Oral Prolonged-Release Ketamine for Treatment-Resistant Depression: Two Randomized Clinical Trials.
Martin Walter, Christine Zu Eulenburg, Ani Damyanova, Karin Schmid, Isabel Schwienbacher, Evangelos Papanastasiou, Katarina Maiboe, Lars Arvastson, Caren Strote, Daniel Gehrlach, Hans Eriksson
JAMA Network Open June 1, 2026 DOI: 10.1001/jamanetworkopen.2026.19121 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized clinical trial (phase 1 and phase 2) Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Sample size | 148 |
| Population | Healthy adult male volunteers and adult outpatients with treatment-resistant depression |
| Intervention | intranasal esketamine |
| Dose | 120 or 240 mg/d |
| Duration | 3-week intervention, with follow-up at 4 weeks |
| Topics | Depression Esketamine Ketamine |
| Citations | 1 |
| Key findings | KET01 did not meet the primary efficacy endpoint at day 21 for treatment-resistant depression, but showed early antidepressant effects and minimal dissociation or cardiovascular changes. |
Abstract
Ketamine exerts rapid antidepressant effects. However, currently available ketamine-based treatments are associated with dissociative and cardiovascular adverse effects. To evaluate the antidepressant efficacy and tolerability of KET01, a novel, oral, prolonged-release racemic ketamine tablet formulation. KET01-03 was an active-comparator, double-blind, double-dummy, crossover phase 1 randomized clinical trial (RCT) conducted among healthy adult male volunteers (aged ≥18 years) between July and August 2023 at a single trial site in Germany. KET01-02 was a placebo-controlled, double-blind phase 2 RCT conducted between May 2022 and May 2023 among adult outpatients (aged ≥18 years) with treatment-resistant depression across 29 trial sites in the Czech Republic, Germany, and Poland. KET01-02 data were analyzed from May to October 2023 and KET01-03 data from August to October 2024. KET01-03 investigated a single dose of KET01 (240 mg) vs intranasal esketamine (84 mg), and KET01-02 evaluated KET01 dosages of 120 or 240 mg/d (adjunctive to ongoing standard therapy) against placebo for 3 weeks. The primary end points were the difference in mean maximum change in Clinician-Administered Dissociative States Scale (CADSS) score between KET01 and intranasal esketamine within the first 24 hours in KET01-03 and the least squares (LS) mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 21 for 240 mg/d of KET01 vs placebo in KET01-02. KET01-03 randomized 26 males (median age, 32 years [range, 21-45 years]), and KET01-02 randomized 122 outpatients with treatment-resistant depression (72 [59.0%] female; median age, 41 years [range, 19-65 years]). In KET01-03, intranasal esketamine but not KET01 induced significant dissociation within 24 hours after dosing (mean [SD] maximum change in CADSS score, 29.6 [12.5] points vs 0.7 [1.7] points; P < .001). The maximum plasma concentration was lower for KET01 (39.1 ng/mL) than esketamine (104.1 ng/mL); conversely, exposure to metabolites was higher for KET01 (eg, area under the curve [AUC] from baseline to last measurement for norketamine was 3.5 µg × h/mL) than esketamine (AUC for [S]-norketamine, 1.4 µg × h/mL). Pulse and blood pressure did not change markedly in the KET01 group in both trials, in contrast to rapid increases after intranasal esketamine in KET01-03. In KET01-02, the primary efficacy end point at day 21 was not met: LS mean MADRS score difference for 240 mg/d of KET01 vs placebo was -1.82 points (95% CI, -6.21 to 2.57 points; P = .41). However, a reduction in MADRS scores was observed 7 hours after administering the first 240 mg dose of KET01, with an LS mean difference vs placebo at day 4 (-3.66 [95% CI, -6.74 to -0.59] points; nominal P = .02) and day 7 (-3.95 [95% CI, -7.75 to -0.15] points; nominal P = .04). During follow-up, the LS mean MADRS point difference vs placebo at 4 weeks was -3.35 (95% CI, -7.62 to 0.93; nominal P = .13). The antidepressant properties and tolerability profile of KET01 in these RCTs, including minimal dissociation and cardiovascular effects, support further development of oral KET01 formulation for at-home administration. EU Clinical Trials Register Identifiers: 2023-503971-45-00 and 2021-004927-34.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.