Jury Still Out on Lithium's Antisuicidal Effects

Lithium did not help reduce repeated suicidal behaviors among U.S. military veterans, a randomized trial found.

Over 1 year of follow-up, there was no difference in time to first repeated suicide-related event -- the study's primary endpoint -- between those receiving either lithium or placebo on top of usual care (​​HR 1.10, 95% CI 0.77-1.55, P=0.61), reported Ryan Ferguson, MPH, ScD, of the VA Boston Healthcare System, and colleagues.

Patients from either study group who stopped treatment early saw nearly a threefold jump in the rate of suicidal behaviors (HR 2.86, 95% CI 1.48-5.53, P=0.007), the group wrote in JAMA Psychiatry, with no significant difference between groups (HR 1.11, 95% CI 0.78-1.57, P=0.55).

The 52-week trial, which was ultimately stopped due to futility, included 519 veterans with bipolar I or II disorder (15.4%) or major depressive disorder (84.6%) -- all of whom had previously survived a suicide-related event in the last 6 months. Patients all received usual care and were randomized 1:1 to either placebo or the intervention (600 mg/day of extended-release lithium carbonate titrated upward until they reached a steady lithium concentration between 0.6 and 0.8 mEq/L). All participants continued to use their usual VA mental healthcare, which provides other medications and psychosocial treatment.

"In our opinion, this rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk," wrote accompanying editorial authors Ross Baldessarini, MD, and Leonardo Tondo, MD, both of Harvard Medical School in Boston, who proceeded to list various studies that support lithium's antisuicidal effects.

"An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not," the editorialists concluded.

While the study authors pointed out that the study benefitted from representation of both diagnoses, other factors may have worked against them.

"For example, the participants had a predominance of depression rather than bipolar disorder, the most common indication for lithium use, and most participants had substance use disorder, posttraumatic stress disorder, or both as comorbidities, possibly influencing outcomes," the researchers acknowledged. "The study did not have enough participants to evaluate outcomes for patients with bipolar disorder, to test whether outcomes differed among patients with bipolar disorder and depression, or to assess whether comorbidities attenuated the effects of lithium."

In fact, concerns about the rate of enrollment expressed by the trial's data monitoring committee prompted the futility analysis, which ultimately led to the plug being pulled on the trial.

On top of its enrollment issues, the authors noted that the study's high attrition rates, low adherence rates, and brief treatment exposure were major limitations to their findings. The potential for generalizability, they added, was yet another issue.

Study Details

At the 3-month mark, mean lithium concentrations were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depression. However, only about half of lithium concentrations measured during the analysis were 0.5 mEq/L or greater, and only 17% of all participants took 80% or more of their study medication.

Average participant age was 43 years, 84% were male, about three-fourths were white, 16% were Black, and 15% identified as Hispanic or Latino.

Notably, nearly 25% of all patients had suicide-related outcomes -- including repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide -- 65 from the lithium group and 62 from the placebo group. There was one suicide death reported in the lithium group and three in the placebo group.

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