Provocative results?
The investigators also assessed a negative control group of 236,610 individuals using cyanocobalamin during the study period. Cyanocobalamin is a form of vitamin B12 that is essential for metabolism, blood cell synthesis, and the nervous system. It does not contain folic acid and is commonly used to treat anemia.
Results showed no association between cyanocobalamin and suicidal events in the adjusted analysis (HR, 1.01; 95% CI, 0.80-1.27) or unadjusted analysis (HR, 1.02; 95% CI, 0.80-1.28).
Dr. Gibbons noted this result boosts the argument that the association between folic acid and reduced suicidal attempts “isn’t just about health-seeking behavior like taking vitamin supplements.”
Another sensitivity analysis showed every additional month of treatment was associated with a 5% reduction in the suicidal event rate.
“This means the longer you take folic acid, the greater the benefit, which is what you would expect to see if there was a real association between a treatment and an outcome,” said Dr. Gibbons.
The new results “are so provocative that they really mandate the need for a well-controlled randomized controlled trial of folic acid and suicide events,” possibly in a high-risk population such as veterans, he noted.
Such a study could use longitudinal assessments of suicidal events, such as the validated Computerized Adaptive Test Suicide Scale, he added. This continuous scale of suicidality ranges from subclinical, signifying helplessness, hopelessness, and loss of pleasure, to suicide attempts and completion.
As for study limitations, the investigators noted that this study was observational, so there could be selection effects. And using claims data likely underrepresented the number of suicidal events because of incomplete reporting. As the researchers pointed out, the rate of suicidal events in this study was much lower than the national rate.
Other limitations cited were that the association between folic acid and suicidal events may be explained by healthy user bias; and although the investigators conducted a sensitivity analysis in women of childbearing age, they did not have data on women actively planning for a pregnancy.
‘Impressive, encouraging’
In a comment, Shirley Yen, PhD, associate professor of psychology, Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, described the new findings as “quite impressive” and “extremely encouraging.”
However, she noted “it’s too premature” to suggest widespread use of folic acid in patients with depressive symptoms.
Dr. Yen, who has researched suicide risks previously, was not involved with the current study.
She did agree with the investigators that the results call for “more robustly controlled studies. These could include double-blind, randomized, controlled trials that could “more formally assess” all folic acid usage as opposed to prescriptions only, Dr. Yen said.
The study was funded by the NIH, the Agency for Healthcare Research and Quality, and the Center of Excellence for Suicide Prevention. Dr. Gibbons reported serving as an expert witness in cases for the Department of Justice; receiving expert witness fees from Merck, GlaxoSmithKline, Pfizer, and Wyeth; and having founded Adaptive Testing Technologies, which distributes the Computerized Adaptive Test Suicide Scale. Dr. Yen reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.