Lithium's Anti-suicidal Effects Questioned

Megan Brooks

November 19, 2021

Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.

The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.

"Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events," study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, Massachusetts, told Medscape Medical News.

The study was published online November 17 in JAMA Psychiatry.

Surprising Findings

The results were somewhat surprising, Ferguson added. "Lithium showed little, or no, effect in our study compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide," he said.

However, the authors of an accompanying editorial urge caution in concluding that lithium has no anti-suicidal effects. 

This "rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk," write Ross Baldessarini, MD, and Leonardo Tondo, MD, Department of Psychiatry, Harvard Medical School, Boston.

Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event.  In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.

The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.

The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.

There was no significant difference in the primary outcome (hazard ratio [HR], 1.10; 95% CI, 0.77 - 1.55; P = .61).

A total of 127 participants (24.5%) had suicide-related outcomes — 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. There were no unanticipated drug-related safety concerns. 

Caveats, Cautionary Notes

The researchers note that the study did not reach its original recruitment goal. "One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/US Department of Defense Clinical Practice Guideline," they point out.

They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.

As a result of small numbers, it wasn't possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.

The study's protocol increased participants' contacts with the VA, which also may have affected outcomes, the researchers note.

In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.

Editorial writers Baldessarini and Tondo note the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.

"In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret," they point out.

Evidence supporting an anti-suicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as "marked, temporary" increases in suicidal behavior soon after stopping lithium treatment.

Baldessarini and Tondo note the current findings "cannot be taken as evidence that lithium lacks anti-suicidal 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 anti-suicidal effects of lithium is already settled, which it certainly is not," they write.

Ferguson "agrees that more work needs to be done to understand the anti-suicidal effect of lithium.

The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, US Department of Veterans Affairs. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.

Baldessarini and Tondo have disclosed no relevant financial relationships. Th eir editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.

JAMA Psychiatry. Published online November 17, 2021. Abstract, Editorial

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