Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial

Bipolar Disord. 2017 May;19(3):176-183. doi: 10.1111/bdi.12487. Epub 2017 Apr 28.


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.

Keywords: bipolar disorder; depression; ketamine; midazolam; suicidal ideation.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Anesthetics, Dissociative / administration & dosage
  • Anesthetics, Dissociative / adverse effects
  • Biomarkers / analysis
  • Bipolar Disorder* / diagnosis
  • Bipolar Disorder* / drug therapy
  • Bipolar Disorder* / psychology
  • Brain-Derived Neurotrophic Factor / analysis
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Monitoring / methods
  • Female
  • GABA Modulators / administration & dosage
  • GABA Modulators / adverse effects
  • Humans
  • Ketamine* / administration & dosage
  • Ketamine* / adverse effects
  • Male
  • Memory / drug effects*
  • Midazolam* / administration & dosage
  • Midazolam* / adverse effects
  • Middle Aged
  • Suicidal Ideation*
  • Treatment Outcome


  • Anesthetics, Dissociative
  • Biomarkers
  • Brain-Derived Neurotrophic Factor
  • GABA Modulators
  • Ketamine
  • BDNF protein, human
  • Midazolam