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.
A novel oral prolonged-release ketamine formulation (KET01) produces a low and delayed peak concentration of ketamine, high hydroxynorketamine levels, and minimal dissociative effects. In a phase 2 trial in outpatients with treatment-resistant depression, 240 mg/day KET01 added to ongoing treatment reduced depressive symptoms within 7 hours, with a statistically significant separation from placebo on day 4 and day 7, though the difference was not significant at day 21. In a separate phase 1 trial in healthy volunteers, the mean maximum dissociative score was 0.7 for KET01 versus 29.6 for intranasal esketamine. The formulation appears to be a safe, take-at-home adjunct treatment with minimal dissociation.