Repeated intranasal ketamine for treatment-resistant depression - the way to go? Results from a pilot randomised controlled trial
In a halted double‑blind pilot RCT of repeated intranasal 100 mg ketamine for treatment‑resistant depression, acute cardiovascular, psychotomimetic and neurological side effects and marked interindividual variability in ketamine/norketamine absorption produced poor tolerability and impractical administration, with no clear efficacy advantage over midazolam. Using the formulation and delivery device tested, intranasal ketamine was not a viable treatment approach, although no hepatic, cognitive or urinary adverse changes were observed.
Authors
- Paul Glue
- Colleen Loo
- Anthony Rodgers
Published
Abstract
Background
Ketamine research in depression has mostly used intravenous, weight-based approaches, which are difficult to translate clinically. Intranasal (IN) ketamine is a promising alternative but no controlled data has been published on the feasibility, safety and potential efficacy of repeated IN ketamine treatments.
Methods
This randomised, double-blind, placebo-controlled pilot study compared a 4-week course of eight treatments of 100 mg ketamine or 4.5 mg midazolam. Each treatment was given as 10 separate IN sprays, self-administered 5 min apart. The study was stopped early due to poor tolerability after five treatment-resistant depressed participants were included. Feasibility, safety (acute and cumulative), cognitive and efficacy outcomes were assessed. Plasma ketamine and norketamine concentrations were assayed after the first treatment.
Results
Significant acute cardiovascular, psychotomimetic and neurological side effects occurred at doses < 100 mg ketamine. No participants were able to self-administer all 10 ketamine sprays due to incoordination; treatment time occasionally had to be extended (>45 min) due to acute side effects. No hepatic, cognitive or urinary changes were observed after the treatment course in either group. There was an approximately two-fold variation in ketamine and norketamine plasma concentrations between ketamine participants. At course end, one participant had remitted in each of the ketamine and midazolam groups.
Conclusions
IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.
Research Summary of 'Repeated intranasal ketamine for treatment-resistant depression - the way to go? Results from a pilot randomised controlled trial'
Introduction
Earlier randomised controlled trials have shown that a single sub-anaesthetic dose of ketamine produces rapid and large antidepressant effects in both unipolar and bipolar depression, but these benefits are often short-lived, typically lasting 1–2 weeks. Open-label reports and case series suggest repeated ketamine dosing can prolong response, yet there have been no prior published randomised trials that systematically compare repeated ketamine administration with an active control. Most controlled work has used intravenous (IV), weight-based dosing, which requires infusion equipment and anaesthetic monitoring and is therefore challenging to translate into routine clinical settings. This pilot randomised, double-blind, placebo-controlled study examined the feasibility and safety of a repeated intranasal (IN) ketamine regimen for treatment-resistant depression (TRD). Gálvez and colleagues chose a fixed 100 mg IN dose given as ten 10 μL sprays (self-administered) across eight sessions over 4 weeks to approximate the antidepressant exposure of the common 0.5 mg/kg IV protocol, and they measured plasma ketamine and norketamine concentrations after the first treatment to assess bioavailability and inter-individual variability. The primary focus was feasibility and acute plus cumulative safety; mood and cognitive outcomes were also collected but the trial was explicitly a pilot study to inform future approaches.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Gálvez, V., Li, A., Huggins, C., Glue, P., Martin, D., Somogyi, A. A., Alonzo, A., Rodgers, A., Mitchell, P. B., & Loo, C. K. (2018). Repeated intranasal ketamine for treatment-resistant depression - the way to go? Results from a pilot randomised controlled trial. Journal of Psychopharmacology, 32(4), 397-407. https://doi.org/10.1177/0269881118760660
References (6)
Papers cited by this study that are also in Blossom
Andrade, C. · Journal of Clinical Psychiatry (2015)
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F. et al. · Journal of Affective Disorders (2014)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
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Papers in Blossom that reference this study
Meshkat, S., Haikazian, S., Di Vincenzo, J. D. et al. · Biological Psychiatry (2023)
Hassan, K., Struthers, W. M., Sankarabhotla, A. et al. · Frontiers in Psychiatry (2022)
Conley, A. A., Norwood, A. E. Q., Hatvany, T. C. et al. · Psychopharmacology (2021)
Domany, Y., McCullumsmith, C. B. · Archives of Suicide Research (2021)
Bahji, A., Vazquez, G. H., Zarate, C. A. · Journal of Affective Disorders (2021)
Schenberg, E. E. · Frontiers in Pharmacology (2018)
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