Medline ® Abstracts for References 97,99

OBJECTIVE: To assess whether lithium has a specific preventive effect for suicide and self harm in people with unipolar and bipolar mood disorders.

DESIGN: Systematic review and meta-analysis.

DATA SOURCES: Medline, Embase, CINAHL, PsycINFO, CENTRAL, web based clinical trial registries, major textbooks, authors of important papers and other experts in the discipline, and websites of pharmaceutical companies that manufacture lithium or the comparator drugs (up to January 2013).

INCLUSION CRITERIA: Randomised controlled trials comparing lithium with placebo or active drugs in long term treatment for mood disorders.

REVIEW METHODS: Two reviewers assessed studies for inclusion and risk of bias and extracted data. The main outcomes were the number of people who completed suicide, engaged in deliberate self harm, and died from any cause.

RESULTS: 48 randomised controlled trials (6674 participants, 15 comparisons) were included. Lithium was more effective than placebo in reducing the number of suicides (odds ratio 0.13, 95% confidence interval 0.03 to 0.66) and deaths from any cause (0.38, 0.15 to 0.95). No clear benefits were observed for lithium compared with placebo in preventing deliberate self harm (0.60, 0.27 to 1.32). In unipolar depression, lithium was associated with a reduced risk of suicide (0.36, 0.13 to 0.98) and also the number of total deaths (0.13, 0.02 to 0.76) compared with placebo. When lithium was compared with each active individual treatment a statistically significant difference was found only with carbamazepine for deliberate self harm. Lithium tended to be generally better than the other active comparators, with small statistical variation between the results.

CONCLUSIONS: Lithium is an effective treatment for reducing the risk of suicide in people with mood disorders. Lithium may exert its antisuicidal effects by reducing relapse of mood disorder, but additional mechanisms should also be considered because there is some evidence that lithium decreases aggression and possibly impulsivity, which might be another mechanism mediating the antisuicidal effect.

Lithium used as a drug treatment for major mental disorders such as bipolar disorder and depression is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of novel lithium-mimetic compounds that may help reduce suicide risk with fewer undesirable side effects. Suicide is a complex behavior, complicated to study in humans, and impossible to fully reproduce in animal models. The endophenotype approach, by which quantitative measures of neurobiological function are used to assess and subclassify psychiatric illness, may present a path to new discoveries. Aggression and impulsivity are candidate endophenotypes strongly associated with suicide; we review the evidence supporting aggression and impulsivity as suicide endophenotypes, as well as the effects of lithium on these constructs in both humans and rodents. Examining the mechanisms that contribute to lithium's antiaggressive and antiimpulsive effects may assist in understanding how lithium acts to reduce the risk of suicide and in elucidating the neurobiological underpinnings of suicidal behavior.