Lithium Better Than Divalproex In Keeping Suicides Down

Three potential outcomes were tracked: completed suicides, suicide attempts resulting in an emergency room visit or hospitalization, and suicide attempts resulting in assessment and discharge.

The researchers identified nearly 21,000 patients in the two health plans treated for bipolar disorder with one of the three mood stabilizers during the study period. In that group, there were 53 suicides, 338 attempts resulting in hospitalization, and 642 attempts identified in the emergency room and discharged. Suicide attempts resulting in hospitalization occurred 6.2 times more frequently than completed suicides.

After adjusting for a number of potentially confounding variables—age, sex, health plan, year of diagnosis, comorbid medical conditions, and other psychotropic medication use—the risk of each of the three outcomes was significantly greater during exposure to either divalproex or carbamazepine, compared with lithium. Most comparisons of carbamazepine and lithium, however, while qualitatively similar to those of divalproex and lithium, were not statistically significant due to the relatively small number of patients taking carbamazepine. Only one result was statistically significant: Patients taking carbamazepine were 2.9 times more likely to attempt suicide resulting in hospitalization than those taking lithium.

Interestingly, the eight-year study captured a significant shift in prescribing habits in the treatment of bipolar patients. In 1994 the ratio of prescriptions for lithium to divalproex was roughly 6 to 1, while at the end of the study in 2001, the ratio was closer to 1 to 2. (That trend has continued and is now nearer to 1 to 3 today, according to IMS Health data.)

Regardless of the shifting habits in prescribing, rates for suicide attempts of patients receiving lithium were remarkably stable during the period. Rates for suicide death were less consistent, however; Goodwin believes that may be due to the relatively small number of deaths over the eight-year period.

In addition, a history of any medication switch—whether from lithium to divalproex, or the other way around—was associated with a higher risk of suicide attempt. Many patients were taking more than one mood stabilizer at a time, either as a combination therapy or while being switched from one medication to another. This could confound the results.

Goodwin stressed, however, that “only a randomized trial can completely exclude the possibility of confounding or bias, but large observational studies such as this one may be the only realistic option for studying relatively rare outcomes such as suicide death.”

In an accompanying editorial, Ross Baldessarini, M.D., a professor of psychiatry at Harvard Medical School and McLean Hospital, along with Leonardo Tondo, M.D., a lecturer in psychiatry at Harvard and McLean, wrote that bipolar disorder, because of its episodic nature, high depressive morbidity, comorbidity with substance abuse and anxiety disorders, and consequently high mortality rate, is “a major unresolved public health challenge.”

Suicide death in patients with bipolar disorder “represents an extraordinarily high risk” with an estimated rate of 0.4 percent a year, compared with the international background rate of 0.017 percent a year.

The two noted that “no currently available treatment provides full protection from recurrences of manic, mixed, manic-depressive, major depressive, or highly prevalent milder depressive states.”

In particular, Baldessarini and Tondo said, Goodwin’s study “not only has merits in its methods and findings, but also represents a significant contribution to a newly emerging interest in suicide as the major unresolved medical problem that it is.”