The relationship between dissociation and antidepressant effects of esketamine nasal spray in patients with treatment-resistant depression
In post-hoc analyses of two phase 3 trials in treatment-resistant depression, dissociative symptoms after esketamine (peak CADSS scores) were not significantly correlated with or mediators of antidepressant response on the MADRS. Dissociation decreased across repeated doses while the antidepressant benefit persisted, indicating the therapeutic effect is independent of dissociative side-effects.
Authors
- William Drevets
- Robert Lane
- Ella Daly
Published
Abstract
Background
In this post-hoc analysis, data from 2 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 significantly differ between patients who did vs 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 SUSTAIN-1. 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 with the first.
Conclusion
Within the dose range tested, the dissociative and antidepressant effects of ESK were not significantly correlated. Trial registration NCT02417064 (TRANSFORM-1); NCT02418585(TRANSFORM-2); NCT02493868 (SUSTAIN-1)
Research Summary of 'The relationship between dissociation and antidepressant effects of esketamine nasal spray in patients with treatment-resistant depression'
Introduction
Chen and colleagues situate this post-hoc analysis within an ongoing debate about whether the transient dissociative effects produced by N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine are causally linked to their rapid antidepressant effects. Earlier studies of intravenous ketamine in treatment-resistant depression (TRD) have reported mixed findings: some found correlations between dissociation and symptom improvement, while others did not. Esketamine nasal spray (ESK) has demonstrated antidepressant efficacy in several Phase III trials, but comparable analyses examining the relationship between dissociation and antidepressant response for ESK were lacking. The present study therefore aimed to evaluate whether clinically meaningful dissociative symptoms after ESK dosing are associated with, or mediate, antidepressant outcomes. Using data from large Phase III trials of ESK in TRD, the investigators carried out responder, correlation and causal mediation analyses to test relationships between peak Clinician-Administered Dissociative States Scale (CADSS) scores after dosing and changes in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at defined post-dose timepoints. The analysis emphasises results from the short-term flexible-dose trial (TRANSFORM-2) and the randomized withdrawal maintenance trial (SUSTAIN-1), with complementary TRANSFORM-1 data presented in supplemental material, because those trials produced statistically significant primary efficacy results.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Chen, G., Chen, L., Zhang, Y., Li, X., Lane, R., Lim, P., Daly, E. J., Furey, M. L., Fedgchin, M., Popova, V., Singh, J. B., & Drevets, W. C. (2022). The relationship between dissociation and antidepressant effects of esketamine nasal spray in patients with treatment-resistant depression. International Journal of Neuropsychopharmacology, 25(4), 269-279. https://doi.org/10.1093/ijnp/pyab084
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References (7)
Papers cited by this study that are also in Blossom
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
Ionescu, D. F., Qiu, X., Lane, R. et al. · International Journal of Neuropsychopharmacology (2020)
Ionescu, D. F., Bentley, K. H., Eikermann, M. et al. · Journal of Affective Disorders (2019)
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F. et al. · Journal of Affective Disorders (2014)
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Niciu, M. J., Shovestul, B. J., Jaso, B. A. et al. · Journal of Affective Disorders (2018)
Singh, J. B., Fedgchin, M., Daly, E. J. et al. · American Journal of Psychiatry (2016)
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Papers in Blossom that reference this study
Janik, A., Qiu, X., Lane, R. et al. · JAMA Psychiatry (2025)
Pepe, M., Bartolucci, G., Marcelli, I. et al. · Brain Sciences (2023)
Mathai, D. S., Nayak, S., Yaden, D. B. et al. · Psychopharmacology (2023)
Breeksema, J. J., Niemeijer, A. R., Kuin, B. et al. · Frontiers in Psychiatry (2022)
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