The relationship between dissociation and antidepressant effects of esketamine nasal spray in patients with treatment-resistant depression

This posthoc 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.”

Authors: 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

Summary

The relationship between dissociation and antidepressant effects of esketamine nasal spray (ESK) in patients with treatment-resistant depression was assessed. No significant correlation was found between the antidepressant effects of ESK and clinically significant dissociation in short-term trials or long-term maintenance trials.

In this post-hoc analysis, the relationship between dissociation and antidepressant effects of esketamine nasal spray in treatment resistant depression was assessed using data from the positive pivotal phase 3 trials TRANSFORM-2 and SUSTAIN-1. Results: The percentage of responders did not differ significantly between patients who manifested significant dissociation and those who did not following the first ESK dose, and CADSS scores did not significantly mediate the reduction in MADRS or time to depression relapse.

Intravenous infusions of ketamine and esketamine at subanesthetic doses have demonstrated rapid and robust antidepressant effects in patients with treatment-resistant depression. The clinical improvement has been observed to persist fo r several days after a single infusion of ketamine. Esketamine nasal spray (ESK) has been shown to have significant antidepressant effects following short -term treatment (4 weeks) or maintenance treatment in patients with treatment-resistant depression (TRD) and in severely ill patients with major depressive disorder (MDD) and active suicidal ideation with intent.

Ketamine and esketamine have been used to treat patients with TRD. Some studies have found no relationship between ketamine use and depression, while others have found a correlation between ketamine use and depression. In a post-hoc analysis of two phase 3 trials and a long-term maintenance study, the relationship between the antidepressant and dissociative effects of esketamine was examined. The temporal relationships between changes from baseline in the CADSS and MADRS total scores across time were characterized.

This post-hoc analysis used data from three randomized, double-blind, active-controlled, multicenter, phase 3 studies of ESK. Patients were randomized to ESK 56 mg, ESK 84 mg, or placebo nasal spray, administered with a newly initiated, open-label oral AD, for 4 weeks. Then, ESK was reduced to once weekly for 4 weeks, and then to weekly or every 2 weeks based on the severity of depressive symptoms.

Participants were randomly assigned to either continue ESK + AD or switch to placebo nasal spray during the variable duration (randomized relapse event -based) maintenance phase. The presence and severity of dissociative symptoms were assessed using the CADSS. In TRANSFORM-1, the ESK (84 mg) + AD treatment group did not show a statistically significant difference from the AD + placebo group in MADRS total score at day 28.

ESK (flexibly dosed between 56 and 84 mg) + AD significantly improved depressive symptoms in patients with TRD. The post-hoc results from assessments between clinical improvement in depression symptoms and dissociation are presented in the main body of this manuscript. The correlation analysis and mediation analysis were based on the post-dose peak changes in CADSS total and component scores, and on changes from baseline in MADRS total scores.

Data from SUSTAIN-1 was used only for the mediation analysis, and patients who were stable after 16 weeks of treatment were included.

Causal mediation analysis was performed to examine the mediating role of dissociative side effects on antidepressant effects in TRANSFORM-1 and TRANSFORM-2 studies. In the mediation analysis framework, a direct effect is an independent treatment effect on the outcome, while an indirect effect is a treatment effect on the outcome that is accounted for by its effect on the mediator.

Spearman coefficients were computed to assess the relationships between reductions in MADRS total scores and post-dose peak values in the CADSS total and component scores following the first and last nasal spray treatment.

Patients and baseline characteristics of the TRANSFORM-1, TRANSFORM-2 and SUSTAIN-1 studies were similar between patients who achieved stable response or stable remission following 16 weeks of treatment with ESK + AD and entered the maintenance phase.

In the TRANSFORM-2 study, patients who received ESK + AD had an average CADSS score of 4, and 3.8 % had a CADSS score >4 at day 1. After receiving the first ESK dose, 12% of patients manifested an antidepressant response 24 hours after dosing, while 21% of patients manifested an antidepressant response at day 2 with dissociation observed acutely after dosing. At day 28, 70% of patients had achieved antidepressant response without dissociation having been observed after the initial ESK dose.

The correlation between the dissociation (increases in CADSS total scores) after first ESK dose at day 1 and the antidepressant response at day 2 and 28 was nonsignificant, and there was also no correlation between the improvement in depression severity and the individual subcomponent scores. The mediation analysis showed no evidence of a mediation effect of dissociation on the antidepressant efficacy after either the first (day 1) or last (day 25) ESK treatment. However, the direct effect of ESK on the antidepressant effect was significant.

In TRANSFORM-2, patients treated with ESK had a lower peak mean CADSS total score and a higher MADRS total score at day 2 compared to AD + placebo, but the difference between groups did not significantly differ across assessments between day 2 and 28.

The data presented here do not support a correlation between dissociative symptoms and antidepressant effects when using ESK in patients with TRD.

The proportion of treatment responders did not differ significantly between patients who manifested dissociation (CADSS total score >4) and those who did not, and there was no significant correlation between the peak increases in dissociative symptom severity and the improvement in depressive symptoms. Two studies found a significant correlation between antidepressant effects and dissociative symptoms following administration of ketamine in patients with treatment-resistant depression, while two other studies found no association between these ratings.

Three large cohorts of patients with TRD treated with ESK + AD did not show a significant association between dissociation and antidepressant response, which was further supported by outcomes from responder distribution, mediation, and temporal profile analyses. The dissociation induced by the first esketamine nasal spray administration appeared lower in magnitude than that induced by the single IV infusion of ketamine, with only a small number of patients having CADSS scores >25. Different pharmacokinetic profiles and statistical methods may contribute to differences in CADSS scores between studies using esketamine nasal spray versus ketamine IV. The findings regarding the association between dissociation and antidepressant effects should be interpreted within the context of several differences between the studies of IV ketamine and esketamine nasal spray, including the stereochemistry of the compounds, route of administration, dosing frequency, and rating scales used to assess change in depression severity.

MADRS assessments were performed at various timepoints after ESK administration to assess dissociative and antidepressant responses. The mean difference between ESK and active control groups did not significantly change between day 2 and day 28 assessments. The current post hoc analysis and primary phase 3 clinical trials were not designed to address mechanistic questions, but the extant evidence suggests that NMDAR antagonism mediates the antidepressant and dissociative effects of esketamine, as supported by direct and indirect brain imaging measures reflecting NMDAR engagement.

Esketamine appears to inhibit NMDARs and thus mediate antidepressant effects, however, it is unclear whether esketamine and ketamine directly interact with HCN1 at antidepressant doses in humans. The mechanism of dissociation proposed for ketamine and esketamine is different from the mechanism of action proposed for psychedelics such as psilocybin and MDMA (3,4-ethylenedioxymethamphetamine). The results from the current study showed that the dissociative effects are neither necessary for achieving nor correlated with the antidepressant effects. Esketamine nasal spray for TRD produces antidepressant effects but minimal dissociative effects. This means that the presence of dissociative effects is not needed to ensure adequate antidepressant dosing. The transient increase in CADSS scores following the administration of AD + placebo in the control arm of TRANSFORM-2 may reflect the “nocebo” effect, where a patient develops side effects or symptoms that can occur with the active study drug just because the patient expects them to occur.

The CADSS score threshold has not been established for detecting dissociation in patients with posttraumatic stress disorder receiving esketamine nasal spray. Therefore, additional analyses were performed using CADSS cutoffs of 2 and 8, and the results were similar. The placebo effect and the small treatment effect introduced noise into the clinical rating scales, which limited the sensitivity for detecting weak correlations. The correlational analysis of the combined data from TRANSFORM-1 and TRANSFORM-2 corroborated the findings from the individual studies.

This study was funded by Janssen Research & Development, LLC, and the sponsor provided assistance with writing the manuscript. The authors thank the study participants and the investigators for their participation in the study.