Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study

This secondary analysis of a Phase III trial (n=174) evaluates the effects of subcutaneous ketamine on anxiety in treatment-resistant depression (TRD). Significant reductions in anxiety (HAM-A scores) were observed in cohort 2 with flexible dosing (35-63mg/70kg) but not in cohort 1 with fixed low dosing (35mg/70kg). These effects, mediated by changes in depression (MADRS), were not sustained 4 weeks post-treatment.

Abstract of Effect of ketamine on anxiety (KADS)

“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.

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.”

Authors: 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, Colleen K. Loo

Summary of Effect of ketamine on anxiety (KADS)