Effects of ketamine and esketamine on death, suicidal behaviour, and suicidal ideation in psychiatric disorders: A systematic review and meta-analysis
Abstract
Obective: 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 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. <h4>Design:</h4> Systematic review and meta-analysis. Data sources: We searched EMBASE, PubMed and PsycINFO from inception until 02.12.2025. Eligibility criteria for selecting studies: Eligible for inclusion were randomised controlled trials which compared the effect of ketamine or esketamine with active or inert placebo for the treatment of people with psychiatric disorders. We included trials with concomitant treatments and excluded those where ketamine/esketamine were used as anaesthics. Data synthesis and study quality: Data were synthesised with meta-analysis, including methods for double-zero events. Risk of bias was assessed using the Cochrane Risk of Bias Tool and quality of the evidence was evaluated using GRADE guidelines. <h4>Results:</h4> We included 73 trials with a total of 5671 participants. The majority of trials (56) examined ketamine, 16 esketamine, and 1 arketamine. Twelve of the ketamine trials were cross-over trials and the rest were parallel group trials. A single dose was used in 35 trials. Median length of treatment and follow-up was 45 days. Rates of suicidal behaviour were 1.63% for ketamine/esketamine and 1.72% for placebo, with the 95% credible interval including the null-effect, OR = 0.98 [0.58 to 1.60] (Bayesian Analysis with weak priors). There were 42 (1.43%) suicide attempts, 6 (0.20%) suicides and 9 (0.31%) deaths with ketamine/esketamine compared to 41 (1.64%), 2 (0.08%) and 5 (0.20%) on placebo. Ketamine/esketamine significantly reduced suicide ideation up to 4 weeks (standardized mean differences [SMD] at 12h to 24h of -0.31 [-0.45 to -0.18], I2 = 26%), but effects were small after 24 hours and dropped to near zero after 4 weeks. Subgroup analysis for suicide ideation revealed that effects of esketamine were close to zero after 24 hours whereas effects for ketamine were small to medium for the first 4 weeks. Effects tended to be larger in trials involving suicidal patients. Repeated dosings were not superior to single doses. Quality assessment revealed unreliable blinding, selective reporting and - especially for suicidal behaviour - imprecision, leading to low or very low certainty ratings for suicidal behaviour and low or moderate certainty ratings for suicide ideation. <h4>Conclusions:</h4> There is insufficient evidence for a preventive effect of ketamine/esketamine for suicidal behaviour. 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 to date, however, more evidence is needed to draw conclusions on suicidal behaviour. Other: No specific funding was involved. The protocol was registered with PROSPERO (CRD42023364156).
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