SUMMARY

• In a phase 3, short-term, flexible-dosed clinical trial (TRANSFORM-3) in elderly patients (≥65 years of age) with treatment-resistant depression (TRD), the SPRAVATO + oral antidepressant (SPRAVATO+AD) group demonstrated a clinically meaningful,^1-3 but not statistically significant, improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to day 28 compared to the oral antidepressant + placebo nasal spray (AD+PBO) group (primary endpoint: -10.0 vs -6.3; least squares mean difference [LSMD; median unbiased estimate]: -3.6; 95% confidence interval [CI]: -7.2, 0.07; P=0.059).⁴
  • In the TRANSFORM-3 trial, the initial dose of SPRAVATO in elderly patients was 28 mg to facilitate improved tolerability.
• The efficacy and safety profile of SPRAVATO nasal spray was compared between younger (18-64 years) and older (≥65 years) patients with TRD in a post hoc analysis of the long-term, open-label, multicenter, phase 3 study (SUSTAIN-2). Patients from both groups had a similar mean reduction in MADRS score in the induction and optimization/maintenance phases. Serious treatment-emergent adverse events (TEAEs) were reported in 2.2% vs 1.9% of patients (induction phase) and 6.7% vs 4.8% of patients (optimization/maintenance phase) in the younger vs older group, respectively.⁵
• Pharmacokinetic analysis from phase 1 studies showed that mean esketamine (ESK) maximum serum concentration (C_max) and area under the curve (AUC) values were higher in elderly patients compared with younger adult patients.^6,7
• A post hoc analysis of the REAL-ESK study evaluated the effectiveness and tolerability of SPRAVATO nasal spray in 30 patients (aged ≥65 years) with TRD. Response was reported in 53.3% of patients at the end of treatment; TEAEs were reported in 63.3% of patients but were temporary and resolved within a day of or after treatment.⁸

Product labeling

Of the total number of patients in randomized, double-blind, placebo-controlled short-term clinical studies exposed to SPRAVATO, (N=2064), 238 (12%) were 65 years of age and older, and 29 (1%) were 75 years of age and older. No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age.⁹ 

CLINICAL DATA

Phase 3 Studies

TRANSFORM-3

Ochs-Ross et al (2020)⁴ evaluated the efficacy and safety of switching elderly patients (≥65 years of age) with TRD from a prior antidepressant treatment (to which they had not responded) to flexibly-dosed SPRAVATO (28 mg, 56 mg, or 84 mg) plus a newly initiated oral antidepressant (SPRAVATO+AD) compared with a newly initiated AD+PBO in a randomized, double-blind, active-controlled, multicenter study (N=137).

Study Design/Methods

The study consisted of a screening/prospective observational phase (4-7 weeks), a double-blind induction phase (4 weeks), and a follow-up phase (2 weeks). Regardless of response to treatment, patients were subsequently eligible to participate in the long-term, open-label safety study SUSTAIN-2, which was up to 1 year in duration. Patients who did not enter the safety study entered a 2-week, post-treatment follow-up phase.⁴ See Figure: Study Design.

• Patients self-administered SPRAVATO or matching PBO nasal spray under direct supervision of clinical site staff twice per week for 4 weeks as a flexible dose regimen in the double-blind induction phase.⁴
  • All patients started with SPRAVATO 28 mg or PBO on day 1; the second dose (day 4) was either placebo or SPRAVATO 28 mg or 56 mg. All subsequent doses were PBO or SPRAVATO 28 mg, 56 mg, or 84 mg. After the first dose, all dosing decisions were determined by the investigator based on efficacy and tolerability. Dose increase in SPRAVATO was not permitted past day 15.
  • Patients simultaneously initiated a new, open-label oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR) on day 1 and continued through the duration of the double-blind induction phase.
• Primary endpoint: Change in MADRS total score from baseline to day 28⁴
• Secondary endpoints included: evaluation of response rate (at least 50% improvement on MADRS total score from baseline), remission rate (MADRS total score ≤12) and Clinical Global Impression-Severity (CGI-S) scores⁴

Key Inclusion Criteria⁴

• Patients ≥65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of single-episode major depressive disorder (MDD) (duration ≥2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI).
• Documented nonresponse to ≥1 but ≤8 antidepressant treatments in the current episode of depression at the start of the screening/prospective observational phase
• Mini Mental State Exam total score ≥25 (or ≥22 for patients with less than the equivalent of a high school education)
• Clinician-rated Inventory of Depressive Symptomatology (IDS-C₃₀) total score of ≥31 at the start of the screening/prospective observational phase
• Nonresponse to 2 or more antidepressants prior to randomization (patient’s current major depressive episode and treatment response in the current depressive episode confirmed using a Site Independent Qualification Assessment)
• Current major depressive episode, depression symptom severity (week 1 MADRS total score ≥24 required)
• Medically stable on the basis of clinical laboratory tests performed in the screening/observational phase

Key Exclusion Criteria⁴

• Previous nonresponse in the current episode to ESK or ketamine, or to all of duloxetine, escitalopram, sertraline, and venlafaxine XR, or to an adequate course of treatment with electroconvulsive therapy (≥7 unilateral/bilateral treatments)
• Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar, or related disorders, obsessive compulsive disorder (current episode only), intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
• Homicidal ideation/intent or suicidal ideation with some intent to act within 6 months or suicidal behavior within the past year, per the investigator’s clinical judgment or based on the Columbia Suicide Severity Rating Scale
• History of moderate or severe substance or alcohol use disorder (DSM-5 criteria)

Results

Baseline Characteristics

Demographic and baseline characteristics among the SPRAVATO+AD (n=72) and the AD+PBO (n=65) group, respectively, included: mean age of 70.6 and 69.4 years; male, 37.5% and 38.5%; mean screening IDS-C₃₀ total score, 44.2 and 43.1; mean baseline MADRS total score, 35.5 and 34.8; the majority of patients had nonresponse to 2 previous antidepressants at the start of screening (in addition to 1 AD being assessed prospectively), 43.1% and 49.2%.⁴

Efficacy

While not statistically significant, the SPRAVATO+AD group showed a clinically meaningful improvement^1-3, and a numerically greater decrease in the MADRS total score from baseline to day 28, compared to the AD+PBO group (primary endpoint -10.0 vs -6.3; LSMD [median unbiased estimate]: -3.6; 95% CI: -7.2, 0.07; P=0.059) (see Figure: LS Mean Change from Baseline in MADRS Total Score Over Time in Elderly Patients). Overall response and remission rates at day 28 favored the SPRAVATO+AD group (see Figure: Response and Remission Rates at Study Endpoint [Day 28] in Elderly Patients).⁴ The number-needed-to-treat to achieve response and remission, respectively, based on MADRS total score at day 28, was 8 and 10.

There was also a clinically meaningful treatment difference, though not formally statistically tested, for improvement in the overall severity of depressive illness based on CGI-S scores for SPRAVATO+AD over AD+PBO (median change from baseline to endpoint, -1.0 vs 0).⁴ Patients in the SPRAVATO+AD arm were 5.3 times more likely than those in the AD+PBO arm to have an improved CGI-S score at the end of the double-blind phase.

Additional Post Hoc Analyses⁴

• Additional efficacy analyses found that patients aged 65-74 years on SPRAVATO+AD had greater improvements on the MADRS total score vs patients ≥75 years (LSMD: -4.9; 95% CI: -8.96, -0.89 vs LSMD: -0.4; 95% CI: -10.38, 9.50).
• In a post hoc analysis, patients on SPRAVATO+AD with an earlier onset of depression (<55 years of age) showed greater improvement on the MADRS total score vs patients diagnosed later (≥55 years of age) (LSMD: -6.1; 95% CI: -10.33, -1.81 vs LSMD: 3.1; 95% CI: -4.51, 10.80).
• An interim analysis was conducted during the study. There were more patients who were assessed post-interim analysis (stage 2) than pre-interim analysis (stage 1); n=86 vs n=51). This resulted in a treatment difference between the 2 phases; an unweighted analysis showed a LSMD of -4.0 (95% CI: -7.71, -0.25) between SPRAVATO+AD vs AD+PBO.
• A slower dose titration occurred in this trial compared to other trials. The percentage of patients in stage 1 and stage 2, respectively, who received 84 mg at day 25 was 52.2% and 71.8%.
• Patients in this study could enter a long-term, open-label safety and efficacy study.¹⁰ Of the 111/138 patients who entered into this study, 88 were nonresponders who received van additional 4 weeks of induction treatment. MADRS total scores continued to decrease in 93% of these nonresponders.

Safety

The most common adverse events (AEs) are found in Table: TEAEs ≥10% in Either Treatment Group During Double-Blind Phase in Elderly Patients.⁴

The incidence of patients with systolic blood pressure (SBP) ≥180 mmHg was 2.8% (2/72) in the SPRAVATO+AD group and 1.5% (1/65) in the AD+PBO group. A diastolic blood pressure (DBP) ≥100 mmHG was reported in 9.7% (7/72) and 4.6% (3/65) of patients in the SPRAVATO+AD and AD+PBO group, respectively. The mean maximum elevations in the SBP and DBP values were 16 mmHg and 9.5 mmHg above the pre-dose values, respectively, in the SPRAVATO+AD group, compared with 11.1 mmHg and 6.8 mmHg increases in the AD+PBO group, respectively. A history of hypertension was reported in 53.3% (73/137) of all patients.⁴

Sedation was evaluated by AE reports and using the Modified Observer’s Alertness/Sedation scale, with a score ≤3 indicating moderate or greater sedation, which was reported by ≤3.4% of SPRAVATO+AD patients on any given dosing day (vs ≤1.5% of AD+PBO patients [only reported on day 4]). AEs of moderate or greater sedation were reported by 8.5% of patients treated with SPRAVATO+AD and 1.5% treated with AD+PBO. Somnolence rates were higher in the AD+PBO arm compared to the SPRAVATO+AD arm (4.6% vs 1.4%).⁴

Dissociation was evaluated by AE reports and the Clinician-Administered Dissociative States Scale (CADSS) questionnaire. A total CADSS score never exceeded 10 on any given dosing day. Dissociation symptoms typically resolved by 1.5 hours postdose and the severity tended to reduce over time with repeated treatments.⁴

Serious AEs were reported by 5 patients during the double-blind phase: 3 in the SPRAVATO+AD group (anxiety, blood pressure increased, hip fracture) and 2 in the AD+PBO group (gait disturbance, dizziness). All were resolved by the end of study. There were no deaths, and no clinically significant changes in laboratory evaluations, electrocardiograms, respiratory rate, or nasal tolerability. No suicidal attempts or behavior were reported.⁴

Cognitive function measurements showed slight improvement or scores comparable to baseline at the end of the double-blind phase. Slowing of simple reaction time was observed at day 28 in both arms and was considered by investigators to have doubtful clinical relevance.⁴

SUSTAIN-2 Post Hoc Analysis

Ochs-Ross et al (2021)⁵ compared the efficacy and safety profile of SPRAVATO nasal spray in younger (18-64 years) vs older (≥65 years) patients with TRD in a post hoc analysis of the long-term (1year), open-label, multicenter, phase 3 SUSTAIN-2 study.

Study Design/Methods

The study consisted of a screening phase (4 weeks; direct-entry patients only), an open-label induction phase (4 weeks; direct-entry patients and transferred-entry nonresponders from TRANSFORM-3), an open-label optimization/maintenance phase (up to 48 weeks; responders from the open-label induction phase of SUSTAIN-2 and transferred-entry responders from TRANSFORM-3), and a follow-up phase (4 weeks; all patients). A diagnosis of MDD and nonresponse to ≥2 oral antidepressant treatments in the current depressive episode were required for inclusion in the study.

• Both direct-entry and transferred-entry nonresponders received flexibly dosed SPRAVATO nasal spray twice weekly (28 mg [≥65 years only], 56 mg, or 84 mg) during the induction phase. Initial doses were 28 mg (≥65 years) or 56 mg (<65 years).
• Direct-entry patients simultaneously received a newly initiated oral antidepressant (duloxetine, escitalopram, sertraline, or venlafaxine XR) not used in the current depressive episode. Transferred-entry patients continued the same oral antidepressant initiated in TRANSFORM-3. This oral antidepressant was continued throughout SUSTAIN2 for all patients.
• Responders (≥50% reduction in baseline MADRS score) from the induction phase entered the optimization/maintenance phase and continued to receive SPRAVATO nasal spray weekly for weeks 5-8 at the same dose.
• For weeks 9-52, changes in dosing frequency (once every week or once every 2 weeks) of SPRAVATO was allowed every 4 weeks based on depressive symptoms.
• Efficacy was assessed at weeks 4 and 12 by measuring the change from baseline in MADRS total score and evaluation of response rate (at least 50% improvement in MADRS total score from baseline) and remission rate (MADRS ≤12). Patient-reported outcomes measured included Sheehan Disability Scale (SDS), Patient Health Questionnaire (PHQ-9), and Generalized Anxiety Disorder (GAD-7).
  • Efficacy for the induction phase was assessed based on the change from pretreatment baseline scores to the scores at the end of the induction phase.
  • Efficacy for the optimization/maintenance phase was assessed based on the change from induction-phase baseline scores to the scores at the end of the optimization/maintenance phase.
• Safety was assessed primarily by monitoring TEAEs, dissociative symptoms (using the CADSS questionnaire), clinical laboratory test results, blood pressure and electrocardiograms.

Results

Baseline Characteristics

Demographic and baseline characteristics of the younger (n=624) vs older (n=178) groups included mean (standard deviation [SD]) age, 47.2 (11.1) vs 69.7 (4.2) years; male, 235 (37.7%) vs 65 (36.5%); mean (SD) baseline MADRS score, 31.4 (5.0) vs 31.4 (6.5); mean (SD) baseline CGI-S score, 4.9 (0.7) vs 4.6 (0.9); and mean (SD) baseline PHQ-9 total score, 17.9 (4.6) vs 15.3 (5.7).

Efficacy

• Efficacy outcomes across treatment groups are summarized in Table: Efficacy Outcomes.

Safety

• The most common TEAEs (≥10%) were consistent between younger and older patients. TEAEs are summarized in Table: TEAEs.

• The most common serious TEAEs in the younger group (depression, suicide attempt, anxiety, suicidal ideation, and gastroenteritis) and older group (depression and suicide attempt) occurred at a rate of <2%.
• CADSS total scores peaked at 40 minutes after administration and resolved by 1.5 hours on the same dosing day in both age groups across all time points during the study. Peak CADSS scores after the first dose were higher in the younger group compared to the older group. The proportion of patients with a CADSS score >4 is summarized in Table: Proportion of Patients With CADSS Score >4.

• In the older vs younger group, transient elevation of blood pressure ≥180 mmHg (systolic) or ≥110 mmHg (diastolic) was observed in 10/134 (7.5%) vs 6/86 (7.0%) patients with pre-existing hypertension and 12/490 (2.4%) vs 5/92 (5.4%) patients without pre-existing hypertension. Elevated blood pressure resulted in discontinuation of treatment in 7 (1.1%) patients in the younger group and 2 (1.1%) patients in the older group.
• Cognitive performance generally improved or remained stable in all patients. Older patients demonstrated a prolongation of simple and choice reaction times during the optimization/maintenance phase without changes in higher cognitive functions. No clinically significant differences in cognitive test performance were observed for older patients during the induction phase.

Phase 1 Studies

In a phase 1, open-label, single-dose, pharmacokinetic study comparing healthy elderly patients (≥65 years of age) to healthy younger adults (≥18 to ≤55 years of age), plasma C_max and AUC of ESK after a single 28-mg intranasal dose were approximately 17 to 21% higher in the elderly compared to younger adult patients. The incidence and severity of AEs were similar in the elderly and younger adult groups, with dysgeusia being the most frequently reported AE in the ESK group. There were no severe TEAEs, discontinuations, or deaths in the study.⁶

In another phase 1, open-label, single-dose, pharmacokinetic study comparing elderly (≥75 years of age) to healthy adults (≥18 and ≤55 years of age) after a single SPRAVATO 84 mg intranasal dose, plasma C_max, AUC up to the last measurable concentration, and total drug exposure across time of ESK were approximately 67%, 34%, and 38% higher, respectively, in the ≥75 years of age group compared to the younger adult group. The incidence of TEAEs was similar, but the incidence of vascular disorders was higher in the elderly (62.5%) compared to younger adults (12.5%), with hypertension most frequently reported (37.5% elderly subjects).⁷

Retrospective Study: REAL-ESK Post Hoc Analysis

d’Andrea et al (2023)⁸ evaluated the effectiveness and tolerability of SPRAVATO nasal spray in 30 patients (aged ≥65 years) with TRD in a post hoc analysis of the real-world, retrospective, observational, multicenter REAL-ESK study in Italy. Patients (mean age, 68 years; female, 70%) received SPRAVATO at an initial dose of 28 mg biweekly for 1 month, followed by a once-weekly flexible dosage (28, 56, or 84 mg) based on efficacy for the next 2 months. Most patients were treated with 28 mg (36.7%) or 56 mg (43.3%) doses of SPRAVATO. A response (defined as a 50% overall decrease from baseline in the MADRS) was reported in 8/30 (26.7%) and 16/30 (53.3%) patients at the end of 1 (T1) and 3 (T2) months of treatment, respectively. Additionally, a significant increase in the remission rate was observed at T2 vs T1 (33.3% vs 10%; P=0.028). TEAEs occurred in 19/30 (63.3%) patients, including dizziness (50%), dissociation (33.3%), sedation (30%), and hypertension (13.3%). The reported TEAEs were temporary and resolved by the following day at the latest. Treatment discontinuation was reported in 6/30 (20%) patients; 2/30 (6.7%) discontinued treatment due to TEAEs.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 20 September 2024.