Lithium and Suicide Prevention: More Thoughts on Recent VA Study

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There has been much discussion of the recently published large (519 participants) US Department of Veterans Affairs (VA)–sponsored randomized clinical trial of lithium versus placebo to prevent suicide attempts, hospitalizations to prevent suicide, and deaths after a previous attempt.¹ The distinguished group of investigators found no advantage for lithium, and the study was actually interrupted earlier than planned because of the negative results on preliminary analysis.

The authors concluded that “simply” adding lithium to existing medication regimens is unlikely to be effective in preventing a broad range of suicide-related events. An editorial by Baldessarini and Tondo, however, proposed instead that the findings “cannot be taken as evidence that lithium lacks antisuicidal effects” due to numerous serious limitations in the study.²

The first of those limitations was that most patients had nonbipolar depression (only 15% had bipolar I or II disorder), a heterogeneous population for which the antisuicidal effects of lithium are perhaps less established. Additionally, the lithium level, which was low overall (0.54 mEq/L), was particularly low in the patients with nonbipolar depression (0.46 mEq/L). Notably, an important previous study (the LiTMUS trial) found no value in general to adding a similar “moderate” dose of lithium for 6 months in patients with bipolar disorder³—so the dose issue could be critical. Length of time on treatment was not much longer in the latest trial: 38 weeks.

In significant recent support of lithium, a systematic review (not cited in the study or the editorial) evaluated studies involving more than 200,000 participants pertinent to the question of suicide prevention, including patients with mood disorder and others, and concluded that lithium was associated with a significant reduction in suicide behaviors.⁴

Another flaw noted by Baldessarini and Tondo was the large dropout rate of 52%, many of them early in the study. This quantity of dropouts would make any study hard to interpret.

The study was also problematic in having a lot of important comorbidities in the participants. Substance use was present in 85%. This would be likely to reduce the impact of any bipolar treatments applied and is a large factor in suicidal behaviors. It is also very likely to reduce the potential for finding a difference between lithium and placebo. Other conditions associated with suicide (matched in the lithium and control groups as best as possible) were present in large numbers including personality, anxiety, and other disorders—and these would also tend to reduce drug-placebo differences.

Furthermore, the editorial notes that there was no analysis of what other medications the patients were on that might have reduced lithium effectiveness. Antidepressants come to mind because they are often included in the regimens of patients with bipolar disorder, and this use is potentially harmful according to some evidence. For example, the STEP-BD study found that inclusion of an antidepressant in the regimen of rapid-cycling patients with bipolar disorder tripled the rate of recurring depression compared with not taking an antidepressant, even if the patient was on a mood stabilizer.⁵

The study was not totally negative with respect to lithium’s potential benefits for patients with bipolar disorder. In the small number (N = 30) of patients with bipolar disorder in the study for which the primary outcomes were available (first and subsequent suicide-related events), there were 10 events in the lithium group and 20 in the placebo group.¹ This was not statistically significant due to the small N, but numerically it is rather impressive in favor of lithium.

In conclusion, despite this new study and the need for further research, the best recommendation at this time regarding lithium in patients with bipolar disorder who are suicidal would be to consider it a worthwhile option. However, it would be important to prioritize treating comorbid substance use disorders and other comorbidities that could affect suicide before—or at least at the same time as—adding lithium to address suicidal thoughts and behaviors. One should not “simply” add lithium.

After adding lithium, if the patient is on an antidepressant, it is advisable to taper off the antidepressant(s). If needed due to persisting or recurrent depression, consider adding evidence-based bipolar depression medications such as lamotrigine, lurasidone, quetiapine, or cariprazine.⁶ Lumateperone received US Food and Drug Administration (FDA) approval for bipolar depression in December 2021, so that could be considered as well.⁷ According to a news release, there have been 2 other unpublished lumateperone studies, with one showing no efficacy and the other showing that using lumateperone as an adjunct to lithium or valproate had a small benefit.

Dr Osser is associate professor of psychiatry at Harvard Medical School in Boston, Massachusetts, and codirector of the US Department of Veterans Affairs National Bipolar Disorder Telehealth Program in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

References

1. Katz IR, Rogers MP, Lew R; Li+ plus Investigators. 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.

2. Baldessarini RJ, Tondo L. Testing for antisuicidal effects of lithium treatment. JAMA Psychiatry. 2022;79(1):9-10.

3. Nierenberg AA, Friedman ES, Bowden CL, et al. Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium. Am J Psychiatry. 2013;170(1):102-110.

4. Del Matto L, Muscas M, Murru A, et al. Lithium and suicide prevention in mood disorders and in the general population: a systematic review. Neurosci Biobehav Rev. 2020;116:142-153.

5. El-Mallakh RS, Vöhringer PA, Ostacher MM, et al. Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial. J Affect Disord. 2015;184:318-321.

6. Wang D, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on bipolar depression. Bipolar Disord. 2020:22(5):472-489.

7. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry. 2021;178(12):1098-1106.