Background Ketamine is a rapid-acting antidepressant that produces acute dissociative symptoms. In routine care, the respective contributions of therapeutic expectations and dissociative symptoms to antidepressant response, and the directionality of their associations with depressive symptom change, remain poorly characterized.

Methods We conducted a retrospective longitudinal observational cohort study of 100 adults with major depressive disorder or bipolar depression receiving six open-label intravenous racemic ketamine infusions over 3 weeks. Therapeutic expectations were rated at baseline and before each infusion. Post-infusion, dissociative symptoms (CADSS) were assessed first, followed by depressive symptom severity (MADRS) within the same session. Linear mixed-effects, mediation, and random intercept cross-lagged panel models (RI-CLPM) were used to distinguish within-person from between-person effects.

Results Depressive symptoms improved across the induction course, with 45% of participants meeting response criteria. At each session, therapeutic expectations consistently predicted post-infusion improvement in depressive symptoms at the within-person level, independently of dissociative symptoms. Moreover, expectations became stronger across sessions in treatment responders. Dissociative symptoms were associated with improvement when examined alone, but were not observed after adjustment for expectations, and were not linked to improvement in depression at the within-person level from session to session. They were associated with greater overall antidepressant benefit at the between-person level. A notable indirect pathway was identified at the between-person level, where expectations determined changes in depression through initial dissociative symptoms and early depressive symptom reductions. This pathway explained 3.2% of the total effect of expectations on improvement in depression by the end of treatment.

Conclusions Therapeutic expectations and dissociative symptoms contributed to antidepressant response through distinct pathways: expectations functioned at the individual level as a dynamic within-person driver, whereas dissociative propensity served on the group level as a stable between-person marker of outcome, highlighting complementary clinical targets to optimize treatment response in routine care.

The authors have declared no competing interest.

This study was funded by the Agence Nationale de la Recherche (ANR-21-CE37-0014).

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The ethics committee of Sorbonne University granted ethical approval for this work (approval number: CER-2025-CANTENYS-KP-00431).

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