SPRAVATO - Outcomes Following Adjustments in Dosing Frequency

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 phase 4, randomized, double-blind (DB), placebo-controlled trial in adults with TRD, SPRAVATO monotherapy (fixed-dose 56 mg or 84 mg) administered twice weekly for 4 weeks improved depressive symptoms versus placebo based on Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Mean scores continued to improve in patients who entered into the open-label phase (OL) with twice-weekly dosing for an additional 4 weeks, followed by individualized less frequent dosing.^1,2 
• 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 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.³
• 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.⁴
• 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.⁵
• Dosing regimens outside of the prescribing information should be at the discretion of the clinician.
• Evers et al (2022)⁶ 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.
• Arrighi et al (2024)⁷ reported a case of a 31-year-old female with TRD who required an extended induction regimen of twice-weekly SPRAVATO to achieve sustained clinical response and, ultimately, remission. 

CLINICAL DATA

Data in Patients With TRD Receiving Fixed-Dosed SPRAVATO Monotherapy With Twice-Weekly Induction Followed By Individualized OL Dosing That Included Twice-Weekly Dosing During the First 4 Weeks

Janik et al (2025)¹ evaluated SPRAVATO monotherapy in 378 adults with TRD in a phase 4, multicenter, randomized, DB, placebo-controlled trial. After a ≥2-week antidepressant-free period, eligible participants were randomized (1:1:2) to fixed-dose SPRAVATO 56 mg, SPRAVATO 84 mg, or matching placebo, self-administered intranasally twice weekly for 4 weeks under healthcare provider supervision (double-blind phase; Weeks 1-4). After completing the DB phase, patients could then opt into a 12-week OL phase in which SPRAVATO was administered twice weekly during Weeks 5-8, once weekly during Weeks 9-12, and weekly or every other week during Weeks 13-16; dosing frequency was individualized to the least frequent dosing needed to maintain remission/response.² During the OL period, some patients also received standard-of-care treatment as determined by the site investigators.⁸ 

Results

Efficacy

• Change in MADRS total score from baseline to day 28 showed statistically significant and clinically meaningful improvement with both SPRAVATO doses compared with placebo; the least-square mean difference (SE) versus placebo was -5.1 (1.42) for 56 mg and -6.8 (1.38) for 84 mg (both P<0.001).¹ 
• Mean MADRS total scores continued to improve during the OL phase. See Figure: MADRS total score: change over time in the DB and OL phases (OL analysis dataset).
• Response and remission rates were assessed throughout the DB and OL phases. See Table: Response and Remission Outcomes Over Time.

Safety

• Overall, 72.4% of patients in the SPRAVATO 56 mg group, 75.2% in the SPRAVATO 84 mg group, and 49.2% in the PBO group experienced ≥1 TEAE during the DB phase. The majority of TEAEs were transient.¹ 
• Serious TEAEs were reported in 6 patients in the DB phase. SPRAVATO 56 mg: ankle fracture (n=1); SPRAVATO 84 mg: ophthalmic migraine and suicide attempt (n=1 each); PBO: self-injurious ideation, suicidal ideation, and acute myocardial infarction (n=1 each). Except for acute myocardial infarction in the PBO group, none were considered related to the study medication. No deaths were reported.¹ 
• Overall, 64.6% (56 mg) and 63.8% (84 mg) of patients who continued with SPRAVATO during the OL phase experienced a TEAE. Additionally, 73.4% who transitioned from PBO during the DB phase to SPRAVATO during the OL phase reported a TEAE.¹ 
• Serious TEAEs were reported in 9 patients in the OL phase: SPRAVATO 56 mg/SPRAVATO (n=3): abdominal hernia obstruction, endometrial cancer, and peritonitis (n=1 each); PBO/SPRAVATO (n=6): breast cancer (n=2), colon cancer, constipation, loss of consciousness, syncope, and vomiting (n=1 each). None were considered related to SPRAVATO. No deaths were reported.^1,8 

Data in Patients Who Received a Second Twice-Weekly Induction After Relapse or Nonresponse

Castro et al (2023)³ 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-1⁹ 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.

Ochs-Ross et al (2020)⁵ 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).¹¹ 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)⁶ 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.

Case Report of Patient Who Received Extended Twice-Weekly Induction

Arrighi et al (2024)⁷ presented a case report of a 31-year-old female diagnosed with treatment-resistant MDD, panic disorder, and generalized anxiety disorder.

• She was admitted to an in-patient psychiatric unit following a severe depressive episode (MADRS, 42) with suicidal ideation and sleep disorders. During her hospitalization, she was initiated on SPRAVATO 56 mg and mirtazapine 30 mg/day while continuing on lamotrigine 400 mg/day. SPRAVATO was then increased from 56 mg to 84 mg twice weekly.
• The patient showed clinical response by week 6, but it was not sustained beyond 72 hours post-administration. She then underwent an extended induction phase totaling 20 twice-weekly administrations resulting in remission (MADRS of 4).
• There were no noticeable adverse effects reported except dissociation during the first administration.
• Maintenance treatment with SPRAVATO was continued at 84 mg once weekly followed by 84 mg every two weeks for 6 months. While she continued cognitive behavioral therapy, SPRAVATO and all other pharmacological treatments were discontinued at the end of the maintenance phase with no reports of relapse 2 years post-discontinuation.

Post Hoc Analysis of Patients Who Experienced Improvement After Dose Frequency Adjustments from Every Other Week to Weekly

Nijs et al (2020)⁴ conducted a post hoc analysis of the phase-3, open-label, SPRAVATO safety study (SUSTAIN-2)¹¹ 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.

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 27 November 2025.