Relationship Between Dissociation and Antidepressant Effects of Esketamine Nasal Spray in Patients With Treatment-Resistant Depression
Guang Chen, Li Chen, Yun Zhang, Xiang Li, Rosanne Lane, Pilar Lim, E. Daly, M. Furey, Maggie Fedgchin, Vanina Popova, Jaskaran Singh, Wayne C. Drevets
The International Journal of Neuropsychopharmacology January 12, 2022 DOI: 10.1093/ijnp/pyab084 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Post-hoc analysis of two phase 3 randomized controlled trials Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant depression enrolled in the TRANSFORM-2 and SUSTAIN-1 trials |
| Intervention | Esketamine nasal spray |
| Measures | Clinician Administered Dissociative States Scale (CADSS), Montgomery-Åsberg Depression Rating Scale (MADRS) |
| Topics | Depression Esketamine |
| Registration | NCT02417064 NCT02418585 NCT02493868 |
| Key findings | Within the dose range tested, dissociative and antidepressant effects of esketamine nasal spray were not significantly correlated. Responder rates at days 2 and 28 did not differ significantly between patients with and without significant dissociation after the first dose, correlations were near zero and nonsignificant, and CADSS scores did not significantly mediate MADRS reduction or relapse time. Peak dissociation decreased across repeated doses while the esketamine-versus-active-control MADRS difference persisted beyond day 2. |
Abstract
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)
Comparable studies
Other randomized controlled trials on esketamine for depression, most cited first.
Citations in the library
Cited by 49
- Long-term safety of ketamine and esketamine in treatment of depression Expert Opinion on Drug Safety April 13, 2022
- Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. American Journal of Psychiatry March 1, 2025
- Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial. BMJ April 10, 2024
- Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics? European Archives of Psychiatry and Clinical Neuroscience February 27, 2024
- Toward Synergies of Ketamine and Psychotherapy Frontiers in Psychology March 25, 2022
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and 20 more in the library