SUMMARY

• Popova et al (2019)¹ conducted a randomized, double-blind, multinational study to compare the efficacy and safety of switching patients with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to either SPRAVATO nasal spray plus a newly-initiated oral antidepressant (SPRAVATO+AD) or switching to a newly-initiated oral AD plus placebo nasal spray (AD+PBO).
• The primary endpoint in TRANSFORM-2 was change from baseline to day 28 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The primary endpoint was met, with a statistically significant difference observed between the treatment groups at day 28 (P=0.02, LSMD -4.0 [95% CI: -7.31; -0.64]).¹
• In TRANSFORM-2, there were 3 key secondary endpoints, one of which was onset of sustained clinical response, which was defined as a ≥50% reduction in MADRS total score at 24 hours and maintained at all subsequent timepoints through day 28, with one excursion allowed. Patients with missed assessments or who discontinued early were not considered to have onset of clinical response. This endpoint is considered a high bar to achieve in patients with TRD and with a remote rater. While there were a numerically greater number of patients in the SPRAVATO+AD treatment group who met this definition vs AD+PBO, the difference was not statistically significant.¹
• If examining response at 24 hours alone (i.e., ≥50% reduction in MADRS, but not requiring it be maintained at all timepoints), there were a numerically greater number of patients in the SPRAVATO+AD group who met this definition (see Figure: Least-Squares Mean Change in MADRS Total Score Over Time in Double-Blind Phase [TRANSFORM-2]).^1,2
• Most of the treatment difference observed with SPRAVATO^® (esketamine nasal spray) compared to placebo occurred at 24 hours. Between 24 hours and day 28, both the SPRAVATO and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through day 28.³

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 12 March 2024.