SUMMARY

• SPRAVATO nasal spray must be self-administered under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of SPRAVATO and post-administration observation under supervision. The nasal spray device delivers a total of 28 mg of esketamine. To prevent loss of medication, do not prime the device before use. Use 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5 minute rest between use of each device to allow medication to absorb.¹
• Missed Dose: If a patient misses treatment session(s) during the first 4 weeks of treatment, the patient should continue the current dosing schedule.² For patients who miss treatment session(s) during maintenance treatment and have worsening of depression symptoms, per clinical judgement, consider returning to the previous dosing schedule (e.g., if doses missed during weekly dosing, revert to twice weekly dosing).¹
• Continuation: A post hoc subgroup analysis of the open-label, phase 3, SUSTAIN-3 study evaluated the efficacy and safety of SPRAVATO nasal spray concerning the continuation of maintenance dosing in patients who experienced a >28-day lapse in treatment. Upon resuming maintenance dosing with SPRAVATO (along with an oral antidepressant), improvement in MADRS and PHQ-9 scores continued throughout the optimization/maintenance (OP/M) phase.³ 
• Reinitiation: In a post hoc analysis of SUSTAIN-3, patients who relapsed on SPRAVATO conjunctively with an antidepressant (AD) during the SUSTAIN-1 study, after attaining stable response or remission, were reinitiated on flexibly dosed SPRAVATO in the induction phase followed by OP/M phase. Patients received flexible, twice-weekly dosing of SPRAVATO during the 4-week second induction phase and weekly, every other week, or every 4-week dosing during the variable duration OP/M phase.⁴
• An analysis of real-world safety data collected through required reporting from Risk Evaluation and Mitigation Strategy (REMS) monitoring forms found that patients reinitiating SPRAVATO after gaps in treatment (>60 days) had rates of sedation, dissociation, and increased blood pressure consistent with its established safety profile.⁵

Clinical data

Post Hoc Analysis of Patients Who Continued Maintenance Dosing of SPRAVATO in SUSTAIN-3 After Experiencing a Lapse in Treatment

Zajecka et al (2025)³ conducted a post hoc subgroup analysis of SUSTAIN-3, an open-label, phase 3 extension study to evaluate the efficacy and safety of SPRAVATO nasal spray used in combination with an oral antidepressant among patients with TRD (N=84) who experienced a lapse in treatment of >28 days and were resumed on maintenance dosing (flexibly-dosed SPRAVATO 56 mg or 84 mg; dosing frequency was adjusted based on Clinical Global Impression-Severity scale score and tolerability). Treatment lapse occurred between the time patients ended treatment from one of 5 parent studies^6-10 and entered into the OP/M phase of SUSTAIN-3.

Results

• 84 patients continued maintenance dosing of SPRAVATO in the OP/M phase >28 days after the conclusion of the parent study; the average age was 49.8 years (range, 18-64 years) and 65.5% of patients were female.
• Mean (SD) duration of lapse in maintenance treatment was 163.5 (135.2) days (median, 119.5 days; range, 30-607 days).
• There was an increase in mean (SD) MADRS and PHQ-9 total scores after the conclusion of the parent study and the OP/M baseline of 3.1 (6.79) and 3.1 (5.04), respectively.
• Improvements were observed in mean (SE) MADRS and PHQ-9 scores by week 3 from OP/M baseline with further improvements noted through week 8 and maintained throughout OP/M (see Figure: Mean (SE) (A) MADRS and (B) PHQ-9 total scores during OP/M (observed cases)).
  • The mean (SD) change in MADRS and PHQ-9 total scores from IND baseline to OP/M last visit was -24.1 (10.82) and -11.5 (7.26), respectively.
• Increases in the percentage of patients achieving a response from OP/M baseline, as measured by MADRS and PHQ-9, were also observed and maintained throughout OP/M (see Figure: Response rates per (A) MADRS and (B) PHQ-9 total scores during OP/M upon continuation of ESK maintenance treatment after a >28-day lapse (observed cases)).
  • Response rates at the last OP/M visit were 72.6% as assessed by MADRS and 59.5% as assessed by PHQ-9.
• TEAEs reported aligned with the known safety profile of esketamine nasal spray, with the most common (i.e., dizziness, nausea, and headache) being reported at similar proportions to the overall study cohort during the OP/M period.
• Note, there may have been potential for bias related to which patients chose to continue from the parent study into SUSTAIN-3. Additionally, the exclusion of patients with significant psychiatric or medical comorbidities may limit the generalizability of these findings.

Post Hoc Analysis of Patients Who Reinitiated SPRAVATO in SUSTAIN-3 After Relapsing While Taking or Discontinuing SPRAVATO in SUSTAIN-1

Castro et al (2023)⁴ conducted a post hoc analysis of the open-label, phase 3, SUSTAIN-3 study to assess efficacy and safety outcomes in patients with TRD (N=96) who relapsed during the SUSTAIN-1⁸ study, after attaining stable response and remission, and received a second twice-weekly induction of SPRAVATO followed by OP/M treatment.

Results

• Of the 96 patients (mean [standard deviation (SD)] age, 45.0 [10.59] years; female, 69.8%), 32 had previously relapsed on SPRAVATO+AD (esketamine nasal spray [ESK] plus an oral AD [PR-ESK+AD]) and 64 had previously relapsed on AD+placebo (PBO; PR-AD+PBO) in the maintenance phase of SUSTAIN-1.
• The median duration of time between relapse and start of the second induction phase was 22.0 days and 16.0 days for the PR-ESK+AD and PR-AD+PBO groups, respectively.
• By the end of the SUSTAIN-1 optimization phase, a majority of the patients in the
  PR-ESK+AD group (71.9%) were taking 84 mg SPRAVATO, and before relapse, most patients in both groups were dosed weekly (PR-ESK+AD, 66.7%; PR-AD+PBO, 68.4%).
• In both groups, substantial improvements in depressive symptoms were observed over the second induction phase of SPRAVATO and sustained in the OP/M phase (see Figure: Mean (A) MADRS and (B) PHQ-9 Total Scores (LOCF) During the Reinduction and OP/M Phases of SUSTAIN-3 Among Patients Who Previously Experienced Relapse in SUSTAIN-1).
• At the end of the second induction phase, 71.9% and 62.5% of patients in the PR-ESK+AD group, and 73.4% and 60.9% of patients in the PR-AD+PBO group, achieved response and remission on the MADRS (see Table: Proportion of Patients in SUSTAIN-3 Who Attained Response or Remission Status Based on the MADRS and PHQ-9 Scores (LOCF)).
• Treatment-emergent adverse events (TEAEs) were reported in 58.3% and 83.3% of patients in the second induction and OP/M phases, respectively. Overall, SPRAVATO was well tolerated with no new safety signals reported.
  • The most common (≥10%) TEAEs during the second induction phase (N=96) were dissociation (17.7%), dizziness (13.5%), vertigo (13.5%), and dysgeusia (12.5%).
  • The most common (≥15%) TEAEs during the OP/M phase (N=94) were dissociation (27.1%), headache (25.0%), dizziness (21.9%), vertigo (20.8%), somnolence (18.8%), nausea (18.8%), nasopharyngitis (17.7%), anxiety (16.7%), and dysgeusia (15.6%).
  • No serious adverse events (SAEs) were reported in the second induction phase; 12.8% (n=12) of patients experienced SAEs during the OP/M phase (the most common SAEs were psychiatric disorders, 3.1%; neoplasms [benign, malignant, and unspecified], 2.1%; and nervous system disorders, 2.1%).
  • No discontinuations due to TEAEs occurred during the second induction period, while 4 occurred during the OP/M phase.

Real-World Safety of SPRAVATO Nasal Spray in Patients with Treatment-Resistant Depression Who Reinitiated SPRAVATO After Initial Treatment

Verbanac et al (2021)⁵ evaluated the real-world safety profile of SPRAVATO in patients during their first treatment period and during subsequent reinitiation periods.

Methods

• Safety data (sedation, dissociation, blood pressure) were collected from REMS patient monitoring forms from 5 March 2019 to 5 January 2021 and grouped into 3 sequentially separate treatment periods based on treatment gaps >60 days.
  • Period 1: the first continuous treatment period for patients receiving ≥1 dose of SPRAVATO
  • Period 2: the second continuous treatment period after a first treatment gap of >60 days
  • Period 3: the third continuous treatment period after a second treatment gap of >60 days
• Rates of AEs were summarized by treatment period and by treatment phase (induction vs maintenance) for each treatment period
  • Induction phase: first 8 SPRAVATO treatment sessions
  • Maintenance phase: ≥9^th treatment session

Results

Baseline demographics were similar across all treatment periods (see Table: Baseline Demographics)

• Based on the total number of patients treated, rates of sedation, dissociation, and increased blood pressure generally remained similar across all 3 periods (see Figure: Rates of Reported AEs by Total Patients Treated Per Period).
• SAEs were reported in 2.6% of patients in period 1, 0.8% of patients in period 2, and 0.8% of patients in period 3. The most common SAEs reported were increased blood pressure, dizziness, nausea, dissociation, and vomiting.

• Rates of sedation, dissociation, and increased blood pressure based on the total number of treatment sessions were also comparable across the 3 periods.
• Regarding the induction and maintenance phases, the overall AE rates were also consistent across treatment periods based on the total number of patients and total number of treatment sessions (see Figure: Rates of AEs Reported During (A) Induction and (B) Maintenance Phases by Total Patients Treated).

The authors noted that the results for periods 2 and 3 should be interpreted with caution due to the much smaller sample sizes.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 24 January 2025.