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Original Investigation
November 17, 2021

Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Psychiatry, Michael J. Crescenz Veterans Affairs (VA) Medical Center, Philadelphia, Pennsylvania
  • 2Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 3Department of Psychiatry, VA Maine Healthcare System, Togus
  • 4Department of Psychiatry, Tufts University School of Medicine, Boston, Massachusetts
  • 5Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, Boston, Massachusetts
  • 6Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  • 7Department of Sexual and Reproductive Health and Rights, World Health Organization, Geneva, Switzerland
  • 8Department of Psychiatry, William S. Middleton VA Medical Center, Madison, Wisconsin
  • 9Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin, Madison
  • 10Department of Psychiatry, VA Palo Alto Healthcare System, Palo Alto, California
  • 11Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California
  • 12Department of Psychiatry, Cambridge Health Alliance, Cambridge Hospital, Cambridge, Massachusetts
  • 13Department of Psychiatry, VA Bedford Healthcare System, Bedford, Massachusetts
  • 14Department of Psychiatry, University of Massachusetts Medical School, Worcester
  • 15Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico
  • 16Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
  • 17Harvard Medical School, Boston, Massachusetts
  • 18Department of Nephrology, VA New York Harbor Healthcare System, New York
  • 19Renal Division, New York University School of Medicine, New York
  • 20New England Geriatric Research Education and Clinical Center and Renal Section, VA Boston Healthcare System, Boston, Massachusetts
  • 21Department of Cardiology, VA Boston Healthcare System, Boston, Massachusetts
  • 22Cooperative Studies Program, Office of Research and Development Department of Veterans Affairs, Washington, DC
  • 23Department of Medicine, Section of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts
  • 24Department of Medicine, Section of Rheumatology, VA Boston Healthcare System, Boston, Massachusetts
JAMA Psychiatry. Published online November 17, 2021. doi:10.1001/jamapsychiatry.2021.3170
Key Points

Question  Does lithium augmentation of usual care reduce the rate of repeated suicide-related events in participants with bipolar disorder or depression who have survived a recent event?

Findings  This randomized clinical trial was stopped for futility after 519 veterans had been enrolled. No overall differences between lithium and placebo treatments were found.

Meaning  The findings of this study suggest that in patients who are actively being treated for mood disorders and substantial comorbidities, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events.

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.

Trial Registration  ClinicalTrials.gov Identifier: NCT01928446

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    1 Comment for this article
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    Query
    Andrew Tuck |
    A fine study, but is the conclusion really justified? Specifically, this sentence: "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." Can a single RCT whose findings are in opposition with numerous meta-analyses really make this bold of a claim?

    Cipriani et al.'s 2013 meta-analysis included more than 10x as many RCT patients as this single RCT, and found a drastic anti-suicidal effect (odds ratio 0.13, 95% confidence interval 0.03 to 0.66). Of
    note, this was the outcome we actually care about: deaths from suicide, not hospitalizations for SI etc. (Also of note, all-cause deaths was also lower in lithium patients OR = 0.36].)

    We know very well that there is a difference between suicide attempts/ideation and completed suicides. They involve different populations, different psychiatric comorbidities, and even different genetics. We have reason to think that lithium's effects are specifically *anti-suicidal* and not *anti-suicide attempts* or *anti-SI*. For example, Cipriani et al 2013 concluded that lithium did not have anti-self injurious behavior effects. And it would be far easier to detect a significant difference between lithium patients versus controls for SIB compared to suicide deaths, since the former is faaaar more common.

    Consequently, while the authors may be justified in claiming that lithium doesn't appear to reduce suicidal ideation, attempts, or SI-related hospitalizations (at least in their population---see below), I think this study was far too small to comment on whether lithium actually reduces the risk of *suicide deaths*. Their lithium group had 1 death (a suicide) compared to 3 in the control group (2 suicides, 1 OD). This 1:3 ratio is consistent with Cipriani et al's OR for all-cause deaths in lithium patients: 0.36. Obviously, 4 total deaths is far too small of a number to make conclusions about lithium's anti-suicide or anti-death effects. But that's exactly the point.

    Last, I do have some concerns about whether this sample is representative of our patients as a whole. The vast majority (~85%) of participants were substance users. They were similarly (~85%) male. All, of course, were veterans. Additionally, from my time working in a VA compared to other academic settings, my hunch is that the distinctions between SI, suicide attempts, hospitalizations for SI, and actual deaths from suicide are extremely important in this patient population. The threshold for hospitalization for SI, for example, was drastically lower in the VA that I worked act compared to other hospitals.
    CONFLICT OF INTEREST: None Reported
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