The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study

Major depressive disorder (MDD) with suicidal ideation remains a major clinical challenge, and interest has grown in ketamine's rapid-acting antidepressant and anti‑suicidal properties. Feeney and colleagues note that intravenous (IV) ketamine has shown rapid reductions in depressive symptoms and suicidal ideation in prior studies, but durability beyond the first week has been inconsistent across double‑blind trials. They contrast this with intranasal esketamine, which is FDA‑approved for treatment‑resistant depression (TRD) and for depressive symptoms in adults with acute suicidal thoughts or actions, and highlight methodological issues in earlier IV ketamine trials—particularly partial unblinding and allowance of medication changes during follow‑up—that complicate interpretation of longer‑term effects. This paper reports a post‑hoc analysis from a previously published randomized, double‑blind trial, examining change in the Montgomery‑Åsberg Depression Rating Scale (MADRS) suicide item over 30 days after a single IV ketamine infusion versus an active midazolam control in adults with TRD. The investigators aimed to assess whether a single ketamine infusion produced sustained reductions in suicidal ideation when follow‑up was conducted under conditions intended to preserve blinding and without permitted changes to concomitant antidepressant treatment.

The analysis derives from a multisite, randomized, double‑blind, active placebo‑controlled trial in adults with treatment‑resistant major depressive disorder who were on stable antidepressant treatment. Participants had a MADRS total score > 20 at screening and baseline, were stratified by body mass index, and were randomized in equal blocks to five arms: ketamine 0.1 mg/kg (n = 18), 0.2 mg/kg (n = 20), 0.5 mg/kg (n = 22), 1.0 mg/kg (n = 20) or midazolam 0.045 mg/kg (n = 19). Midazolam was chosen as an active placebo to better mimic some psychotropic effects of ketamine and reduce unblinding. For the present post‑hoc report the ketamine 0.2 mg/kg arm was excluded because it did not differ from placebo in the original trial; the remaining ketamine doses were pooled for analyses focused on suicidal ideation because sample sizes for each dose with baseline suicidality were insufficient for dose‑specific comparisons. At baseline (Day 0) participants received the assigned drug by continuous IV infusion over 40 minutes, with monitoring of vital signs during and after infusion. Follow‑up assessments occurred at days 1, 3, 5, 7, 14 and 30. The primary outcome in the parent trial was the 6‑item HAM‑D (HAM‑D‑6); this report concentrates on the MADRS suicide item (range 0–6) as a secondary measure. Clinically significant suicidal ideation was defined as MADRS suicide item ≥2 (where 2 corresponds to “weary of life, only fleeting suicidal thoughts”); absence of clinically significant ideation was defined as a score of 0 or 1. Patients judged to be at imminent suicide risk were excluded, and concomitant psychotropic medications were required to remain stable for at least four weeks prior to randomization and through the follow‑up period. Statistical analyses used SAS v9.4. For this post‑hoc analysis the investigators created a subset of participants with baseline MADRS suicide item ≥2. Group comparisons of mean suicide item scores and mean change from baseline were performed with independent samples t‑tests. They further examined the subgroup who achieved a reduction to <2 at day 3 and plotted the proportion who experienced recurrence (MADRS suicide item ≥2) at subsequent visits. Time‑to‑recurrence among day‑3 responders was analysed using Kaplan‑Meier survival curves and the lifetest procedure; the hazard ratio (HR) was reported, where HR quantifies the relative rate of relapse over the follow‑up interval.

Of 79 participants in the original analysis set for this report, 60 received pooled doses of IV ketamine (0.1, 0.5 or 1.0 mg/kg) and 19 received IV midazolam. Forty patients in the ketamine group and 16 in the midazolam group had baseline MADRS suicide item scores ≥2 and were included in this analysis (total N = 56). The analysed subgroup comprised 28 male and 28 female participants with mean age 45.75 ± 12.32 years. The overall mean (SD) baseline MADRS suicide item score was 2.84 ± 0.73 (ketamine 2.90 ± 0.74; midazolam 2.69 ± 0.70). Forty‑eight of the 56 participants (85.7%) completed the 30‑day observation period. When comparing mean MADRS suicide item scores over time in the 56 participants with baseline scores ≥2, the investigators report a statistically significant difference between groups at day 30, with lower mean scores in the pooled ketamine group than in the midazolam group. The extract reports a day‑30 comparison as 2.03 ± 1.59 for ketamine versus 3.00 ± 1.41 for midazolam with a t‑test p = 0.049; figure annotations in the text also report day‑30 t‑test p = 0.027 and Hedges' g = 0.71. Among the 56 participants, 31 (24 ketamine, 7 midazolam) had an early anti‑suicidal response defined as a MADRS suicide item <2 at day 3. For this subgroup, mean changes from baseline did not differ significantly between treatment groups at any follow‑up point (all t‑tests p > 0.10), with a reported Hedges' g of 0.64 at day 30. Time‑to‑recurrence analysis among the 31 day‑3 responders found no significant difference in survival probability over 30 days (log‑rank p = 0.9364; HR 0.97, SE 0.51). Recurrence rates among day‑3 responders at day 30 were 10/22 (45.5%) in the ketamine group and 5/7 (71.4%) in the midazolam group. The authors note that patients who initially improved tended, on average, to experience an increase in MADRS suicide item scores over the 30‑day follow‑up, and that recurrence of clinically significant suicidal ideation was common in both groups. Safety events reported in the parent trial included one intentional overdose in the 0.2 mg/kg ketamine arm and two events classified as self‑injury in the midazolam arm; a full safety report is contained in the original publication.

Feeney and colleagues interpret these findings to indicate that a single IV ketamine infusion may produce a small reduction in clinician‑rated suicidal ideation out to 30 days in patients with TRD when all participants with baseline suicidality are considered, but that the early anti‑suicidal effect diminishes rapidly. They emphasise concordance with prior work showing rapid onset of ketamine's anti‑suicidal effects and generally weak durability beyond the first few days. The investigators cite meta‑analytic evidence concluding that anti‑suicidal effects after IV ketamine are not typically sustained beyond 72 hours and discuss trials of repeated infusions that produced cumulative or transient benefits but did not clearly maintain effects long term. The authors outline strengths of the parent trial that bolster confidence in the observations: randomized, double‑blind design with an active placebo; remote independent raters to help preserve blinding; no antidepressant washout and prohibition of medication changes during follow‑up, creating a pragmatic augmentation model; and good retention through 30 days. At the same time they acknowledge several limitations relevant to interpretation: the analysis was post‑hoc and restricted to the MADRS suicide item rather than dedicated suicidality scales; the original trial did not specifically recruit for suicidal ideation so subgroup numbers were small; participants at imminent risk of suicide or with severe ideation were excluded, limiting generalisability to those populations; relatively few participants were randomised to placebo because the parent trial included multiple ketamine dose arms; and participants were not re‑randomised at day 3, limiting causal comparisons of sustained effects beyond that point. Additional limitations noted include a broad definition of TRD (allowing up to seven failed antidepressant trials), restriction of TRD definition to pharmacological treatments only, potential contribution of stable benzodiazepine use, and other exclusion criteria that narrow applicability. Finally, the investigators suggest directions for future research, including trials of repeated ketamine infusions or strategies to maintain rapid benefit, investigation of effects in more severely suicidal or more refractory TRD populations, assessment of the role of concomitant benzodiazepines, and exploration of combining ketamine with acute psychological interventions. Their concluding position is that a single IV ketamine dose may have a modest adjunctive role in reducing suicidal ideation in TRD, but early effects tend to wane quickly and further research is required to define optimal use and durability.