Oral Prolonged-Release Ketamine for Treatment-Resistant Depression: Two Randomized Clinical Trials

Ketamine has become an important rapid-acting treatment for depression, particularly treatment-resistant depression (TRD), but the currently available intravenous and intranasal formulations can cause dissociative and cardiovascular adverse effects that limit use and require supervised administration. Earlier research had shown antidepressant benefits for ketamine and esketamine, yet direct comparisons between formulations were limited, and it remained unclear whether dissociation was necessary for antidepressant effects. Oral immediate-release ketamine had also been associated with acute adverse effects, while the tolerability profile of a prolonged-release oral formulation had not been established. Walter and colleagues therefore examined KET01, a novel prolonged-release oral racemic ketamine tablet, to assess whether it could reduce depressive symptoms while causing less dissociation and fewer acute haemodynamic effects than established ketamine-based treatments. They report analyses from two randomised clinical trials: a Phase I head-to-head tolerability study against intranasal esketamine in healthy volunteers, and a Phase II placebo-controlled trial in outpatients with TRD. The paper’s broader aim was to determine whether an oral formulation might support safer outpatient, and potentially home, administration if efficacy and tolerability were acceptable.

The researchers conducted two randomised clinical trials. KET01-03 was a single-centre, double-blind, double-dummy, crossover Phase I trial in healthy adult male volunteers in Germany. Participants received a single 240 mg dose of oral KET01 and a single 84 mg dose of intranasal esketamine in two treatment periods separated by a 14 to 28 day washout. The trial was designed primarily to compare dissociative effects and safety, with pharmacokinetic sampling over the first 10 hours and again at 24 hours after dosing. KET01-02 was a multicentre, double-blind, placebo-controlled Phase II trial in adult outpatients with TRD at 29 sites in the Czech Republic, Germany and Poland. TRD was defined as non-response to two different antidepressant courses during the current major depressive episode. Participants were randomised 1:1:1 to oral placebo, KET01 120 mg/day, or KET01 240 mg/day, given once daily in the morning for 3 weeks as adjunctive treatment to ongoing standard antidepressant therapy. The first dose was supervised at the site, and follow-up occurred 28 days after end of treatment. In KET01-03, the primary endpoint was the maximum change in Clinician-Administered Dissociative States Scale (CADSS) score within 24 hours of dosing. Secondary endpoints included the incidence of dissociative symptoms, changes at expected peak plasma concentration, blood pressure and pulse changes, pharmacokinetic measures, and treatment-emergent adverse events. In KET01-02, the primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to day 21 for the 240 mg/day arm versus placebo. Secondary endpoints included response and remission rates, MADRS change at each visit, Hamilton Depression Rating Scale change, dissociation, safety variables, and pharmacokinetic parameters. The statistical approach used mixed models. KET01-03 used a crossover mixed model with sequence, period and treatment as fixed effects and participant as a random effect, with hierarchical testing for noninferiority and superiority. KET01-02 used a mixed model for repeated measures with treatment, visit, treatment-by-visit interaction and baseline MADRS as fixed effects, country as a random effect, and sensitivity analyses using analysis of covariance and different estimand strategies. Safety and pharmacokinetic outcomes were described descriptively, and efficacy analyses used all treated participants with at least one post-baseline assessment.

KET01-03 randomised 26 healthy men, with a median age of 32 years. KET01-02 randomised 122 outpatients with TRD: 42 to KET01 120 mg/day, 40 to KET01 240 mg/day, and 40 to placebo. The median age was 41 years, 59.0% were female, and all participants were White. Treatment discontinuation during KET01-02 was uncommon, and adherence was generally high. In KET01-03, intranasal esketamine, but not oral KET01, produced marked dissociation within 24 hours. The mean maximum CADSS increase was 29.6 points with esketamine versus 0.7 points with KET01, a highly significant difference. KET01 also showed a lower peak ketamine concentration than esketamine, while exposure to downstream metabolites such as norketamine and hydroxynorketamine was higher with KET01. Pulse and blood pressure rose rapidly after esketamine but did not change markedly with KET01. In KET01-02, the primary efficacy endpoint was not met. The day 21 least-squares mean difference in MADRS change for KET01 240 mg/day versus placebo was -1.82 points (95% CI -6.21 to 2.57; P = .41). However, improvement in depressive symptoms was seen earlier in treatment: the paper reports a reduction in MADRS scores 7 hours after the first 240 mg dose and a significant difference versus placebo at day 4, with a similar signal at day 7. The extracted text is incomplete at this point, so the exact day 4 and day 7 values are not fully visible, but the authors describe an approximately 4-point improvement at these early time points. HAM-D17 changes were said to be consistent with the MADRS findings. Dissociative symptoms were uncommon in KET01-02 and similar across arms: 15.0% with KET01 240 mg/day, 11.9% with KET01 120 mg/day, and 10.0% with placebo. No significant CADSS differences were seen at any time point. Safety findings suggested minimal haemodynamic effects with KET01, whereas esketamine caused rapid increases in pulse and blood pressure in KET01-03. Treatment-emergent adverse events occurred in 61.5% of KET01-treated volunteers and 100% of esketamine-treated volunteers in KET01-03, with no serious adverse events. In KET01-02, adverse events were reported in 62.5% of the 240 mg/day group, 50.0% of the 120 mg/day group, and 47.5% of the placebo group. Liver enzyme elevations were noted in the KET01 arms, including several cases of ALT and GGT rising to more than 3 times the upper limit of normal, particularly in the 240 mg/day group.

Walter and colleagues interpret the findings as showing that, although KET01 did not meet the primary efficacy endpoint in the Phase II trial, the drug produced early signals of antidepressant activity and had a notably favourable dissociation profile. They emphasise that KET01 caused almost no dissociative symptoms, whereas esketamine produced dissociation in nearly all participants in the Phase I comparison, and they argue that KET01 may therefore be better tolerated than intranasal esketamine in relation to dissociation and acute haemodynamic change. The authors place these results in the context of earlier work showing that ketamine and esketamine can improve depressive symptoms but are often limited by transient psychotomimetic and cardiovascular adverse effects. They note that prior studies have been mixed on whether dissociation is linked to antidepressant response, and they interpret their own data as suggesting that antidepressant effects may occur without prominent dissociation. They also compare their findings with previous oral ketamine studies, including work with immediate-release or other prolonged-release formulations, and suggest that differences in pharmacokinetics may explain differences in dissociation and efficacy signals. A major part of their discussion concerns pharmacokinetics. KET01 produced a lower and delayed ketamine peak, which the authors attribute to extensive first-pass metabolism, and this may reduce acute dissociation while allowing higher exposure to metabolites such as norketamine and hydroxynorketamine. They suggest, cautiously, that these metabolites could contribute to the antidepressant effect, although they note that the role of ketamine metabolites remains controversial and needs further study. The authors also acknowledge that a placebo response could have contributed to the lack of a significant difference at day 21, particularly given the substantial response in the placebo arm. They further state that future outpatient use would require risk mitigation. The limitations they identify include small sample sizes, the male-only Phase I sample, absence of an active comparator in KET01-02, incomplete early pharmacokinetic sampling in the Phase II trial, the short duration of both studies, and the possibility of functional unblinding in KET01-03 because esketamine caused obvious dissociation. They conclude that larger, longer Phase III studies in more diverse TRD populations are needed to assess durability of benefit, safety, and remission over time.

The authors conclude that KET01 at 240 mg/day showed an exploratory signal for reducing depression severity and had a substantially lower risk of dissociation and acute haemodynamic effects than intranasal esketamine under the conditions studied. They state that the overall efficacy and tolerability profile supports further development of KET01, including the possibility of outpatient or home administration in future larger Phase III trials with longer follow-up and broader participant populations.