCOVA LSMD (SE): −3.5 (1.63); one-sided p = 0.017

A randomized, double-blind, multicenter, active-controlled study to evaluate the efficacy, safety, and tolerability of intranasal esketamine plus an oral antidepressant in elderly patients with treatment-resistant depression (TRANSFORM-3) NCT02422186, CR107129, ESKETINTRD3005, 2014-004588-19

Adults 65 years and older. Patients receive by self-administration intranasal ESK or matching PBO, twice per week for 4 weeks as a flexible dose regimen (First dose on day 1 is 28 mg, second dose on day 4 is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability). In addition, patients simultaneously initiate a new, openlabel oral AD (duloxetine, escitalopram, sertraline, or venlafaxine extended release) on day 1 that will be continued for the duration of DB phase.

Change from Baseline to the 4-week endpoint in MADRS total score

Enrollment: 139 Study Start Date: 8/2015 Study Completion Date: 9/2017 Primary endpoint not met (p = 0.059). ANCOVA MADRS total score LSMD −3.6, 85% confidence interval −7.20 to +0.07.

A randomized, double-blind, multicenter, active-controlled study of intranasal esketamine plus an oral antidepressant for relapse prevention in treatment-resistant depression (SUSTAIN-1) NCT02493868, CR107128, ESKETINTRD3003, 2014-004586-24

Phase III. Adults 18–64 Years. Aim is to assess the efficacy of intranasal ESK plus an oral AD compared with an oral AD plus intranasal PBO in delaying relapse of depressive symptoms. Oral AD include duloxetine, escitalopram, sertraline or venlafaxine extended release. The study consists of 5 phases: Screening/prospective observational phase (4–7 weeks) for direct-entry participants only, Open-label induction

Time to relapse in patients with stable remission who were randomized in the maintenance phase (up to an anticipated maximum of 104 weeks; relapse defined as any of the following: (1) MADRS total score ≥ 22 for 2 consecutive assessments separated by 5–15 days (inclusive) or (2) hospitalization for worsening depression or any other clinically relevant event determined per clinical

Enrollment: 719 Study Start Date: 10/2015 Study Completion Date: 2/2018 Met the primary endpoint (p = 0.003). Results showed a statistically significantly longer time to relapse in patients randomized to continue ESK compared with those randomized to discontinue ESK based on the weighted combination log-rank test. Overall, 24 (26.7%) patients in the intranasal

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Table 1 (continued) Study Title and Identifiers

Key Design Characteristics

Primary Outcome

Summary of Results

phase (4-weeks) for direct-entry participants only, Optimization phase (12-weeks; open-label for direct-entry participants and DB for transferred-entry participants from studies TRANSFORM-1 or 2), Maintenance phase (variable duration; DB for all participants) and Follow-up phase (2weeks). Open-label induction phase: Direct entry participants start at a dose of 56 mg on day 1. On day 4, the dose may be increased to 84 mg or remain at 56 mg. From day 8 to 22, dose may be increased to 84 mg, remain the same or be reduced to 56 mg from 84 mg per protocol, at investigator's discretion based on efficacy and/or tolerability. On day 25, a dose reduction from 84 mg to 56 mg is permitted but no dose increase is permitted. Optimization Phase: Directentry and transferred-entry participants will self-administer intranasal ESK (same dose) for first 4 weeks, then individualized to either once-weekly or once every other week based on depressive symptoms. Maintenance Phase: All participants assigned to ESK will self-administer intranasal ESK onceweekly or once every other week based on depressive symptoms.

judgment to be suggestive of a relapse of depressive illness such as suicide attempt, completed suicide, or hospitalization for suicide prevention).

ESK + oral AD group and 39 (45.3%) patients in the oral AD + intranasal PBO group experienced a relapse event during the maintenance phase. The estimated hazard ratio of intranasal ESK + oral AD relative to oral AD + intranasal PBO was 0.49 (95% CI: 0.29; 0.84). Based on Kaplan–Meier estimates, the median time to relapse (timepoint at which the cumulative survival function equals 0.5 [or 50%]) for the intranasal ESK + oral AD arm was not estimable (NE), as this group never reached 50%, whereas the median time to relapse (95% CI) for oral AD + intranasal PBO was 273.0 (97.0; NE) days.

Abbreviations: AD: antidepressant; ANCOVA: analysis of covariance; DB: double-blind; ESK: esketamine; LSMD: least-square mean difference; MADRS: Montgomery–Asberg Depression Rating Scale; MMRM: mixed model repeated measures; PBO: placebo.

2.4. Formulae used

difference from placebo was greater in magnitude, with results as robust as a NNT of 6 (4–19) at Day 28/ET for the definition of remission using the threshold of MADRS total score ≤ 12. Estimates for NNT were not statistically significant for the outcome of a CGI-S of 1 or 2, nor for MADRS shifts from baseline to Day 15 or to Day 28/ET, nor for CGI-S shifts ≥2 points. Discontinuation due to an AE was more common for esketamine+AD compared to placebo+AD, with a NNH of 17 (10–95). LHH comparing response vs. discontinuation due to an AE was 17/8, or approximately 2. Hence it is twice as likely to encounter a response as it is to encounter a discontinuation because of an AE. For the efficacy outcome of a MADRS total score ≤ 12 vs. discontinuation because of an AE, the LHH was 17/6, or approximately 2.8. There are several AEs that have a NNH value < 10, and hence would be relatively common and can be expected to occur as often as therapeutic response. These included dissociation, vertigo, nausea, dizziness, and dysguesia. Their time course will dictate whether or not these AEs would be obstacles to use, but because the rate of discontinuation due to an AE was low, it appeared that these common AEs do not necessarily lead to stopping the medication. A similar pattern of effect sizes was observed in the fixed-dose esketamine trial (Supplemental Table 1) and to a lesser degree in the elderly patient trial (Supplemental Table 2). Longer-term (maintenance) use of esketamine 56–84 mg to delay relapse was evaluated in a separate study that utilized a randomized withdrawal design (Table 3). NNT values regarding relapse and/or maintenance of remission were in favor of esketamine+AD vs. placebo+AD, with NNT values <10 and as robust as 4 (3–7), the latter observed for the outcome of relapse in patients with stable response at the time of randomization. Discontinuation because of an AE was seldom encountered for either esketamine- or placebo-treated patients, with a NNH estimate of 178 (ns).

• Absolute Risk Increase (ARI) = (incidence with intranasal esketamine) – (incidence with intranasal placebo) = f – f • The 95% confidence interval (CI) was calculated by 1

Lower bound of CI = ARI - z a 95% CI

f1 (1

Upper bound of CI = ARI + z

f1 )

n1 f1 (1

for a 95% CI

n1

+

f2 (1

f1 )

+

f2 )

n2 f2 (1 n2

2

where, z = 1.96 for f2 )

where, z = 1.96

• NNT (or NNH) = 1/ARI, and rounded up to the next highest whole number • The CI for the NNT (or NNH) was calculated by taking the reciprocal of the lower and upper bounds of the CI for the ARI • LHH = NNH/NNT. 3. Results 3.1. Results from the individual studies The NNT and NNH values for the outcomes of interest from the phase III acute flexible-dose and the phase III maintenance trial study of esketamine+AD are shown in Tables 2 and 3. Supplemental Table 1 contains the analagous data for the phase III fixed dose acute trial, and Supplemental Table 2 shows the data from the acute study done in elderly patients. In the flexible-dose trial (Table 2), patients randomized to esketamine 56–84 mg demonstrated superiority over those randomized to placebo on the efficacy outcomes of response at Day 22 and at Day 28/ET, with NNT (95% CI) values of 6 (4–19) and 8 (4–111), respectively. Remission, as defined by a MADRS total score ≤8 was also demonstrated for esketamine+AD vs. placebo+AD at Day 28/ET with a NNT of 9 (5–123). When less conservative definitions of remision were used, the effect size

3.2. Pooled data Pooling together the results for all doses of esketamine nasal spray across all three available acute studies, including that for elderly adults, 231

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increased the sample size; however, heterogeneity was increased (greater variability in the doses tested and in the ages of the patients). Table 4 illustrates the resulting efficacy and tolerability findings. MADRS response vs. placebo at endpoint yielded a NNT value of 8, and MADRS remission at endpoint resulted in a NNT vs. placebo of 10 at all MADRS thresholds tested. CGI-S remission yielded a NNT of 12. CGI-S shifts from baseline ≥2 points at endpoint resulted in a NNT of 8; this latter outcome was statistically significant in favor of esketamine at all the timepoints where this was assessed (Day 8, 15, 22, and 28). AEs where the NNH vs. placebo was statistically significant include dissociation (NNH 5), vertigo (NNH 6), nausea (NNH 6), dizziness (NNH 7), paraesthesia (NNH 11), hypoaesthesia oral (NNH 12), hypoaesthesia (NNH 12), vomiting (NNH 15), vision blurred (NNH 15), somnolence (NNH 16), blood pressure increased (NNH 16), dizziness postural (NNH 19). Discontinuation rates because of an AE were 4.8% for esketaminetreated patients and 1.7% for patients receiving placebo, yielding a statistically significant NNH value of 33. LHH comparing MADRS

response vs. discontinuation because of an AE was 33/8, or approximately 4.1. Hence from the pooled data it is 4.1 times as likely to encounter a response as it is to encounter a discontinuation because of an AE. For the efficacy outcome of a MADRS total score ≤8, 10 or 12, the LHH vs. discontinuation because of an AE was 33/10, or 3.3. There are several AEs that have a NNH value of less than 10, and hence these would be relatively common and can be expected to occur as often as therapeutic response. These AEs included dissociation, vertigo, nausea, and dizziness. As previously noted, it is evident that the occurence of an AE does not necessarily lead to discontinuation because of that AE. Data for the pooled doses of 56 and 84 mg doses of esketamine from the acute fixed-dose study are shown in Supplemental Table 3. Data for the pooled doses of 56 and 84 mg doses of esketamine from the acute fixed-dose study combined with the data from the pivotal acute flexibledose study are shown in Supplemental Table 4.

Table 2 NCT02418585 (ESKETINTRD3002, TRANSFORM-2): A randomized, double-blind, multicenter, active-controlled study to evaluate the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus an oral antidepressant in adult patients with treatment-resistant depression Outcome

Esketamine (56–84 mg)+AD n

N

Placebo+AD %

n

N

NNT or NNH (95%CI) vs. placebo %

EFFICACY Response, ≥ 50% decrease from baseline on the MADRS total score Day 2 18 109 Day 8 15 109 Day 15 29 107 Day 22 54 103 Day 28/ET 71 112 Remission, MADRS total score ≤ 8 Day 2 7 109 Day 8 3 109 Day 15 7 107 Day 22 19 103 Day 28/ET 34 112 Remission, MADRS total score ≤ 10 Day 2 8 109 Day 8 6 109 Day 15 10 107 Day 22 24 103 Day 28/ET 43 112 Remission, MADRS total score ≤ 12 Day 2 10 109 Day 8 8 109 Day 15 13 107 Day 22 32 103 Day 28/ET 54 112 Remission, CGI-S = 1 or 2 Day 8 7 108 Day 15 9 105 Day 22 15 102 Day 28/ET 34 112 MADRS Shifts from Baseline at Day 15 ≥35 to 18–34 (severe to moderate) 45 107 ≥35 to 9–17 (severe to mild) 10 107 ≥35 to 0–8 (severe to recovered) 5 107 18–34 to 9–17 (moderate to mild) 9 107 18–34 to 0–8 (moderate to recovered) 2 107 MADRS Shifts from Baseline at Day 28/ET ≥35 to 18–34 (severe to moderate) 19 112 ≥35 to 9–17 (severe to mild) 27 112 ≥35 to 0–8 (severe to recovered) 20 112 18–34 to 9–17 (moderate to mild) 5 112 18–34 to 0–8 (moderate to recovered) 14 112 CGI-S shifts from baseline ≥ 2 points Day 8 29 108 Day 15 41 105 Day 22 55 102 Day 28/ET 68 112

NNT 16.5% 13.8% 27.1% 52.4% 63.4%

11 13 23 35 54

102 105 102 104 109

10.8% 12.4% 22.5% 33.7% 49.5%

18 (ns) 73 (ns) 22 (ns) 6 (4–19) 8 (4–111)

6.4% 2.8% 6.5% 18.4% 30.4%

2 3 9 11 20

102 105 102 104 109

2.0% 2.9% 8.8% 10.6% 18.3%

23 (ns) −954 (ns) −44 (ns) 13 (ns) 9 (5–123)

7.3% 5.5% 9.3% 23.3% 38.4%

3 6 11 16 26

102 105 102 104 109

2.9% 5.7% 10.8% 15.4% 23.9%

23 (ns) −477 (ns) −70 (ns) 13 (ns) 7 (4–41)

9.2% 7.3% 12.1% 31.1% 48.2%

6 7 13 20 33

102 105 102 104 109

5.9% 6.7% 12.7% 19.2% 30.3%

31 (ns) 149 (ns) −168 (ns) 9 (5–821) 6 (4–19)

6.5% 8.6% 14.7% 30.4%

3 7 16 25

100 103 101 109

3.0% 6.8% 15.8% 22.9%

29 (ns) 57 (ns) −89 (ns) 14 (ns)

42.1% 9.3% 4.7% 8.4% 1.9%

31 6 7 8 2

102 102 102 102 102

30.4% 5.9% 6.9% 7.8% 2.0%

9 (ns) 29 (ns) −46 (ns) 176 (ns) −1092 (ns)

17.0% 24.1% 17.9% 4.5% 12.5%

22 22 14 7 6

109 109 109 109 109

20.2% 20.2% 12.8% 6.4% 5.5%

−32 (ns) 26 (ns) 20 (ns) −52 (ns) 15 (ns)

26.9% 39.0% 53.9% 60.7%

19 31 51 57

100 103 101 109

19.0% 30.1% 50.5% 52.3%

13 12 30 12

(ns) (ns) (ns) (ns)

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Table 2 (continued) Outcome

Esketamine (56–84 mg)+AD n

Placebo+AD

N

%

n

NNT or NNH (95%CI) vs. placebo

N

%

TOLERABILITY

NNH

Discontinuation because of an AE 8 115 AEs with incidence ≥ 5% with esketamine and > rate with placebo Dysgeusia 28 115 Dizziness 24 115 Headache 23 115 Somnolence 15 115 Paraesthesia 13 115 Dizziness postural 8 115 Hypoaesthesia 8 115 Dissociation 30 115 Anxiety 12 115 Insomnia 11 115 Nausea 30 115 Vomiting 11 115 Dry mouth 9 115 Hypoaesthesia oral 9 115 Paraesthesia oral 9 115 Vertigo 30 115 Feeling drunk 9 115 Throat irritation 9 115 Nasal discomfort 8 115 Vision blurred 14 115 Blood pressure increased 11 115

7.0%

1

109

0.9%

17 (10–95)

24.3% 20.9% 20.0% 13.0% 11.3% 7.0% 7.0% 26.1% 10.4% 9.6% 26.1% 9.6% 7.8% 7.8% 7.8% 26.1% 7.8% 7.8% 7.0% 12.2% 9.6%

13 5 19 7 1 1 1 4 5 5 7 2 3 1 1 3 1 5 2 3 0

109 109 109 109 109 109 109 109 109 109 109 109 109 109 109 109 109 109 109 109 109

11.9% 4.6% 17.4% 6.4% 0.9% 0.9% 0.9% 3.7% 4.6% 4.6% 6.4% 1.8% 2.8% 0.9% 0.9% 2.8% 0.9% 4.6% 1.8% 2.8% 0.0%

9 (5–41) 7 (5–13) 39 (ns) 16 (ns) 10 (7–24) 17 (10–95) 17 (10–95) 5 (4–8) 18 (ns) 21 (ns) 6 (4–10) 13 (8–56) 20 (ns) 15 (9–60) 15 (9–60) 5 (4–7) 15 (9–60) 31 (ns) 20 (ns) 11 (7–37) 11 (7–24)

Abbreviations: AD: antidepressant, AE: adverse events; CGI-S: Clinical Global Impression-Severity; CI: confidence interval; ET: early termination; MADRS: Montgomery–Asberg Depression Rating Scale; n: numerator; N: denominator [for efficacy outcomes: number of randomized patients who received at least one dose of study drug and had at least one post-baseline assessment on the efficacy outcome of interest; for safety outcomes: all randomized patients who received at least one dose of study drug]; NNH: number needed to harm; NNT: number needed to treat; ns: not significant at the P < 0.05 threshold, thus the 95% CI is not shown.

4. Discussion

esketamine can be contrasted with commonly used interventions for similar indications, notably adjunctive use of second-generation antipsychotics (SGAs) for which US FDA approval was based on data from double-blind randomized controlled clinical trial in patients who have not adequately responded to antidepressant monotherapy (Citrome, 2010a, 2015). Although the esketamine studies were shorter in

In general, efficacy outcomes yielded NNT values for esketamine +AD vs. placebo+AD that were <10 and thus denote that esketamine could potentially be an efficacious intervention for TRD (Citrome and Ketter, 2013; Pinson and Gray, 2003). The clinical usefulness of

Table 3 NCT02493868 (ESKETINTRD3003, SUSTAIN-1): A randomized, double-blind, multicenter, active-controlled study of intranasal esketamine plus an oral antidepressant for relapse prevention in treatment-resistant depression. Outcome (double-blind maintenance phase) EFFICACY Relapse, patients with stable remission at randomization Relapse, patients with stable response at randomization Remission, MADRS total score ≤ 8, all patients, at endpoint Remission, MADRS total score ≤ 10, all patients, at endpoint Remission, MADRS total score ≤ 12, all patients, at endpoint Remission, CGI-S = 1 or 2, all patients, at endpoint

Esketamine (56–84 mg)+AD

Placebo+AD

NNT or NNH (95% CI) vs. placebo

n

N

%

n

N

%

24 16 69 79 87 70

89 62 151 151 151 151

27.0% 25.8% 45.7% 52.3% 57.6% 46.4%

39 34 41 45 51 49

86 59 145 145 145 144

45.3% 57.6% 28.3% 31.0% 35.2% 34.0%

TOLERABILITY Discontinuation because of an AE, all patients

NNT 6 4 6 5 5 9

(4–23) (3–7) (4–16) (4–10) (3–9) (5–82)

NNH 4

152

2.6%

3

145

2.1%

178 (ns)

Abbreviations: AD: antidepressant, AE: adverse events; CGI-S: Clinical Global Impression-Severity; CI: confidence interval; MADRS: Montgomery–Asberg Depression Rating Scale; n: numerator; N: denominator [for efficacy outcomes: number of randomized patients who received at least one dose of study drug and had at least one post-baseline assessment on the efficacy outcome of interest; for safety outcomes: all randomized patients who received at least one dose of study drug]; NNH: number needed to harm; NNT: number needed to treat; ns: not significant at the P < 0.05 threshold, thus the 95% CI is not shown. Definitions: Stable remission: MADRS total score ≤ 12 for the last 4 weeks of the optimization phase. Stable response: ≥ 50% reduction in the MADRS total score from baseline (Day 1 of induction phase; pre-randomization/prior to the first intranasal dose) in each of the last 4 weeks of the optimization phase, with at least 1 MADRS total score of >12 in these 4 weeks. Note: For transferred-entry patients, Day 1 of the open-label induction phase will take place in ESKETINTRD3001 or ESKETINTRD3002. Relapse: (1) MADRS total score ≥22 for 2 consecutive assessments separated by 5–15 days (the date of the second MADRS assessment will be used for the date of relapse), or (2) hospitalization for worsening depression, for a suicide attempt, or for suicide prevention (the start date of hospitalization will be used for the date of relapse), or (3) in case both relapse criteria are met, the earlier date will be defined as the date of relapse for this patient. 233

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Table 4 NCT02417064 (ESKETINTRD3001, TRANSFORM-1), NCT02418585 (ESKETINTRD3002, TRANSFORM-2), and NCT02422186 (ESKETINTRD3005, TRANSFORM-3) – Esketamine doses pooled. Outcome

Pooled Esketamine (28–84 mg)+AD

Placebo+AD

n

n

N

%

N

NNT or NNH (95%CI) vs. placebo %

EFFICACY Response, ≥ 50% decrease from baseline on the MADRS total score Day 8 Day 15 Day 28/ET Remission, MADRS total score ≤ 8 Day 8 Day 15 Day 28/ET Remission, MADRS total score ≤ 10 Day 8 Day 15 Day 28/ET Remission, MADRS total score ≤ 12 Day 8 Day 15 Day 28/ET Remission, CGI-S = 1 or 2 Day 8 Day 15 Day 22 Day 28/ET MADRS Shifts from Baseline at Day 15 ≥35 to 18–34 (severe to moderate) ≥35 to 9–17 (severe to mild) ≥35 to 0–8 (severe to recovered) 18–34 to 9–17 (moderate to mild) 18–34 to 0–8 (moderate to recovered) MADRS Shifts from Baseline at Day 28/ET ≥35 to 18–34 (severe to moderate) ≥35 to 9–17 (severe to mild) ≥35 to 0–8 (severe to recovered) 18–34 to 9–17 (moderate to mild) 18–34 to 0–8 (moderate to recovered) CGI-S shifts from baseline ≥2 points Day 8 Day 15 Day 22 Day 28/ET

NNT 56 87 203

396 384 412

14.1% 22.7% 49.3%

21 46 104

279 270 286

7.5% 17.0% 36.4%

16 (9–51) 18 (ns) 8 (5–19)

17 30 106

396 384 412

4.3% 7.8% 25.7%

4 19 45

279 270 286

1.4% 7.0% 15.7%

35 (19–236) 129 (ns) 10 (7–25)

24 41 126

396 384 412

6.1% 10.7% 30.6%

8 22 56

279 270 286

2.9% 8.1% 19.6%

32 (16–746) 40 (ns) 10 (6–22)

32 50 145

396 384 412

8.1% 13.0% 35.2%

9 27 70

279 270 286

3.2% 10.0% 24.5%

21 (13–69) 34 (ns) 10 (6–26)

16 32 48 115

389 377 365 411

4.1% 8.5% 13.2% 28.0%

5 12 33 56

273 268 258 287

1.8% 4.5% 12.8% 19.5%

44 (ns) 25 (13–381) 278 (ns) 12 (7–47)

141 35 23 20 7

384 384 384 384 384

36.7% 9.1% 6.0% 5.2% 1.8%

82 11 14 16 5

270 270 270 270 270

30.4% 4.1% 5.2% 5.9% 1.9%

16 (ns) 20 (12–76) 125 (ns) −140 (ns) −3456 (ns)

92 62 75 20 31

412 412 412 412 412

22.3% 15.0% 18.2% 4.9% 7.5%

65 35 32 17 13

286 286 286 286 286

22.7% 12.2% 11.2% 5.9% 4.5%

−252 (ns) 36 (ns) 15 (9–56) −92 (ns) 34 (ns)

84 132 170 218

389 377 365 411

21.6% 35.0% 46.6% 53.0%

39 65 95 112

273 268 258 287

14.3% 24.3% 36.8% 39.0%

14 (8–68) 10 (6–27) 11 (6–52) 8 (5–16)

TOLERABILITY Discontinuation because of an AE AEs with incidence ≥ 5% with esketamine and > rate with placebo Dizziness Headache Somnolence Dysgeusia Hypoaesthesia Paraesthesia Dizziness postural Nausea Hypoaesthesia oral Vomiting Diarrhea Dissociation Anxiety Vertigo Fatigue Throat irritation Vision blurred Blood pressure increased Insomnia

NNH 20

418

4.8%

5

287

1.7%

33 (18–202)

97 79 61 69 42 47 24 111 42 37 26 101 33 86 34 23 33 39 33

418 418 418 418 418 418 418 418 418 418 418 418 418 418 418 418 418 418 418

23.2% 18.9% 14.6% 16.5% 10.0% 11.2% 5.7% 26.6% 10.0% 8.9% 6.2% 24.2% 7.9% 20.6% 8.1% 5.5% 7.9% 9.3% 7.9%

20 40 23 33 4 6 1 22 3 5 14 9 17 7 16 11 3 8 19

287 287 287 287 287 287 287 287 287 287 287 287 287 287 287 287 287 287 287

7.0% 13.9% 8.0% 11.5% 1.4% 2.1% 0.3% 7.7% 1.0% 1.7% 4.9% 3.1% 5.9% 2.4% 5.6% 3.8% 1.0% 2.8% 6.6%

7 (5–9) 21 (ns) 16 (9–51) 20 (ns) 12 (9–19) 11 (8–18) 19 (13–33) 6 (5–8) 12 (9–17) 15 (10–25) 75 (ns) 5 (4–7) 51 (ns) 6 (5–8) 40 (ns) 60 (ns) 15 (11–25) 16 (11–32) 79 (ns)

Abbreviations: AD: antidepressant, AE: averse events; CGI-S: Clinical Global Impression-Severity; CI: confidence interval; ET: early termination; MADRS: Montgomery–Asberg Depression Rating Scale; n: numerator; N: denominator [for efficacy outcomes: number of randomized patients who received at least one dose of study drug and had at least one post-baseline assessment on the efficacy outcome of interest; for safety outcomes: all randomized patients who received at least one dose of study drug]; NNH: number needed to harm; NNT: number needed to treat; ns: not significant at the P < 0.05 threshold, thus the 95% CI is not shown.

234

(d)

235

63.4% 49.5% 49.3% 36.4% 40.3% 27.8% 37.4% 22.5% 56.0% 46.3% 25.2% 15.6% 51.5% 34.1% 53.1% 38.1% 44.8% 34.6% 51.7% 32.7% 48.3% 30.6% 40.7% 28.3% 48.9% 37.0% 8 (6–17)

vs.

vs.

vs.

vs.

vs.

vs.

vs.

vs.

vs.

vs.

9 (7–11)

8 (6–16)

6 (5–9)

6 (4–13)

10 (8–16)

7 (5–11)

6 (5–8)

11 (8–20)

11 (6–34)

7 (5–11)

8 (5–19)

vs.

vs.

8 (4–111)

vs.

cited source

19 (11–56)

9 (6–19)

8 (6–13)

13 (8–40)

10 (6–22)

7 (4–41)

Not available from cited source

Not available from cited source

Not available from cited source

Not available from cited source

Not available from cited source

Not available from cited source

38.4% vs. 23.9% 30.6% vs. 19.6% 25.5% vs. 17.3% 29.3% vs. 16.6% 44.0% vs. 32.1% 16.0% vs. 10.5% Not available from

NNT (95% CI)

Rates

Rates

NNT (95% CI)

Remission vs. placebo (MADRS ≤10)

Response vs. placebo(e) NNT (95% CI)

Not available from cited source

Not available from cited source

Not available from cited source

48.2% vs. 6 (4–19) 30.3% 35.2% vs. 10 (6–26) 24.5% Not available from cited source

Rates

Remission vs. placebo (MADRS ≤ 12)

6.3% vs. 3.9%

17.4% vs. 2.0% 17.1% vs. 4.3% 7.0% vs. 3.1%

8.8% vs. 3.3%

5.2% vs. 1.9%

8.5% vs. 4.4%

12.1% vs. 2.3% 2.6% vs. 0.7%

11.6% vs. 2.6% 3.8% vs. 1.5%

4.8% vs. 1.7%

7.0% vs. 0.9%

Rates

43 (28–91)

27 (15–104)

8 (7–11)

7 (5–12)

19 (14–27)

31 (19–92)

25 (17–51)

53 (30–235)

11 (8–15)

43 (24–225)

12 (9–18)

33 (18–202)

17 (10–95)

NNH (95% CI)

Discontinuation because of an AE

5.1

3.3

1.4

1.2

1.8

4.6

4.3

4.8

1.0

6.1

1.5

4.1

2.1

LHH for response vs. discontinuation due to AE

Abbreviations: AD: antidepressant, AE: adverse events; CI: confidence interval; LHH: likelihood to be helped or harmed; MADRS: Montgomery–Asberg Depression Rating Scale; NNH: number needed to harm; NNT: number needed to treat; XR: extended release. (a) From: Table 2 (acute flexible-dose study) and Table 6 (all acute studies pooled). Duration of the randomized phase was 4 weeks for each study. For non-elderly adults only, all doses pooled, see Supplemental Table 4. (b) From: (Citrome, 2010a). For olanzapine-fluoxetine combination, data reported are taken from a published integrated analysis (Trivedi et al., 2009) as the individual study reports did not always contain the information required. The olanzapine-fluoxetine combination analysis pooled the first 8 weeks for the 5 included studies as the length of double-blind treatment ranged from 8 to 12 weeks. For adjunctive aripiprazole, three trials were included in the calculations although only two were used to meet registrational requirements; remitters were also required to meet the criterion for response. For adjunctive quetiapine extended-release results shown are with pooled doses of 150 mg and 300 mg/d, although the paper reports each dose separately. The length of the randomized phase for the aripiprazole and quetiapine extended-release clinical trials was 6 weeks for each study. (c) From: (Citrome, 2015). Efficacy data reported are from the 2 phase III trials (doses of 1–3 mg/d) and the available phase II trial (1.5 mg/d dose); remitters were also required to meet the criterion for response. The length of the randomized phase for each study was 6 weeks. (d) From: (Citrome, 2016). Data on remission were not assessed. LHH calculations were reported as calculated from the NNT and NNH outcomes prior to rounding. Randomized treatment duration for the studies ranged from 6 to 10 weeks, with a modal duration of 8 weeks. (e) Response defined as a ≥ 50% decrease from baseline on the primary outcome measure for the relevant study (usually the MADRS).

Vortioxetine(d)

Vilazodone(d)

Venlafaxine

(d)

Sertraline(d)

Levomilnacipran(d)

Escitalopram

Duloxetine

(d)

Adjunctive brexpiprazole(c)

Adjunctive quetiapine XR(b)

Adjunctive aripiprazole

(b)

Esketamine 56–84 mg (+AD) - from the flexible-dose study Esketamine 28–84 mg pooled (+AD) – elderly and non-elderly patients(a) Olanzapine-fluoxetine(b)

Agent

Table 5 Endpoint NNT, NNH, and LHH for esketamine for treatment-resistant depression: indirect comparison with data for olanzapine-fluoxetine combination, adjunctive aripiprazole, adjunctive quetiapine extended release, adjunctive brexpiprazole, and from the pivotal registration trials of selected SSRIs and SNRIs used as monotherapy for major depressive disorder.

L. Citrome, et al.

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duration, NNT for response and remission, and NNH for discontinuation due to an AE can be indirectly compared (Table 5). There is overlap in terms of the 95% CIs for the NNT estimates for response and remission, suggesting that although the mechanism of action of esketamine differs substantially from that of dopamine receptor blocking agents, efficacy has been demonstrated with a similar level of magnitude of effect size. Although tolerability outcomes that result in NNH values vs. placebo >10 are preferred so that benefits are encountered more often than harms (Citrome and Ketter, 2013), the occurrence of AEs with esketamine nasal spray does not necessarily lead to discontinuation of treatment. In general, in clinical trials, patients often remain on their assigned treatment provided that the AE is time-limited and/or mild in severity. With regard to the single-digit NNH values for specific AEs observed with esketamine, the AEs of dissociation, vertigo, nausea, and dizziness were generally limited to the day of administration (Popova et al., 2019; Daly et al., 2019; Fedgchin et al., 2019; OchRoss et al., 2020). An overall index of tolerability can be better approximated by examining discontinuations due to AEs and when using this perspective the use of esketamine appears reasonably tolerated. As such, the NNH vs. placebo for discontinuation because of an AE for esketamine (NNH 31 for non-elderly adults [Supplemental Table 4]) was similar to that observed with the tolerability options of aripiprazole (NNH 43) and brexpiprazole (NNH 53), and more advantageous when compared with the more poorly tolerated options of adjunctive quetiapine (NNH 11) or olanzapine-fluoxetine combination (NNH 12), although as noted these studies for the other options were somewhat longer in length and data reflects 6–8 weeks of randomized drug exposure vs. the 4 weeks for the acute esketamine trials (see Table 5 for citations and additional details). Of interest, esketamine+AD vs. placebo+AD in TRD also evidenced similar NNT values for response compared to first-line antidepressant monotherapy treatments vs. placebo monotherapy (Table 5). Overall tolerability as measured by discontinuation because of an AE was also generally similar, and the NNH on this outcome for esketamine+AD vs. placebo+AD (approximately 30), was well within the range observed for the monotherapy interventions for the first-line treatments (range 7–43). LHH for esketamine for response vs. discontinuation because of an AE (3.4 for non-elderly adults) also fell within the range observed for these other treatments (1.2–5.1). In a recent relevant meta-analysis of intravenous ketamine for MDD (Han et al., 2016), response rate at day 7 timepoint was available for nine studies (Berman et al., 2000; Ghasemi et al., 2014; Hu et al., 2016, 2014; Lapidus et al., 2014; Murrough et al., 2013; Singh et al., 2016; Sos et al., 2013; Zarate et al., 2006); 39.8% (78 of 196) and 13.4% (23 of 172) of patients receiving ketamine and placebo, respectively, were classified as responders (defined as 50% or greater reduction in the absolute Hamilton Depression Rating Scale [HDRS] or MADRS score from baseline, or significant improvement in the CGI). Remission rate was available for six studies (Berman et al., 2000; Ghasemi et al., 2014; Hu et al., 2016; Murrough et al., 2013; Sos et al., 2013; Zarate et al., 2006) and overall, 26.2% (33 of 126) and 4.8% (5 of 105) of patients receiving ketamine and placebo, respectively, met the remission criteria (set in each study as either HDRS total score ≤ 7 or a MADRS ≤ 10). NNT values vs. placebo was 4 (3–6) for response and 5 (4–8) for remission. Data regarding effects beyond day 7 has not been commonly tested in double-blinded studies of intravenous ketamine and has not been described in meta-analyses. Thus of substantial interest is the esketamine data regarding the longer-term maintenance treatment of TRD. NNT vs. placebo on the outcome of relapse was 6 for esketamine patients who were in stable remission at randomization, and 4 for those who were in stable response (Table 3). NNT for being in remission demonstrated an advantage for esketamine+AD vs. AD+placebo and was the case for all tested definitions of remission, including MADRS total score ≤8, 10 or 12, and for CGI-S = 1 or 2. Rates of discontinuation because of an AE were low for both esketamine+AD and placebo+AD, 2.6% vs. 2.1%,

resulting in a NNH value of 178 (ns). This latter value is somewhat difficult to interpret within the context of a study design where patients are initially treated in an open-label stabilization phase where there is an opportunity to discontinue participation; those patients remaining in the randomized phase are likely to have fewer tolerability problems. There are no comparable placebo-controlled, randomized-withdrawal, relapse-prevention studies of treatment-resistant patients with MDD in the literature. However, the effect size observed for esketamine nasal spray plus a newly initiated oral antidepressant vs. placebo nasal spray plus a newly initiated oral antidepressant is similar to the effect sizes seen in positive studies of antidepressant monotherapy vs. the placebo condition in patients who are not treatment-resistant (Table 6). Additional information is available from an FDA review of 15 maintenance trials for MDD submitted to the agency between 1987 and 2012 (Borges et al., 2014). The mean relapse rate difference vs. placebo was 18% (NNT 6), with an average percent reduction in relapse rate of 52% (Borges et al., 2014). Maintenance electroconvulsive therapy (ECT) has also been the subject of a systematic review, where relapse rates while receiving this intervention was 37.2% at 6 months, similar to what was observed in modern-era pharmacologically treated patients (Jelovac et al., 2013). When only modern day randomized controlled trials were considered, relapse rate on placebo reached 78.0% at 6 months (Jelovac et al., 2013). It is unclear if the patients enrolled in esketamine clinical trial program were similar to those patients enrolled in the above mentioned ECT studies. The existence of any clinically relevant efficacy differences between esketamine nasal spray and intravenous ketamine remains unknown. There are no available studies directly comparing the two formulations and indirect comparisons are hampered by the lack of placebo-controlled longitudinal data for intravenous ketamine. In any event, ease of use of esketamine nasal spray compared to intravenous approaches will likely increase patient acceptability and make this type of therapeutic intervention more accessible. Limitations: Analyses are post hoc. Moreover, due to the nature of NNT/NNH analysis, the data analyzed in this study are limited to dichotomous outcomes. The results may not be generalizable to patients outside the confines of a clinical trial; this is always a concern for results of registration trials because of the strict inclusion/exclusion criteria that these studies require. The metrics of NNT and NNH are not appropriate for continuous outcomes, such as mean changes in the MADRS total score. Reasons for clinical trial discontinuation can be complex, so that the NNH for discontinuation due to AEs in the study may not always generalize to overall tolerability in clinical practice. The brief durations of the available controlled studies of esketamine limit the sensitivity of calculating NNH for delayed adverse outcomes, and the relatively small sample sizes of the studies limit sensitivity of calculating NNH for uncommon adverse outcomes and sub-population effects. Lastly, the NNT and NNH values may differ slightly from those contained in the briefing document provided to the FDA (Janssen Research and Development, 2019) because the definitions used to extract the numerators and denominators were not identical to that used in this study. 5. Conclusion In general, efficacy outcomes for esketamine nasal spray plus a newly-initiated oral antidepressant vs. placebo nasal spray plus a newly-initiated oral antidepressant in patients with TRD, as assessed in the pivotal phase III studies, demonstrated NNT values < 10, denoting that esketamine plus an oral antidepressant is a potentially efficacious intervention for TRD both acutely and in longer-term maintenance use. Although dissociation, vertigo, nausea, and dizziness are common AEs, they do not necessarily lead to discontinuation. Esketamine plus an oral antidepressant is 3 times as likely to result in an acute remission vs. discontinuation because of an AE. 236

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Table 6 Placebo-controlled randomized-withdrawal studies in major depressive disorder. Agent

Length of double-blind period

N

Kaplan–Meier analysis: relapse/recurrence HR vs. placebo (95% CI)

Observed relapse/recurrence rates vs. placebo

NNT vs. placebo (95% CI)

Esketamine (+AD)(a) Vilazodone(b)

Variable 28 weeks

175 564

Desvenlafaxine(c) Vortioxetine(d) Quetiapine(e) Agomelatine(f) Sertraline(g)

6 months 24–64 weeks 52 weeks 6 months 16 weeks

548 400 776 339 235

0.49 (0.29–0.84) 20 mg/d: 0.91 (0.51–1.63); 40 mg/d: 1.07 (0.61–1.87) Ranges from 0.42 to 0.56 0.50 (0.31–0.79) 0.34 (0.25–0.46) 0.46 (0.31- 0.69) HR not reported

27.0% vs. 45.3% 20 mg/d: 11.4% vs. 12.6%; 40 mg/d: 13.4% vs. 12.6% 13.6% vs. 28.3% 15.0% vs. 30.0% 14.2% vs. 34.4% 20.6% vs. 41.4% 8.5% vs. 19.5%

6 (4–23) 20 mg/d: 84 (ns); 40 mg/d: −125 (ns) 7 (5–13) 7 (5–15) 5 (4–7) 5 (4–9) 10 (6–46)

Abbreviations: AD: antidepressant; CI: confidence interval; NNT: number needed to treat; ns: not significant at the P < 0.05 threshold, thus the 95% CI is not shown. (a) Patients in remission at the time of randomization. (b) From: (Durgam et al., 2018). This was a failed study. A low relapse rate was observed with placebo. (c) From: (Rosenthal et al., 2013). Hazard ratios reported based on different models. 95% CI not provided. (d) From: (Boulenger et al., 2012). Hazard ratios as reported in the paper were placebo vs. vortioxetine. Primary efficacy analysis includes only the first 24 weeks of the double-blind period. Observed relapse/recurrence rates reported for the entire duration. (e) From (Liebowitz et al., 2010). Monotherapy trial of the extended release formulation of quetiapine. Not approved in the US as a monotherapy for major depressive disorder. (f) From (Goodwin et al., 2009; Goodwin et al., 2013). Not approved in the US. Another study of agomelatine for relapse prevention failed as there was a low relapse rate observed with placebo. (g) From (Kamijima et al., 2006). Conducted in Japan.

Author statement

References

Contributors

Andrade, C., 2017. Ketamine for depression, 3: does chirality matter? J. Clin. Psychiatry 78, 674–677. Bartoli, F., Riboldi, I., Crocamo, C., Di Brita, C., Clerici, M., Carrà, G., 2017. Ketamine as a rapid-acting agent for suicidal ideation: a meta-analysis. Neurosci. Biobehav. Rev. 77, 232–236. Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S., Krystal, J.H., 2000. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354. Borges, S., Chen, Y.F., Laughren, T.P., Temple, R., Patel, H.D., David, P.A., Mathis, M., Unger, E., Yang, P., Khin, N.A., 2014. Review of maintenance trials for major depressive disorder: a 25-year perspective from the US food and drug administration. J. Clin. Psychiatry 75, 205–214. Boulenger, J.P., Loft, H., Florea, I., 2012. A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder. J. Psychopharmacol. 26, 1408–1416. Citrome, L., 2008. Compelling or irrelevant? Using number needed to treat can help decide. Acta. Psychiatr. Scand. 117, 412–419. Citrome, L., 2009. Quantifying risk: the role of absolute and relative measures in interpreting risk of adverse reactions from product labels of antipsychotic medications. Curr. Drug Saf. 4, 229–237. Citrome, L., 2010a. Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive disorder: an analysis of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Postgrad. Med. 122 July, 39–48. Citrome, L., 2010b. Relative vs. absolute measures of benefit and risk: what’s the difference? Acta. Psychiatr. Scand. 121, 94–102. Citrome, L., 2015. Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int. J. Clin. Pract. 69, 978–997. Citrome, L., 2016. Vortioxetine for major depressive disorder: an indirect comparison with duloxetine, escitalopram, levomilnacipran, sertraline, venlafaxine, and vilazodone, using number needed to treat, number needed to harm, and likelihood to be helped or harmed. J. Affect. Disord. 196, 225–233. Citrome, L., Kantrowitz, J., 2008. Antipsychotics for the treatment of schizophrenia: likelihood to be helped or harmed, understanding proximal and distal benefits and risks. Expert Rev. Neurother. 8, 1079–1091. Citrome, L., Ketter, T.A., 2013. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int. J. Clin. Pract. 67, 407–411. Daly, E.J., Singh, J.B., Fedgchin, M., Cooper, K., Lim, P., Shelton, R.C., Thase, M.E., Winokur, A., Van Nueten, L., Manji, H., Drevets, W.C., 2018. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 75, 139–148. Daly, E.J., Trivedi, M.H., Janik, A., Li, H., Zhang, Y., Li, X., Lane, R., Lim, P., Duca, A.R., Hough, D., Thase, M.E., Zajecka, J., Winokur, A., Divacka, I., Fagiolini, A., Cubala, W.J., Bitter, I., Blier, P., Shelton, R.C., Molero, P., Manji, H., Drevets, W.C., Singh, J.B., 2019. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 76, 893–903. DeWilde, K.E., Levitch, C.F., Murrough, J.W., Mathew, S.J., Iosifescu, D.V., 2015. The promise of ketamine for treatment-resistant depression: current evidence and future directions. Ann. N. Y. Acad. Sci. 1345, 47–58. Durgam, S., Gommoll, C., Migliore, R., Chen, C., Chang, C.T., Aguirre, M., Thase, M.E.,

All authors contributed to the data interpretation, development and review of this manuscript and confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Disclosures Leslie Citrome, in the past 12 months, consultant: Acadia, Alkermes, Allergan, Avanir, BioXcel, Eisai, Impel, Indivior, Intra-Cellular Therapies, Janssen, Lundbeck, Luye, Merck, Neurocrine, Noven, Osmotica, Otsuka, Pfizer, Sage, Shire, Sunovion, Takeda, Teva, Vanda; speaker: Acadia, Alkermes, Allergan, Janssen, Lundbeck, Merck, Neurocrine, Otsuka, Pfizer, Sage, Shire, Sunovion, Takeda, Teva; stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased > 10 years ago; royalties: Wiley (Editor-in-Chief, International Journal of Clinical Practice), UpToDate (reviewer), Springer Healthcare (book). Allitia DiBernardo and Jaskaran Singh are employees and stockholders of Johnson & Johnson. Funding Funding for this study was provided by Janssen Global Services, LLC. Acknowledgments All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, had final approval of the document and made the final decision about where to publish these data. Lakshmi Kasthurirangan, Ph.D. (SIRO Clinpharm Pvt. Ltd.) provided medical writing assistance and Ellen Baum, Ph.D. (Janssen Global Services, LLC) provided additional editorial support for this manuscript. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jad.2020.03.106. 237

Journal of Affective Disorders 271 (2020) 228–238

L. Citrome, et al.

Liebowitz, M., Lam, R.W., Lepola, U., Datto, C., Sweitzer, D., Eriksson, H., 2010. Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial. Depress. Anxiety 27, 964–976. McGirr, A., Berlim, M.T., Bond, D.J., Fleck, M.P., Yatham, L.N., Lam, R.W., 2015. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol. Med. 45, 693–704. Müller, M.J., Szegedi, A., Wetzel, H., Benkert, O., 2000. Moderate and severe depression. Gradations for the Montgomery–Asberg depression rating scale. J. Affect. Disord. 60, 137–140. Murrough, J.W., Iosifescu, D.V., Chang, L.C., Al Jurdi, R.K., Green, C.E., Perez, A.M., Iqbal, S., Pillemer, S., Foulkes, A., Shah, A., Charney, D.S., Mathew, S.J., 2013. Antidepressant efficacy of ketamine in treatment-resistant major depression: a twosite randomized controlled trial. Am. J. Psychiatry 170, 1134–1142. Naughton, M., Clarke, G., O′Leary, O.F., Cryan, J.F., Dinan, T.G., 2014. A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J. Affect. Disord. 156, 24–35. Ochs-Ross, R., Daly, E.J., Zhang, Y., Lane, R., Lim, P., Morrison, R.L., Hough, D., Manji, H., Drevets, W.C., Sanacora, G., Steffens, D.C., Adler, C., McShane, R., Gaillard, R., Wilkinson, S.T., Singh, J.B., 2020. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depressionTRANSFORM-3. Am J Geriatr Psychiatry 28, 121–141. Pinson, L., Gray, G.E., 2003. Psychopharmacology: number needed to treat: an underused measure of treatment effect. Psychiatr. Serv. 54, 145–146 154. Popova, V., Daly, E.J., Trivedi, M., Cooper, K., Lane, R., Lim, P., Mazzucco, C., Hough, D., Thase, M.E., Shelton, R.C., Molero, P., Vieta, E., Bajbouj, M., Manji, H., Drevets, W.C., Singh, J.B., 2019. 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. Am. J. Psychiatry 176, 428–438. Rosenthal, J.Z., Boyer, P., Vialet, C., Hwang, E., Tourian, K.A., 2013. Efficacy and safety of desvenlafaxine 50mg/d for prevention of relapse in major depressive disorder: a randomized controlled trial. J. Clin. Psychiatry 74, 158–166. Rush, A.J., Kraemer, H.C., Sackeim, H.A., Fava, M., Trivedi, M.H., Frank, E., Ninan, P.T., Thase, M.E., Gelenberg, A.J., Kupfer, D.J., Regier, D.A., Rosenbaum, J.F., Ray, O., Schatzberg, A.F., ACNP Task Force, 2006a. Report by the ACNP task force on response and remission in major depressive disorder. Neuropsychopharmacology 31, 1841–1853. Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D., Niederehe, G., Thase, M.E., Lavori, P.W., Lebowitz, B.D., McGrath, P.J., Rosenbaum, J.F., Sackeim, H.A., Kupfer, D.J., Luther, J., Fava, M., 2006b. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry 163, 1905–1917. Singh, J.B., Fedgchin, M., Daly, E.J., De Boer, P., Cooper, K., Lim, P., Pinter, C., Murrough, J.W., Sanacora, G., Shelton, R.C., Kurian, B., Winokur, A., Fava, M., Manji, H., Drevets, W.C., Van Nueten, L., 2016. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatmentresistant depression. Am. J. Psychiatry 173, 816–826. Sos, P., Klirova, M., Novak, T., Kohutova, B., Horacek, J., Palenicek, T., 2013. Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. Neuroendocrinol. Lett. 34, 287–293. Straus, S.E., 2002. Individualizing treatment decisions. the likelihood of being helped or harmed. Eval. Health Prof. 25, 210–224. Trivedi, M.H., Thase, M.E., Osuntokun, O., Henley, D.B., Case, M., Watson, S.B., Campbell, G.M., Corya, S.A., 2009. An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression. J. Clin. Psychiatry 70, 387–396. U.S. Burden of Disease Collaborators, 2013. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA 310, 591–608. Wilkinson, S.T., Ballard, E.D., Bloch, M.H., Mathew, S.J., Murrough, J.W., Feder, A., Sos, P., Wang, G., Zarate, C.A.Jr., Sanacora, G., 2018. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am. J. Psychiatry 175, 150–158. Zarate Jr., C.A., Singh, J.B., Carlson, P.J., Brutsche, N.E., Ameli, R., Luckenbaugh, D.A., Charney, D.S., Manji, H.K., 2006. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864.

2018. Relapse prevention in adults with major depressive disorder treated with vilazodone: a randomized, double-blind, placebo-controlled trial. Int. Clin. Psychopharmacol. 33, 304–311. Eli Lilly and Company, 2018. SYMBYAX (Olanzapine and Fluoxetine Hydrochloride) Capsule for Oral Use. Prescribing Information, revised March 2018. Available at: http://pi.lilly.com/us/symbyax-pi.pdf. Accessed June 30, 2019. Fedgchin, M., Trivedi, M., Daly, E.J., Melkote, R., Lane, R., Lim, P., Vitagliano, D., Blier, P., Fava, M., Liebowitz, M., Ravindran, A., Gaillard, R., Ameele, H.V.D., Preskorn, S., Manji, H., Hough, D., Drevets, W.C., Singh, J.B, 2019. Efficacy and safety of fixeddose esketamine nasal spray combined with a new oral antidepressant in treatmentresistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int. J. Neuropsychopharmacol. 22, 616–630. Feifel, D., Malcolm, B., Boggie, D., Lee, K., 2017. Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. J. Affect. Disord. 221, 283–288. Ghasemi, M., Kazemi, M.H., Yoosefi, A., Ghasemi, A., Paragomi, P., Amini, H., Afzali, M.H., 2014. Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Res. 215, 355–361. Goodwin, G.M., Boyer, P., Emsley, R., Rouillon, F., de Bodinat, C., 2013. Is it time to shift to better characterization of patients in trials assessing novel antidepressants? An example of two relapse prevention studies with agomelatine. Int. Clin. Psychopharmacol. 28, 20–28. Goodwin, G.M., Emsley, R., Rembry, S., Rouillon, F., Agomelatine Study Group, 2009. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J. Clin. Psychiatry 70, 1128–1137. Greenberg, P.E., Fournier, A.A., Sisitsky, T., Pike, C.T., Kessler, R.C., 2015. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J. Clin. Psychiatry 76, 155–162. Grunebaum, M.F., Galfalvy, H.C., Choo, T.H., Keilp, J.G., Moitra, V.K., Parris, M.S., Marver, J.E., Burke, A.K., Milak, M.S., Sublette, M.E., Oquendo, M.A., Mann, J.J., 2018. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am. J. Psychiatry 175, 327–335. Han, Y., Chen, J., Zou, D., Zheng, P., Li, Q., Wang, H., Li, P., Zhou, X., Zhang, Y., Liu, Y., Xie, P., 2016. Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatr. Dis. Treat. 12, 2859–2867. Hu, C., Liu, F., Wang, X., Chen, Y., Zhang, T., 2014. The effects of ketamine on patients receiving general antidepression therapy. J. Clin. Anesthesiol. 30, 848–850. Hu, Y.D., Xiang, Y.T., Fang, J.X., Zu, S., Sha, S., Shi, H., Ungvari, G.S., Correll, C.U., Chiu, H.F., Xue, Y., Tian, T.F., Wu, A.S., Ma, X., Wang, G., 2016. Single IV ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol. Med. 46, 623–635. Janssen Pharmaceuticals, Inc. SPRAVATO™ (Esketamine) Nasal Spray, CIII, 2019. Prescribing Information, revised 05/2019. Available at:http://www.janssenlabels. com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi. pdf.Accessed June 30, 2019. Janssen Research & Development, LLC, 2019. Advisory Committee Briefing Document, Esketamine Nasal Spray for Patients With Treatment-Resistant Depression, JNJ54135419 (Esketamine). January 16, 2019. Available at:https://www.fda.gov/ media/121377/download. Accessed June 30, 2019. Jelovac, A., Kolshus, E., McLoughlin, D.M., 2013. Relapse following successful electroconvulsive therapy for major depression: a meta-analysis. Neuropsychopharmacology 38, 2467–2474. Kamijima, K., Burt, T., Cohen, G., Arano, I., Hamasaki, T., 2006. A placebo-controlled, randomized withdrawal study of sertraline for major depressive disorder in Japan. Int. Clin. Psychopharmacol. 21, 1–9. Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R., Rush, A.J., Walters, E.E., Wang, P.S., National Comorbidity Survey Replication, 2003. The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R). JAMA 289, 3095–3105. Lapidus, K.A., Levitch, C.F., Perez, A.M., Brallier, J.W., Parides, M.K., Soleimani, L., Feder, A., Iosifescu, D.V., Charney, D.S., Murrough, J.W., 2014. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol. Psychiatry 76, 970–976. Leucht, S., Fennema, H., Engel, R.R., Kaspers-Janssen, M., Lepping, P., Szegedi, A., 2017. What does the MADRS mean? Equipercentile linking with the CGI using a company database of mirtazapine studies. J. Affect. Disord. 210, 287–293.

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