Suicidal ideation and suicide attempt following ketamine prescription in patients with treatment-resistant depression: a nation-wide cohort study

Abstract Ketamine, including esketamine, is an effective treatment for patients with treatment-resistant depression (TRD); however, its long-term efficacy in real-world populations remains poorly characterized. This is a retrospective cohort study using TriNetX US Collaborative Network, a platform aggregating electronic health records (EHRs) data from 93 million patients from 56 health care organizations in the US, and the study population includes 321,367 patients with a diagnosis of TRD who were prescribed relevant treatment in their EHRs. The prescription of ketamine (including esketamine) was associated with significant decreased risk of suicidal ideation compared to prescription of other common antidepressants: HR = 0.65 (95% CI: 0.53 – 0.81) at 1 day – 7 days, 0.78 (95% CI: 0.66 – 0.92) at 1 day – 30 days, 0.81 (95% CI: 0.70 – 0.92) at 1 day – 90 days, 0.82 (95% CI: 0.72 – 0.92) at 1 day – 180 days, and 0.83 (95% CI: 0.74 – 0.93) at 1 day – 270 days. This trend was especially robust among adults over 24 years of age, males, and White patients with TRD. No significant difference was observed for suicide attempts, except significantly increased risk for adolescents (aged 10-24) at 1 day – 30 days with HR = 2.22 (95% CI: 1.01-4.87). This study provides real-world evidence that ketamine has long-term benefits in mitigating suicidal ideation in patients with treatment-resistant depression. Future work should focus on optimizing dosage regimens for ketamine, understanding the mechanism, and the difference in various demographic subpopulations.