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. Method This randomized clinical trial tested the effect of adjunctive sub-anesthetic intravenous ketamine on clinically significant suicidal ideation in major depressive disorder (MDD). Adults (N=80) with current MDD and score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomized to ketamine or midazolam infusion. The primary outcome was Day 1 SSI score (24 hours post-infusion). Other outcomes included global depression and adverse effects. Results Reduction of SSI score was 4.96 points greater after ketamine compared with midazolam at Day 1 (95% confidence interval (CI)=2.33 to 7.59; p=0.0003; Cohen’s d=0.75). Proportion of responders (≥50% reduction in SSI) at Day 1 was 55% after ketamine and 30% after midazolam (OR=2.85 (95% CI=1.14 to 7.15); p=0.0237; NNT=4.00). Improvement in the Profile of Mood States (POMS) depression subscale was greater at Day 1 compared with midazolam treatment (Estimate=7.65 (95% CI=1.36 to 13.94), df=75, t=2.42, p=0.0178), and this effect mediated 33.6% of ketamine’s effect on SSI score. Side effects were short-lived. Benefit was sustained for up to six weeks with clinical pharmacotherapy. Conclusions Adjunctive ketamine demonstrated greater reduction of clinically significant suicidal ideation in depressed patients within 24 hours compared to midazolam, partially independent of antidepressant effect. Research is needed to understand ketamine’s mechanism of action and to develop safe, longer-term treatment.

What Is New about New Antidepressants?

“…The conclusion that CBT prolonged the response to ketamine is limited by the small sample, the open-label design, the lack of a control group, the absence of a direct comparison to ketamine without CBT, and open adjustment of concomitant medications in 25% of the patients. In the comparison of ketamine and midazolam discussed earlier [51], open-label follow-up found a continued reduction of suicidality rating scale scores over 6 weeks, but during this time antidepressants and other medications were adjusted openly.…”

“…However, there has only been one dose-finding study [50], and the optimal dose for an individual patient remains to be determined [8]. A single intravenous dose of ketamine was superior to intravenous midazolam in reducing a rating of suicidality over 24 h (effect size, 0.75), but improvement on the Hamilton Depression Rating Scale was not significantly superior to that on benzodiazepine and patients had a lifetime history of taking only 4 antidepressants in 2 antidepressant classes [51]. The reduction of suicidality ratings was within the range reported for antidepressants in depressed, suicidal patients.…”

Ketamine for Depression, 6: Effects on Suicidal Ideation and Possible Use as Crisis Intervention in Patients at Suicide Risk

“…At least 2 RCTs, 18,19 not included in the meta-analyses discussed, 13,15 have recently been published. Both RCTs recruited patients with clinically significant suicidal ideation, operationalized as a Scale for Suicidal Ideation (SSI) score of at least 4.…”

“…In perhaps the largest and most important RCT to date, Grunebaum et al 19 randomized 80 inpatients with moderately severe major depressive disorder and clinically significant suicidal ideation (mean SSI score of approximately 15) to receive a single infusion of either ketamine (0.5 mg/ kg) or midazolam (0.02 mg/kg); ongoing antidepressant medications, if any, were continued unchanged, but benzodiazepine use was barred. Nearly half of the patients had a prior history of suicide attempt.…”

“…The mean SSI score in the ketamine group, which fell to about 5 a day after the infusion, remained in the 5-6 point range during a 6-week follow-up period in which treatments were optimized to individual needs. This study 19 is important because of the large sample size, the use of midazolam as a biologically active control, and the assessment of suicidal ideation using the SSI. Another strength is that patients were not limited to those who were antidepressant-refractory; this makes the sample more representative of depressed and suicidal patients in clinical practice.…”