Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis
- “Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis” by Andrea Cipriani and colleagues (BMJ 2013;346:f3646, doi:10.1136/bmj.f3646).
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.
Why do the study?
Patients with a mood disorder such as depression or manic depression have a twofold to threefold increased mortality compared with the general population. This increase in mortality rate for the most part results from suicides. Findings since the 1970s suggest that the lifetime risk of suicide for patients with recurrent depressive or manic depressive disorders is between 15% and 19%. Drugs specifically used to moderate symptoms in patients with depressive or manic depressive illnesses have been estimated to play a minor part in the prevention of suicide.
Lithium is the only drug for which a suicide preventive effect has been continuously postulated. Lithium salts have been used successfully for the acute and long term treatment of affective disorders since the 1950s. Large cohort studies were designed to support evidence of the antisuicidal effects of lithium in patients with affective disorders. Randomised control trials were also conducted, designed to test the clinical efficacy of lithium. The meta-analysis by Cipriani and colleagues was performed to generate a statistical synthesis of all the results of those randomised controlled trials. In evidence based medicine and evidence based treatment guidelines positive results from a meta-analysis are considered the highest level of evidence for a treatment effect.
What did the authors do?
A meta-analysis is based on a systematic search and review of existing studies. To avoid the distortion of results, or bias, every step in the systematic approach is planned and documented in a study protocol before starting the review. The first step is to decide which types of study should be included and to define accurately the inclusion and exclusion criteria for the studies, such as language, date published, study design, patient’s diagnoses, and treatment. The authors defined suicide, deliberate self harm, and all cause mortality as their main outcome measures.
The major challenge of a systematic review and meta-analysis is to find all the important data, especially any unpublished studies with negative results because overlooking results like this could distort the result of the meta-analysis in a subtle way. The authors decided on a search strategy including Medline, PreMedline, Embase, CINAHL, PsycINFO, LILACS, CENTRAL (the Cochrane register of randomised controlled trials), and trial registers of the regulatory agencies in the United States, United Kingdom, European Union, and Australia from their inception to January 2013, without restrictions on language. They independently searched for all randomised trials (blinded or open) comparing lithium with placebo or other drugs in the treatment of all forms of affective disorders over at least 12 weeks. If they became aware of an unpublished trial during a search of the grey literature or if reported data were incomplete, they contacted the researchers to obtain or complete the original data.
The authors extracted information on sample size, patient characteristics, dropout rates, and treatment outcomes of each study they planned to include. This is done so that the meta-analysis is completely transparent and replicable by other researchers, and is therefore essential to the quality of the review. These extractions are provided as additional material for interested readers, as inclusion would go beyond the scope of the publication. Finally, the authors calculated the pooled odds ratios and 95% confidence intervals of all the included studies using Peto’s method, a well established statistical procedure. The odds ratio represents the odds that a suicide will occur under lithium treatment, compared with the odds of a suicide occurring with use of placebo or the active comparator drug.
What did the study find?
The meta-analysis included 6674 participants from 48 randomised controlled trials. Figure 1 1 shows which studies were excluded and why, and highlights the effort that is necessary to perform a systematic review.
The core result of a meta-analysis is the forest plot. It displays the results of each included study using a square, and the pooled results of all included studies using a rhomb. The authors performed three separate analyses for the three endpoints: suicide events, deliberate self harm events, and all cause mortality. The authors pooled the data of only those studies with identical comparators to lithium—that is, studies comparing lithium with a single drug. The horizontal lines show the confidence intervals. Confidence intervals crossing the midline imply statistical non-significance. The columns on the left comprise the number of events (of the outcome variable) and the total number of patients in the study. The columns on the right show the weight of the individual study in the pool, as well as the odds ratio of the individual study data and the pooled data. A precise study (with a high number of patients and a low variance) has a higher weight than an imprecise study (with a small number of patients and a high variance). If the rhomb is located in the left half of the grey bar (“favours lithium”) the pooled data proves the effect of lithium on the outcome variable. A rhomb in the right half shows a significant stronger effect of the comparator (placebo or another drug) on the outcome variable, and a rhomb on the midline represents inconclusive results.
The meta-analysis of Cipriani and colleagues showed that in patients with affective disorders lithium is superior to placebo in reducing suicidal events (fig 2 2 ) and overall mortality (fig 3 3 ). Lithium also tends to be better than other mood stabilising and antidepressant drugs.
What are the strengths and limitations of this study?
This meta-analysis included only randomised controlled trials and excluded observational studies of cohorts or case series and case-control studies. Randomised controlled trials are able to prove the efficacy of a treatment because they can control for confounders and bias, but patients within these studies represent only a small and highly selected population of patients and therefore may not reflect clinical reality. Other study types such as large cohort studies that cover a non-selected patient population more similar to that in clinical practice are excluded. In addition, high risk patients with suicidal ideation or even overt suicidal behaviour are typically excluded from randomised controlled trials. This causes a selection bias of the patient sample towards one that comprises fewer suicidal patients than average patients with mood disorders. Therefore, suicidal behaviour will be a rare event in these randomised controlled trials, and accordingly will be a rare event in the pooled data of the meta-analysis—as a consequence of this any possible suicidal effect of a drug will be more difficult to detect.
Secondly, most of the randomised controlled trials included in this meta-analysis were not performed to investigate the occurrence of suicidal behaviour as a primary outcome but rather to prove the effect on affective symptoms in terms of clinical response—therefore the sample size in these randomised controlled trials was not sufficient to show statistical differences in suicide rates. Only one of the included studies was designed to examine the preventive effect of lithium on suicides compared with a placebo by defining suicidal events as the primary endpoint.
A strength of the meta-analysis is that the authors also included overall mortality as one outcome variable. This ensured that they did not overlook a possible adverse effect of lithium. Lithium treatment is associated with toxicity and increased mortality if not monitored regularly, as well as potential use in overdose to commit suicide. The pooled analysis favoured lithium in most studies with lithium and placebo or active comparisons.
What does this study mean?
The meta-analysis estimated lithium’s efficacy on suicidal behaviour, the results of which have implications for clinical practice. Lithium is recommended as a first line treatment for affective disorders in all recent guidelines. Despite this, lithium’s routine use is decreasing because of its toxicity and the need for careful prescribing and complex monitoring. Doctors prefer drugs with a broader therapeutic index and that can be handled easily. In addition, the modern alternatives to lithium are promoted by the pharmaceutical industry, whereas lithium—no longer protected by a patent—is not.
The results of the meta-analysis confirm lithium’s status as a suitable drug for the treatment of patients with affective disorders to moderate their symptoms, as well as to reduce the numbers of suicides. Doctors should not lose sight of this helpful drug.Anne Berghöfer, senior scientist
1Institute for Social Medicine, Epidemiology, and Health Economics, Charité-Universitätsmedizin Berlin, Berlin 10098, Germany
Correspondence to: Anne.Berghoefer@charite.de
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed
- Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry 2005;162:1805-19.
- Lauterbach E, Felber W, Müller-Oerlinghausen B, Ahrens B, Bronisch T, Meyer T, et al. Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: a randomised, placebo-controlled, 1-year trial. Acta Psychiatr Scand 2008;118:469-79.
Cite this as: Student BMJ 2013;21:f5578