Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study
In this secondary analysis of a multisite, double-blind RCT (n=174) in treatment‑resistant depression, subcutaneous racemic ketamine given twice weekly for 4 weeks at flexible, response‑guided doses (35-63mg/70kg) produced a significant short‑term reduction in anxiety (HAM‑A) versus midazolam, whereas a fixed low dose (35mg/70kg) did not. The anxiolytic effect was mediated by antidepressant response and was not maintained 4 weeks after the end of treatment.
Authors
- Paul Glue
- Colleen Loo
- Anthony Rodgers
Published
Abstract
Background
Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties.
Aims
To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD.
Method
The Ketamine for Adult Depression Study was a multisite 4-week randomised, double-blind, active (midazolam)-controlled trial. The study initially used fixed low dose ketamine (0.5 mg/kg, cohort 1), before protocol revision to flexible, response-guided dosing (0.5–0.9 mg/kg, cohort 2). This secondary analysis assessed anxiety using the Hamilton Anxiety (HAM-A) scale (primary measure) and ‘inner tension’ item 3 of the Montgomery–Åsberg Depression Rating Scale (MADRS), at baseline, 4 weeks (end treatment) and 4 weeks after treatment end. Analyses of change in anxiety between ketamine and midazolam groups included all participants who received at least one treatment (n = 174), with a mixed effects repeated measures model used to assess the primary anxiety measure. The trial was registered as (ACTRN12616001096448).
Results
In cohort 1 (n = 68) the reduction in HAM-A score was not statistically significant: −1.4 (95% CI [−8.6, 3.2], P = 0.37), whereas a significant reduction was seen for cohort 2 (n = 106) of −4.0 (95% CI [−10.6, −1.9], P = 0.0058), favouring ketamine over midazolam. These effects were mediated by total MADRS and were not maintained at 4 weeks after treatment end. MADRS item 3 was also significantly reduced in cohort 2 (P = 0.026) but not cohort 1 (P = 0.96).
Conclusion
Ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.
Research Summary of 'Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study'
Blossom's Take
This paper has been (temporarily) been retracted. Please see the full journal update below. We will replace the publication once we have the new paper. The conclusions from the article - which was a secondary analysis - still hold. "In October 2025, the authors of this paper voluntarily informed the journal that errors had been identified during analyses of the open-label extension phase of the Ketamine for Adult Depression Study (KADS). Specifically, total HAM-A scores for two participants at the end of the randomised controlled treatment phase and one participant at the four-week after treatment end visit, which should have been coded as ‘missing’, had been incorrectly scored as ‘0’. The authors repeated all analyses. There were small changes to means, standard deviations, p-values and confidence intervals, but all p-values originally reported as <0.05 remained <0.05, and the overall interpretation and conclusions of the study were unchanged. The Editors conducted an additional review and agreed that the errors did not alter the study’s findings or final conclusions. However, given the extent of the corrections required, they concluded that a corrigendum would not be sufficient. They agreed that retraction of the original article with subsequent resubmission of a corrected paper would be the best course of action. All authors have confirmed agreement to the retraction."
Introduction
The paper frames anxious distress as a common and clinically important feature of major depressive disorder (MDD), noting that comorbid high levels of anxiety are associated with poorer antidepressant outcomes. Earlier studies and case reports have suggested that ketamine can produce rapid reductions in depressive and anxiety symptoms, but the literature is limited by small samples, open-label designs, variable dosing and mixed patient populations. Few trials have specifically examined ketamine's anxiolytic effects in people with treatment-resistant depression (TRD), and prior TRD studies that reported anxiety change used single infusions or small samples, leaving uncertainty about dose, durability and whether anxiety improvements are independent of mood improvement. Mills and colleagues set out to examine whether subcutaneous racemic ketamine administered twice weekly for 4 weeks reduces anxiety in people with TRD. Using data from the Ketamine for Adult Depression Study (KADS), a multicentre randomised, double-blind, active (midazolam) controlled trial, the authors report secondary analyses with the Hamilton Anxiety Rating Scale (HAM-A) as the primary anxiety measure and MADRS item 3 (inner tension) as a supplementary measure. Specific hypotheses were that ketamine would reduce HAM-A and MADRS item 3 scores versus midazolam, that effects would be larger in participants with comorbid anxiety disorders independent of antidepressant effects, and that higher ketamine doses would produce greater anxiolytic effects.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Mills, N. T., Nikolin, S., Glozier, N., Barton, D., Baune, B. T., Fitzgerald, P. B., Glue, P., Sarma, S., Rodgers, A., Hadzi-Pavlovic, D., Alonzo, A., Dong, V., Martin, D., Mitchell, P. B., Berk, M., Carter, G., Hackett, M. L., Somogyi, A. A., Mihalopoulos, C., . . . Loo, C. K. (2025). Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study. The British Journal of Psychiatry, 227(3), 601-607. https://doi.org/10.1192/bjp.2024.250
References (4)
Papers cited by this study that are also in Blossom
Salloum, N. C., Fava, M., Freeman, M. P. et al. · Depression and Anxiety (2018)
Daly, E. J., Turkoz, I., Salvadore, G. et al. · Depression and Anxiety (2021)
Glue, P., Medlicott, N. J., Harland, S. et al. · Journal of Psychopharmacology (2017)
Wilkinson, S. T., Taeho, G., Rhee et al. · Psychotherapy and Psychosomatics (2021)
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