Translated from our German original by AI. The German text was researched, written, and edited by the Psychedelia Foundation team and remains the authoritative version.
A newly developed oral prolonged-release formulation of ketamine (KET01) did not meet its primary efficacy endpoint in a randomised phase 2 trial in patients with treatment-resistant depression. The results do, however, point to a rapidly emerging antidepressant effect and to a favorable tolerability profile with minimal dissociative and cardiovascular effects.
The double-blind, placebo-controlled phase 2 trial enrolled 122 adults with treatment-resistant depression. In addition to their existing standard antidepressant therapy, they received either KET01 at a dose of 120 or 240 mg daily or placebo over three weeks. The primary endpoint was the change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 21 days. It was not met with the 240 mg dose: the adjusted mean difference versus placebo was -1.82 points (95% confidence interval: -6.21 to 2.57; p = 0.41).
The researchers nevertheless observed early improvements in depressive symptoms. MADRS scores had already declined seven hours after the first 240 mg dose. Compared with placebo, the differences were nominally significant on day 4 (-3.66 points; 95% CI: -6.74 to -0.59; nominal p = 0.02) and day 7 (-3.95 points; 95% CI: -7.75 to -0.15; nominal p = 0.04). Four weeks after the start of treatment a numerical advantage over placebo remained (-3.35 points), but it was not statistically significant (p = 0.13).
The tolerability of KET01 was examined additionally in a double-blind phase 1 crossover study with 26 healthy male participants. A single dose of 240 mg KET01 was compared with 84 mg of intranasal esketamine. While esketamine caused pronounced dissociative symptoms, almost no dissociation occurred under KET01. The maximum change on the Clinician-Administered Dissociative States Scale (CADSS) averaged 29.6 points under esketamine compared with 0.7 points under KET01 (p < 0.001). Blood pressure and pulse also remained largely unchanged under KET01 in both studies, whereas after intranasal esketamine they rose rapidly, as expected.
Pharmacokinetically, KET01 reached lower maximum ketamine plasma concentrations than intranasal esketamine, while exposure to metabolites such as norketamine was higher.
In the authors’ assessment, the results indicate a favorable safety and tolerability profile for the oral prolonged-release formulation. Although the phase 2 trial missed its primary efficacy endpoint, the early improvements in depressive symptoms observed and the absence of relevant dissociative and cardiovascular side effects justify the further clinical development of KET01, particularly with a view to potential use at home.
