Data from two positive, pivotal, phase 3 trials of esketamine nasal spray (ESK) in treatment-resistant depression (TRD)—a short-term study (TRANSFORM-2) and a maintenance study (SUSTAIN-1)—were analyzed in the post-hoc analysis to assess the relationship between dissociation and the antidepressant effects of ESK. The relationships between peak Clinician Administered Dissociative States Scale (CADSS) scores after the first (day 1) and last (day 25) ESK doses and change in Montgomery-sberg Depression Rating Scale (MADRS) total scores at the first (day 2) and last assessments (day 28) in TRANSFORM-2 and peak CADSS after the first maintenance ESK dose and time to relapse in SUSTAIN-1 were examined using responder status analysis, correlation analysis, and mediation analysis (only for mediation analysis). 

The percentage of responders (>50% reduction in MADRS) at day 2 and day 28 in TRANSFORM-2 did not differ substantially between patients who did and did not display severe dissociation (peak CADSS scores >4 or 4, respectively) following the first ESK dosage. The Spearman correlation coefficients between dissociation and depression improvement were insignificant and around zero. In TRANSFORM-2, CADSS scores did not substantially influence the reduction in MADRS at day 2 or 28 or the time to depressive relapse in SUSTAIN-1. The mean difference in MADRS between the ESK and active-control arms persisted beyond day 2 without significant change over time, despite the fact that the mean peak CADSS scores decreased significantly across consecutive doses and fewer patients experienced significant dissociation after the last ESK dose compared to the first. The dissociative and antidepressant effects of ESK were not substantially associated within the dosage range studied.