Effect of ketamine on anxiety

Mills, N. T., Nikolin, S., Glozier, N., Barton, D., Baune, B. T., Fitzgerald, P. B., … & Loo, C. K. (2025). Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study. The British Journal of Psychiatry, 1-7.

Rationale

Anxiety disorders and TRD frequently co-occur, and the presence of anxiety can negatively impact treatment outcomes for depression.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has shown promise as a rapid-acting antidepressant.

Previous studies have suggested that ketamine may also have anxiolytic properties. However, research on the effects of ketamine on anxiety in individuals with TRD has been limited.

This study aimed to address this gap by investigating the effects of subcutaneous racemic ketamine on anxiety symptoms in a well-controlled randomized clinical trial setting.

The findings of this study have the potential to inform clinical practice and guide the development of more effective treatment strategies for individuals with TRD and comorbid anxiety.  

Method

The study was a multisite, randomized, double-blind, active-controlled trial.

Participants were randomly assigned to receive either subcutaneous ketamine or midazolam twice weekly for 4 weeks.

The study initially used a fixed low dose of ketamine (0.5 mg/kg, cohort 1), but later revised the protocol to allow for flexible, response-guided dosing (0.5-0.9 mg/kg, cohort 2).  

Sample:

The study included 174 participants with TRD. Demographic characteristics such as age, gender, and ethnicity were not reported in this secondary analysis.  

Measures:

• Hamilton Anxiety Rating Scale (HAM-A): The primary outcome measure was the change in HAM-A scores from baseline to 4 weeks (end of treatment) and 4 weeks after treatment ended. The HAM-A is a clinician-administered scale that assesses the severity of anxiety symptoms.  
• Montgomery-Åsberg Depression Rating Scale (MADRS) item 3 (inner tension): A secondary outcome measure was the change in MADRS item 3 scores from baseline to 4 weeks (end of treatment) and 4 weeks after treatment ended. MADRS item 3 specifically assesses inner tension, a component of anxiety.  

Statistical Measures:

• Mixed-effects repeated measures model (MRMM): Used to assess the primary outcome (change in HAM-A scores) over time between the ketamine and midazolam groups.  
• Mediation analysis: Conducted to determine whether the effect of ketamine on anxiety was mediated by its effect on depression symptoms (total MADRS score).  
• Subgroup analyses: Performed to explore potential differences in treatment effects based on factors such as HAM-A psychic and somatic factors and comorbid anxiety disorders.  

Results

• Hypothesis 1: Ketamine was associated with a significant reduction in total HAM-A scores compared to midazolam in the combined cohorts (p = 0.0071) and cohort 2 (p = 0.0058), but not in cohort 1 (p = 0.38).  
• Hypothesis 2: The effect of ketamine on anxiety was mediated by its effect on depression symptoms (total MADRS score).  
• Hypothesis 3: The study did not find evidence to support the hypothesis that the effect of ketamine on anxiety was dose-dependent.  
• Additional findings:
  • The anxiolytic effects of ketamine were not maintained at 4 weeks after treatment ended.  
  • There was a significant reduction in MADRS item 3 (inner tension) scores in cohort 2 (p = 0.026), but not in cohort 1 (p = 0.96) or the combined cohorts (p = 0.16).  
  • The reduction in HAM-A scores was primarily driven by a decrease in the psychic subscale, with no significant difference observed in the somatic subscale.  
  • In participants with comorbid anxiety disorders, there was a significant reduction in total HAM-A scores (p = 0.019) and MADRS item 3 scores (p = 0.016) in the ketamine group compared to the midazolam group.  

Insight

This study provides valuable insights into the effects of ketamine on anxiety in individuals with TRD.

The key finding is that ketamine can significantly reduce anxiety symptoms, particularly when administered at adequate doses, as demonstrated in the response-guided titration cohort.

This is consistent with previous research suggesting the anxiolytic potential of ketamine.

However, the study also highlights that the anxiolytic effects of ketamine may not be sustained after the treatment period ends, suggesting the need for maintenance treatment or combination therapies to achieve long-term benefits.  

The study’s findings extend previous research by demonstrating the anxiolytic effects of ketamine in a well-controlled randomized clinical trial setting with a substantial sample size.

The use of midazolam as an active placebo control helps to rule out non-specific effects of treatment, strengthening the evidence for ketamine’s specific anxiolytic properties.

Additionally, the study’s exploration of the relationship between ketamine’s effects on anxiety and depression provides a more nuanced understanding of its mechanisms of action.  

These findings suggest that ketamine may be a valuable treatment option for anxiety in individuals with TRD, but further research is needed to determine the optimal dosing and treatment duration for sustained benefits.

Future studies could explore the use of ketamine in combination with other therapies, such as cognitive-behavioral therapy (CBT) or psychotherapy, to enhance its long-term effects.

Additionally, research on the effects of ketamine on specific anxiety disorders comorbid with TRD could help to tailor treatment strategies to individual needs.  

Clinical Implications

The findings of this study have several implications for practitioners and policymakers involved in the care of individuals with TRD and comorbid anxiety.  

For practitioners

• Consider ketamine as a potential treatment option for anxiety in people with TRD, particularly when other treatments have been unsuccessful.
• Monitor patients closely for anxiety symptoms during and after ketamine treatment, as the anxiolytic effects may not be sustained after the treatment period ends.
• Consider combining ketamine treatment with other therapies, such as CBT or psychotherapy, to enhance its long-term effects.
• Tailor treatment strategies to individual needs, taking into account the specific anxiety disorders comorbid with TRD.

For policymakers

• Support further research on the effects of ketamine on anxiety in people with TRD, including studies on optimal dosing, treatment duration, and long-term effects.
• Consider the inclusion of ketamine in treatment guidelines for TRD and comorbid anxiety, based on the growing evidence of its efficacy.
• Address potential barriers to accessing ketamine treatment, such as cost and availability, to ensure that patients who could benefit from this treatment have access to it.

Strengths

• Randomized, double-blind, active-controlled design.  
• Large sample size.  
• Use of multiple anxiety measures.  
• Controlling for change in mood.  
• Few missing data.  

Limitations

• Secondary analysis of a trial not specifically designed to assess anxiety outcomes.  
• Limited information on demographic characteristics of the sample.  
• Uncorrected results, potentially prone to false positives.  
• Short follow-up period, limiting the assessment of long-term effects.  
• Relatively few participants with comorbid anxiety disorders in some groups.  

References

Mills, N. T., Nikolin, S., Glozier, N., Barton, D., Baune, B. T., Fitzgerald, P. B., … & Loo, C. K. (2025). Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study. The British Journal of Psychiatry, 1-7.

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