Abstract
Evidence supporting specific therapies for late-life treatment-resistant depression (LL-TRD) is necessary. This study used Bayesian adaptive randomization to determine the optimal dose for the probability of treatment response (≥50% improvement from baseline on the Montgomery-Åsberg Depression Rating Scale) 7 days after a 40 min intravenous (IV) infusion of ketamine 0.1 mg/kg (KET 0.1), 0.25 mg/kg (KET 0.25), or 0.5 mg/kg (KET 0.5), compared to midazolam 0.03 mg/kg (MID) as an active placebo. The goal of this study was to identify the best dose to carry forward into a larger clinical trial. Response durability at day 28, safety and tolerability, and effects on cortical excitation/inhibition (E/I) ratio using resting electroencephalography gamma and alpha power, were also determined. Thirty-three medication-free US military veterans (mean age 62; range: 55–72; 10 female) with LL-TRD were randomized double-blind. The trial was terminated when dose superiority was established. All interventions were safe and well-tolerated. Pre-specified decision rules terminated KET 0.1 (N = 4) and KET 0.25 (N = 5) for inferiority. Posterior probability was 0.89 that day-seven treatment response was superior for KET 0.5 (N = 11; response rate = 70%) compared to MID (N = 13; response rate = 46%). Persistent treatment response at day 28 was superior for KET 0.5 (response rate = 82%) compared to MID (response rate = 37%). KET 0.5 had high posterior probability of increased frontal gamma power (posterior probability = 0.99) and decreased posterior alpha power (0.89) during infusion, suggesting an acute increase in E/I ratio. These results suggest that 0.5 mg/kg is an effective initial IV ketamine dose in LL-TRD, although further studies in individuals older than 75 are required.
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Acknowledgements
The opinions expressed reflect those of the authors and not necessarily those of the Department of Veterans Affairs, or the U.S. government. This work is supported by a Department of Veterans Affairs Merit Award (Grant # CX-001205-01AI), and by facilities and resources of the Michael E DeBakey VA Medical Center.
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The study was conceptualized by SJM, RAJ, ACS, CEG, and ML. Study procedures and data collection were performed by SI, LCC, TI, ML, SJM, ACS, LH, and DAF. Data pre-processing and analysis was performed by CG, NM, CNH, and NR. Interpretation of the data was performed by SJM, CEG, ML, NM, and CNH. The first draft of the article was written by ML, NM, and SJM. All authors contributed to the drafting and revising of the manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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SJM has served as a consultant to Allergan, Alkermes, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, and Signant Health. He has served as an investigator for studies funded by Janssen, Merck, NeuroRx, and Sage Therapeutics, and has received research support from Biohaven Pharmaceuticals and VistaGen Therapeutics. RKA has served on the Janssen advisory and speaker board. ML has served as principal investigator for trials funded by NeuroRx and VistaGen Therapeutics. The remaining authors have nothing to disclose.
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Lijffijt, M., Murphy, N., Iqbal, S. et al. Identification of an optimal dose of intravenous ketamine for late-life treatment-resistant depression: a Bayesian adaptive randomization trial. Neuropsychopharmacol. 47, 1088–1095 (2022). https://doi.org/10.1038/s41386-021-01242-9
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DOI: https://doi.org/10.1038/s41386-021-01242-9
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