Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder

Abstract

IMPORTANCESuicide 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. RESULTSThe 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 RELEVANCEIn 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.

Interventions for attempted suicide

“…On a similar note, a double-blind, randomized, placebo-controlled trial that examined the effectiveness of extended-release lithium (600 mg per day) versus placebo augmentation of treatment as usual among military veterans with major depression or bipolar disorder, all of whom had experienced a recent suicide-related event (including suicide attempt), found no benefits for the intervention on repeat suicide-related events; in fact, the trial was terminated for futility before completion [11 ▪ ]. Two reasons were offered by the authors for negative findings: lack of statistical power to test whether outcomes differed between diagnostic subgroups and to test the attenuating effects of comorbidities, and the nonspecific elements of study participation, which increased participant contact with the health system and, possibly, affected outcomes.…”

“…Much of the literature on effective interventions for suicide is limited by lack of statistical power, short follow-up periods, and low quality of available evidence. Specifically, about pharmacological interventions, it is unclear whether the underlying diagnosis may moderate treatment effects, as noted by investigators in the JAMA lithium trial [11 ▪ ]. Given that suicide is a multifactorial, low-incidence phenomenon [35], and given that effect size of any individual treatment strategy for suicide is likely to be small, there is a need to determine the optimal comparator interventions when designing RCTs of interventions for suicide; indeed, caring contact sessions, educational sessions, or even brief visits have all been associated with decreased risk of repeat attempts [22].…”

Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigation

“…Indeed, some have linked GSK3 inhibition to reductions in stress-induced inflammation, aggression, impulsivity, and depression ( Beurel and Jope, 2014 ), all of which have been discussed here as predictors of suicide. In addition to recent findings challenging the efficacy of lithium in reducing suicide-related events (see Katz et al, 2022 ), lithium requires long-term administration to reduce suicidal behavior and traits that predict suicide risk (e.g., impulsivity, aggression) (for a review, see Tondo and Baldessarini, 2018 ). Other modalities may also be of interest to this discussion, including brain stimulation (electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS)) or psychotherapy.…”

Psychopharmacology research: Pandemic reverberations

“…I'll start with that third study, by Katz and colleagues, 1 which has the cachet of having been published in JAMA Psychiatry and is arguably a bigger deal for us in our day-to-day work. It's a large-scale controlled, randomized clinical trial that evaluated the effects of lithium on suicidal behavior in patients with depression or bipolar disorder.…”

“…Observational studies have long suggested that lithium reduces suicide risk in patients with mood disorders. Indeed, Katz et al 1 state that the belief in lithium's "established" efficacy for this purpose -as formalized in a VA/Department of Defense practice guideline -contributed to their inability to meet their recruitment target (why refer your patient to this study if it's already "clear" that lithium works? ).…”