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For a patient at a high risk of suicide, should you prescribe lithium? Will that raise risk given that lithium is potentially lethal in overdose? Or might it lower risk, as multiple epidemiologic studies have suggested? The United States Veterans Administration (VA) has recommended lithium in their 2019 guidelines for the management of patients at risk of suicide. Have you been following that recommendation, and would you want to see some data supporting it?
Hi! Jim Phelps here for the Psychopharmacology Institute. Before putting that recommendation in their guidelines in 2019, the VA designed a study to test the value of lithium as a suicide prevention agent way back in 2013. The results were just published in November 2021. Let’s see if those results support the 2019 recommendation.
Here’s the study design. You need a population at high risk of suicide, right? Otherwise, this study could take a really long time. Knowing that one of the best predictors of a subsequent suicide attempt include a recent suicide attempt, the investigators recruited veterans who had a suicide attempt or hospitalization to prevent suicide within the previous 6 months. Across 29 VA centers, during a recruitment period of about 4 years, they identified 22,000 such veterans.
Following a long list of exclusion criteria, like pregnancy, not using birth control, and being on a diuretic, among others, 521 patients were randomized to lithium or placebo. Why am I telling you so much about the study design? Well, lithium was started at 600 mg a day, but if not tolerated, it could go back down to 300 mg a day, with a serum level goal of 0.6 mEq/L to 0.8 mEq/L. This is what I’d call medium-dose lithium—not like treating active mania but not subtherapeutic either. Given the effects of trace lithium in epidemiologic studies, we can say that they didn’t underdose.
The primary outcome measure is suicide or a suicide attempt. However, the study was interrupted midway through because the midpoint results suggested “futility.” The team preordained that midway through they’d have a blinded look at the results and decide whether to keep going because this was such a huge and long undertaking. These midpoint results suggested that patients taking lithium were no less likely to attempt or complete suicide than those taking placebo. Credit to the team and JAMA Psychiatry for publishing this negative result and without much statistical wiggling to explain it. The team did note a predominance of depression, not bipolar disorder, implying that perhaps lithium might have more of an antisuicide effect in patients with bipolar disorders.
Here’s an important finding. More than half of the patients in each group, lithium and placebo, stopped taking their study medications during the trial. Attrition in a study that goes on for a year is of course going to be a problem.
Recall, though, that several studies have found that people who stop lithium had a higher rate of relapse into subsequent bipolar mood episodes than those who had never started lithium in the first place. So, one could worry that suicide rates might be higher in this study amongst patients who stopped lithium, and that was true. Their risk was almost 3 times higher. But the same was true for patients who stopped taking placebo. Their rate also was about 3 times higher than those who did not stop taking placebo. The suicide rates went up in both groups to about the same extent.
To conclude, several years of moderate-dose lithium did not lower suicide or self-harm rates. Because the data from epidemiologic studies strongly suggest that effective exposure to trace doses over many years can actually lower suicide, one can’t conclude that lithium has no antisuicide effect. Rather, it may be that starting lithium after symptom onset has no antisuicide effect, that this veteran population is not representative of the general public, or that the medical care patients received in this study was sufficiently strong to lower the floor of suicide risk so that there wasn’t really any room for a subtle lithium effect to appear, no further down the rate could go in this population.
For more on this, see the article, which is linked here at the Psychopharmacology Institute, for interesting details regarding lithium levels and the maintenance of blinding.
Abstract
Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression.
Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event.
Design, setting, and participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019.
Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo.
Main outcomes and measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.
Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. 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.
Conclusions and relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities.
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Reference
Katz, I. R., Rogers, M. P., Lew, R., Thwin, S. S., Doros, G., Ahearn, E., … & Li+ plus Investigators. (2022). Lithium treatment in the prevention of repeat suicide-related outcomes in veterans with major depression or bipolar disorder: a randomized clinical trial. JAMA Psychiatry, 79(1), 24-32.
