Lithium for the prevention of suicide in US veterans: a target trial emulation

BACKGROUND: Lithium has long been considered to reduce suicidal behaviour in patients with affective disorders, but evidence from large real-world populations remains limited. OBJECTIVE: To estimate the effects of lithium initiation and continuation on suicide deaths and non-lethal suicidal behaviours among adults with bipolar disorder or major depressive disorder. METHODS: We emulated two target trials using electronic health records and administrative claims from US veterans between January 2010 and December 2022. The first trial benchmarked results against the CSP-590 randomised trial by estimating the 1-year risk of suicide-related events (non-fatal suicide attempts, hospitalisations to prevent suicide or suicide deaths) among patients with a recent suicide attempt initiating lithium versus not initiating lithium. The second trial extended follow-up to 10 years to estimate risks of suicide deaths and non-lethal suicidal behaviours separately, including subgroup analyses by age and diagnosis. An additional analysis removed the requirement of a prior suicide attempt. FINDINGS: In the benchmarking analysis, the 1-year risk ratio for suicide-related events comparing lithium initiation with no initiation was 1.06 (95% CI 1.01 to 1.12), consistent with findings from the CSP-590 trial. In the extended analysis, the 10-year per-protocol risk ratio for suicide death was 1.00 (95% CI 0.86 to 1.15) and for non-lethal suicidal behaviours was 0.96 (95% CI 0.90 to 1.02). Results were similar among individuals with and without a prior suicide attempt. CONCLUSION: When added to ongoing pharmacological treatment for patients with affective disorders, lithium may not substantially reduce suicide risk highlighting the need for additional suicide prevention strategies in this population. Limitations include lack of information on adherence, dosage or blood levels of lithium which may have obscured existing differences. CLINICAL IMPLICATIONS: Our findings suggest that adding lithium therapy to the ongoing treatment regimens of patients with affective disorders for the sole purpose of reducing suicide may not be well-tolerated or meaningfully reduce suicide risk.