Dissociation Does Not Mediate Antidepressant Response to Esketamine: A Real-World Longitudinal Study with 6-Month Follow-Up
M. Olivola, V. Martiadis, K. La Monica, C. M. Angeletti, A. Frediani, V. Casati, R. Anniverno, G. Versaci, T. Prodi, N. Brondino, B. M. Dell’OssoIntroduction
The role of dissociation in mediating antidepressant response to intranasal esketamine remains debated. While dissociative experiences are often observed during treatment, their predictive value for clinical outcomes is uncertain.
Objectives
We aimed to assess whether (i) baseline dissociative traits (DES-II) and (ii) early changes in dissociation (ΔDES T0→T2) predict short-term antidepressant response, and to explore whether dissociation mediates depressive symptom improvement across 6 months of follow-up.
Methods
This multicenter naturalistic cohort included 31 patients with treatment-resistant depression (mean age 44.7±11.6) treated at academic community clinics in Pavia and Milan. Clinical assessments included MADRS at baseline (T0), 2 weeks (T1), 1 month (T2), 2 months (T3), 3 months (T4), and 6 months (T5) (Montgomery & Åsberg, Br J Psychiatry 1979). Dissociation was measured with DES-II at T0 and T2 (Carlson & Putnam, Dissociation 1993). Outcomes: % MADRS change and responder status (≥50% reduction). Predictors: DES-II at baseline and ΔDES T0→T2. Covariates: baseline MADRS, age, RMET (Baron-Cohen et al., J Child Psychol Psychiatry 2001), Psychache . Analyses included linear/logistic regressions and exploratory mediation (Preacher & Hayes, Behav Res Methods 2008).
Results
Mean MADRS decreased from 31.9±7.9 to 16.7±9.6 at T2 (−47%, responders 48%). Baseline DES-II (mean 0.185±0.12) showed no independent association with response (OR 0.18; 95%CI 0.00–15.5; p = 0.38). ΔDES T0→T2 did not predict response (OR 0.01; 95%CI 0.00–80.5; p = 0.36) nor % improvement (β = 12.7; p = 0.33). Mediation analysis revealed no significant indirect effect (a*b ≈ 10.7%; 95%CI −21.7–79.9). By DES tertiles, % improvement was comparable (Low 42.6%; Mid 51.0%; High 46.5%). Longitudinal follow-up (T1–T5) confirmed sustained MADRS reduction independent of dissociation. (Figure 1 Madrs reduction across timepoints, Figure 2 %madrs improvement by baseline DES, Figure 3 mediation model)
Image 1: Long description.