1. In a randomized controlled trial amongst veterans with major depression or bipolar disorders, lithium in addition to usual care did not reduce incidence of suicide-related events after a recent suicide event.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Suicide has become a rising public health concern across the world. The rate of suicide is especially high amongst veterans in the United States. Mental illness, especially affective disorders, account for many suicide events. As a result, many treatments, such as psychotherapies, ketamine, clozapine, and antidepressants, are being studied to determine if they reduce the risk of suicidal behaviour. Some research studies have shown that lithium may prevent suicide and suicide attempts in patients with bipolar disorder and depression. However, due to their observational or cohort designs, it is unclear if this is due to a clinician’s decreased propensity to prescribe lithium to patients prone to suicide. Although randomized controlled trials have been conducted, they have been largely underpowered, thus no conclusions could be made. Therefore, this randomized clinical trial sought to determine whether lithium can prevent or delay repeated suicide-related events specifically amongst veterans with bipolar disorders and major depression.
This was a double-blind, placebo-controlled 52-week randomized clinical trial. Veterans were recruited from 29 different Veteran Affairs centers and then randomized within permuted blocks of 4 within each site and within 4 strata: bipolar disorder with prior suicide attempt, bipolar disorder without prior suicide attempt, depression with prior suicide attempt, and depression without suicide prior attempt. The trial was stopped for futility after 519 participants were enrolled and randomized to one of two groups. Participants randomized to the intervention group received lithium at a dose of 600 mg/d or 300 mg/d, if there were contraindications to this dose, and titrated upward until a steady state with a lithium concentration between 0.6 and 0.8 mEq/L was achieved. Participants randomized to the control group received a placebo which was 98% microcrystalline cellulose. The primary outcome measured was the time to the first episode of any 1 of a set of suicide-related events over a 1-year follow-up period. These events included nonfatal suicide attempts, interrupted attempts, deaths by suicide, and hospitalizations to prevent suicide. The study found that there was no treatment difference between lithium and placebo for the primary outcome. Additionally, the incidence of serious events was evenly distributed amongst the two groups.
This was one of the largest randomized controlled trial to examine the effects of lithium on suicide-related behaviours. Thus, it addressed an important unanswered clinical question that can be used to help decision making. The study was double-blinded, reducing bias and improving internal validity. The large sample size allowed the study to be adequately powered unlike past similar trials. Additionally, it measured and controlled for baseline characteristics of race, ethnicity, sex, and psychiatric and medical comorbidities, all of which are known to be associated with suicidal behaviour. Despite the strengths, this study did have limitations. Firstly, it had a high attrition rate of 20% thereby introducing a significant bias. Additionally, there was a low rate of adherence to lithium treatment as only 88 participants took more than 80% of their study medication. Overall, although the methodology was sound, these factors put to question the conclusions of the study. Before a conclusion can be made, additional randomized controlled trials are needed.
In-Depth [ randomized controlled trial]: 519 participants (mean [SD] age = 42.8 [12.4] years; 437 [84.2%] male) were included in the study, from which 255 participants were assigned to the lithium group and 264 to the placebo. From the participants assigned to the lithium group, 65 (25.5%) had primary outcome events; among those assigned to receive the placebo, 62 (23.5%) had primary outcome events. Overall, there was no treatment difference found between lithium and placebo for the primary outcome (Hazard Ratio,1.10; 95% CI, 0.77-1.55; p = 0.61). Participants who stopped taking lithium and placebo had an increased rate of primary events (HR, 2.86; 95% CI, 1.48-5.53; p = 0.007), compared to those who continued. However, there was once again no difference between the lithium or the placebo group (HR, 1.11; 95% CI, 0.78-1.57; p = 0.55). The study also found no differences in mental health symptoms as measured through baseline scores on the standardized instruments. The incidence of serious adverse events was evenly distributed between the two groups. Overall, the study concluded that lithium did not prevent suicide-related events when added to usual mental health care of veterans with major depressive disorder or bipolar disorder.
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