Comparative Efficacy and Safety of Ketamine Versus Midazolam for Suicidality: A GRADE-Assessed Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Acute suicidality is an emergency psychiatric condition that requires urgent treatment. Traditional treatment approaches, such as antidepressant pharmacotherapy and psychotherapy, take weeks to achieve optimal effectiveness, hence exposing patients in imminent crisis to significant risk. Ketamine is a fast-acting N-methyl-D-aspartate (NMDA) receptor antagonist that has been suggested as a possible treatment option for suicidality. The current meta-analysis aims at comparing the relative efficacy and safety of ketamine with midazolam, an active sedative/anxiolytic comparator used in ketamine trials to support masking/blinding and control nonspecific acute effects, for reducing suicidal ideation and co-occurring depression severity.

Methods: The systematic search was done on PubMed, Embase, and Cochrane Central databases by July 2025. Randomized controlled trials (RCTs) that involved ketamine and midazolam in adults with acute suicidality were chosen. The major outcomes were the variations in suicidal ideation as assessed by the Montgomery-Åsberg Depression Rating Scale-Suicidal Ideation item (MADRS-SI) and Beck Scale of Suicide Ideation (BSS). Additional outcomes were the severity of depression in general (Montgomery-Åsberg Depression Rating Scale (MADRS) total score) and adverse events. Pooled effects were calculated using a random-effects model.

Results: This systematic review comprised ten randomized controlled trials (RCTs) with 649 participants. The meta-analysis showed that the administration of ketamine was linked to a considerable decrease in suicidal ideation in comparison to midazolam with mean differences of -1.23 points on the Montgomery-Åsberg Depression Rating Scale (MADRS-SI; 95% confidence interval (CI) -2.14 to -0.32) and -4.30 points on the Beck Scale for Suicide Ideation (BSS; 95% CI -8.01 to -0.59). Ketamine was also associated with reduced severity of depressive symptoms compared to midazolam, with a difference of -6.23 (95% CI -10.37 to -2.08) on the MADRS total score. At the same time, adverse events such as nausea, emotional disturbance, derealization, and dizziness were much more frequent in the ketamine group.

Conclusions: Ketamine is much more effective than midazolam in the short-term improvement of suicidal ideation and depressive symptoms in adult patients with acute suicidality. Despite the fact that ketamine is linked to increased rates of transient adverse effects, its quick action makes it an especially appealing intervention in emergency psychiatric treatment. Further research is thus needed to clarify the long-term effectiveness of the agent and to optimize the best treatment regimes.