SUMMARY

• Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (ie, a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance has been reported with prolonged use of ketamine. Similar tolerance would be expected with prolonged use of esketamine.¹
• Data from 3 long-term studies indicate that continued treatment with SPRAVATO and an oral antidepressant (AD) appeared to sustain the antidepressant effect, without evidence of attenuation of the antidepressant effect.^2-4

CLINICAL DATA

Zaki et al (2023)² conducted a phase 3, open-label extension study to evaluate the long-term safety and efficacy of individualized, intermittently dosed SPRAVATO with an oral AD in patients with treatment-related depression (TRD). Patients from 1 of 6 phase 3 parent studies (TRANSFORM-1,-2,-3, SUSTAIN-1,-2, and TRD 3006 [US only]) were enrolled into either a 4-week induction (IND) phase or the optimization/maintenance (OP/M) phase depending on their status at the end of the parent study.  

• During the IND phase, patients self-administered a twice weekly, flexible dose of SPRAVATO (28 mg [patients aged ≥65 years], 56 mg, or 84 mg).
• In the OP/M phase (variable duration) patients were administered SPRAVATO (28 mg [patients aged ≥65 years], 56 mg, or 84 mg) weekly, every other week, or every 4 weeks based on the assessment of Clinical Global Impressions-Severity (CGI-S) and tolerability.
• A total of 1148 patients were enrolled, of whom 458 were included in the IND phase and 1110 were included in the OP/M phase. A total of 690 patients entered the OP/M phase directly, and 420 of 458 patients entered the OP/M phase from the IND phase.
• Mean (standard deviation [SD]) exposure to SPRAVATO was 42.9 (24.22) months, with the duration of exposure ranging from ≥12 months (in 81.0% of patients) to ≥48 months (in 43.2% of patients); total exposure was 3777 cumulative patient-years.
• A reduction in Montgomery-Åsberg Depression Rating Scale [MADRS] total score was observed during the IND phase (mean [SD] change from baseline to IND phase endpoint: -12.8 [9.73]), which was maintained during the OP/M phase (mean [SD] change from baseline to OP/M phase endpoint: +0.2 [9.93]); see Figure: Mean MADRS Total Score Over Time (Observed Cases).

• During the IND phase, the percentage of responders (≥50% reduction in MADRS total score) increased over time from 15% (66/439) at day 8 to 50.6% (224/443) at day 28; the percentage of responders was 49.2% (224/455) at the endpoint of the IND phase.
• Remission (MADRS total score ≤12) was reported in 35.6% of patients at the IND phase endpoint and 50.0% at the OP/M phase endpoint.
• 61.3% (n=680) of patients completed the OP/M phase. Nearly 5% (n=52) withdrew the study due to lack of efficacy and 6% (n=67) withdrew due to adverse events.

Daly et al (2019)³ conducted a long-term, double-blind, maintenance-of-effect study to assess the efficacy of SPRAVATO+AD compared with an AD + placebo nasal spray (PBO) in delaying relapse of depressive symptoms in patients with TRD who were in stable remission (defined as a MADRS total score ≤12 for at least 3 of the last 4 weeks, with MADRS total score missing once or >12 at week 13 or 14 permitted, and ≤12 at weeks 15 and 16 required) after an IND and optimization course of SPRAVATO+AD (N=705). The study continued until the requisite number of relapses occurred.

• During the IND phase (initial 4 weeks), patients self-administered either SPRAVATO or PBO twice per week. Patients were not allowed to change their dose after the IND phase.
• In the optimization (12 weeks) and maintenance (variable duration) phases, nasal spray medication was administered weekly for the first 4 weeks, then individualized to once weekly or once every other week based on severity of depression symptoms. A new oral AD (duloxetine, escitalopram, sertraline, venlafaxine XR) was administered daily for the duration of the study.
• Primary efficacy endpoint: time to relapse among stable remitters during the maintenance phase. Relapse was defined as MADRS total score ≥22 for 2 consecutive assessments separated by 5 to 15 days or hospitalization for worsening depression, suicide attempt, suicide prevention or completed suicide, or any other clinically relevant event suggestive of relapse.
  • Among stable remitters, median exposure to intranasal study drug during the maintenance phase was 17.7 weeks of SPRAVATO and 10.2 weeks of PBO.
  • Among stable remitters, 26.7% of patients in the SPRAVATO+AD and 45.3% of patients in the AD+PBO groups experienced a relapse event during the maintenance phase.
  • The median time to relapse (95% confidence interval) was not estimable (NE) for the SPRAVATO+AD group as the 50% relapse rate was not reached based on Kaplan–Meier estimates. The median time to relapse was 273.0 (97.0; NE) days for the AD+PBO group.
  • Of the patients randomized to SPRAVATO, 60.5% received 84 mg and 39.5% received the 56 mg dose.⁵
  • Based on depressive symptomatology, 69% of stable remitters received every-other-week dosing and 23% received weekly dosing for the majority of time during the maintenance phase of the study.⁵
  • The majority of AEs were observed post dose on dosing days, and generally resolved in the same day.

Wajs et al (2020)⁴ conducted an open-label, multicenter, phase 3 study to evaluate the long-term (up to 1 year of exposure) safety, tolerability, and efficacy of SPRAVATO (28, 56 or 84 mg) plus a newly initiated oral AD in patients with TRD.

• MADRS total score improved throughout the IND phase (mean [SD] change: -16.4 [8.76]) and appeared to be maintained from OP/M baseline to OP/M endpoint (mean [SD] change: 0.3 [8.12]) (Figure: Mean MADRS Total Score Over Time).

• The percentage of responders (≥50% reduction in the MADRS total score) increased over time during the IND phase. At the IND endpoint, 78.4% (593/756) patients were responders. Of the patients who entered the OP/M phase, 76.5% (461/603) patients were responders at the OP/M endpoint.
• The percentage of patients in remission (MADRS total score ≤12) also increased over time during the IND phase. At the IND endpoint, 47.2% (357/756) patients achieved remission. Of the patients who entered the OP/M phase, 58.2% (351/603) patients achieved remission at the OP/M endpoint.
• Of 603 patients in the OP/M phase (weeks 5-52), the percentage of patients dosed weekly throughout, had one change from weekly to every other week, and changed back and forth from weekly to every other week were 24%, 38.1%, and 37.8%, respectively. The final SPRAVATO dose was 56 mg in 45.6%, 84 mg in 50.2%, and 28 mg in 4% of patients.
• Overall, 90.1% of patients in the IND and OP/M phases experienced ≥1 treatment-emergent AE which were primarily mild or moderate in intensity, occurred on dosing days and resolved on the same day.

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 23 September 2024.