While there is some evidence that the number of U.S. suicides has leveled off or even declined slightly in the 2 most recent years for which statistics are available (2019 and 2020), there continues to be great reason for concern. The annual number of U.S. suicides exceeds 45,000, according to the CDC, an increase of 36% compared with the number in the year 2000.

Moreover, the CDC estimates that over 12 million adults gave serious thought to suicide in 2020; over 3 million made a plan; and 1.2 million made a suicide attempt. Thus, nonfatal suicide attempts clearly are also a major public health problem. Even as social scientists seek reasons that may help account for the trend, psychiatric researchers have been looking for concrete ways to reduce rates of suicidal behavior.

One approach is to develop better ways of predicting suicidal behavior, for example through analysis of behavioral patterns indicating imminent risk, or via discovery of genetic and biological markers of risk traits. Another approach is to develop preventive measures—interventions, including behavioral and pharmacologic, which might be tested in those who are considered at high risk.

A promising lead in prevention has now emerged from research led by Robert D. Gibbons, Ph.D., of the University of Chicago, and J. John Mann, M.D., of Columbia University, a BBRF Scientific Council member, 2022 BBRF Colvin Prize winner, and 2008 BBRF Distinguished Investigator. The research was reported in JAMA Psychiatry.

Following up on a clue from past research, the team sought to discover whether taking folic acid supplements might be related to lower rates of suicidal behavior. Folate, sometimes called vitamin B9, for years has been recommended in the form of folic acid supplements for pregnant women. Higher maternal folic acid levels are associated with lower risk of neural-tube and heart defects in the fetus.

In prior research, Drs. Gibbons, Mann and colleagues developed a drug-safety algorithm, in which they examined associations between suicide attempts and 922 drugs on the U.S. market in 2014 that had been prescribed more than 3,000 times. Ten drugs were associated with increased suicide risk; 44 with decreased risk. One of 5 drugs with the strongest association with decreased risk was folic acid—and this was a surprise to the team.

Analysis revealed that over half of patients receiving prescriptions for folic acid (which is more often purchased over the counter) had a pain diagnosis; and 31% who were prescribed folic acid also filled a prescription for the drug methotrexate, which is often given to those suffering from rheumatoid arthritis. Methotrexate is known to deplete folate, explaining why folic acid is often co-prescribed to such patients.

The team hypothesized that low folate levels produced by methotrexate may increase suicide risk, which is then decreased after folic acid supplementation. A similar pattern was postulated for two other drugs that records showed were prescribed, for different reasons, in the year before folic acid was prescribed in the same patients. The team identified folic acid as having potential benefit in terms of lowering suicide attempt risk.

To put this idea to the test, the team made use of large databases which registered inpatient, outpatient, and prescription claims from over 100 insurers. The researchers singled out individuals aged 18 or over who filled a folic acid prescription between 2012 and 2017. Using the database, the team could cross-reference which of these individuals either attempted suicide or intentionally harmed themselves in the same years. They also looked to flag other diagnoses such as depression and anxiety, relevant for suicide risk; conditions such as arthritis which are linked to folate deficiency; and drugs like methotrexate that reduce folate.

The investigators identified a cohort of over 866,000 individuals that formed the basis of their analysis, which compared months in which these individuals filled folic acid prescriptions with months in which they did not. The same analysis was repeated with another vitamin supplement, vitamin B12, with no known relationship to suicidality, in a sample of over 259,000 individuals drawn from the same databases.

In the cohort that was prescribed folic acid over the 5-year period, there were 261 “suicidal events” (suicide attempts and intentional self-harm) specifically during times when folic acid was being taken. There were 895 such events recorded when folic acid was not being taken by the same individuals. When adjusted for various statistical factors, this worked out to a 44% lower rate of suicidal events while folic acid was being taken—in most cases, at the dosage of 1mg/day, which is typical and considered the “upper tolerable limit.”

As expected, no association was found between the taking of vitamin B12 and suicidal events.

Importantly, the team was able to calculate that for every additional month of folic acid treatment, those prescribed had a 5% reduction in the rate of suicidal events.

The team found the same folic acid/suicide reduction linkage in men and women, as well as across all age groups, indicating that the effect was not restricted to pregnant women.

These results, the team concluded, “warrant conducting a randomized controlled trial” focusing on suicidal ideation and behavior. “If confirmed, folic acid may be a safe, inexpensive, and widely available treatment for suicidal ideation and behavior.”

The study's co-principal investigator, Dr. J. John Mann, will address the 2022 BBRF International Mental Health Research Symposium on Friday, Oct. 28. His topic is: "Unlocking the Mysteries of Mood Disorders by Science Instead of Guesswork." To register for the Symposium, please visit: https://mediasiteconnect.com/site/register-bbrf2022.