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.
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)
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.
This is a post-hoc analysis of three randomized, double-blind, active-controlled, multicentre Phase III trials of esketamine nasal spray: TRANSFORM-1 (fixed-dose, n=346), TRANSFORM-2 (flexible-dose, n=227) and SUSTAIN-1 (maintenance, n=297 for randomized maintenance phase). In TRANSFORM-1 and TRANSFORM-2 patients received adjunctive oral antidepressant (AD) therapy plus either ESK (56 mg or 84 mg, fixed or flexible) or placebo nasal spray, administered twice weekly during a 4-week double-blind induction phase. SUSTAIN-1 enrolled patients who had achieved stable response or remission on ESK + AD during an optimization phase and randomised them to continue ESK + AD or switch to placebo nasal spray in a variable-duration, relapse-prevention maintenance phase; dosing frequency in SUSTAIN-1 was individualised (weekly or every other week) based on MADRS scores. Depressive symptoms were measured using the MADRS total score; dissociative symptoms were measured with the CADSS total and component scores recorded pre-dose, 40 minutes post-dose (Tmax), and 1.5 hours post-dose on treatment days. A CADSS total score >4 was predefined as indicating clinically meaningful dissociation (based on prior healthy participant ranges); additional sensitivity analyses used cutoffs of ≤2 and ≤8. Primary analyses reported here focus on TRANSFORM-2 and SUSTAIN-1, with TRANSFORM-1 outcomes in supplementary material because TRANSFORM-1's primary efficacy comparison was not statistically significant for one dosage arm. Statistical approaches included responder analyses (≥50% reduction in MADRS), Spearman correlation coefficients (with 95% CIs) between peak post-dose CADSS and MADRS change at specified timepoints, and causal mediation analysis to partition direct and indirect (mediated via CADSS) treatment effects. The mediation framework used ANCOVA models adjusting for region/country, class of oral AD (SNRI vs SSRI) and baseline MADRS; indirect and direct effects were estimated using parametric bootstrapping via the R "mediation" package. For SUSTAIN-1 an approach following Lange et al. was used (R package "timereg") to assess whether CADSS change on the first maintenance day mediated time to relapse. Temporal profiles of CADSS and MADRS over repeated dosing were estimated using mixed models for repeated measures (MMRM). The investigators note these are post-hoc analyses and specify covariates included in models.
Responder analyses in TRANSFORM-2 showed no significant differences in antidepressant response rates between patients who did versus did not exhibit clinically meaningful dissociation (CADSS >4) after the first or last ESK doses. At day 2, 12% of patients with CADSS ≤4 and 21% with CADSS >4 showed a ≥50% MADRS reduction (p=0.182). By day 28, responder rates were 70% (CADSS ≤4) versus 69% (CADSS >4) after the initial dose (p=0.854). Considering dissociation after the final ESK dose (day 25), 68% (CADSS ≤4) versus 71% (CADSS >4) were responders at day 28 (p=0.721). Similar distributions were reported for TRANSFORM-1 in supplementary analyses. Correlation analyses produced Spearman coefficients close to zero and statistically nonsignificant. In TRANSFORM-2, correlations between CADSS after the first ESK dose and MADRS change were r = -0.05 (95% CI: -0.23, 0.14) at day 2 and r = -0.08 (95% CI: -0.27, 0.12) at day 28. The correlation between CADSS after the last dose (day 25) and MADRS at day 28 was r = -0.16 (95% CI: -0.36, 0.04). Analyses of CADSS components, including depersonalisation, likewise showed no significant correlations. Causal mediation analyses found insufficient evidence that dissociation mediated antidepressant effects. In TRANSFORM-2 the indirect (mediated) effects had 95% CIs that included zero, whereas the direct effect of ESK on MADRS change—independent of CADSS—was statistically significant: LS mean differences were -3.62 (95% CI: -6.62, -0.74) after the first dose and -4.83 (95% CI: -8.37, -1.28) after the last dose. SUSTAIN-1 mediation analysis similarly showed no mediation of time to relapse by CADSS change (indirect effect estimate 0.12, CI including zero), while the direct effect of continued ESK on delaying relapse was significant (LS mean difference -2.44; 95% CI: -4.04, -0.84). Temporal analyses demonstrated that peak CADSS scores declined across consecutive ESK doses (main effect of study day and day × treatment interaction p<0.0001), whereas the antidepressant advantage of ESK + AD over AD + placebo on MADRS persisted through the 4-week induction phase. The treatment difference in MADRS did not change significantly between day 2 and day 28 (interaction p=0.5341). Average CADSS scores were generally <4; in TRANSFORM-2 only 3.8% of patients had CADSS >4 at day 1 and 4.2% at day 25. The authors additionally report that CADSS magnitudes after ESK nasal spray were substantially lower than those typically reported after a single IV ketamine infusion (median CADSS ~6–8 vs ~25), and sensitivity analyses using alternative CADSS thresholds (≤2 and ≤8) produced the same null association.
Chen and colleagues interpret the convergent findings from responder, correlation, mediation and temporal analyses as evidence that dissociative symptoms elicited by esketamine nasal spray are neither necessary for, nor predictive of, antidepressant benefit in patients with TRD within the dose range studied. They contrast these results with prior mixed findings from IV ketamine studies, noting that some earlier reports identified correlations between CADSS subscales and later antidepressant response whereas others did not. The authors highlight several factors that may explain differences between studies of IV ketamine and ESK nasal spray: stereochemical differences, route and formulation (IV versus nasal), dosing frequency (single infusion versus twice-weekly dosing), concomitant oral antidepressants in the ESK trials, timing of clinical assessments, and differences in the magnitude and variance of CADSS scores that affect statistical sensitivity. They note that CADSS peak magnitudes after intranasal ESK were much lower on average than those reported after standard IV ketamine, which could reduce the power to detect an association. The discussion also summarises mechanistic considerations: while NMDAR antagonism is implicated in both dissociative and antidepressant effects, distinct downstream mechanisms may separate the two phenomena; a recent preclinical hypothesis implicating HCN1 in dissociation is mentioned but not resolved. Limitations acknowledged by the authors include the post-hoc nature of the analyses, timing of assessments that precluded examining some temporal relationships (for example an isolated association between dissociation after a single dose and antidepressant response several days later without intervening doses), potential noise from placebo/nocebo effects and small treatment effect sizes, and limited sensitivity to detect weak correlations in individual study samples. They note that combined analyses across studies were conducted to mitigate sample size limitations and that sensitivity analyses using different CADSS cutoffs and subcomponents corroborated the null findings. Clinically, the investigators suggest dose selection for ESK should prioritise antidepressant efficacy and tolerability rather than attempting to induce dissociative symptoms, since dissociation was neither necessary nor sufficient for response. Finally, they call for additional research to clarify the potentially distinct mechanisms by which NMDAR antagonism produces antidepressant and dissociative effects.
There is disagreement in the literature regarding whether a significant association exists between antidepressant and dissociative effects produced by intravenous ketamine in patients with treatment-resistant depression (TRD). Some studies reported that dissociative effects are linked to the antidepressant efficacy, while others found no evidence for such an association. Using data from phase 3 studies of esketamine nasal spray (ESK) in TRD, we assessed the relationship between antidepressant and dissociative effects. Our findings indicate no significant correlation between the antidepressant efficacy of ESK and either the presence or severity of clinically significant dissociation in short-term (4-week) trials. In a long-term maintenance study followed by randomized withdrawal, the time to depressive relapse was not mediated by dissociation. Furthermore, the peak increase in dissociation diminished over time without any corresponding attenuation of antidepressant response. In conclusion, we did not find any significant correlation between the antidepressant effects and dissociative adverse effects induced by ESK.. The clinical improvement in patients with TRD has been observed to persist for several days after a single infusion of ketamine. Among the clinical trials evaluating efficacy and safety of esketamine, Singh et al. demonstrated that the antidepressant effect size of esketamine administered at 0.2 mg/kg IV was similar to that of ketamine racemate administered at 0.5 mg/kg IV in patients with TRD, consistent with the 2 to 2.5 fold greater potency of esketamine, as compared to ketamine, for N-methyl-D-aspartate receptor (NMDAR) binding.improvement in depressive symptoms following 1-week of treatment with esketamine nasal spray (ESK) administered adjunctively to an oral antidepressant (AD) in patients with TRD. Subsequently multiple phase 3 studies have shown meaningful antidepressant effects of ESK following short-term treatment (4 weeks) or maintenance treatment in patients with TRDand in severely ill patients with major depressive disorder (MDD) and active suicidal ideation with intent. The efficacy of ESK in delaying relapse and its long-term safety and tolerability in TRD have also been demonstrated in two phase 3 studies. The US Food and Drug Administration (FDA) approved ESK nasal spray (SPRAVATO ® ), in conjunction with an oral AD for the treatment of TRD in 2019, with EU approval following in 2020. In July 2020, the US FDA also approved SPRAVATO ® in conjunction with an oral AD for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behaviorwith EU approval for rapid reductions in depressive symptoms in a Downloaded fromby 11400 Instituto Politécnico de Portalegre user on 14 January 2022 Both antidepressant and dissociative effects have been observed in the clinical dose range of ketamine and esketamine used in previous studies of TRD. In studies using racemic ketamine (0.5 mg/kg IV) in patients with TRD, findings have been inconsistent regarding whether changes in depression severity correlate with changes in dissociation severity and if the dissociation is causally required for the subsequent antidepressant effects. While two studies found no relationship between these clinical variables, two others reported a significant correlation between the increases in the depersonalization subdomain and overall dissociation measures of the Clinician-Administered Dissociative States Scale (CADSS)and the improvement in depressive symptoms after a single ketamine infusion. Given the inconsistency in the findings reported in the literatureand the lack of similar published data for esketamine, the current study examined whether the antidepressant response to ESK treatment is correlated with and/or mediated by dissociative effects. We evaluated the relationship between the antidepressant and dissociative effects of ESK in a post-hoc analysis of two phase 3 trials conducted to assess the short-term efficacy of ESK, as well as in a post hoc analysis of a long-term maintenance study that evaluated the efficacy of ESK in sustaining the antidepressant effects in patients with TRD using a randomized withdrawal design. The relationships between changes in CADSS total score and changes in depression severity based on the Montgomery-Åsberg Depression Rating Scale (MADRS) total scorewere assessed using correlation analysis, mediation analysis, and analysis by responder status. In addition, the temporal relationships between changes from baseline in the CADSS and MADRS total scores across time were characterized. Notably, of studies that have examined this relationship to date, the sample studied herein was substantially larger in size than the samples assessed in previous studies.
This post-hoc analysis used data from three randomized, double-blind (DB), activecontrolled, multicenter, phase 3 studies of ESK: TRANSFORM-1 (short-term, fixed-dose study; NCT02417064), TRANSFORM-2 (short-term, flexible-dose study; NCT02418585), and SUSTAIN-1 (long-term, maintenance study; NCT02493868). Details of the study design and eligibility criteria of these three studies were reported elsewhere. Briefly, eligible patients (n=346) in the TRANSFORM-1 study were randomized to a fixed-dose regimen of either 56 mg ESK, 84 mg ESK, or placebo nasal spray, administered with a newly initiated, open-label oral AD (abbreviated ESK [84 mg] + AD, ESK [56 mg] + AD, AD + placebo). In the TRANSFORM-2 study, patients (n=227) were randomized to either a flexible-dose regimen of ESK (56 or 84 mg) + AD or AD + placebo. In both studies, ESK or placebo nasal spray was administered twice a week during the 4-week DB induction phase. In SUSTAIN-1, direct entry patients or stable response (≥50% reduction in the MADRS total score from baseline in each of the last 2 weeks prior to randomization, but without achieving remission) at the end of the optimization phase (n=297) were randomly assigned 1:1 to either continue ESK + AD or switch to placebo nasal spray while continuing the same AD + placebo nasal spray during the variable duration (randomized relapse event-based) maintenance phase. Dosing of the nasal spray medication during the maintenance phase was individualized to weekly or every other week using a MADRS-based algorithm. Changes in depression severity were assessed by the change in MADRS total score from baseline over time during the DB treatment induction phase of the TRANSFORM-1 and TRANSFORM-2 studies and throughout the SUSTAIN-1 study. The presence and severity of dissociative symptoms were assessed using the CADSS. The total and component scores were recorded on each ESK treatment day at predose, 40 min post-dose, and 1.5 hours post-dose during the DB treatment phase of the TRANSFORM-1 and TRANSFORM-2 studies, and during all treatment administration visits of SUSTAIN-1. A CADSS total score >4 was used as the threshold for indicating the presence of clinically meaningful dissociative symptoms based on a previous reported range of CADSS scores in heathy participants. In TRANSFORM-1, the difference between the ESK (84 mg) + AD and AD + placebo treatment groups was not statistically significant for the change from baseline in MADRS total score at day 28. Therefore, in accordance with the predefined testing sequence, the ESK (56 mg) + AD treatment group could not be formally evaluated. Notably, the median unbiased estimate (95% confidence interval [CI]) of the treatment difference between the ESK [56 mg] + AD group and the AD + placebo group) was comparable to the estimated treatment differences in the other phase 3 studies. In TRANSFORM-2, treatment with ESK A c c e p t e d M a n u s c r i p t 9 (flexibly dosed between 56 and 84 mg) + AD significantly improved depressive symptoms in patients with TRD. Since the primary efficacy analysis was significant for both the TRANSFORM-2 study (least squares [LS] mean difference [95% CI]: -4.0; p=0.020) and SUSTAIN-1 study (significant delay in relapse among patients achieving stable remission with ESK: hazard ratio [HR], 0.49; 95% CI, 0.29-0.84; p=0.003 and stable response: HR, 0.30; 95% CI, 0.16-0.55; p <0.001), the post-hoc results from assessments between clinical improvement in depression symptoms and dissociation for these two studies are presented in the main body of this manuscript, and the corresponding results for the TRANSFORM-1 study are presented in the online Supplement. The protocols and their respective amendments for all three studies were reviewed by an independent ethics committee or institutional review board at each site. The studies were conducted in accordance with the Declaration of Helsinki, Good Clinical Practices, and applicable regulatory requirements. Written informed consent was obtained from all patients before participating in the study.
The analyses presented herein are considered post-hoc. The correlation analysis for TRANSFORM-1 and TRANSFORM-2 studies was based on the post-dose peak changes in CADSS total and component scores, while the mediation analysis used post-dose changes in CADSS total scores on the first (day 1) and last (day 25) day of nasal spray treatment and changes from baseline in MADRS total scores at day 2 (the day after the first nasal spray treatment) and day 28 (the day of last MADRS assessment of the induction phase). Data from SUSTAIN-1 was used only for the mediation analysis based on post-dose changes in CADSS total score on the first day of the DB maintenance phase and time to relapse in A c c e p t e d M a n u s c r i p t 10 those patients who were stable remitters after an initial 16-weeks of treatment with ESK + AD and had proceeded to the randomized withdrawal/maintenance phase.
Causal mediation analysis using a simulation-based approach was performed to examine the mediating role of dissociative side effects on antidepressant effectsin TRANSFORM-1 and TRANSFORM-2 studies. An analysis of covariance (ANCOVA) model was used to assess changes from predose in CADSS total scores at 40 min post-dose (mediator), with treatment, region (for TRANSFORM-1) or country (for TRANSFORM-2), class of oral antidepressant (serotonin and norepinephrine reuptake inhibitors [SNRI] or selective serotonin reuptake inhibitors [SSRI]) as factors and the baseline MADRS total score as a covariate. The ANCOVA model for changes in MADRS total score from baseline (outcome) included the same factors and covariates in addition to the mediator. In the mediation analysis framework, a direct effect is considered as an independent treatment effect on the outcome that is above and beyond its effect on the mediator; while an indirect effect is considered as a treatment effect on the outcome that is accounted for by its effect on the mediator. The direct and indirect effects were estimated by parametric bootstrapping via Rpackage "mediation". The proportion of mediated effects is calculated as the ratio of the indirect effect to the sum of the direct and indirect effects. Causal mediation analysis based on the approach of Lange et al.was also performed for the SUSTAIN-1 data. The mediator was change from predose in CADSS total score at 40 min post-dose on day 1 of maintenance treatment, and the outcome was the time to relapse. The direct and indirect effects were estimated via R-package "timereg".
Spearman coefficients along with 95% CIs 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. Scatter plots were used for graphical representation.
Changes from baseline in MADRS total scores over time expressed using the LS means (±SE) based on the mixed model for repeated measures (MMRM) were graphed (details of the MMRM have been described previously). The peak CADSS scores across time were analyzed in a similar model, and the arithmetic mean (±SE) CADSS score over time was plotted.
Demographic and baseline characteristics and clinical outcomes of the TRANSFORM-1, TRANSFORM-2 and SUSTAIN-1 studies have been described previously. In general, the demographic or baseline clinical characteristics were balanced between the ESK + AD and AD + placebo groups in the two short-term studies (Supplementary Table). In SUSTAIN-1, a total of 297 patients with mean (SD) age of) years and the majority being women (197 [66.3%]) were randomized in the maintenance phase. The demographics and baseline characteristics were generally comparable between patients who achieved stable response versus stable remission following 16 weeks of treatment with ESK +AD and entered the maintenance phase (Supplementary Table).
Supplementary Tableshows mean baseline and peak CADSS total scores in ESK + AD and AD + placebo groups in the TRANSFORM-2 study. In both treatment groups, increases in CADSS score peaked at the 40 min timepoint (Tableand review of patients" data at individual level). The CADSS scores on average were <4 (Table). Moreover, the percentage of patients with CADSS score >4 was 3.8 % (4/104) at day 1 and 4.2 % (4/95) at day 25.
In TRANSFORM-2, after receiving the first ESK dose, 12% of patients manifested an antidepressant response 24 hours after dosing (day 2) without having experienced dissociation (CADSS total score ≤4) acutely after dosing, while 21% of patients showed antidepressant response at day 2 with dissociation observed acutely after dosing (CADSS total score >4) (p=0.182) (Figureand). At day 28 (end of the DB period), 70% of patients had achieved antidepressant response without dissociation having been observed after the initial ESK dose, while 69% showed antidepressant response along with dissociation following the initial ESK dose (p=0.854) (Figureand). Similarly, after the last ESK dose administration (day 25), 68% of patients showed antidepressant response at day 28 without dissociation observed after the final ESK dose (which occurred at day 25), while 71% of patients showed antidepressant response at day 28 with dissociation occurring after the final ESK dose at day 25 (p=0.721) at the end of the DB period (day 28) (Figureand). Thus, the responder rates in the CADSS score ≤4 and >4 groups did not differ significantly at any of the time-points tested. Similar results were observed for the TRANSFORM-1 study (Supplementary Figure).
In TRANSFORM-2, the correlation analysis of the relationship between dissociation (increases in CADSS total scores) after first ESK dose at day 1 and the antidepressant response (i.e., reductions in MADRS total scores) at day 2 (r = -0.05 [95% CI: -0.23, 0.14]) and day 28 (r = -0.08 [95% CI: -0.27, 0.12]) showed nonsignificant Spearman correlation coefficients (based on 95% CIs containing 0) which were close to zero (Table). Similarly, no significant correlation was identified between the CADSS total scores following the last ESK dose at day 25 and the depression response at day 28 (r = -0.16 [95% CI: -0.36, 0.04]). A lack of significant correlation was also observed for the corresponding analyses in the TRANSFORM-1 data (Supplementary Table). Finally, no significant correlation was observed between the improvement in depression severity and the individual subcomponent scores of the CADSS considered separately in the TRANSFORM-2 data (Table) and the TRANSFORM-1 data (Supplementary Table).
In TRANSFORM-2, the mediation analysis showed insufficient evidence of a mediation effect of dissociation on the antidepressant efficacy after either the first (day 1) ESK treatment or the last (day 25) ESK treatment (based on 95% CIs containing 0) (Table). In contrast, the direct effect of ESK on the antidepressant effect was significant: the LS mean difference (95% CI) between treatment groups for the change in MADRS total score that was independent of dissociation effect was -3.62 (-6.62, -0.74) and -4.83 (-8.37, -1.28) after initiation of the first and last ESK dose, respectively. Similar results were observed in the TRANSFORM-1 study at day 2 (Supplementary Table). The mediation analysis was not performed at the day 28 timepoint for the TRANSFORM-1 study, however, due to lack of significant difference of antidepressant responses between ESK (84 mg) + AD and AD + placebo groups, as described above. Likewise, the mediation analysis of SUSTAIN-1 results also showed a lack of a mediation effect of dissociation on the time to relapse after the first ESK dosing in the maintenance phase (LS mean difference [95% CI]: 0.12), while the direct effect of ESK was significant (LS mean difference [95% CI]: -2.44 [-4.04; -0.84]) (Table).
In TRANSFORM-2, the peak mean CADSS total score in patients treated with ESK decreased over time with consecutive doses; the main effect of study day and the interaction of day x treatment type were significant (p<0.0001; Figure). The results for changes in MADRS total scores (LS mean [95% CI] treatment difference) from baseline favored ESK + AD over AD + placebo at day 2 (-3.3 [-5.75; -0.85]), day 8 (-2.9 [-5.17; -0.59]), day 15 (-2.0 [-4.78; 0.82]), day 22 (-3.8 [-6.87; -0.65]), and day 28 (-4.0 [-7.31; -0.64]); the 95% CI did not contain 0 at any time point except for day 15. For both treatment groups, over a third of the improvement from baseline occurred at day 2 (24 hours) and both groups continued to improve to the end of the DB induction phase (day 28) (Figure). However, the mean difference between groups did not significantly differ across assessments between day 2 and 28 (p=0.5341 for the interaction of day x treatment type (Figure). Observations from TRANSFORM-1 were similar, favoring the ESK + AD group (Supplementary Figure).
The data presented herein do not support a correlation between dissociative symptoms and antidepressant effects when using ESK (56 or 84 mg) in conjunction with a newly Of the previous studies that evaluated the relationship between antidepressant effects and dissociative symptoms following administration of ketamine (0.5 mg/kg IV) in patients with TRD, two (from the same research group) reported a significant correlation between the ketamine-induced dissociative symptoms and the antidepressant effect size, while two others found no association between these ratings. Following a single ketamine infusion,
Rating Scale (HAM-D) scores (at 230 min and 7 days post dose) and dissociative symptom ratings at 40 min on CADSS total and depersonalization scores. A second study from the same research group (patient sample overlapping with Luckenbaugh et al. study) also reported that the changes in CADSS scores obtained at 40 min after a single dose of ketamine infusion significantly correlated with improvements in HAM-D scores assessed at both 230 min post-dose (p=0.007) and at day 7 (p=0.01) in 126 patients with treatment-resistant MDD or bipolar disorder. Contradicting these findings, however, two earlier reports (n=24; n=10detected no significant association between ketamineinduced dissociative symptoms and antidepressant effects. The current findings in three large cohorts of patients with TRD treated with ESK + AD in a short-term (TRANSFORM-2)and a long-term maintenance (SUSTAIN-1)study did not show a significant association between dissociation and antidepressant response; these findings were further corroborated by observations from another short-term study in patients with TRD (TRANSFORM-1). The lack of association between ESK-induced dissociation and antidepressant response from the correlation analyses was supported by outcomes from the responder distribution, mediation, and temporal profile analyses. These convergent data showed no association between dissociative and antidepressant effects that manifested while using ESK in patients with TRD, which is in contrast to some, but not other, reports that conducted correlation analyses of similar data obtained following ketamine IV treatmentdiscussed above. Notably, the dissociation induced by the first ESK administration appeared lower in magnitude (based on CADSS scores) than that reported following the single IV infusion of ketamine, with the highest CADSS scores on average ranging from 6 to 8 for initial esketamine nasal spray administrations (Figure, Supplementary Figure) compared to about 25 after initial administration of ketamine 0.5 mg IV infused over 40 min. Furthermore, only a small number of patients had CADSS score >25 in the TRANSFORM-2 and TRANSFORM-1 cohorts (Figureand Supplementary Figure). These findings appear consistent with findings from a study comparing putatively A c c e p t e d M a n u s c r i p t 17 equipotent (for NMDAR antagonism) doses of IV esketamine (0.25 mg/kg) and IV ketamine (0.5 mg/kg), in which patients with TRD in the esketamine group had numerically lower median CADSS scores as compared to those in the ketamine group. Differences in the pharmacokinetic profiles obtained using differing formulation types or routes of administration (IV vs nasal spray) may contribute to the differential CADSS scores observed. Moreover, differences in the magnitude and variance of the CADSS conceivably may influence the statistical sensitivity for detecting a relationship between antidepressant and dissociative effects in studies using esketamine nasal spray versus ketamine IV. Cumulatively, the findings regarding the association between dissociation and antidepressant effects should be interpreted within the context of several differences that are noted between the studies of IV ketamine and esketamine nasal spray, including the stereochemistry of the compounds, route of administration, dosing frequency, presence of adjunctive antidepressant treatments, and rating scales used to assess change in depression severity. Furthermore, differences existed in the timing of the clinical assessments between the present analysis and those reported in the Luckenbaugh and Niciu studies. Of note, in the single administration, ketamine IV study, dissociation observed immediately after the ketamine administration was found to be significantly associated with antidepressant response at day 7 after the infusion. In TRANSFORM-1 and TRANSFORM-2 studies, patients received ESK dosing twice a week for 4 weeks, with MADRS ratings conducted at day 2 and thereafter on a weekly basis post baseline. Given this design difference, it was not possible to assess the association between dissociation response immediately after the first ESK dosing only and the antidepressant response 6-7 days later in the absence of intervening esketamine doses. In our analysis, we instead sought to evaluate the association between post-dose changes in CADSS total and component scores immediately after first and last dosing and MADRS total Downloaded fromby 11400 Instituto Politécnico de Portalegre user on 14 January 2022 A c c e p t e d M a n u s c r i p t 18 scores at day 2 (the day after the first nasal spray treatment) and day 28 (the day of last MADRS assessment of the induction phase). We selected these timepoints based on the distinct temporal courses of dissociative and antidepressant responses over repeated dosing. As shown in Figure, the magnitude of the CADSS ratings was highest at T max for ESK (about 40 min) but the peak CADSS score declined across sessions. CADSS scores after first dosing thus generally captured the initial and on average most robust dissociation responses; while CADSS score after last dosing reflected an attenuation of the dissociation responses. In contrast, the MADRS score reductions at day 2 (24 hours after the initial ESK administration) and day 28 measured the initial and on average greatest antidepressant responses, respectively, although the mean difference between the ESK and active control groups did not significantly change between the day 2 and day 28 assessments. Neither the current post hoc analysis nor the primary phase 3 clinical trials were designed to address mechanistic questions and therefore the present findings have limited interpretation regarding target engagement. However, the extant evidence suggests both the antidepressant and dissociative effects of ESK are mediated via NMDAR antagonism, as supported by directbrain imaging measures reflecting NMDAR engagement. Also consistent with the conclusion that NMDAR antagonism mediates the antidepressant effects of ketamine and esketamine, the antidepressant dose ratio of esketamine versus ketamine approximates their equipotent ratio for NMDAR antagonism based on Ki values (~1:2). For example, the magnitude of antidepressant effect of 0.2 mg/kg esketamine IVis comparable to that of 0.5 mg/kg of ketamine IV, and a randomized trial that directly compared the antidepressant efficacy of 0.25 mg/kg of esketamine IV versus 0.5 mg/kg of ketamine IV showed non-inferiority, as well as comparable antidepressant and adverse effects between study arms (Correia-Melo et al., ). Finally, the involvement of NMDARs in producing antidepressant and dissociative effects was corroborated by evidence that traxoprodil (CP-101606), a NR2B selective NMDAR antagonist, produced antidepressant and (dose-dependentsee below) dissociative effects in patients with TRD that appeared similar to those reported in studies using ketamine or esketamine. Therefore, the extant data support the hypothesis that NMDAR antagonism mediates the antidepressant effects of esketamine. Nevertheless, a recent preclinical study hypothesized that the hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) mediates the dissociative effects of ketamine. The reported affinity of ketamine and esketamine for HCN1 is several folds lower than their affinities for NMDAR, and it remains unclear whether ketamine and esketamine directly interact with HCN1 at their 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), which are under evaluation for possible efficacy in psychiatric disorders including depression. For esketamine, the results from the current study showed that the dissociative effects are neither necessary for achieving nor correlated with the antidepressant effects. A crucial clinical implication of our data is that dose selection and titration during esketamine treatment should focus on the antidepressant response and the balance between efficacy and tolerability. In contrast, dose selection should not focus on producing dissociative symptoms to ensure that an adequate therapeutic has been administered. As illustrated in Figureand Supplementary Figure, some patients developed dissociation without adequate antidepressant response, while others achieved robust antidepressant responses without evidence of dissociation. Moreover, the association between dissociative and antidepressant effects changed during repeated dosing, as the severity and frequency of Downloaded fromby 11400 Instituto Politécnico de Portalegre user on 14 January 2022 A c c e p t e d M a n u s c r i p t 20 dissociation diminished while the antidepressant effect persisted across the 4-week doubleblind period. In addition, studies assessing the relationships between antidepressant and dissociative effects at different esketamine doses (0.2 and 0.4 mg/kg IV) showed comparable antidepressant effects at both doses while the severity of dissociation increased at the higher dose. Similarly, traxoprodil, also showed at least partial separation between the antidepressant and dissociative effects at distinct dose levels. Of the two doses tested (0.75 mg/kg per hour for 1.5 hours followed by 0.15 mg/kg per hour for 6.4 hours, versus 0.5 mg/kg per hour for 1.5 hour), the higher dose produced prominent dissociative effects, prompting the switch to the lower dose, which produced antidepressant effects but minimal dissociative effect. Taken together, these data imply that the presence of dissociative effects is not needed to ensure the adequacy of antidepressant dosing in individual patients receiving esketamine nasal spray for TRD. The transient increases in CADSS scores following the administration of AD + placebo in the control arm of TRANSFORM-2 merit contextualization with literature from other areas of medicine indicating that the adverse events listed in Informed Consent Documents influenced the types of adverse events reported by study participants randomized to the placebo arm of double-blind clinical trials. In the AD + placebo group of TRANSFORM-2 about 4% of patients were rated as having CADSS scores >4. Transient dissociative side effects also were reported by some participants who received placebo in a ketamine IV study in patients with TRD. The dissociative effects reported in some participants who received placebo + AD in esketamine studies may reflect the "nocebo" effect (i.e., in which a patient who receives placebo develops side effects or symptoms that can occur with the active study drug just because the patient expects them to occur). The nocebo phenomenon had been well-characterized in studies performed across many areas of medicine. Some. Currently, the optimal CADSS score threshold has not been established for detecting the presence or absence of dissociation in a population of patients with TRD receiving esketamine nasal spray. Therefore, to investigate the impact of using different CADSS thresholds, additional analyses were performed using CADSS cutoffs of ≤ 2 and ≤ 8 (Supplementary Figure). Both cutoffs showed similar results as with the ≤4 threshold, supporting the absence of an association between the antidepressant response and dissociation, irrespective of the threshold applied for identifying dissociation. Furthermore, other analyses (e.g., correlation, mediation, and temporal analyses) that were independent of the CADSS cutoff also demonstrated no significant association between antidepressant and dissociative effects. Notably, these negative results also extended to the subcomponent score of the CADSS (depersonalization; Table) reported to be predictive of antidepressant response in a previous study of ketamine. Another significant limitation of the methods is the noise introduced by both the placebo effect (which impacts both the active treatment and control arms) and the small treatment effect (which is driven by biological heterogeneity inherent within the clinical population as well as the limited sensitivity and specificity of the clinical outcome measure). Thus, the sensitivity for detecting inter-relationships between two pharmacodynamic effects assessed using clinical rating scales in antidepressant trials is limited. In addition, the relatively small sample sizes of the ESK + AD group in the individual studies limited sensitivity for detecting weak correlations. To mitigate this latter limitation, we performed a correlational analysis of the combined data from TRANSFORM-1 and TRANSFORM-2 (Supplementary Table). These results corroborated the findings from the individual studies in supporting the absence of In summary, post-hoc analyses from the TRANSFORM-1 and TRANSFORM-2 short term studies of ESK + ADin patients with TRD did not support a correlation between the severity or presence of dissociative symptoms and the antidepressant treatment response to ESK. In addition, there was no evidence of a mediation effect of dissociation on time to depression relapse based on the analysis of data from the SUSTAIN-1 relapse prevention maintenance study. Additional research is needed to elucidate the presumably distinct modes of action through which the NMDAR antagonist mechanism mediates the antidepressant response relative to the dissociative effects of esketamine.Yes ~0% Note: The results show no significant effect of dissociation symptoms on mediating the antidepressant effect, but a significant direct effect of esketamine on the antidepressant effect (based on the inclusion and exclusion, respectively, of 0 by the 95% CI).
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The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) subjects from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.
Papers cited by this study that are also in Blossom
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
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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)
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