Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial

Abstract

Objective: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder.

Method: In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1).

Results: The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.

Conclusions: Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.

Trial registration: ClinicalTrials.gov NCT01700829.

Keywords: Clinical Trial; Depression; Ketamine; Suicidal Ideation.

FIGURE 1. Change in Suicidal Ideation^a Over Time in Suicidal Patients with Major Depression Randomized to a Sub-anesthetic Infusion of Ketamine or Midazolam^b,c

^aScale for Suicidal Ideation (SSI) scores range 0 to 38, higher scores indicating greater severity. ^bModified intent-to-treat sample (N=40 per group). Ketamine 0.5 mg/kg or midazolam 0.02 mg/kg in 100 ml normal saline infused over 40 minutes, adjunctive to current, nonbenzodiazepine medications. Remission defined as Day 1 post-infusion SSI score ≥50% below baseline and less than study eligibility threshold of 4. For non-remitters, the blind was broken and those allocated to midazolam were offered an open ketamine infusion usually the following day: N=35 midazolam non-remitters received an open ketamine infusion and 1 withdrew before Day 1 assessment. ^cReduction in SSI from baseline to 24 hours after the randomized infusion (Day1 Post-infusion) was the primary outcome and was greater for the ketamine group than for the midazolam group (p=0.0003).

FIGURE 2. Change in 17-item Hamilton Depression Rating Scale Score^a Over Time in Suicidal Patients with Major Depression Randomized to a Sub-anesthetic Infusion of Ketamine or Midazolam^b,c

^aHDRS-17 scores range 0 to 53, higher scores indicating greater severity. ^bModified intent-to-treat sample (N=40 per group). Ketamine 0.5 mg/kg or midazolam 0.02 mg/kg in 100 ml normal saline infused over 40 minutes, adjunctive to current, non-benzodiazepine medications. Remission defined as Day 1 post-infusion SSI score ≥50% below baseline and less than study eligibility threshold of 4. For non-remitters, the blind was broken and those allocated to midazolam were offered an open ketamine infusion usually the following day: N=35 midazolam non-remitters received an open ketamine infusion and 1 withdrew before Day 1 assessment. ^cHDRS-17 at 24 hours after the randomized infusion (Day1 Post-infusion) was a secondary outcome and there was a trend toward greater reduction in the ketamine group compared to the midazolam group (p=0.0600).