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Lithium and Suicide Risk in Bipolar Disorder

Researchers conclude that lithium maintenance provides a sustained protective effect against suicidal behavior in manic-depressive disorders, a benefit that has not been shown with any other medical treatment.

Can timely diagnosis and treatment of depression reduce the risk of suicide? Studies of treatment effects on mortality in major mood disorders remain rare and are widely considered difficult to carry out ethically. Despite close associations of suicide with major affective disorders and related comorbidity, the available evidence is inconclusive regarding for sustained reductions of suicide risk by most mood-altering treatments, including antidepressants. Studies designed to evaluate clinical benefits of mood-stabilizing treatments in bipolar disorders, however, provide comparisons of suicidal rates with and without treatment or under different treatment conditions. This emerging body of research provides consistent evidence of reduced rates of suicides and attempts during long-term treatment with lithium. This effect may not generalize to proposed alternatives, particularly carbamazepine. Our recent international collaborative studies found compelling evidence for prolonged reduction of suicidal risks during treatment with lithium, as well as sharp increases soon after its discontinuation, all in close association with depressive recurrences. Depression was markedly reduced, and suicide attempts were less frequent, when lithium was discontinued gradually. These findings indicate that studies of the effects of long-term treatment on suicide risk are feasible and that more timely diagnosis and treatment for all forms of major depression, but particularly for bipolar depression, should further reduce suicide risk.

INTRODUCTION

Risk of premature mortality significantly increases in bipolar manic-depressive disorders.(1-12) Mortal risk arises from very high rates of suicide in all major affective disorders, which are at least as great in bipolar illness as in recurrent major depression.(1, 2, 13-16) A review of 30 studies of bipolar disorder patients found that 19% of deaths (range in studies from 6% to 60%) were due to suicide.(2) Rates may be lower in never-hospitalized patients, however.(6, 11, 12) In addition to suicide, mortality is probably also increased due to comorbid, stress-related, medical disorders, including cardiovascular and pulmonary diseases. (3-5, 7, 10) High rates of comorbid substance use disorders contribute further to both medical mortality and to suicidal risk (11, 17), especially in young persons (18), in whom violence and suicide are leading causes of death.(11, 12, 19)

Researchers conclude that  lithium maintenance provides a unique sustained protective effect against suicidal behavior in manic-depressive disorders. Learn more.Suicide is strongly associated with concurrent depression in all forms of the common major affective disorders.(2, 9, 20, 21) Lifetime morbid risk for major depression may be as high as 10%, and lifetime prevalence of bipolar disorders probably exceeds 2% of the general population if cases of type II bipolar syndrome (depression with hypomania) are included. (2, 22, 23) Remarkably, however, only a minority of persons affected with these highly prevalent, often lethal, but usually treatable major affective disorders receive appropriate diagnosis and treatment, and often only after years of delay or partial treatment. (8 ,9, 22, 24-28) Despite grave clinical, social, and economic effects of suicide, and its very common association with mood disorders, specific studies on the effects of mood-altering treatments on suicidal risk remain remarkably uncommon and inadequate to guide either rational clinical practice or sound public health policy.(7, 8, 11, 12, 22, 29, 30)

In view of the clinical and public health importance of suicide in manic-depressive disorders, and the rarity of evidence proving that modern mood-altering treatments reduce suicide rates, an emerging body of research has been reviewed. It indicates a significant, sustained, and possibly unique reduction of suicidal behavior during long-term treatment with lithium salts. These important effects have not been demonstrated with other mood-altering treatments.

THERAPEUTICS RESEARCH IN SUICIDE

Despite broad clinical use and intensive study of antidepressants for four decades, evidence that they specifically alter suicidal behavior or reduce long-term suicidal risk remains meager and inconclusive.(9, 11, 17, 31-37) The introduction of selective serotonin reuptake inhibitors (SSRIs) and other modern antidepressants that are much less toxic on acute overdose than older drugs appears not to have been associated with a decrease in suicide rates.(34, 38) Instead, their introduction may have been associated with a shift toward more lethal means of self-destruction.(39) We found only one report of a significantly lower rate of suicide in depressed patients treated with antidepressants compared to placebo (0.65% vs 2.78% per year), with an even lower rate with an SSRI than with other antidepressants (0.50% vs 1.38% per year).(37) Nevertheless, suicide rates during antidepressant treatment in that study were far greater than the general population rate of 0.010% to 0.015% per year, uncorrected for persons with mood disorders and other illnesses associated with increased suicide rates.(40)

Bipolar depression accounts for much or most of the time one is stricken with bipolar disorder (24) and can be disabling or fatal.(2, 7, 11, 12) Remarkably, however, the treatment of this syndrome remains much less studied than depressive to manic, agitated or psychotic unipolar major depression.(24, 38, 41) Indeed, bipolarity is typically a criterion for exclusion from studies of antidepressant treatment, apparently to avoid risks of switching from depressive to manic, agitated or psychotic phases when patients are not protected with lithium or another mood-stabilizing agent.(38)

Reasons for the rarity of studies of the effects of modern psychiatric treatments on suicide rates are not entirely clear. Therapeutic research on suicide is appropriately constrained ethically when fatality is a potential outcome, and particularly when discontinuation of ongoing treatment is required in a research protocol. Treatment discontinuation is increasingly recognized as being followed by at least temporary, sharp increases in morbidity that may exceed the morbid risk associated with untreated illness. This evidently iatrogenic phenomenon has been associated with discontinuation of maintenance treatment with lithium (42-46), anti-depressants (47), and other psychotropic agents.(44, 48) Mortality can also increase following treatment discontinuation. (9, 11, 21, 22) Such reactions can complicate clinical management. Moreover, they may also confound many research findings in that typically reported "drug vs. placebo" comparisons may not represent straightforward contrasts of treated vs untreated subjects when placebo conditions represent discontinuation of an ongoing treatment.

Avoiding such risks, most studies of treatment effects on suicide have been naturalistic or have examined suicidal behavior post-hoc as an unintended outcome of controlled treatment trials. Such studies have provided evidence that maintenance treatment with lithium is associated with a strong, and possibly unique, protective effect against suicidal behavior in major affective disorders, and particularly in bipolar syndromes. (6, 8, 11, 12, 21, 22, 49-56) Moreover, lithium's protective effect may extend more broadly to all causes of mortality in these disorders, although this possibility remains much less studied. (2, 3, 5, 7)

Last Updated: 06 April 2017
Reviewed by Harry Croft, MD

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