From the Journals

Mood stabilizers, particularly lithium, potential lifesavers in bipolar disorder



Mood stabilizers protect against suicide and all-cause mortality in patients with bipolar disorder (BD), including natural mortality, with lithium emerging as the most protective agent, new research suggests.

Investigators led by Pao-Huan Chen, MD, of the department of psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in more than 25,000 patients with BD and found that those with BD had higher mortality.

However, they also found that patients with BD had a significantly decreased adjusted 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.

“The present findings highlight the potential role of mood stabilizers, particularly lithium, in reducing mortality among patients with bipolar disorder,” the authors write.

“The findings of this study could inform future clinical and mechanistic research evaluating the multifaceted effects of mood stabilizers, particularly lithium, on the psychological and physiological statuses of patients with bipolar disorder,” they add.

The study was published online in Acta Psychiatrica Scandinavica.

Research gap

Patients with BD have an elevated risk for multiple comorbidities in addition to mood symptoms and neurocognitive dysfunction, with previous research suggesting a mortality rate due to suicide and natural causes that is at least twice as high as that of the general population, the authors write.

Mortality risk by type of mood stabilizer

Lithium, in particular, has been associated with decreased risk for all-cause mortality and suicide in patients with BD, but findings regarding anticonvulsant mood stabilizers have been “inconsistent.”

To fill this research gap, the researchers evaluated 16 years of data from Taiwan’s National Health Insurance Research Database, which includes information about more than 23 million residents of Taiwan. The current study, which encompassed 25,787 patients with BD, looked at data from the 5-year period after index hospitalization.

The researchers hypothesized that mood stabilizers “would decrease the risk of mortality” among patients with BD and that “different mood stabilizers would exhibit different associations with mortality, owing to their varying effects on mood symptoms and physiological function.”

Covariates included sex, age, employment status, comorbidities, and concomitant drugs.

Of the patients with BD, 4,000 died within the 5-year period. Suicide and natural causes accounted for 19.0% and 73.7% of these deaths, respectively.

Cardioprotective effects?

The standardized mortality ratios (SMRs) – the ratios of observed mortality in the BD cohort to the number of expected deaths in the general population – were 5.26 for all causes (95% confidence interval, 5.10-5.43), 26.02 for suicide (95% CI, 24.20-27.93), and 4.68 for natural causes (95% CI, 4.51-4.85).

The cumulative mortality rate was higher among men vs. women, a difference that was even larger among patients who had died from any cause or natural causes (crude hazard ratios, .60 and .52, respectively; both Ps < .001).

The suicide risk peaked between ages 45 and 65 years, whereas the risks for all-cause and natural mortality increased with age and were highest in those older than 65 years.

Patients who had died from any cause or from natural causes had a higher risk for physical and psychiatric comorbidities, whereas those who had died by suicide had a higher risk for primarily psychiatric comorbidities.

Mood stabilizers were associated with decreased risks for all-cause mortality and natural mortality, with lithium and valproic acid tied to the lowest risk for all three mortality types (all Ps < .001).

Lamotrigine and carbamazepine were “not significantly associated with any type of mortality,” the authors report.

Mortality risk by duration of lithium use and cumulative dose

Longer duration of lithium use and a higher cumulative dose of lithium were both associated with lower risks for all three types of mortality (all Ps < .001).

Valproic acid was associated with dose-dependent decreases in all-cause and natural mortality risks.

The findings suggest that mood stabilizers “may improve not only psychosocial outcomes but also the physical health of patients with BD,” the investigators note.

The association between mood stabilizer use and reduced natural mortality risk “may be attributable to the potential benefits of psychiatric care” but may also “have resulted from the direct effects of mood stabilizers on physiological functions,” they add.

Some research suggests lithium treatment may reduce the risk for cardiovascular disease in patients with BD. Mechanistic studies have also pointed to potential cardioprotective effects from valproic acid.

The authors note several study limitations. Focusing on hospitalized patients “may have led to selection bias and overestimated mortality risk.” Moreover, the analyses were “based on the prescription, not the consumption, of mood stabilizers” and information regarding adherence was unavailable.

The absence of a protective mechanism of lamotrigine and carbamazepine may be attributable to “bias toward the relatively poor treatment responses” of these agents, neither of which is used as a first-line medication to treat BD in Taiwan. Patients taking these agents “may not receive medical care at a level equal to those taking lithium, who tend to receive closer surveillance, owing to the narrow therapeutic index.”


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