Antidepressant effect of ketamine unrelated to dissociation: Results from an exploratory mediation analysis of the KET01-02 study
European Psychiatry April 1, 2025 L. Arvastson, E. Papanastasiou, K. Schmid et al.
A novel oral prolonged-release ketamine formulation (KET01) produces lower and delayed peak ketamine concentrations and higher levels of its metabolites, with limited dissociative effects compared to other ketamine formulations. In a randomized, double-blind phase 2 trial, 122 outpatients with treatment-resistant depression received 120 mg, 240 mg, or placebo daily for three weeks. A mediation analysis showed that the antidepressant effect of KET01 was not significantly mediated through dissociation, with an estimated mediation of -1.28% (confidence interval -28% to +11%). This challenges the common view that dissociation is necessary for ketamine's antidepressant effect, suggesting dissociative symptoms are merely adverse events of certain formulations.