In addition, self-harm rates in those prescribed valproate were not higher than in those on other nonlithium maintenance therapies, contrary to the an existing FDA warning, Joseph Hayes, MSc, MBChB, of University College London, and colleagues reported online in JAMA Psychiatry.
After propensity score adjustment to reduce confounding, the study showed that self-harm rates were higher in the 392 patients prescribed valproate (HR 1.31, 95% CI, 1.01-1.70), 409 prescribed olanzapine (HR 1.33, 95% CI, 1.01-1.75), and 582 prescribed quetiapine (HR 1.36, 95% CI, 1.00-1.87) than in the 205 patients prescribed lithium.
Unintentional injury rates also were also higher for those on valproate (HR, 1.32; 95% CI, 1.10-1.58) and quetiapine (HR, 1.34; 95% CI, 1.07-1.69) compared with lithium, but not olanzapine, they reported.
Although suicide rates appeared to be lowest in patients taking lithium, there were too few events to permit accurate estimates or comparisons, the researchers said.
“We found increased rates of self-harm in individuals prescribed valproate, olanzapine, or quetiapine compared with those prescribed lithium,” Hayes and colleagues wrote. “We did not find differences in rates among valproate, olanzapine, and quetiapine. We also found reduced rates of unintentional injury in those prescribed lithium, an important association that has not been widely investigated or found previously. We did not find differences in rates of suicide because of the small number of suicides in the cohort.”
Joseph Stoklosa, MD, medical director of the schizophrenia and bipolar disorder inpatient program at Maclean Hospital in Belmont, Mass., said the study “adds credence to the hypothesis that lithium may have effects on impulsive aggression.”
“These results extend the potential benefits from lithium to these nonsuicidal forms of self-harm and injury,” Stoklosa, who was not affiliated with the study, told MedPage Today. “In many ways, the question to ask ourselves in choosing the right medication for a person with bipolar disorder may be less of which one, so much as ‘Why not lithium?'”
Stoklosa noted that since medications such as anticonvulsants and antipsychotics are commonly used to treat bipolar disorder, comparing the effects of these treatments with lithium — “the gold standard treatment for bipolar disorder” — is important.
“People with bipolar disorder have significant morbidity and mortality from self-harm, unintentional injury, and suicide,” he explained. “We need to continue to study all means to reduce self-harm and unintentional injury through both medication and non-medication modalities. We need to look at medication combinations as well, given that polypharmacy in bipolar disorder is unfortunately more the rule than the exception.”
Restoring patients with bipolar disorder to full function means addressing the ongoing stigma associated with treatment for mental illness, Stoklosa said, “so that people can be increasingly comfortable reaching out for help [and so that] we can get further [away] from reacting and closer to prevention.”
The study looked at primary care data from the electronic records of 6,671 patients with bipolar disorder who had received 2 or more consecutive prescriptions of lithium, valproate, olanzapine, or quetiapine lasting 28 days or longer to stabilize mood. All data were collected by The Health Improvement Network (THIN) system between Jan. 1, 1995 and Dec. 31, 2013. A total of 2,148 patients were prescribed lithium, 1,670 were prescribed valproate, 1,477 were prescribed olanzapine, and 1,376 were prescribed quetiapine.
Data on the association between antipsychotic medication and self-harm are “sparse,” the researchers said. “Small retrospective cohorts have shown no difference in suicidal self-harm in patients taking olanzapine or quetiapine and have demonstrated higher rates of suicide attempts in those prescribed second-generation antipsychotics compared with lithium or valproate.”
Not surprisingly, unintentional injuries associated with bipolar disease have been associated with hypomanic morbidity, they pointed out, “in which case drugs with the strongest anti-unintentional injury properties may not be those with the strongest anti-suicidal effects.”
The researchers acknowledged that despite the use of propensity score adjustment and matching, there may have been residual confounding. In addition, the risk score didn’t capture factors such as educational level and socioeconomic status, which “are likely to be associated with increased risk of self-harm, unintentional injury, and suicide” but shouldn’t influence treatment allocation.