Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression

Demographic and clinical characteristics differed across the three study samples, prompting inclusion of study as a covariate in all models. The confirmatory factor analysis of CADSS items at 40 minutes post-infusion (n = 126) supported the proposed three-factor structure: RMSEA = .06 (95% CI .042–.077), CFI = .97, and TLI = .96, indicating acceptable to good model fit by conventional criteria. Four mixed models were run predicting percent change in HAM-D using CADSS total score and each of the three CADSS subscales (derealization, depersonalization, amnesia). For CADSS total score there was a significant three-way interaction of CADSS total × study × time (F(4,204) = 2.70, p = .03). Follow-up simple-slope testing showed that greater CADSS total score predicted greater reduction in HAM-D at Day 7 within the Ket-MOA study (B = -0.62, SE = 0.30, t(204) = -2.09, p = .04), and this slope differed from the Ket-BD study (comparison t(204) = -1.99, p = .048). Across all studies, the CADSS total score–HAM-D relationship was negative but not statistically significant at 230 minutes (B = -0.25, SE = 0.14, t = -1.70, p = .09) or Day 1 (B = -0.10, SE = 0.14, t = -0.72, p = .47). The Derealization subscale produced a very similar pattern: a significant three-way interaction (F(4,204) = 2.73, p = .03) and a significant negative association with HAM-D percent change at Day 7 in the Ket-MOA study (B = -1.55, SE = 0.65, t(204) = -2.37, p = .019). That Ket-MOA Day 7 slope differed significantly from the Ket-BD and Ket-Riluzole slopes in pairwise comparisons. Like the total score, derealization was not significantly related to HAM-D percent change at 230 minutes (B = -0.52, SE = 0.28, t = -1.89, p = .06) or Day 1 (B = -0.29, SE = 0.27, t = -1.04, p = .30) when pooling across studies. In contrast, the Depersonalization subscale showed a consistent relationship across studies and timepoints: higher depersonalization predicted greater antidepressant response (i.e. larger reductions in HAM-D percent change) with B = -0.79, SE = 0.38, t(118) = -2.07, p = .04; this effect did not interact with study or time. The Amnesia subscale was unrelated to HAM-D percent change in all analyses.

Niciu and colleagues interpret these findings as an extension of their earlier report: specific dissociative experiences during ketamine infusion—particularly depersonalization and, to a more limited extent, derealization—are modest predictors of subsequent antidepressant response. Depersonalization showed a consistent negative association with HAM-D percent change across all studies and timepoints, making it less likely to be a spurious result. Derealization's association was observed only at Day 7 and only in the Ket-MOA sample, and the investigators acknowledge the possibility that this isolated finding could represent a Type I error. The authors discuss methodological differences that might account for between-study variation. For example, Ket-BD participants were maintained on mood stabilisers (lithium or valproate) whereas Ket-MOA participants were unmedicated, and Ket-BD subjects tended to have longer and more severe courses of illness. A recent meta-analysis cited by the authors suggests bipolar disorder patients may be less prone to dissociation than patients with other disorders, although the present pooled analysis did not find significant diagnostic (MDD vs BD) differences in dissociation, implying diagnosis alone does not fully explain the study-to-study variability. Neurobiological interpretation is offered cautiously. The investigators propose that depersonalization may index neurobiological processes related to ketamine's antidepressant mechanism—potentially glutamate receptor modulation leading to altered glutamatergic tone, downstream circuit-level changes, and shifts in default mode network connectivity—while acknowledging that off-target effects cannot be dismissed. They also note that this study provides the first reported validation of the CADSS subscales proposed by Bremner and colleagues in an actively depressed MDD/BD population, supporting the instrument's psychometric structure for capturing distinct aspects of ketamine-induced dissociation. Key limitations highlighted by the authors include the potential for inadequate blinding—patients and staff may detect active ketamine due to its psychoactive and sympathomimetic effects, which could inflate observed antidepressant responses—use of combined MDD and BD datasets which might underrepresent ketamine's efficacy in MDD alone, and the possibility of Type I errors in secondary or exploratory analyses. The investigators conclude that future a priori studies are required to confirm these observations. Pragmatically, they suggest that if time is limited, clinicians and researchers administering ketamine might focus on the Depersonalization subscale of the CADSS as a predictor of subsequent antidepressant response, while continuing to investigate underlying mechanisms and potential confounds.