Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study
This double-blind, cross-over study (n=10) finds that arketamine (35mg/70kg, the 'right-handedness of ketamine) isn't superior to placebo, but does find it to be safe in a population with treatment-resistant depression (TRD).
Authors
- Gustavo Leal
Published
Abstract
Background
Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo.
Methods
This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model.
Results
Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal.
Limitations
This was a pilot study with a small sample and underpowered.
Conclusions
Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations.
Research Summary of 'Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study'
Introduction
Ketamine at subanaesthetic doses has been shown across many trials to produce rapid, though often transient, antidepressant effects in major depressive disorder (MDD), including treatment-resistant depression (TRD). Racemic ketamine contains two enantiomers, (R)-ketamine (arketamine) and (S)-ketamine (esketamine); esketamine is typically considered more active clinically because of higher NMDAR affinity and greater anaesthetic potency. Nonetheless, preclinical work has suggested that arketamine may have more potent and longer-lasting antidepressant effects with fewer psychotomimetic or abuse-related properties, and human data remain very limited to date. Leal and colleagues designed the present study to explore the feasibility of conducting controlled clinical trials of arketamine in patients with TRD and to provide an initial, exploratory comparison of its efficacy and safety against placebo. As the first randomised, double-blind, placebo-controlled trial using arketamine in depressed patients, the study aimed to test procedures, tolerability, and to generate preliminary efficacy signals that could inform future, better-powered trials.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Author
- APA Citation
Leal, G. C., Souza-Marques, B., Mello, R. P., Bandeira, I. D., Caliman-Fontes, A. T., Carneiro, B. A., Faria-Guimarães, D., Guerreiro-Costa, L. N., Jesus-Nunes, A. P., Silva, S. S., Lins-Silva, D. H., Fontes, M. A., Alves-Pereira, R., Cordeiro, V., Rugieri-Pacheco, S., Santos-Lima, C., Correia-Melo, F. S., Vieira, F., Sanacora, G., . . . Quarantini, L. C. (2023). Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study. Journal of Affective Disorders, 330, 7-15. https://doi.org/10.1016/j.jad.2023.02.151
References (9)
Papers cited by this study that are also in Blossom
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Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Kishimoto, T., Chawla, J. M., Hagi, K. et al. · Psychological Medicine (2016)
Leal, G. C., Bandeira, I. D., Correia-Melo, F. S. et al. · European Archives of Psychiatry and Clinical Neuroscience (2020)
Chen, X., Hou, X., Bai, D. et al. · American Journal of Psychiatry (2019)
Singh, J. B., Fedgchin, M., Daly, E. J. et al. · American Journal of Psychiatry (2016)
Yang, C., Shirayama, Y., Zhang, J-C. et al. · Translational Psychiatry (2020)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
Zhang, J., Hashimoto, K., Li, S. · Pharmacology Biochemistry and Behavior (2014)
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