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, Ella J Daly, Maura L Furey, Maggie Fedgchin, Vanina Popova, Jaskaran B Singh, Wayne C Drevets, Guang Chen, Li Chen, Yun Zhang, Xiang Li, Rosanne Lane, Pilar Lim, Ella J Daly, Maura L Furey, Maggie Fedgchin, Vanina Popova, Jaskaran B Singh, Wayne C Drevets

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).

Keywords: Antidepressant; dissociation; esketamine; treatment-resistant depression.

© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Distribution of participants by dissociative response (assessed by Clinician-Administered Dissociative States Scale [CADSS] score obtained 40 minutes post esketamine administration) and the corresponding antidepressant effect (assessed by change from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) in TRANSFORM-2. (A–C) Changes in CADSS total scores 40 minutes post esketamine nasal spray (ESK) and corresponding reductions in MADRS total score for each participant (depicted by “O” symbol) for the following correlations: (A) CADSS after first ESK (day 1) and MADRS at day 2: CADSS increase after first ESK treatment session and MADRS change assessed 24 hours later (day 2), n = 109; (B) CADSS after first ESK (day 1) and MADRS at day 28: CADSS after first ESK session and MADRS change at the end of the double blind treatment period (day 28), n = 101; (C) CADSS after last ESK (day 25) and MADRS at day 28: CADSS assessed after last ESK session (day 25) and MADRS change at day 28, n = 101; (D) CADSS scores ≤4 or >4 and antidepressant responders and non-responders: percentage of treatment responders (defined by ≥50% improvement in MADRS total score) and non-responders among patients with CADSS total scores ≤4 vs patients with CADSS total scores >4 for study days indicated on each graph. Shaded areas in graphs A–C correspond to patients who had a response (MADRS) without significant dissociation (CADSS). * Nominal P values (chi-squared test) for proportion of responder patients with and without dissociation. CI, confidence interval; r, Spearman correlation coefficient.
Figure 2.
Figure 2.
Temporal profiles of dissociation symptoms and antidepressant effects in the TRANSFORM-2 study cohort. (A) Dissociation symptoms assessed using the Clinician-Administered Dissociative States Scale (CADSS) total score over repeated dosing. Data are mean ± SE. Significant effects of day (P < .0001), treatment type (P < .0001), and day × treatment type (P < .0001) were detected. (B) Mean changes in depression severity from baseline assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) over repeated dosing. Significant effects of day (P < .0001) and treatment type (P = .0049), but not day × treatment type (P = .5341) were detected. Data are least squares (LS) mean ± SE. MADRS. AD, antidepressant; ESK, esketamine nasal spray; H, hour; M, minute; SE, standard error.

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