Antidepressant effect of ketamine unrelated to dissociation: Results from an exploratory mediation analysis of the KET01-02 study
Lars Arvastson, Evangelos Papanastasiou, Karin Schmid, Ani Damyanova, A. Glas, Caren Strote, C. Eulenburg, Daniel Gehrlach, Katarina Maiboe, Hans Eriksson
European Psychiatry April 1, 2025 DOI: 10.1192/j.eurpsy.2025.471 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 122 |
| Population | Outpatients with treatment-resistant depression |
| Dose | 120 mg or 240 mg once daily |
| Duration | 3-week intervention |
| Measures | Montgomery-Åsberg Depression Rating Scale (MADRS), Clinician-Administered Dissociative States Scale (CADSS) |
| Topics | Esketamine Ketamine |
| Key findings | The antidepressant effect of KET01 was achieved with minimal to no dissociation and with no significant mediation through dissociation. |
Abstract
IntroductionCurrent ketamine-based therapies for treatment-resistant depression (TRD) can induce dissociative symptoms. A novel oral prolonged-release ketamine formulation (KET01) results in a lower and delayed peak concentration of ketamine, and a higher concentration of the metabolites norketamine and hydroxynorketamine than after intravenous administration. KET01 has limited dissociative properties, compared to other ketamine formulations.ObjectivesTo explore the relation between dissociative and antidepressant effects of KET01.MethodsKET01-02 (EudraCT 2021-004927-34) was a randomized, double-blind phase 2 trial in outpatients with TRD comparing adjunct 120 mg (n=42) or 240 mg (n=40) oral KET01 once-daily for 3 weeks to placebo (PBO, n=40). The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score on day 21. Dissociation was assessed using the Clinician-Administered Dissociative States Scale (CADSS).The association between CADSS scores at 7 hours after first dosing and MADRS scores on day 4 was investigated with a statistical mediation analysis. The 7-hour timepoint was selected since it coincides with the average Tmax (time-to-peak) when the highest dissociation is expected. Depression scores at the first subsequent visit (on day 4) were selected for the analysis. It was also the time point where change in MADRS score from baseline differentiated the most between KET01 and placebo with a difference of 4.32 (p=0.006) to the benefit of KET01 – based on the model used in the mediation analysis.ResultsThe antidepressant effect of KET01 that was mediated through dissociation was estimated to the negligible -1.28% (CI: (-28%) – (+11%)).ConclusionsThe antidepressant effect of KET01 was achieved with minimal to no dissociation and with no significant mediation through dissociation. Our findings challenge the commonly held clinical view that some degree of dissociation is necessary to guarantee ketamine’s antidepressant effect. Instead, it appears that dissociative symptoms are merely adverse events associated with certain formulations of ketamine.Disclosure of InterestL. Arvastson Consultant of: HMNC Brain Health, E. Papanastasiou Employee of: HMNC Brain Health, K. Schmid Employee of: Develco Pharma, A. Damyanova Employee of: HMNC Brain Health, A. Glas Employee of: HMNC Brain Health, C. Strote Employee of: HMNC Brain Health, C. Eulenburg Consultant of: HMNC Brain Health, D. Gehrlach Employee of: HMNC Brain Health, K. Maiboe Consultant of: HMNC Brain Health, H. Eriksson Employee of: HMNC Brain Health
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |