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Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression—TRANSFORM-3

Open AccessPublished:October 17, 2019DOI:https://doi.org/10.1016/j.jagp.2019.10.008

      Highlights

      • What is the primary question addressed by this study?
      • This first-in-kind randomized, double-blind, active-controlled trial for treatment-resistant depression (TRD) (i.e., nonresponse to ≥2 antidepressants in the current episode of depression) in patients ≥65 years of age, assessed the efficacy and safety of esketamine nasal spray plus a newly initiated oral antidepressant (esketamine/antidepressant) as compared with a newly initiated oral antidepressant and placebo nasal spray (antidepressant/placebo).
      • What is the main finding of the study?
      • The primary efficacy analysis did not show a statistically significant treatment difference between esketamine/antidepressant and antidepressant/placebo following 4 weeks of treatment. Subgroup analyses suggested improvement in depression in participants in the esketamine/antidepressant group who were aged 65–74 years and in those with an onset of depression <55 years of age. Further research is needed to assess esketamine treatment in the elderly.
      • What is the meaning of the finding?
      • The study was designed to assess efficacy and safety of esketamine in a dedicated study of older patients. The primary results were not statistically significant. However, subgroup analyses suggest improvement in “younger” elderly patients. Additional analyses were supportive and suggested longer treatment duration may be useful; the safety profile was comparable with other esketamine studies in younger patients.

      Abstract

      Background

      Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment.

      Methods

      This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65–74 versus ≥75 years) and post-hoc analyses including age at depression onset.

      Results

      For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was −3.6 (−7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was −4.9 (−8.96, −0.89; t = −2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus −0.4 (−10.38, 9.50; t = −0.09, two-sided nominal p = 0.930) for those ≥75 years, and −6.1 (−10.33, −1.81; t = −2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (−4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks.

      Conclusions

      Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65–74 years) and patients with earlier onset of depression (<55 years).

      Keywords

      INTRODUCTION

      Major depressive disorder (MDD) significantly impacts older adults, and is associated with increased disability, diminished quality of life, functional and cognitive decline, increased hospitalization, and increased caregiver burden.
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      Electroconvulsive therapy (ECT) is used more frequently in older, compared with younger, patients because of poorer response and remission rates to conventional therapies in older MDD patients.
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      While ECT is beneficial, despite recent methodological improvements, patients may experience increased blood pressure (BP),
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      impaired cognition, and significant tolerability issues.
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      Therefore, an unmet need for novel antidepressant treatment exists. Recently, results from a double-blind crossover pilot study in older patients with treatment-resistant depression (TRD) showed greater efficacy of ketamine, compared with an active control (midazolam).
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      Esketamine, the S-enantiomer of ketamine racemate, has a three- to four-fold higher affinity to N-methyl-D-aspartate receptors than the R-enantiomer.
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      Two phase 2 randomized clinical trials of esketamine (intravenous and nasal spray) in TRD patients under 65 years, demonstrated rapid-onset, dose-related antidepressant effects.
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      Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study.
      A nasal spray, versus intravenous administration, was developed for easier patient access. Phase 3 studies of esketamine nasal spray administered with a newly initiated oral antidepressant in TRD aged patients 18–64 years
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      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.
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      Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1).
      subsequently demonstrated rapid onset versus a newly initiated oral antidepressant (active comparator) plus placebo nasal spray, with maintenance of the treatment effects following long-term intermittent dosing.
      • Montgomery SA
      • Asberg M
      A new depression scale designed to be sensitive to change.
      This phase 3, randomized, double-blind, multicenter study compared the efficacy and safety of flexibly dosed (28 mg, 56 mg, or 84 mg) esketamine nasal spray plus a newly initiated oral antidepressant with a newly initiated oral antidepressant (active comparator) plus placebo nasal spray in adults ≥65 years of age with TRD. Additional efficacy analyses included a pre-planned assessment by age subgroup at study entry and post-hoc analyses assessing age of depression onset, impact of the interim analysis (IA) including an unweighted analysis, dose effects, and potential impact of an additional four weeks of treatment. Safety and tolerability were assessed.

      METHODS

      Ethical Practices

      An Institutional Review Board (United States) or Independent Ethics Committee (Europe) approved study protocol and amendments. The study (NCT02422186; clinicaltrials.gov) was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices, and applicable regulatory requirements. All participants provided written informed consent.

      Study Design

      This phase 3, randomized, double-blind, active-controlled, multicenter study, conducted in 13 countries between August 2015 and August 2017, had 3 phases: 1) 4-week screening/prospective observational phase assessing response to current antidepressant treatment; 2) 4-week double-blind induction phase with flexibly-dosed nasal spray study medication (esketamine or placebo) plus a newly-initiated oral antidepressant; 3) 2-week post-treatment follow-up phase assessing safety and tolerability, including potential withdrawal symptoms.
      Following the 4-week double-blind induction phase, regardless of treatment response, patients could participate in a long-term open-label safety study (NCT02497287).
      • Wajs E
      • Aluisio L
      • Holder R
      • et al.
      Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of Long-term safety in a phase 3, Open-label Study (SUSTAIN-2).
      Otherwise, patients who received ≥1 dose of nasal spray study medication, and either withdrew early from the double-blind induction phase or did not participate in the long-term open-label safety study, entered the 2-week follow-up.

      Study Participants

      Patients were ≥65 years old and diagnosed with recurrent moderate to severe MDD without psychotic features (Table 1). Randomized patients had TRD, defined as no clinically meaningful improvement following treatment with ≥2 different antidepressant agents, prescribed in adequate dosages for adequate duration, during the current episode of depression (Table 1).
      TABLE 1Key Inclusion Criteria
      Key Inclusion Criteria
      • DSM-5
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5.
      diagnosis of recurrent MDD without psychotic features, or had a single episode of MDD lasting ≥2 years, based upon clinical assessment and confirmed by the MINI
      • Sheehan DV
      • Lecrubier Y
      • Sheehan KH
      • et al.
      The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.
      • MMSE total score of ≥25 (or ≥22 for patients with less than the equivalent of a high school education)
      • Folstein MF
      • Folstein SE
      • McHugh PR
      “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician.
      • IDS-C30 total score of ≥31, corresponding to moderate to severe depression
      • Trivedi MH
      • Rush AJ
      • Ibrahim HM
      • et al.
      The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation.
      • TRD: lack of clinically meaningful improvement after treatment with ≥2 different antidepressant agents prescribed in adequate dosages for adequate duration during the current episode of depression
      • Documented nonresponse
      A nonresponse was defined as minimal, or no clinically meaningful, benefit from their ongoing antidepressant, defined as ≤25% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from week 1 to week 4 and a MADRS total score of ≥24 at weeks 2 and 4.
      to ≥1 but ≤8 oral antidepressant treatments taken at adequate dosage and for an adequate duration, within the current episode of depression (as assessed on the geriatric version of the MGH-ATRQ
      • Chandler GM
      • Iosifescu DV
      • Pollack MH
      • et al.
      RESEARCH: Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ).
      and confirmed by documented records) at the start of the 4-week screening/prospective observational phase
      • Nonresponse
      A nonresponse was defined as minimal, or no clinically meaningful, benefit from their ongoing antidepressant, defined as ≤25% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from week 1 to week 4 and a MADRS total score of ≥24 at weeks 2 and 4.
      to ≥1 one of the 2 failed antidepressant medications was confirmed prospectively during the screening phase of the study (Supplementary Digital Content S2)
      • All patients had to have been nonresponsive
      A nonresponse was defined as minimal, or no clinically meaningful, benefit from their ongoing antidepressant, defined as ≤25% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from week 1 to week 4 and a MADRS total score of ≥24 at weeks 2 and 4.
      to at least 2 oral antidepressants prior to randomization
      • Patients who failed only one oral antidepressant at screening, had to currently have been taking another antidepressant for ≥2 weeks prior to screening and show a non- response to that antidepressant during the 4-week screening period
      DSM-5: Diagnostic and Statistical Manual of Mental Disorders-5th Edition; IDS-C30: Inventory of Depressive Symptomatology-Clinician Rating; MDD: major depressive disorder; MGH-ATRQ: Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; MINI: Mini International Neuropsychiatric Interview; MMSE: Mini Mental State Exam.
      a A nonresponse was defined as minimal, or no clinically meaningful, benefit from their ongoing antidepressant, defined as ≤25% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from week 1 to week 4 and a MADRS total score of ≥24 at weeks 2 and 4.
      Key exclusion criteria included diagnosis of a psychotic disorder, MDD with psychotic features, bipolar or related disorders, current obsessive-compulsive disorder, intellectual disability, cognitive impairment, suicidal ideation with intent to act within 6 months and uncontrolled hypertension. Patients were required to have normal vital signs (including BP and pulse oximetry) and normal 12-lead ECG. Supplementary Digital Content S1 lists complete inclusion/exclusion criteria.

      Randomization and Blinding

      A computer-generated randomization schedule was used to randomize patients (1:1) to nasal spray treatment, either esketamine or placebo, stratified by country and by class of the oral antidepressant medication (serotonin-norepinephrine reuptake inhibitor [SNRI] or selective serotonin reuptake inhibitor [SSRI]). Patients, investigators, site personnel, and those involved in study design, implementation, data management, or statistical analysis were blinded to study treatment. Placebo and esketamine nasal spray devices were indistinguishable, and to simulate the taste of esketamine, a bittering agent (denatonium benzoate) was added to the placebo solution.

      Nasal Spray Study Drug

      Patients were randomized (1:1) to flexibly-dosed esketamine or placebo nasal spray (28 mg, 56 mg, or 84 mg), and dosed twice-weekly for 4 weeks. Patients self-administered the study drug at the study site under direct supervision of site staff (Table 2).
      TABLE 2Esketamine Dosing
      DayDoseDose Titration
      Day 128 mg
      Day 428 or 56 mgThe dose may remain at 28 mg or be increased to 56 mg, as determined by the investigator based on efficacy and tolerability
      Days 8, 11, 1528, 56, or 84 mgThe dose may be maintained or increased or reduced by 28 mg from the previous dosing session, as determined by the investigator based on efficacy and tolerability. No dose increase is permitted beyond day 15.
      Days 18, 22, 2528, 56, or 84 mgNo dose increase is permitted beyond day 15. If needed for tolerability, dose reduction by 28 mg from the previous dose is permitted on days 18, 22 and 25.
      Notes: Dose changes are determined by the investigator based on efficacy and tolerability and in accordance with blood pressure guidelines.
      Patients initially received 28 mg of esketamine or placebo nasal spray. Subsequent study drug dose adjustments (28 mg, 56 mg, or 84 mg) were based on investigator determination of efficacy and tolerability (Table 2).

      Newly Initiated Oral Antidepressant

      Antidepressant/(s) was (were) tapered/discontinued at the end of the screening/prospective observational phase. Investigators, using clinical judgment and prior history, selected one of four new open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR) not used in the current depressive episode. Daily dosing, beginning on Day 1, was titrated to the maximally tolerated dose.

      Efficacy Assessments

      The primary efficacy endpoint, change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to endpoint, was assessed telephonically by remote raters (since transient dissociation, caused by esketamine, may have biased research staff) using the MADRS structured interview guide.
      • Williams JB
      • Kobak KA
      Development and reliability of a structured interview guide for the Montgomery-Åsberg Depression Rating Scale (SIGMA).
      Additional efficacy endpoints included: rates of response (≥50% reduction from baseline in the MADRS total score) and rates of remission (MADRS ≤12) at Day 28, change from baseline to endpoint in severity of depressive illness (Clinical Global Impression–Severity [CGI-S],
      • Busner J
      • Targum SD
      The clinical global impressions scale: applying a research tool in clinical practice.
      Patient Health Questionnaire 9-Item [PHQ-9]),
      • Spitzer RL
      • Kroenke K
      • Williams JB
      Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary care evaluation of mental disorders. Patient Health Questionnaire.
      and function assessed by the Sheehan Disability Scale (SDS).
      • Leon AC
      • Olfson M
      • Portera L
      • et al.
      Assessing psychiatric impairment in primary care with the Sheehan Disability Scale.
      Rapidity of response was not assessed because of anticipated subtherapeutic efficacy of the initial 28-mg dose.

      Safety

      Treatment-emergent adverse events (TEAEs) and other safety assessments (hematology and serum chemistry, urinalysis, physical examination, electrocardiogram, suicidal ideation and behavior based on Columbia Suicide Severity Rating Scale C-SSRS
      • Posner K
      • Brown GK
      • Stanley B
      • et al.
      The Columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults.
      ) were monitored throughout the study. Vital signs, dissociative symptoms (using the Clinician-Administered Dissociative States Scale [CADSS]
      • Bremner JD
      • Krystal JH
      • Putnam FW
      • et al.
      Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS).
      ), and the 4-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS)
      • Overall JE
      • Gorham DR
      The brief psychiatric rating scale.
      were assessed on dosing days at baseline and at 40 minutes, 1 hour (vital signs only), and 1.5 hours after dosing. Computerized cognitive battery (Cogstate)
      • Fredrickson J
      • Maruff P
      • Woodward M
      • et al.
      Evaluation of the usability of a brief computerized cognitive screening test in older people for epidemiological studies.
      ,
      • Maruff P
      • Thomas E
      • Cysique L
      • et al.
      Validity of the CogState brief battery: relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia complex.
      was used to assess multiple cognitive domains, including attention (simple and choice reaction time), visual learning and memory, executive function; the Hopkins Verbal Learning Test-Revised (HVLT-R)
      • Benedict RHB
      • Schretlen D
      • Groninger L
      • et al.
      Hopkins verbal learning test—revised: normative data and analysis of inter-form and test-retest Reliability.
      was used to measure verbal learning and memory.
      Postdose sedation was measured prior to dosing, and every 15 minutes up to 1.5 hours after dosing, using the Modified Observer's Assessment of Alertness/ Sedation scale (MOAA/S).
      • Chernik DA
      • Gillings D
      • Laine H
      • et al.
      Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam.
      Investigators assessed patients’ discharge readiness (based on overall clinical status, including sedation, BP, and adverse events) using the Clinical Global Assessment of Discharge Readiness (CGADR) scale at 1 hour and 1.5 hours after dosing. The 20-item Physician Withdrawal Checklist (PWC-20) was used to assess withdrawal effects during the follow-up phase.
      • Rickels K
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      • et al.
      Physician Withdrawal Checklist (PWC-20).

      Statistical Methods

      Efficacy analyses in the double-blind phase were based on analysis sets that included all randomized patients who received ≥1 dose of nasal spray study medication and one dose of oral antidepressant. Safety assessments during double-blind phase were summarized for the safety analysis set which included all randomized patients who received ≥1 dose of study drug or one dose of oral antidepressant. Analyses were performed using SAS, version 9.2.
      The maximum sample size planned for this study was calculated assuming a treatment difference, after the double-blind induction phase, of 6.5 points in MADRS total score between esketamine and the active comparator, with a standard deviation (SD) of 12, a two-sided significance level of 0.05, and a drop-out rate of 25%. A maximum of approximately 74 patients were to be randomized to each treatment group to achieve 80% power using a fixed design assuming no IA. The treatment difference and SD were based on results of Panel A from a phase 2 study
      • Daly EJ
      • Singh JB
      • Fedgchin M
      • et al.
      Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial.
      and on clinical judgment.
      An IA occurred after 51 patients were randomized to re-estimate sample size or stop the study due to futility. No esketamine team members, or investigational site personnel, were informed of the results of the IA or of any adjustments made to the sample size.
      Statistical tests used a two-sided significance level of 0.05 unless otherwise specified.
      The primary efficacy variable was analyzed using a mixed-effect model for repeated measures (MMRM) with baseline MADRS total score as a covariate with treatment, region, class of antidepressant (SSRI or SNRI), day, and day-by-treatment interaction as fixed effects. Least square (LS) means (i.e., adjusted for terms included in the MMRM model) were provided at each timepoint. To adjust for the IA, the primary endpoint was analyzed using a weighted combination test that defined test statistics from the MMRM analyses as a weighted sum of stage 1 (pre-IA) and stage 2 (post-IA) test statistics. Stages were weighted equally regardless of the sample size in each stage. The median-unbiased estimate and flexible confidence interval were used for estimation of the treatment difference from antidepressant/placebo at Day 28.
      • Brannath W
      • König F
      • Bauer P
      Estimation in flexible two stage designs.
      Additional measures of efficacy including response and remission rates were summarized at each visit. Additionally, number needed to treat (NNT), the average number of patients needed to produce one more responder/remitter in the esketamine/antidepressant group than in the antidepressant/placebo group was calculated for response and remission. The odds ratio for an improved CGI-S score was estimated by mapping the ordinal scale to a continuous scale using item response modeling via the logit model
      • Fox J-P
      Bayesian Item Response Modeling: Theory and Applications.
      ,
      • Wong WL
      • Li X
      • Li J
      • et al.
      Accounting for standard errors of vision-specific latent trait in regression models.
      and analyzed using an ANCOVA model. Descriptive statistics of actual values and changes from baseline were provided for PHQ-9 and SDS.
      Additional efficacy analyses for the primary endpoint using MMRM models were performed for a preplanned assessment of age (65–74 or ≥75 years) and a post-hoc assessment of age at MDD onset (<55 or ≥55 years). Models included baseline MADRS total score as a covariate, and treatment, region, class of antidepressant (SSRI or SNRI), age, day, treatment-by-day, treatment-by-age, and treatment-by-day-by-age interaction as fixed effects. Additional analyses investigating age at study enrollment, and at MDD onset, as continuous variables were performed using a similar MMRM model. The estimated change in MADRS total score at Day 28 and the 95% confidence band versus age and age of onset were plotted for each treatment group. Additional post-hoc analyses included MMRM analysis by study stage and using an unweighted analysis.
      Frequency distributions or descriptive statistics were provided for adverse events, clinical laboratory tests, vital signs, electrocardiograms values, cognitive tests, and scores for clinician-reported outcomes (including C-SSRS, MOAA/S, CADSS, and CGADR).

      RESULTS

      The preplanned IA of efficacy data conducted 4 weeks after randomizing 51 patients determined a final sample size of 100, the minimum sample size for the study. Patients in, or about to enter, the screening phase could continue the study resulting in over 100 patients being randomized.

      Participants

      Of 302 screened patients, 138 were randomized (esketamine/antidepressant [n = 72]; antidepressant/placebo [n = 66]); 122 (88.4%) completed the double-blind phase (Fig. 1). A total of 77.8% patients in the esketamine/antidepressant, and 81.5% in the antidepressant/placebo, group received treatment on all eight dosing days.
      One patient in the antidepressant/placebo group did not receive study medication and was not included in the safety and full analysis sets; 16 (11.6%) patients withdrew prior to completing the double-blind phase. Six (4.3%) withdrew following a TEAE (most common reason): four treated with esketamine/antidepressant and two with antidepressant/placebo.
      Fifteen patients entered the follow-up phase (n = 11 completed, n = 4 withdrew); 111/138 (80.4%) entered the long-term safety study
      • Wajs E
      • Aluisio L
      • Holder R
      • et al.
      Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of Long-term safety in a phase 3, Open-label Study (SUSTAIN-2).
      and 2 entered the long-term safety extension study (NCT02782104).
      Baseline characteristics were similar between treatment groups (Table 3). The mean (SD) baseline MADRS total score was 35.2 (6.16). Based on CGI-S scores, 49.6% (67/137) of patients were markedly ill and 24.8% (34/137) were severely ill.
      TABLE 3Demographics and Baseline Characteristics
      Esk + Oral AD (N = 72)Placebo + Oral AD (N = 65)Total (N = 137)
      Age (years), mean (SD)70.6 (4.79)69.4 (4.15)70.0 (4.52)
       Male27 (37.5)25 (38.5)52 (38.0)
       Female45 (62.5)40 (61.5)85 (62.0)
      Age category (years), n (%)
       65–7459 (81.9)57 (87.7)116 (84.7)
       ≥7513 (18.1)8 (12.3)21 (15.3)
      Race, n (%)
       White66 (91.7)64 (98.5)130 (94.9)
       Multiple4 (5.6)04 (2.9)
       Not reported1 (1.4)1 (1.5)2 (1.5)
       Unknown1 (1.4)01 (0.7)
      Region, n (%)
       European Union35 (48.6)24 (36.9)59 (43.1)
       United States34 (47.2)36 (55.4)70 (51.1)
       Other3 (4.2)5 (7.7)8 (5.8)
      Class of oral AD, n (%)
       SNRI31 (43.1)30 (46.2)61 (44.5)
       SSRI41 (56.9)35 (53.8)76 (55.5)
      Oral AD
       Duloxetine25 (34.7)23 (35.4)48 (35.0)
       Escitalopram25 (34.7)25 (38.5)50 (36.5)
       Sertraline15 (20.8)10 (15.4)25 (18.2)
       Venlafaxine XR7 (9.7)7 (10.8)14 (10.2)
      Age when diagnosed with MDD (years), mean (SD)42.6 (16.18)43.7 (16.28)43.1 (16.18)
      Baseline MADRS total score, mean (SD)35.5 (5.91)34.8 (6.44)35.2 (6.16)
      Range: 19–51. In some cases, the baseline MADRS score was obtained after patients were qualified to enter the trial so the baseline MADRS could be ≤24.
      Screening IDS-C30 total score, mean (SD)44.2 (6.50)43.1 (6.71)43.7 (6.60)
      Duration of current episode (weeks), mean (SD)163.1 (277.04)274.1 (395.47)215.8 (341.71)
      Baseline CGI-S, mean (SD)5.1 (0.76)4.8 (0.80)5.0 (0.79)
      Number of previous AD trial in addition to 1 AD trial assessed prospectively,
      Number of antidepressant medications with nonresponse (defined as <25% improvement) taken for at least 6 weeks during the current episode as obtained from MGH-ATRQ.
      n (%)
       115 (20.8)6 (9.2)21 (15.3)
       231 (43.1)32 (49.2)63 (46.0)
       313 (18.1)17 (26.2)30 (21.9)
       412 (16.7)4 (6.2)16 (11.7)
       ≥51 (1.4)6 (9.2)7 (5.1)
      AD: antidepressant; CGI-S: Clinical Global Impression-Severity; Esk: esketamine; IDS-C30: Inventory of Depressive Symptoms-Clinician rated-30-item; MADRS: Montgomery-Ǻsberg Depression Rating Scale; MDD: major depressive disorder; MGH-ATRQ: Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; SD: standard deviation; SNRI: serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.
      a Range: 19–51. In some cases, the baseline MADRS score was obtained after patients were qualified to enter the trial so the baseline MADRS could be ≤24.
      b Number of antidepressant medications with nonresponse (defined as <25% improvement) taken for at least 6 weeks during the current episode as obtained from MGH-ATRQ.

      Efficacy

      Primary Endpoint

      Change in MADRS total score from baseline to Day 28, based on the weighted MMRM analysis, did not reach statistical significance (Table 4). The median unbiased estimate of the difference (95% CI) between the esketamine/antidepressant and the antidepressant/placebo group was −3.6 (−7.20, 0.07); weighted combination test (based on MMRM analyses) z = 1.89, two-sided p = 0.059.
      TABLE 4MADRS Total Score: Change From Baseline to Day 28
      Esk + Oral AD (N = 72)Placebo + Oral AD (N = 65)
      Baseline
       N7265
       Mean (SD)35.5 (5.91)34.8 (6.44)
      Day 28
       N6360
       Mean (SD)25.4 (12.70)28.7 (10.11)
      Change from baseline to Day 28
       N6360
       Mean (SD)−10.0 (12.74)−6.3 (8.86)
      MMRM analysis
      Weighted combination test for treatment effect is based on MMRM analyses with change from baseline as the response variable and the fixed effect model terms for treatment (esketamine/antidepressant, antidepressant/placebo), day, region, class of oral antidepressant (SNRI or SSRI), and treatment-by-day, and baseline value as a covariate. A negative difference favors esketamine.
       Difference of LS Means (95% CI)
      Difference from placebo is the median unbiased estimate, which is a weighted combination of the least squares means of the difference from placebo; two-sided flexible confidence interval.
      −3.6 (−7.20; 0.07)
       Two-sided p value
      p value is based on the weighted combination test statistics; z = 1.89.
      0.059
      Notes: MADRS total score ranges from 0 to 60; a higher score indicates a more severe condition. Negative change in score indicates improvement. AD: antidepressant; CI: confidence interval; Esk: esketamine; LS: least squares; MADRS: Montgomery-Ǻsberg Depression Rating Scale; MMRM: mixed model for repeated measures; SD: standard deviation; SNRI: serotonin and norepinephrine inhibitor; SSRI: selective serotonin reuptake inhibitor.
      a Weighted combination test for treatment effect is based on MMRM analyses with change from baseline as the response variable and the fixed effect model terms for treatment (esketamine/antidepressant, antidepressant/placebo), day, region, class of oral antidepressant (SNRI or SSRI), and treatment-by-day, and baseline value as a covariate. A negative difference favors esketamine.
      b Difference from placebo is the median unbiased estimate, which is a weighted combination of the least squares means of the difference from placebo; two-sided flexible confidence interval.
      c p value is based on the weighted combination test statistics; z = 1.89.

      Additional Endpoints

      Response rates were 27.0% (17/63) in the esketamine/antidepressant and 13.3% (8/60) in the antidepressant/placebo group (Fig. 2). The NNT for response at Day 28 was 8. Remission rates were 17.5% (11/63) in the esketamine/antidepressant versus 6.7% (4/60) in the antidepressant/placebo group. NNT for remission at Day 28 was 10.
      FIGURE 2
      FIGURE 2Response and remission rates based on MADRS total score. AD: antidepressant; Esk: esketamine; MADRS: Montgomery-Åsberg Depression Rating Scale; NNT: number needed to treat; PBO: placebo.
      Decreased severity of depressive symptoms based on the CGI-S is shown in Fig. 3. The median (range) change from baseline was −1.0 (−4, 1) in the esketamine/antidepressant versus 0 (−4, 3) in the antidepressant/placebo group. The odds ratio (95% credible interval) of 5.3 (1.85, 15.85) showed odds of an improved CGI-S score for patients treated with esketamine/antidepressant that was 5.3 times that of those treated with antidepressant/placebo.
      FIGURE 3
      FIGURE 3Frequency distribution of illness severity-based CGI-S scores at baseline and double-blind phase endpoint. AD: antidepressant; CGI-S: Clinical Global Impression–Severity; ESK: esketamine; PBO: placebo.
      The mean (SD) changes from baseline for SDS (esketamine/antidepressant: −6.1 [8.35] versus antidepressant/placebo: −3.8 [5.95]) and PHQ-9 total scores (esketamine/antidepressant: −6.0 [7.17] versus antidepressant/placebo: −3.3 [7.09]) are in Fig. 4.
      FIGURE 4
      FIGURE 4Mean change (±SE) from baseline to endpoint in PHQ-9 and SDS total scores. Notes: Number of patients are given at top of each group. AD: antidepressant; Esk: esketamine; PHQ-9: Patient Health Questionnaire 9-Item; SDS: Sheehan Disability Scale; SE: standard error.

      Additional Efficacy Analyses

      A forest plot of the LS means (95% CI) treatment difference of change in MADRS total score using MMRM from baseline to Day 28 by subgroups including patient age during the study, age of onset of depression and impact of the IA is shown in Fig. 5 and discussed below.
      • (1)
        Prespecified analysis by age at study entry (age groups required by the European Medicines Agency [EMA]), showed a LS mean difference (95% CI) of −4.9 (−8.96, −0.89) (t = −2.4, df = 127; two-sided nominal p value = 0.017) between treatment groups for change in MADRS total score at Day 28 for patients 65–74 years versus -0.4 (−10.38, 9.50) for patients ≥75 years (t = −0.09, df = 127; two-sided nominal p value = 0.930; Figs. 5 and 6). Patients 65–74 years had an earlier separation between treatment groups, compared with those ≥75 years. Assessment of age as a continuous variable also showed greater improvement with esketamine/antidepressant in younger patients (Fig. 7).
        FIGURE 6
        FIGURE 6Least squares mean change (±SE) in MADRS total score for (A) 65–74 years of age and (B) ≥75 years of age. Notes: LS mean and SE were based on MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (ESK+AD, AD+PBO), day, region, class of oral antidepressant (SNRI or SSRI), age group (65–74 or ≥75), and treatment-by-day, treatment-by-age group, treatment-by-day-by-age group, and baseline value as a covariate. Results are not adjusted for sample size re-estimation. Negative change in score indicates improvement. AD: antidepressant; ESK: esketamine; LS: least squares; MADRS: Montgomery-Åsberg Depression Rating Scale; MMRM: mixed model for repeated measures; PBO: placebo; SE: standard error; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
        FIGURE 7
        FIGURE 7Change in MADRS total score with age. Notes: Regression lines and confidence bands were based on MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (ESK+AD, AD+PBO), day, region, class of oral antidepressant (SNRI or SSRI), age and treatment-by-day, treatment-by-age, treatment-by-day-by-age, and baseline value as a covariate. Results are not adjusted for sample size re-estimation. Negative change in score indicates improvement. A 95% CI that does not contain ‘0’ implies significant association between age versus MADRS. AD: antidepressant; CI, confidence interval; ESK: esketamine; LS: least squares; MADRS: Montgomery-Åsberg Depression Rating Scale; MMRM: mixed model for repeated measures; PBO: placebo; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
      • (2)
        Age of patient at depression onset showed greater improvement in patients with an earlier age of depression onset based on a post-hoc analysis. LS means (95% CI) treatment difference for the change in MADRS total score at Day 28 was −6.1 (−10.33, −1.81) (t = −2.8, df = 127; two-sided nominal p value = 0.006) with an onset of depression <55 years versus 3.1 (−4.51, 10.80) (t = 0.8, df = 127; two-sided nominal p value = 0.407) with onset ≥55 years (Fig. 8). Using age of depression onset as a continuous variable, showed greater improvement for the esketamine/antidepressant at earlier ages of depression onset (Fig. 9).
        FIGURE 8
        FIGURE 8Least squares mean change (±SE) in MADRS total score for age of onset of depression (A) <55 years of age and (B) ≥55 years of age Notes: LS mean and SE were based on MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (ESK+AD, AD+PBO), day, region, class of oral antidepressant (SNRI or SSRI), age of onset (<55 or ≥55), and treatment-by-day, treatment-by-age of onset, treatment-by-day-by-age of onset, and baseline value as a covariate. Results are not adjusted for sample size re-estimation. Negative change in score indicates improvement. AD: antidepressant; ESK: esketamine; LS: least squares; MADRS: Montgomery-Åsberg Depression Rating Scale; MMRM: mixed model for repeated measures; PBO: placebo; SE: standard error; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
        FIGURE 9
        FIGURE 9Change in MADRS total score with age of onset of depression. Notes: Regression lines and confidence bands were based on MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (ESK+AD, AD+PBO), day, region, class of oral antidepressant (SNRI or SSRI), age of onset, and treatment-by-day, treatment-by-age of onset, treatment-by-day-by-age of onset, and baseline value as a covariate. Results are not adjusted for sample size re-estimation. Negative change in score indicates improvement. A 95% CI that does not contain ‘0’ implies significant association between age of onset of depression versus MADRS. AD: antidepressant; CI, confidence interval; ESK: esketamine; LS: least squares; MADRS: Montgomery-Åsberg Depression Rating Scale; MMRM: mixed model for repeated measures; PBO: placebo; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
      • (3)
        A treatment difference for change in MADRS total scores between treatment groups was seen between stage 1 and 2 (pre and post IA; Fig. 10): LS mean (95% CI) difference of −1.6 (−6.85, 3.70) in stage 1 versus −5.6 (−10.78, −0.32) in stage 2. Since an IA was performed, the primary analysis used a weighted combination test with equal weights pre-specified for each stage. However, stage 2 (n = 86) had more patients than stage 1 (n = 51). Therefore, data from stage 2 were down-weighted (86 patients in stage 2 given the same weight as 51 in stage 1). An unweighted analysis using MMRM showed a LS mean difference of −4.0 (95% CI: −7.71, −0.25) between esketamine/antidepressant versus antidepressant/placebo (Fig. 11).
        FIGURE 10
        FIGURE 10Least squares mean change (±SE) in MADRS total score at (A) pre-IA and (B) post-IA. Notes: LS mean and SE were based on MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (ESK+AD, AD+PBO), day, region, class of oral antidepressant (SNRI or SSRI), treatment-by-day, and baseline value as a covariate. Negative change in score indicates improvement. AD: antidepressant; ESK: esketamine; IA: Interim analysis; LS: least squares; MADRS: Montgomery-Åsberg Depression Rating Scale; MMRM: mixed model for repeated measures; PBO: placebo; SE: standard error; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
        FIGURE 11
        FIGURE 11Least squares mean change (±SE) in MADRS total score over time in double-blind phase. Notes: LS mean and SE were based on MMRM with change from baseline as the response variable and the fixed effect model terms for treatment (ESK+AD, AD+PBO), day, region, class of oral antidepressant (SNRI or SSRI), treatment-by-day, and baseline value as a covariate. Results are not adjusted for sample size re-estimation. Negative change in score indicates improvement. AD: antidepressant; ESK: esketamine; LS: least squares; MADRS: Montgomery-Åsberg Depression Rating Scale; MMRM: mixed model for repeated measures; PBO: placebo; SE: standard error; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
      • (4)
        Doses used in this trial were lower compared with doses used in esketamine trials of patients aged 18–64 years (56 and 84 mg). Investigators increasingly used higher doses of esketamine during the later portion of the study, possibly due to familiarity with the compound (Fig. 12). As a result, the percentage of patients who received 84 mg at Day 25 was 52.2% (stage 1) versus 71.8% (stage 2).
        FIGURE 12
        FIGURE 12Percent of patients at 84 mg esketamine dose by stage of interim analysis.
      • (5)
        Treatment duration: 111/138 (80.4%) patients entered the long-term open-label safety and efficacy study
        • Wajs E
        • Aluisio L
        • Holder R
        • et al.
        Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of Long-term safety in a phase 3, Open-label Study (SUSTAIN-2).
        that included 88 (79.3%) nonresponders (entered a second 4-week induction period) and 23 (20.7%) responders (entered the optimization/maintenance phase). Similar percentages of patients received 84 mg at the end of the second induction period (68%) as in the current study (65%).
        • Wajs E
        • Aluisio L
        • Holder R
        • et al.
        Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of Long-term safety in a phase 3, Open-label Study (SUSTAIN-2).
        The oral antidepressant was unchanged in all patients. MADRS total scores continued to decrease in 93% (82/88) of patients who completed the additional 4-week second induction phase with 69.5% (52/82) responders and 46.3% (38/82) remitters (Fig. 13). Improvements were observed in both patients aged 65–74 years and in those ≥75 years (Supplementary Digital Content S3).
        FIGURE 13
        FIGURE 13Mean change (±SE) in MADRS from initial baseline total score in the follow-up long-term safety study. Notes: All patients received ESK+AD in the open-label study (circles represent patients who received AD+PBO in the primary study). AD: antidepressant; ESK: esketamine; FU: follow-up; IND: induction; MA: maintenance; MADRS: Montgomery-Åsberg Depression Rating Scale; OP: optimization; PBO: placebo; SE: standard error.
      FIGURE 5
      FIGURE 5Least squares mean (95% CI) treatment difference of change in MADRS total score from baseline to Day 28 by subgroup. Notes: The primary analysis of the change in MADRS total score using MMRM was weighted to account for the interim analysis for sample size re-estimation. The unweighted analysis does not take into account that an interim analysis was performed. AD: antidepressant; CI: confidence interval; ESK: esketamine; MADRS: Montgomery-Åsberg Depression Rating Scale; PBO: placebo.

      SAFETY

      During the double-blind phase, TEAEs occurred in 70.8% (51/72) of patients receiving esketamine/antidepressant, and 60.0% (39/65) receiving antidepressant/placebo (Table 5). The most common TEAEs in the esketamine/antidepressant group were dizziness (20.8%), nausea (18.1%), a generally transient elevation in BP (resolved in 2 hours in approximately 80% of patients), fatigue, headache, and dissociation (12.5% for each). In the antidepressant/placebo group, the most common TEAEs were anxiety, fatigue, and dizziness (7.7% for each).
      TABLE 5Treatment-Emergent Adverse Events in at Least 5% of Patients in the Double-Blind Phase
      Esk + Oral AD, n (%) (N = 72)Placebo + Oral AD, n (%) (N = 65)
      Any TEAE51 (70.8)39 (60.0)
      TEAE
      Dizziness15 (20.8)5 (7.7)
      Nausea13 (18.1)3 (4.6)
      Blood pressure increased9 (12.5)3 (4.6)
      Fatigue9 (12.5)5 (7.7)
      Headache9 (12.5)2 (3.1)
      Dissociation9 (12.5)1 (1.5)
      Vertigo8 (11.1)2 (3.1)
      Urinary tract infection6 (8.3)1 (1.5)
      Hypoesthesia oral5 (6.9)0
      Vomiting5 (6.9)1 (1.5)
      Dysgeusia4 (5.6)3 (4.6)
      Dysphoria4 (5.6)0
      Hypoesthesia4 (5.6)1 (1.5)
      Insomnia4 (5.6)3 (4.6)
      Paresthesia4 (5.6)2 (3.1)
      Anxiety2 (2.8)5 (7.7)
      Notes: Incidence is based on the number of patients experiencing at least one AE, not the number of events. AEs were coded using MedDRA version 20.0. AD: antidepressant; AE: adverse event; Esk: esketamine; TEAE: treatment-emergent adverse event.
      Discontinuation due to ≥1 TEAE occurred in 5.6% (4/72) in the esketamine/antidepressant versus 3.1% (2/65) in the antidepressant/placebo group (Table 6). Most TEAEs were mild or moderate in severity and resolved on the nasal dosing day.
      TABLE 6Treatment-Emergent Adverse Events Leading to Discontinuation of Study Medication and Serious Adverse Events (Safety Analysis Set)
      Esk + Oral AD, n (%) (N = 72)Placebo + Oral AD, n (%) (N = 65)Relationship to Study Nasal Spray/Oral AD
      TEAEs leading to discontinuation
      An adverse event that started in the double-blind phase and resulted in discontinuation in the follow-up phase is counted as treatment-emergent in the double-blind phase.
      4 (5.6)2 (3.1)
       Blood pressure increased1 (1.4)0Probable/doubtful
       Blood pressure systolic increased1 (1.4)0Possible/not related
       Hip fracture1 (1.4)0Not related/not related
       Anxiety disorder1 (1.4)0Possible/possible
       Anxiety01 (1.5)Possible/not related
       Feeling of despair01 (1.5)Possible/not related
       Dry eye01 (1.5)Possible/possible
       Eye color change01 (1.5)Possible/possible
       Eye inflammation01 (1.5)Possible/possible
       Eye pruritus01 (1.5)Possible/possible
       Gait disturbance01 (1.5)Possible/very likely
      SAEs
       Anxiety1 (1.4)Possible/possible
       Blood pressure increases1 (1.4)0Probably/not related
       Hip fracture1 (1.4)0Not related/not related
       Gait disturbance01 (1.5)Possible/very likely
       Dizziness01 (1.5)Doubtful/doubtful
      Notes: Incidence is based on the number of patients experiencing at least one adverse event, not the number of events. Adverse events are coded using MedDRA version 20.0. AD: antidepressant; Esk: esketamine; SAE, serious adverse event; TEAE: treatment-emergent adverse event.
      a An adverse event that started in the double-blind phase and resulted in discontinuation in the follow-up phase is counted as treatment-emergent in the double-blind phase.
      Serious adverse events (SAEs) were reported in five patients during the double-blind phase: three in the esketamine/antidepressant and two in the antidepressant/placebo group (Table 6). No deaths were reported.
      History of hypertension was reported in 73/137 (53.3%) patients. The greatest mean increase in systolic BP was 16.0 mm Hg (esketamine/antidepressant) versus 11.1 mm Hg (antidepressant/placebo) and 9.5 mm Hg (esketamine/antidepressant) versus 6.8 mm Hg in diastolic BP. Increases in BP peaked at 40 minutes post-dose and generally returned to near pre-dose values by 1.5 hours post-dose (Supplementary Digital Content S4); increases in mean BP in the antidepressant/placebo group occurred at each post-dose timepoint. In the induction phase, the TEAE of BP increased was reported in 12.5% (9/72) of patients in esketamine/antidepressant, and 4.6% (3/65) in the antidepressant/placebo group. Treatment-emergent acute hypertension with a systolic BP ≥180 mm Hg was seen in 2/72 (2.8%) patients in the esketamine/antidepressant and 1/65 (1.5%) patient in the antidepressant/placebo group; diastolic BP ≥100 mm Hg was seen in 7/72 (9.7%) patients in the esketamine/antidepressant and 3/65 (4.6%) in the antidepressant/placebo group. One patient in each group had a diastolic BP ≥105 mm Hg while no patients had diastolic BP ≥110 mm Hg (Supplementary Digital Content S5).
      No clinically significant changes in laboratory evaluations, electrocardiograms, nasal tolerability (using the nasal examination) were reported in the double-blind phase. No clinically significant decreases in respiratory rate or cases of interstitial cystitis were reported.
      No suicide attempts or suicidal behavior were reported; most patients (≥79.4%) had a score of 0 on the C-SSRS at baseline. In the esketamine/antidepressant group, the maximum baseline C-SSRS score of 3 (active suicidal ideation—no intent) was reported in one (1.4%) patient. In the antidepressant/placebo group, the maximum baseline score on the C-SSRS was 2 (non-specific suicidal thought) reported in two (3.1%) patients. Eight of 70 (11.4%) patients in the esketamine/antidepressant and 9/65 (13.8%) in the antidepressant/placebo group had postbaseline suicidal ideation; none had suicidal ideation at baseline (Supplementary Digital Content S6).
      Mean CADSS scores in the esketamine/antidepressant group peaked at the 40-minute post-dose assessment and returned to near pre-dose values at 1.5-hour post-dose (Supplementary Digital Content S7), indicating that dissociative and perceptual symptoms occurred shortly after the start of esketamine dosing, generally resolving by 1.5 hours post-dose.
      Moderate or greater sedation (MOAA/S score ≤3) was reported in ≤3.4% of patients in the esketamine/antidepressant group on each treatment day (Supplementary Digital Content S8). Six patients (8.3%) manifested moderate or greater sedation at any time during the induction phase in the esketamine/antidepressant group versus one (1.5%) patient in the antidepressant/placebo group.
      During the induction phase, one (1.4%) patient reported the TEAE of somnolence in the esketamine/antidepressant versus three (4.6%) patients in the antidepressant/placebo group.
      Most patients were considered ready for discharge at 1.5 hours after dosing: 90% in the esketamine/antidepressant (range: 1.5–3 hours [median 1.75 hours]), and 95% in the antidepressant/placebo (range: 1.5–3.25 hours [median 1.75 hours]) group, based on the CGADR. Approximately 50% of patients in the esketamine/antidepressant and 85% in the antidepressant/placebo arm were considered ready for discharge 1 hour after dosing. For the remaining patients, readiness for discharge post-dose in the esketamine/antidepressant group ranged from 1.5 to 3 hours (median 1.75 hours) versus 1.5 to 3.25 hours (median 1.75 hours) in the antidepressant/placebo group.
      The 2-week follow-up phase included 15 patients (n = 12, esketamine/antidepressant; n = 3, antidepressant/placebo). The most frequently reported (≥2 patients) new or worsened symptoms in the esketamine/antidepressant group on the PWC-20 included difficulty concentrating, remembering (n = 3), loss of appetite (n = 2), anxiety-nervousness (n = 2), and nausea-vomiting (n = 2) versus two patients with dizziness-lightheadedness in the antidepressant/placebo group. There was no evidence of a withdrawal syndrome with esketamine.
      Analyses of cognitive test performances conducted for the safety analysis set showed slight improvement, or findings comparable to baseline, at the end of the double-blind induction phase, including all measures of higher cognitive function (visual, verbal, and working memory, executive function) in both treatment groups (Supplementary Digital Content S9). Slowing of simple reaction time (Cogstate Detection Test) was observed at Day 28 versus baseline for both treatment groups. The slowing for each group was small; the Cohen's d value for change in simple reaction time from baseline to Day 28 in the esketamine/antidepressant group was 0.12 versus 0.18 in the antidepressant/placebo group. Therefore, this finding was considered to have doubtful clinical relevance.

      DISCUSSION

      While the primary endpoint of change in MADRS total score from baseline showed 3.6 points mean reduction in the esketamine/antidepressant versus the antidepressant/placebo group, this difference was not statistically significant. Notably, this between treatment group difference is comparable to the average two- to three-point difference observed between previously approved antidepressant and placebo groups and is in a range typically considered clinically meaningful.
      • Kim J
      • Farchione T
      • Potter A
      • et al.
      Esketamine for treatment-resistant depression—first FDA-approved antidepressant in a new class.
      ,
      • Montgomery SA
      • Moller HJ
      Is the significant superiority of escitalopram compared with other antidepressants clinically relevant?.
      This observation was corroborated by the secondary and subgroup analyses from this study and were consistent with observations from esketamine studies in younger patients.
      • Daly EJ
      • Singh JB
      • Fedgchin M
      • et al.
      Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial.
      • Singh JB
      • Fedgchin M
      • Daly E
      • et al.
      Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study.
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      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.
      • Fedgchin M
      • Trivedi M
      • Daly EJ
      • et al.
      Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1).
      A treatment difference was suggested by the difference between treatment groups for patients aged 65–74 years and for patients with an earlier depression onset (Fig. 8).
      Notably, the sample size estimation was based on an anticipated -6.5-point difference between treatment groups was considerably larger than the typical two- to three-point difference seen in antidepressant studies; this optimistic assumption may have contributed to the lack of statistical significance in the primary outcome. The sample size determination was based on results from a phase 2 study in younger patients who did not initiate a new oral antidepressant at randomization.
      • Daly EJ
      • Singh JB
      • Fedgchin M
      • et al.
      Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial.
      CGI-S, PHQ-9, and SDS showed magnitudes of changes consistent with those found in 18–64-year-old patients from other esketamine studies. Values for response and remission rates, while lower than rates seen in younger patients from other esketamine studies, showed comparable between group differences as those shown in previous studies of younger patients.
      • Daly EJ
      • Singh JB
      • Fedgchin M
      • et al.
      Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial.
      • Singh JB
      • Fedgchin M
      • Daly E
      • et al.
      Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study.
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      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.
      • Fedgchin M
      • Trivedi M
      • Daly EJ
      • et al.
      Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1).
      For example, the response rate in the antidepressant/placebo group (13.8%) was relatively lower than those reported in studies of younger patients (38.9% and 52.0% in the two phase 3 short-term studies).
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      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.
      ,
      • Fedgchin M
      • Trivedi M
      • Daly EJ
      • et al.
      Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1).
      Additional analyses assessed factors that potentially contributed to lack of statistical significance in the primary endpoint.
      Analysis of age of patients at study entry, a pre-specified assessment, suggested a greater reduction in MADRS total scores in 65-74-year-old patients treated with esketamine compared to placebo that was not observed in patients aged ≥75 years. Separation in the curves for the change in MADRS total score was also noted earlier in the study for 65–74-year-old patients (Fig. 6). Some delay in separation may be related to the lower 28 mg starting dose in this study, compared with the 56 mg starting dose in esketamine studies with younger patients.
      The lack of treatment response in patients ≥75 years may be related to the small number of patients (n = 21) who were ≥75 years. Factors such as comorbid medical illness (including cardiovascular disease), cognition, adverse events, or concomitant medications did not appear to influence the treatment response in either patients 65–74 years or in those ≥75 years. Adverse event rates were similar to those seen in other esketamine studies in younger patients.
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      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.
      ,
      • Fedgchin M
      • Trivedi M
      • Daly EJ
      • et al.
      Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1).
      Additionally, evaluating age as a continuous variable (without pre-defined age cut offs) showed less efficacy in the oldest patients (Fig. 7). A later age of onset of depression does not fully explain this finding since the age on onset of depression was <55 years in 52.4% of the patients ≥75 years. Comparison of other variables assessed for the full data set was unlikely to yield meaningful information given the limited number of ≥75-year-old patients. Therefore, data for patients ≥75 years of age must be interpreted with caution.
      Age of depression onset was explored because late-onset depression (LOD) has been associated with greater treatment resistance in some studies.
      • Naismith SL
      • Norrie LM
      • Mowszowski L
      • et al.
      The neurobiology of depression in later-life: clinical, neuropsychological, neuroimaging and pathophysiological features.
      Patients with onset under 55 years of age had greater responses to esketamine versus placebo than those with onset ≥55 years. Additionally, evaluation of age of depression onset as a continuous variable (without the predefined age cutoff) showed decreased efficacy with onset at later ages (Fig. 9). This decrease in efficacy is consistent with literature reports of LOD associated with diverse pathophysiological underpinnings (especially cerebrovascular disease), potentially related to increased neuromorphological changes and MRI signal hyperintensities
      • Katona C
      • Hansen T
      • Olsen CK
      A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder.
      ,
      • Knochel C
      • Alves G
      • Friedrichs B
      • et al.
      Treatment-resistant late-life depression: challenges and perspectives.
      and treatment resistance.
      • Naismith SL
      • Norrie LM
      • Mowszowski L
      • et al.
      The neurobiology of depression in later-life: clinical, neuropsychological, neuroimaging and pathophysiological features.
      Stages 1 and 2 of the IA yielded disparate results, potentially affected by operational changes during the study and by increased dosing as the study progressed (Fig. 10). Operational changes implemented because of a >90% screen failure rate (three patients recruited in 9 months), occurred months prior to, and independent of the IA. For example, a program to train remote MADRS raters on interviewing older patients was implemented following a concern that elderly patients were reticent to report their symptoms over the telephone.
      • Fiske A
      • Wetherell JL
      • Gatz M
      Depression in older adults.
      Additionally, sites with geriatric expertise were selected that enrolled more patients after the IA. Screen failures dropped to approximately 55% following these modifications. Use of higher doses of esketamine as the study progressed, described below, potentially influenced efficacy in stage 2, after the IA.
      Dosing may have impacted efficacy because the 28 mg dose (used initially in all patients) was not included in esketamine trials in younger patients.
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      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.
      ,
      • Fedgchin M
      • Trivedi M
      • Daly EJ
      • et al.
      Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1).
      The 28 mg dose was considered subtherapeutic in a phase 2 trial in younger adults, but was included in the elderly study to improve tolerability.
      • Daly EJ
      • Singh JB
      • Fedgchin M
      • et al.
      Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial.
      However, esketamine concentrations in the current study (both in patients ≥65 years of age and those ≥75 years) were similar to those in patients <65 years of age.
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      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.
      Initially, investigators used lower esketamine doses, following the adage for elderly patients “start low, go slow.” During the trial, investigators increased the dose and rate of dose escalation, possibly because of a lower than anticipated adverse events, similar to that seen in younger patients.
      The 4-week study duration was potentially too short for an optimal effect in elderly patients. Over 80% of patients who continued in the open-label safety study demonstrated sustained reduction in the mean MADRS total score, suggesting benefits of longer treatment duration (Fig. 13). Response and remission rates at 8 weeks resembled those in younger adults following a 4 weeks of treatment (69.5% [52/82], and 46.3% [38/82], respectively).
      • Popova V
      • Daly EJ
      • Trivedi M
      • et al.
      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.
      Available evidence from the literature also supports increased efficacy with longer treatment periods in older patients.
      • Katona C
      • Hansen T
      • Olsen CK
      A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder.
      ,
      • Lenze EJ
      • Mulsant BH
      • Blumberger DM
      • et al.
      Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.

      Safety Profile

      TEAEs in this study (including patients ≥75 years) were consistent with those in esketamine studies of younger patients.
      • Daly EJ
      • Singh JB
      • Fedgchin M
      • et al.
      Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial.
      The rate of TEAEs was not higher in patients with associated comorbidities (including cardiovascular and thyroid disease) and/or on concomitant medications. Most TEAEs occurred and typically resolved on dosing days. Patients tolerated higher doses; 64.5% received 84 mg.
      Cognitive impairment was limited to slight slowing of simple reaction time in both esketamine and the placebo-treated patients, suggesting a lack of systematic cognitive changes following esketamine/antidepressant treatment.
      Based on CADSS assessment, dissociative changes occurred shortly after dosing and generally resolved 1.5 hours post-dose. The magnitude of mean change in the CADSS was consistent with, and slightly lower than that seen in younger adults (possibly because of the 28 mg dose).
      • Daly EJ
      • Singh JB
      • Fedgchin M
      • et al.
      Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial.
      ,
      • Singh JB
      • Fedgchin M
      • Daly E
      • et al.
      Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study.
      Overall, safety results, including those in patients ≥75 years, were consistent with those reported in previous esketamine studies in younger adults.
      • Daly EJ
      • Singh JB
      • Fedgchin M
      • et al.
      Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial.
      ,
      • Singh JB
      • Fedgchin M
      • Daly E
      • et al.
      Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study.
      Patients in this trial (as in younger patients in the esketamine TRD program) were medically stable, meeting inclusion and exclusion criteria (Supplementary Digital Content S1); approximately half had pre-existing controlled hypertension, and followed BP guidelines for dosing. No new safety concerns were identified.
      Limitations included potential unblinding as a result of dissociation or other side effects following esketamine administration, despite mitigation measures such as including remote independent raters to assess the primary endpoint, and addition of a bittering agent in the placebo nasal spray. Additionally, a longer double-blind treatment duration may potentially demonstrate clearer treatment effects.

      CONCLUSIONS

      Esketamine/antidepressant did not achieve statistical significance for the primary endpoint in this study of patients with TRD ≥65 years. Additional analyses suggested improvement for esketamine/antidepressant versus antidepressant/placebo in younger patients (65–74 years) and in patients with earlier onset of depression (<55 years). Factors that may have contributed to the failure to achieve statistical significance conceivably included lower dosing and a need for a longer treatment duration in older patients. Overall, the adverse event profile in older patients was similar to that seen in esketamine studies of younger patients; no new safety concerns were identified. Further studies are required to better evaluate esketamine in elderly patients given several factors that potentially influenced the efficacy of esketamine in this study.

      Disclosure

      This work was supported by Janssen Research and Development , LLC, Titusville, NJ, USA.
      Stacey E. Shehin, PhD, (PRA Health Sciences) and Priya Ganpathy, MPharm CMPP (SIRO Clinpharm Pvt. Ltd, India) provided medical writing assistance, which was funded by Janssen Research & Development, LLC, and Harry Ma, PhD (Janssen Global Services) provided additional editorial support. The authors thank the study patients, their families, and the investigators (Supplementary Digital Content S10) for their participation in this study.
      Portions of these results have been previously presented at the American Association for Geriatric Psychiatry Annual Meeting, March 1–4, 2019, Atlanta, GA, USA.
      Rachel Ochs-Ross, Ella J. Daly, Yun Zhang, Rosanne Lane, Pilar Lim, Randall L. Morrison, David Hough, Husseini Manji, Wayne C. Drevets and Jaskaran B. Singh are employees of Janssen Research & Development and may hold company stock and/or stock options. Rupert McShane reports grants and consultation fees from Janssen and consultation fees from Sage. Raphaël Gaillard reports personal fees from Janssen, Lundbeck, Roche, Takeda, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pierre Fabre, Eli Lilly, Lundbeck, Otsuka, Sanofi, and Servier Pharmaceuticals. Samuel Wilkinson reports grants and consulting fees from Janssen. He also acknowledges support from the Agency for Healthcare Research and Quality (K12HS023000), the American Foundation for Suicide Prevention, the Brain and Behavior Research Foundation (formerly NARSAD), and the Robert E. Leet and Clara Guthrie Patterson Foundation. Caleb Adler has received research support through the University of Cincinnati from Activas, Alkermes, Allergan, Cephalon, Forest, Janssen, Johnson and Johnson, Lundbeck, Merck, Otsuka, Pfizer, Shire, Sunovion, Supernus, Syneurex, and Takeda, and has received grant support from Merck and Forest. He is a consultant to Sunovion, Assurex Health, and Neurocrine, and is on the Speaker's Bureau for Janssen. Gerard Sanacora has received consulting fees from Alkermes, Allergan, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Hoffmann–La Roche, Intra-Cellular Therapies, Janssen, Merck, Minerva Neurosciences, Naurex, Navitor Pharmaceuticals, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, and Vistagen Therapeutics. He has also received research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffmann–La Roche, Merck, Naurex, and Servier Pharmaceuticals. No-cost medication was provided to Dr. Sanacora for an NIH-sponsored study by Sanofi-Aventis. In addition, he holds shares in Biohaven Pharmaceuticals Holding Company and is a co-inventor on the patent “Glutamate agents in the treatment of mental disorders” (patent 8778979) and a provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01 Abdallah, C, Krystal, JH, Duman, R, Sanacora, G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. David Steffens reports consulting income from Janssen Research & Development. All authors meet ICMJE criteria, had access to the study data, and made the final decision about where to publish these data.

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