Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study
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(Published version)
Date
2025
Authors
Mills, N.T.
Nikolin, S.
Glozier, N.
Barton, D.
Baune, B.T.
Fitzgerald, P.B.
Glue, P.
Sarma, S.
Rodgers, A.
Hadzi-Pavlovic, D.
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Journal article
Citation
The British journal of psychiatry. Supplement, 2025; 227(3):601-607
Statement of Responsibility
Natalie T Mills, Stevan Nikolin, Nick Glozier, David Barton, Bernhard T Baune, Paul B Fitzgerald, Paul Glue, Shanthi Sarma, Anthony Rodgers, Dusan Hadzi-Pavlovic, Angelo Alonzo, Vanessa Dong, Donel Martin, Philip B Mitchell, Michael Berk, Gregory Carter, Maree L Hackett, Andrew A. Somogyi, Cathrine Mihalopoulos, Mary Lou Chatterton, Sean Hood, and Colleen K. Loo
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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 at www.anzctr.org.au (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.
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Published online by Cambridge University Press: 07 January 2025
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© The Author(s), 2025. Published by Cambridge University Press on behalf of Royal College of Psychiatrists. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.