Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial
Burke, A. K., Cooper, T. B., Ellis, S. P., Grunebaum, M. F., Keilp, J. G., Mann, J. J., Marver, J. E., Milak, M. S., Moitra, V. K., Oquendo, M. A., Sublette, M. E.
This midazolam-controlled randomised clinical trial study (n=16) compares ketamine and midazolam (another anesthetic) to investigate their feasibility and effect on suicidal ideation (SI) in bipolar depression (BD) using the Scale for Suicidal Ideation (SSI) score. The results substantiate feasibility with improvement in memory and BDNF as promising biomarkers and that ketamine effects showing more reduction in suicidal thoughts than with midazolam, although it was not statistically significant; this was possibly due to a small sample so a full-scale trial is needed.
Abstract
Objectives: To evaluate feasibility and effects of a sub-anesthetic infusion dose of ketamine versus midazolam on suicidal ideation in bipolar depression. Neurocognitive, blood and saliva biomarkers were explored.Methods: Sixteen participants with bipolar depression and a Scale for Suicidal Ideation (SSI) score of ≥4 were randomized to ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg). Current pharmacotherapy was maintained excluding benzodiazepines within 24 hours. The primary clinical outcome was SSI score on day 1 post-infusion.Results: Results supported feasibility. Mean reduction of SSI after ketamine infusion was almost 6 points greater than after midazolam, although this was not statistically significant (estimate=5.84, SE=3.01, t=1.94, P=.074, 95% confidence interval ([CI)]=−0.65 to 12.31). The number needed to treat for response (SSI <4 and at least 50% below baseline) was 2.2, and for remission (SSI=0) was 3.2. The strongest neurocognitive correlation was between memory improvement on the Selective Reminding Test (SRT) and reduction in SSI score on day 1 after ketamine (ρ=−.89, P=.007). Pre- to post-infusion decrease in serum brain derived neurotrophic factor (BDNF) correlated with reduction in SSI from baseline to day 1 after ketamine (n=5, ρ=0.90, P=.037) but not midazolam (P=.087).Conclusions: The study demonstrated feasibility. Suicidal thoughts were lower after ketamine than after midazolam at a trend level of significance, likely due to the small pilot sample. Memory improvement and BDNF are promising biomarkers. Replication is needed in an adequately powered full-scale trial.