Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders
This meta-analysis (2021) assessed the literature regarding the possibilities of using ketamine to treat anxiety disorders. Six RCTs investigating various disorders were included. Ketamine was associated with treatment response for social anxiety disorder but not for PTSD. Doses of >0.5 mg/kg were associated with a greater reduction in scores of anxiety and these anxiolytic effects could be sustained.
Authors
- Paul Glue
Published
Abstract
Background
Anxiety disorders are common, associated with significant burden of disease, and have high levels of treatment resistance. Low-dose ketamine has been extensively studied in treatment-resistant depression, with fewer reports in treatment-resistant anxiety disorders.
Aims
This systematic review and meta-analysis collected efficacy, safety, and tolerability data for ketamine as a treatment for anxiety spectrum disorders.
Methods
We conducted a systematic search for randomized controlled trials (RCTs) of acute ketamine treatment for patients with anxiety disorders. Open-label trials of ketamine maintenance therapy were also considered. Qualitative and, where possible, quantitative syntheses of findings were performed using Review Manager software (RevMan). Acute dose-response and maintenance treatment data were also collected.
Results
There were six eligible acute RCTs - two in social anxiety disorder (SAD), three in post-traumatic stress disorder (PTSD), and one in obsessive-compulsive disorder (OCD). Four of the six showed significant improvement in anxiety rating scores in ketamine compared with control groups. Pooled analysis showed ketamine was associated with an increased likelihood of treatment response for SAD (odds ratio (OR): 28.94; 95% confidence interval [CI]: 3.45-242.57; p = 0.002) but not for PTSD (OR: 2.03; 95% CI: 0.67-6.15; p = 0.21). A dose-response profile was observed for ketamine and changes in SAD symptoms, with doses ⩾0.5 mg/kg associated with a greater reduction in anxiety rating scores than lower doses. Ketamine maintenance therapy was associated with sustained anxiolytic effects and improved social and/or work functioning.
Conclusion
These preliminary analyses suggest that acute ketamine may be broadly effective across treatment-resistant anxiety spectrum disorders. These effects can be prolonged with maintenance treatment. Future studies will be needed to provide critical knowledge gaps around off-label use, side effects, and potential risks for abuse in clinical settings.
Research Summary of 'Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders'
Introduction
Anxiety disorders (including specific phobia, social anxiety disorder [SAD], generalized anxiety disorder [GAD], panic disorder, and agoraphobia) are highly prevalent and often treatment-resistant, producing substantial burden worldwide. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has established rapid-onset antidepressant effects in treatment-resistant depression, but clinical research on ketamine for treatment-resistant anxiety disorders is comparatively sparse. The introduction highlights potential mechanistic reasons to target the glutamate system in anxiety—glutamate’s roles in fear extinction, stress-responsive neuropeptide regulation, and synaptic plasticity—and notes ketamine’s complex pharmacology beyond NMDAR antagonism, as well as the absence of consistent definitions for treatment resistance in anxiety and limited regulatory development in this area. Whittaker and colleagues set out to systematically review and meta-analyse randomized controlled trials (RCTs) of acute ketamine treatment for anxiety spectrum disorders, with supplementary consideration of open-label maintenance studies and acute dose–response data. The review aimed to summarise efficacy, safety, tolerability, and dose and maintenance effects across disorders commonly associated with anxiety symptoms, including SAD, GAD, post‑traumatic stress disorder (PTSD), and obsessive‑compulsive disorder (OCD).
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Create a free account to open full-text PDFs.
Study Details
- Study Typemeta
- Journal
- Compound
- Topics
- Author
- APA Citation
Whittaker, E., Dadabayev, A. R., Joshi, S. A., & Glue, P. (2021). Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders. Therapeutic Advances in Psychopharmacology, 11. https://doi.org/10.1177/20451253211056743
References (9)
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)
Newport, D. J., Carpenter, L. L., Mcdonald, W. M. et al. · American Journal of Psychiatry (2015)
Taylor, J. H., Landeros-Weisenberger, A., Coughlin, C. et al. · Neuropsychopharmacology (2017)
Pradhan, B. K., Wainer, I. W., Moaddel, R. et al. · Asia Pacific Journal of Clinical Trials Nervous System Diseases (2017)
Glue, P., Medlicott, N. J., Harland, S. et al. · Journal of Psychopharmacology (2017)
Feder, A., Costi, S., Rutter, S. B. et al. · American Journal of Psychiatry (2021)
Sanacora, G., Frye, M. A., McDonald, W. et al. · JAMA Psychiatry (2017)
Cited By (3)
Papers in Blossom that reference this study
Borgogna, N. C., Owen, T., Vaughn, J. et al. · European Journal of Psychotraumatology (2024)
Hack, L. M., Zhang, X., Heifets, B. D. et al. · Nature Communications (2023)
Hartland, H., Mahdavi, K., Jelen, L. A. et al. · Journal of Psychopharmacology (2023)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.