A Global Population-Based Study on the Association Between Ketamine and Esketamine With Suicidality Using WHO...

Background: Ketamine and esketamine have been reported to rapidly alleviate various parameters of suicidality, with antisuicidal effects that may be independent of their rapid-acting antidepressant effects. However, it remains unclear whether ketamine and/or esketamine are associated with the emergence or worsening of suicidality.

Methods: In this global observational pharmacovigilance cohort study, we analyzed suicidality reports associated with ketamine and esketamine using data from the World Health Organization's VigiBase, accessed from its inception through January 2024. Disproportionality was assessed using the reporting odds ratio (ROR), with significance defined as P < .05.

Results: Compared to lithium, esketamine exhibited higher disproportionality for suicidal ideation (ROR = 5.13, 95% CI, 4.48-5.87, P < .0001), while ketamine showed lower disproportionality for suicidal ideation (ROR = 0.76, 95% CI, 0.58-0.99, P = .043), suicide attempt (ROR =0.17, 95% CI, 0.12-0.24, P < .0001), and completed suicide (ROR =0.30, 95% CI, 0.22-0.40, P < .0001). Esketamine also had lower RORs for suicide attempt (ROR = 0.46, 95% CI, 0.39-0.54, P < .0001) and completed suicide (ROR =0.36, 95% CI, 0.30-0.43, P < .0001). When fluoxetine was used as the reference, esketamine showed higher disproportionality for suicidal ideation (ROR = 3.34, 95% CI, 3.06-3.65, P < .0001), while ketamine had a lower ROR (ROR =0.49, 95% CI, 0.39-0.63, P < .0001). For suicidal behavior, esketamine had a lower ROR (ROR =0.37, 95% CI, 0.17-0.81, P = .012), and both ketamine (ROR =0.15, 95% CI, 0.10-0.21, P < .0001) and esketamine (ROR = 0.39, 95% CI, 0.34-0.45, P < .0001) had lower RORs for suicide attempt. Both agents also had lower RORs for completed suicides (ketamine: ROR = 0.24, 95% CI, 0.18-0.32, P < .0001; esketamine: ROR= 0.29, 95% CI, 0.25-0.35, P < .0001).

Conclusion: Both increased and decreased RORs for suicidality parameters were observed with ketamine and esketamine, with similar results regardless of whether lithium or fluoxetine was used as the reference. However, causality between ketamine/esketamine use and changes in suicidality cannot be determined.