Effects of ketamine and esketamine on death, suicidal behaviour, and suicidal ideation in psychiatric disorders: A systematic review and meta-analysis
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Background
Ketamine and esketamine have been claimed to possess anti-suicidal effects and potentially to transform suicide prevention. This study provides an updated overview of evidence from clinical trials.
Methods
We conducted a systematic review and meta-analysis to establish whether ketamine or esketamine reduce death, suicides, suicide attempts or suicidal ideation, compared to active or inert placebo among people with psychiatric disorders. We searched EMBASE, PubMed and PsycINFO until 09.01.25 for randomised controlled trials which compared the effect of ketamine or esketamine with placebo for the treatment of psychiatric disorders. Risk of bias was assessed using the Cochrane Risk of Bias Tool. Data were synthesised with meta-analysis, including methods for double-zero events.
Results
We included 66 trials with a total of 5103 participants. Rates of suicidal behavior were 0.91% for ketamine/esketamine and 1.23% for placebo, with the 95% confidence/credible intervals including the null-effect, OR = 0.86 [0.46 to 1.54] (Bayesian Analysis) and with low heterogeneity. There were 21 (0.77%) suicide attempts, 4 (0.14%) suicides and 6 (0.21%) deaths with ketamine/esketamine compared to 26 (1.18%), 1 (0.05%) and 2 (0.09%) on placebo. Ketamine/esketamine significantly reduced suicide ideation up to 2 weeks (standardized mean differences [SMD] at 12h to 24h of -0.35 [-0.51 to -0.19], I 2 = 12%), but had small effects (SMD < 0.20, I 2 ≤ 25%) thereafter. Quality assessment revealed unreliable blinding and selective reporting.
Discussion
There is insufficient evidence for a preventive effect of ketamine/esketamine for suicidal behavior. The observed immediate but short-term effect on suicide ideation may be overestimated due to unblinding bias. Our review is the most comprehensive on suicidality, however, more evidence is needed to draw conclusions on suicidal behavior.
Other
No specific funding was involved. The protocol was registered with PROSPERO ( CRD42023364156 ).
KEY MESSAGES
What is already known on this topic
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Ketamine and esketamine have been considered to tranform suicide prevention with evidence from multiple studies suggesting they may rapidly alleviate depression and suicide ideation.
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There have been numerous calls for studies to investigate if these findings translate to suicidal behavior. With the many new studies that have emerged only recently, such a review is overdue, together with an update on suicide ideation.
What this study adds
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Despite including studies up to January 2025, evidence on whether ketamine/esketamine can effectively reduce suicidal behavior remains inconclusive.
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A small to medium short-term effect on suicide ideation within the first three days was observed for ketamine but not for esketamine and unblinding bias is likely involved.
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Repeated doses did not show superiority over single administrations in reducing suicide ideation.
How this study might affect research, practice, or policy
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More studies are needed to judge if ketamine/esketamine can reduce suicidal behavior, and how unblinding effects can explain the short-term effect on suicide ideation.
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The practice of repeated dosings should be questioned and needs further investigation.
