The relationship between dissociation and antidepressant effects of esketamine nasal spray in patients with treatment-resistant depression
Chen, G., Chen, L., Daly, E. J., Drevets, W. C., Fedgchin, M., Furey, M., Lane, R., Li, X., Lim, P., Popova, V., Singh, J. B., Zhang, Y.
This post hoc analysis further analyzes the results of the TRANSFORM studies using esketamine for patients with treatment-resistant depression. In TRANSFORM-2 the percentage of responders (>50% reduction in MADRS) at day-2 and day-28 did not differ significantly between patients who did versus did not manifest significant dissociation. The mean peak dissociation (CADSS) scores significantly decreased across consecutive doses and fewer patients experienced significant dissociation after the last esketamine dose compared to the first.
Abstract
Background: In this post-hoc analysis, data from the positive pivotal phase 3 trials of esketamine nasal spray (ESK) in treatment resistant depression (TRD): short-term study (TRANSFORM-2) and maintenance study (SUSTAIN-1) were analyzed to evaluate the relationship between dissociation and antidepressant effects of ESK.Methods: Analysis by responder status, correlation analysis and mediation analysis were performed to assess the relationships between peak Clinician-Administered Dissociative States Scale (CADSS) scores after first (day-1) and last (day-25) ESK dose and change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at the first (day-2) and last assessments (day-28) in TRANSFORM-2 and peak CADSS after first maintenance ESK dose and time to relapse in SUSTAIN-1 (only for mediation analysis).Results: In TRANSFORM-2 the percentage of responders (>50% reduction in MADRS) at day-2 and day-28 did not differ significantly between patients who did versus did not manifest significant dissociation (peak CADSS scores >4 or ≤4, respectively) following the first ESK dose. Spearman correlation coefficients between dissociation and depression improvement were nonsignificant and close to zero. CADSS scores did not significantly mediate the reduction in MADRS at day-2 or 28 in TRANSFORM-2 or the time to depression relapse in SUSTAIN1. The mean difference in MADRS between ESK and active-control arms persisted beyond day-2 without significant change across time, although the mean peak CADSS scores significantly decreased across consecutive doses and fewer patients experienced significant dissociation after the last ESK dose compared to the first.Conclusion: Within the dose range tested, the dissociative and antidepressant effects of ESK were not significantly correlated.