SUMMARY  

• The approved SPRAVATO dosing and administration recommendations are based on the dosing protocol utilized within the phase 3 treatment-resistant depression (TRD) program.
• In a post hoc analysis of the open-label, phase 3, safety study (SUSTAIN3), patients who relapsed on SPRAVATO conjunctively with an oral antidepressant (AD) during the SUSTAIN-1 study (after attaining stable response or remission) benefited from receiving a second induction and optimization/maintenance (OP/M) treatment based on the Montgomery-Åsberg Depression Rating Scale (MADRS) and Patient Health Questionnaire 9-item (PHQ-9) scores. 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.¹
• In a post hoc analysis of the phase 3, open-label, TRD safety study (SUSTAIN-2), adjustments in SPRAVATO dosing frequency based on a symptom-based algorithm during the OP/M phase were associated with a likelihood of positive outcomes based on the Clinical Global Impression-Severity (CGI-S) score. Patients worsening on every other week SPRAVATO dosing experienced improved outcomes when switched to weekly dosing.²
• A majority of patients who were nonresponders from a 4-week study of SPRAVATO in elderly TRD patients experienced improvements in depressive symptoms following a second induction course of twice-weekly dosing when they continued into another open-label safety study. During this open-label study, 69.5% of patients achieved response and 46.3% achieved remission.³
• Dosing regimens outside of the prescribing information should be at the discretion of the clinician. As with existing ADs, there may be a need to individualize treatment if clinically appropriate.
• Evers et al (2022)⁴ reported a case of an elderly woman with TRD treated with SPRAVATO whose symptoms worsened after switching to weekly maintenance treatments but was able to achieve remission after switching back to twice-weekly dosing for a period of 2 months.

CLINICAL DATA

Castro et al (2023)¹ conducted a post hoc analysis of the open-label, phase 3, SUSTAIN-3 study to assess efficacy and safety outcomes in TRD patients (N=96) who relapsed during the SUSTAIN-1⁵ 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.

Nijs et al (2020)² conducted a post hoc analysis of the phase-3, open-label, SPRAVATO safety study (SUSTAIN-2)⁷ to assess the effect of dosing frequency changes (see Figure: Study Treatment Algorithm: SPRAVATO Nasal Spray Dosing Frequency) on efficacy utilizing CGI-S scores.

Patients worsening on every-other-week SPRAVATO dosing experienced better outcomes from weekly dosing. See Table: CGI-S Score After Change in Treatment Frequency. The authors note that the treatment protocol allowed changes in dosing frequency no more often than every 4 weeks, with a maximum of 3 changes. The findings from this analysis suggest a benefit from continued individualization of SPRAVATO dosing frequency. Adjustment of treatment frequency was associated with a higher likelihood of positive outcomes based on the ability to decrease or maintain CGI-S scores. The authors suggest a prompt increase in dosing frequency if a worsening of depressive symptoms is observed sooner than 4 weeks after switching from every week to every other week.

Ochs-Ross et al (2020)³ conducted a 4-week study of elderly patients (≥65 years) who received twice-weekly dosing with SPRAVATO nasal spray plus an oral AD or placebo nasal spray plus an oral AD. Upon study completion, patients meeting the criteria were eligible to enter a long-term, phase 3, open-label, TRD safety study (SUSTAIN2).⁷ A subset of these patients were nonresponders from the short-term elderly trial (n=88). These nonresponders completed a second, twice-weekly induction phase. MADRS scores continued to decrease in 93% (82/88) of the patients completing their second 4-week induction. Of these, 69.5% (52/82) achieved response and 46.3% (38/82) reached remission.

Evers et al (2022)⁴ reported on a woman in her late 70s with recurrent major depressive disorder (MDD) who attained remission with prolonged twice-weekly SPRAVATO treatment. Before initiating SPRAVATO, the patient previously failed electroconvulsive therapy (ECT) and 4 additional trials of ADs. After 6 SPRAVATO twice-weekly treatment sessions, she had a >50% reduction in her depressive symptoms. After an 8-week treatment interruption due to coronavirus disease 2019 (COVID-19), her depression worsened, and twice-weekly SPRAVATO treatment for 4 weeks led to >50% reduction in depressive symptoms. However, once she was transitioned to a once-weekly SPRAVATO maintenance regimen, her symptoms of low mood, anhedonia, and suicidal ideation returned to her pretreatment baseline. The SPRAVATO treatment frequency was again increased to twice weekly, and the patient achieved remission after 2 months of therapy.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (including internal/external databases) pertaining to this topic was conducted on 26 February 2024.