Addition of Lithium to Usual Care Did Not Prevent Suicide-Related Events in Veterans with Previous Suicidal Behavior

June 2022

The risk of suicide is higher in US veterans compared with the general public even after controlling for age and sex. Lithium is an established maintenance therapy for bipolar disorder, and some observational studies have suggested that lithium may reduce suicide attempts in patients with depression or bipolar disorder. Results from small randomized clinical trials and meta-analyses have been mixed, however.

To evaluate the efficacy of lithium for preventing suicide-related events in veterans with a recent history of suicidal behavior, the US Department of Veterans Affairs sponsored a phase 2/3, double-blind, randomized clinical trial.

Conducted at 29 Veterans Affairs medical centers, participants included veterans who had received a diagnosis of major depression or bipolar disorder and had demonstrated suicidal behavior or had been hospitalized to prevent suicide within the previous 6 months. All participants received usual care and were randomly assigned to receive lithium or placebo daily for 52 weeks. Doses were adjusted as needed to reach target serum lithium levels of 0.6 mEq/L to 0.8 mEq/L.

Of 519 participants, 84.2% were male and 15.8% were female with a mean age of 42.8 years. The majority (84.6%) of participants received a diagnosis of major depression, and 15.4% received a diagnosis of bipolar disorder. The primary outcome was time to the first repeat of a suicidal behavior, defined as a suicide attempt, hospitalization to prevent suicide, or completed suicide.

The trial was stopped early for futility after 197 primary outcome events in 127 participants had occurred. No significant difference in repeated suicide-related events was found between the lithium and placebo groups (P = .61). Suicide-related events occurred in 24.5% of participants overall, 25.5% of participants receiving lithium, and 23.5% of participants receiving placebo.

The investigators found that most participants did not reach the target serum lithium levels. For the subset of participants who took ≥80% of their study medication, no significant difference in the outcome event rate was found between groups (P = .38). They also did not find any difference in mental health symptoms measured on rating scales and questionnaires between groups before or after treatment.

Because the trial was stopped early, the investigators did not have statistical power to analyze differences in outcomes between subgroups with bipolar disorder, depression, or comorbidities, such as posttraumatic stress disorder and substance abuse.

The investigators concluded, “Our study suggests that in a population of patients with substantial comorbidities who are actively being treated for mood disorders and coexisting mental health or substance use disorders, simply adding lithium to existing medication regimens is unlikely to be effective for preventing an outcome that draws from a broad range of suicide-related events.”


Katz IR, Rogers MP, Lew R, et al. Lithium treatment in the prevention of repeat suicide-related outcomes in veterans with major depression or bipolar disorder: a randomized clinical trial. JAMA Psychiatry. 2022;79(1):24-32.

Related Items

Subscribe to Value-Based Care in Neurology

Stay up to date with the latest news in neurology by subscribing to receive the free VBCN e‑Newsletter.