Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders

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 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.

Keywords: Ketamine; meta-analysis; structured review; treatment-resistant anxiety disorders.

Figure 1.

PRISMA flow diagram.

Figure 2.

Risk of bias in included acute treatment RCTs (n = 6).

Figure 3.

Responder analysis for patients with SAD and PTSD.

Figure 4.

Effects of ketamine (solid lines) and control (dashed lines) on mean Clinician-Administered Dissociative States Scale (CADSS) scores over time.

Figure 5.

Side effects (ketamine compared to controls).

Figure 6.

Relationship between acute ketamine dose and change in anxiety rating scores at 24 hours post-dose.

Figure 7.

Change in anxiety rating score over time during ketamine maintenance therapy.