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Randomized Controlled Trial
. 2022 Jan 1;79(1):24-32.
doi: 10.1001/jamapsychiatry.2021.3170.

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

Ira R Katz  1   2 , Malcolm P Rogers  3   4 , Robert Lew  5   6 , Soe Soe Thwin  6   7 , Gheorghe Doros  5   6 , Eileen Ahearn  8   9 , Michael J Ostacher  10   11 , Lynn E DeLisi  12 , Eric G Smith  13   14 , Robert J Ringer  15 , Ryan Ferguson  5   16 , Brian Hoffman  17 , James S Kaufman  18   19 , Julie M Paik  20 , Chester H Conrad  16   21 , Erika F Holmberg  5 , Tamara Y Boney  1 , Grant D Huang  22 , Matthew H Liang  5   23   24 ; Li+ plus Investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Ira R Katz et al. JAMA Psychiatry. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ostacher reported being a full-time employee of the US Department of Veterans Affairs (VA) during the conduct of the study, serving on the data monitoring board for Janssen (Johnson & Johnson), serving on the advisory boards for Sage Therapeutics and Alkermes, and receiving grants from Otsuka outside the submitted work. Dr Smith reported receiving grants from VA Clinical Science Research and Development Investigator–Initiated Research on the Prediction of Suicidal Ideation and Behavior, grants from the VA Health Services Research and Development Investigator–Initiated Research on Adverse Effects related to lithium and clozapine, and grants from the VA Health Services Research and Development pilot study related to preventing lithium toxicity outside the submitted work. Dr Kaufman reported receiving payment under a contract with the National Institute of Diabetes and Digestive and Kidney Diseases as chair of the steering committee for the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury consortium and owning stock in Amgen. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Flow Diagram
HIPAA indicates Health Insurance Portability and Accountability Act; ITT, intention to treat.
Figure 2.
Figure 2.. Time to Primary Outcome in the Lithium and Placebo Groups
See this image and copyright information in PMC

Comment in

  • Testing for Antisuicidal Effects of Lithium Treatment.
    Baldessarini RJ, Tondo L. Baldessarini RJ, et al. JAMA Psychiatry. 2022 Jan 1;79(1):9-10. doi: 10.1001/jamapsychiatry.2021.2992. JAMA Psychiatry. 2022. PMID: 34787652 No abstract available.
  • Suicide Risk and Lithium-Reply.
    Katz IR, Ferguson RE, Liang MH. Katz IR, et al. JAMA Psychiatry. 2022 May 1;79(5):513-514. doi: 10.1001/jamapsychiatry.2022.0084. JAMA Psychiatry. 2022. PMID: 35262638 No abstract available.
  • Suicide Risk and Lithium.
    Manchia M, Sani G, Alda M. Manchia M, et al. JAMA Psychiatry. 2022 May 1;79(5):513. doi: 10.1001/jamapsychiatry.2022.0081. JAMA Psychiatry. 2022. PMID: 35262644 No abstract available.

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