Suicidal Ideation Effectiveness and Safety Outcomes from the Ketamine for Adult Depression Study (KADS).
Gregory Carter, Maree Hackett, Stevan Nikolin, Vanessa Dong, Nick Glozier, Shanthi Sarma, Donel Martin, Michael Berk, Verònica Gálvez-Ortiz, Andrew A Somogyi, Natalie T Mills, Sean Hood, Paul Glue, Bernhard Baune, Philip B Mitchell, Anthony Rodgers, Colleen Loo
Archives of suicide research : official journal of the International Academy for Suicide Research May 9, 2026 DOI: 10.1080/13811118.2026.2669779 via PubMed
Summary
AI-generated from the abstractKetamine's effect on suicidal ideation in adults with treatment-resistant depression remains uncertain. In a phase III double-blind randomized trial comparing subcutaneous racemic ketamine to midazolam over four weeks, one cohort showed no significant difference between groups on either the MADRS item 10 or the C-SSRS measure of suicidal ideation. A second cohort showed a non-significant reduction on the MADRS item 10 but a significant reduction on the C-SSRS. Baseline suicidal ideation scores were low in both cohorts. Adverse events requiring clinical review occurred in 13.8% of all treatment sessions. The authors suggest flexible-dose subcutaneous racemic ketamine may have beneficial effects on suicidal ideation scores, but future studies need to be powered for suicidal ideation as a primary outcome.
Study at a glance
| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 174 |
| Population | Adults with treatment resistant depression |
| Interventions | Subcutaneous racemic ketamine Midazolam |
| Duration | 4-week intervention |
| Topics | Ketamine |
| Keywords | Effectiveness Randomized controlled trial Safety Suicidal ideation |
| Key finding | Subcutaneous racemic ketamine showed mixed results on suicidal ideation scores compared to midazolam, with a significant reduction on one measure in one cohort but not on the other measure or in the other cohort. |
Abstract
Ketamine has disputed effects on suicidal ideation scores in depressed populations. This study assessed effectiveness of ketamine in adults with treatment resistant depression, examining a secondary outcome of suicidal ideation. Phase III, double-blind, randomized, active-controlled, multicenter trial. Participants were randomized to twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks; cohort 1 (n = 68) fixed-dose and cohort 2 (n = 106) flexible-dose. Analyses were cumulative link mixed models for change scores (baseline to treatment end), comparing ketamine versus midazolam (active control) for suicidal ideation, using the MADRS item 10 (planned) and C-SSRS (post hoc). Mean baseline ideation scores were low (MADRS-10 cohort 1: 1.93 and cohort 2: 2.0). Cohort 1 had no significant difference between intervention and control: MADRS-10 β = 0.97, (95% CI=-0.95 to 2.90, p = 0.32), C-SSRS β = 0.64, (95% CI=-1.27 to 2.55, p = 0.51). Cohort 2 had a non-significant reduction for MADRS-10: β -0.61 (95% CI=-1.65 to 0.44, p = 0.25), but a significant reduction for C-SSRS: β-1.32 (95% CI=-2.51 to -0.12, p = 0.03). Participants had a higher C-SSRS score than the previous session, each of which triggered a clinical review, in 13.8% of all treatment sessions. Subcutaneous, flexible-dosed, racemic ketamine over four weeks showed beneficial effects on suicidal ideation scores. Future studies should use suicidal ideation powered as a primary outcome, sample the full range of ideation scores, use consensus instruments, and explore treatment discontinuation, in various depressed populations.