Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation - Clinical and safety results
This double-blind, randomised study (n=27) assessed the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in TRD patients as add-on therapy. Patients received either 160 mg/day or 240 mg/day KET01 or placebo for 14 days, with the primary endpoint being the change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. Results suggest a positive trend towards antidepressant efficacy with 240 mg/day KET01.
Authors
- Erich Seifritz
Published
Abstract
Introduction
We investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy.Material and methods: Patients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis.
Results
Twenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01).Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment.
Discussion
Our results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.
Research Summary of 'Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation - Clinical and safety results'
Introduction
Treatment-resistant depression (TRD), commonly defined as insufficient response to multiple adequate antidepressant trials, affects roughly 20–30% of people with major depressive disorder and is associated with higher mortality and poorer quality of life. Ketamine and its S-enantiomer esketamine have shown rapid antidepressant effects when administered intravenously or intranasally, but these routes produce rapid peak plasma concentrations that require supervised administration and are associated with transient increased blood pressure, sedation and perceptual changes. Oral ketamine has been explored previously and offers practical advantages including easier, at-home dosing and lower cost, but oral bioavailability is lower and onset of effect tends to be slower than parenteral routes. Colla and colleagues evaluated KET01, a novel prolonged-release oral racemic ketamine tablet, as an add-on treatment for adults with TRD. The study was conceived as a Phase II proof-of-concept, randomised, double-blind, placebo-controlled trial testing two dose levels (160 mg/day and 240 mg/day, given as twice-daily dosing) administered for 14 days, with the primary efficacy endpoint being change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 15. The investigators aimed to assess both clinical efficacy and safety/tolerability of this formulation when added to ongoing antidepressant therapy.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Author
- APA Citation
Colla, M., Offenhammer, B., Scheerer, H., Kronenberg, G., Vetter, S., Mutschler, J., Mikoteit, T., Bankwitz, A., Adank, A., Schaekel, L., Eicher, C., Brühl, A., & Seifritz, E. (2024). Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation - Clinical and safety results. Journal of Psychiatric Research, 173, 124-130. https://doi.org/10.1016/j.jpsychires.2024.03.002
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Singh, J. B., Fedgchin, M., Daly, E. J. et al. · American Journal of Psychiatry (2016)
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