Lithium Protects Against Suicide in Bipolar Disorder, Study Finds

Psychiatrists in the United States ought to consider prescribing lithium over valproate for bipolar patients with suspected suicidal intentions, according to Jie Song, Ph.D., a researcher in the Department of Medical Epidemiology and Biostatistics at the Karolinska Institutet in Stockholm.

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“Although valproate is used more commonly than lithium in the U.S., the limitation of valproate in suicide prevention needs to be recognized,” wrote Song, in an email to Psychiatric News. “Given the accumulated evidence from literature reporting that lithium potentially has distinct benefits in reducing suicidal behavior, this prescribing practice should be considered more often,” she wrote.

Song is the lead author of a Swedish study published in AJP in Advance in June that found about 12 percent of attempted or completed suicides could have been avoided if the individuals in this population had been continuously taking lithium during the study period and entire follow-up. The study also demonstrated that valproate “probably has no effect on suicidal behavior.”

Researchers relied on Swedish population-based registers to follow 51,535 individuals with bipolar disorder over an eight-year period (2005-2013). During this period, 10,648 suicide-related events occurred in 4,643 individuals (9 percent). The researchers compared periods when patients were taking either lithium or valproate with periods they were not taking either medication.

After excluding participants without suicide-related events or varying covariates during follow-up, 4,405 participants were eligible for the within-individual analysis. These patients had 10,403 suicide-related events, were more often prescribed other drugs, and had more comorbid psychiatric conditions. The suicide-related incidence rate decreased by 14 percent during the time these individuals were receiving lithium compared with periods not receiving lithium. The rate of suicide-related events did not decrease when individuals received valproate.

Patients with bipolar disorder are known to have a high risk of suicidal behavior compared with the general population and patients with other psychiatric disorders. Lithium is considered the first-line treatment for bipolar disorder and some previous studies have suggested it confers an anti-suicidal effect, as well.

“Lithium has multiple clinical effects, including its mood stabilizing action to prevent manic and depressive episode recurrence, treat acute mania, and reduce suicide risk in patients with bipolar disorder,” according to Song.

Although both drugs treat mood disorders, valproate is one of the antiepileptic medications that the Food and Drug Administration requires to include a warning: this class of medications increases the risks of suicidal thoughts or behavior.

Several studies support lithium’s protective effects against suicide. A study published in BMC Psychiatry in 2014 found no significant differences in associations with suicide death between lithium and valproate among U.S. Veterans Health Administration patients over the first year of treatment.

“Yes, this study seems to diverge from our findings, however, the two studies have different designs and outcomes,” Song explained. “They [VA] used propensity score matching to control for potential measured confounding, while we compared an individual to himself or herself … Their study focused on fatal suicides and the follow-up was only for one year. We followed more than 50,000 individuals for over eight years and focused on suicide-related behavior, where the overwhelming majority are non-fatal suicide attempts. Therefore, our findings are not directly comparable.”

The VA study also found a significant increased risk of suicide death after discontinuation or modification of lithium treatment, compared to valproate, for 180 days following the treatment change. Although the Swedish study did not directly compare the difference in rate of suicide-related events between lithium and valproate discontinuation, it also observed an increased rate of suicidal behavior, within 30 days of lithium discontinuation. “Taken together, both studies highlight the positive benefits for lithium against suicidal behavior and the need for close monitoring after discontinuation,” according to Song.

Clinicians may hesitate to prescribe lithium to patients at high risk of suicide due to its potential for lethal toxicity in case of overdose, she suggested, and instead may choose valproate because it takes effect more quickly, and is used when patients require rapid mood stabilization.

The study was financed with grants from the Swedish Research Council, the Swedish Council for Working Life and Social Research, and the China Scholarship Council. ■