In the two negative short-term efficacy trials that did not reach statistical significance (TRANSFORM-1 and -3), the differences in MADRS reductions between esketamine and placebo were –3.2 (P = 0.088) and –3.6 (P = 0.059) after 4 weeks of treatment. The 4.0-point additional reduction in MADRS score with esketamine over placebo in the single positive efficacy trial corresponds to less than "minimal improvement" and has been criticized as being below the threshold for clinically meaningful change. A difference of at least 6.5 points was originally suggested by the trial investigators to be a reasonable threshold for clinical significance. In other literature, MADRS reductions have been interpreted as "very much improved" corresponding to 27–28 points, "much improved" to 16–17 points, and "minimally improved" to 7–9 points. It has additionally been argued that the small advantage in scores with esketamine may have been related to an enhanced placebo response in the esketamine group due to functional unblinding caused by the psychoactive effects of esketamine. In other words, it is argued that the study was not truly a double-blind controlled trial. Dissociation was experienced as a side effect by a majority of participants who received esketamine (61–75% with esketamine and 5–12% with placebo; ~7-fold difference) and "severe" dissociation was experienced by 25%. Deblinding and expectancy confounds are problems with studies of hallucinogens for psychiatric indications in general.
The FDA normally requires at least two positive short-term efficacy studies for approval of antidepressants, but this requirement was loosened for esketamine and a relapse-prevention trial was allowed to fill the place of the second efficacy trial instead. This is the first time that the FDA is known to have made such an exception and the decision has been criticized as lowering regulatory standards. In the relapse-prevention trial (SUSTAIN-2), the rate of depression relapse was significantly lower with esketamine continued than with it discontinued and replaced with placebo in esketamine-treated stable responders and remitters (51% rate reduction in remitters and 70% reduction in responders). Esketamine was approved for the treatment of MDD with co-occurring suicidal ideation or behavior on the basis of two short-term (4-week) phase 3 trials (ASPIRE-1 and -2) of esketamine nasal spray added to a conventional antidepressant. The primary efficacy measure was reduction in MADRS total score after 24 hours following the first dose of esketamine. In both trials, MADRS scores were significantly reduced with esketamine relative to placebo at 24 hours. The mean MADRS scores at baseline were 39.4 to 41.3 in all groups and the MADRS reductions at 24 hours were –15.9 and –16.0 with esketamine and –12.0 and –12.2 with placebo, resulting in mean differences between esketamine and placebo of –3.8 and –3.9. The secondary efficacy measure in the trials was change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) 24 hours after the first dose of esketamine.