Clinical Context

Suicide remains in the top 10 for overall causes of mortality in the United States, and healthcare professionals may exacerbate the risk for suicide through the medications they prescribe. A previous study by the authors of the current research examined medications that might affect the risk for suicide. Their results were published in the November 1, 2019 issue of the Harvard Data Science Review.^[1]

Researchers used a large commercial health insurance database to evaluate the risk for suicide attempts and completions associated with 922 different drugs. Ten drugs were associated with a higher risk for suicide after exposure, and the most prominent of these were alprazolam, butalbital, hydrocodone, and promethazine/codeine. A total of 44 drugs were associated with a lower risk for suicide, including mirtazapine, disulfiram, naltrexone, and hydroxyzine.

The current study by focuses singularly on the potential effects of folic acid supplementation on the risk for suicide.

Study Synopsis and Perspective

Prescription folic acid, a synthetic form of vitamin B9, may provide a safe and effective approach for decreasing suicidal ideation, new research suggests.

After adjusting for multiple factors, results from a large pharmaco-epidemiological study showed taking folic acid was associated with a 44% reduction in suicide events.

"These results are really putting folic acid squarely on the map as a potential for large-scale, population-level prevention," lead author Robert D. Gibbons, PhD, professor of biostatistics, Center for Health Statistics, University of Chicago, Illinois, told Medscape Medical News.

Having such a tool would be extremely important given that suicide is such a significant public health crisis worldwide, he added.

The findings were published online September 28 in JAMA Psychiatry.^[2]

Folate, the naturally occurring form of B9, is essential for neurogenesis, nucleotide synthesis, and methylation of homocysteine. Past research has suggested that taking folate can prevent neural tube and heart defects in the fetus during pregnancy and may prevent strokes and reduce age-related hearing loss in adults.

In psychiatry, the role of folate has been recognized for more than a decade. It may enhance the effects of antidepressants; and folate deficiency can predict poorer response to selective serotonin reuptake inhibitors.

This has led to recommendations for folate augmentation in patients with low or normal levels at the start of depression treatment.

Although previous research has shown a link between folic acid and suicidality, the findings have been "fairly thin," with studies being "generally small, and many are case series," Gibbons said.

The current study follows an earlier analysis that used a novel statistical methodology for generating drug safety signals that was developed by Gibbons and colleagues. That study compared rates of suicide attempts before and after initiation of 922 dugs with at least 3000 prescriptions.

Its results showed 10 drugs were associated with increased risk after exposure, with the strongest associations for alprazolam, butalbital, hydrocodone, and combination codeine/promethazine. In addition, 44 drugs were associated with decreased risk, many of which were antidepressants and antipsychotics.

"One of the most interesting findings in terms of the decreased risk was for folic acid," said Gibbons.

He and his colleagues initially thought this was because of women taking folic acid during pregnancy, but when restricting the analysis to men, they found the same effect.

Their next step was to carry out the current large-scale pharmaco-epidemiological study.

Researchers used a health claims database that included 164 million enrollees. The study cohort was comprised of 866,586 adults with private health insurance (81.3% women; 10.4% aged ≥ 60 years) who filled a folic acid prescription between 2012 and 2017.

More than half of the folic acid prescriptions were associated with pain disorders. About 48% were for a single agent at a dosage of 1 mg/d, which is the upper tolerable limit for adults, including in pregnancy and lactation.

Other single-agent daily dosages ranging from 0.4 mg to 5 mg accounted for 0.11% of prescriptions. The remainder were multivitamins.

The participants were followed for 24 months. The within-person analysis compared suicide attempts or self-harm events resulting in an outpatient visit or inpatient admission during periods of folic acid treatment vs during periods without treatment.

During the study period, the overall suicidal event rate was 133 per 100,000 population, which is one-fourth the national rate reported by the National Institutes of Health of 600 per 100,000.

After adjusting for age, sex, diagnoses related to suicidal behavior and folic acid deficiency, history of folate-reducing medications, and history of suicidal events, the estimated HR for suicide events when taking folic acid was 0.56 (95% CI: 0.48, 0.65), which indicates a 44% reduction in suicide events.

Gibbons noted the decrease in suicidal events may have been even greater, considering the study captured only prescription folic acid and participants may also have also taken over-the-counter products.

"The 44% reduction in suicide attempts may actually be an underestimate," said Gibbons.

Age and sex did not moderate the association between folic acid and suicide attempts, and a similar association was found in women of childbearing age.

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 (aHR 1.01 [95% CI: 0.8, 1.27]) or unadjusted analysis (HR 1.02 [95% CI: 0.8, 1.28]).

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.

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 (CAT-SS), 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.

Commenting for Medscape Medical News, Shirley Yen, PhD, associate professor of psychology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, described the new findings as "quite impressive" and "extremely encouraging."

She noted, however, that "it's too premature" to suggest widespread use of folic acid in patients with depressive symptoms.

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, Yen said.

The study was funded by the National Institutes of Health, the Agency for Healthcare Research and Quality, and the Center of Excellence for Suicide Prevention (US Department of Veterans Affairs). Gibbons reported serving as an expert witness in cases for the US Department of Justice; receiving expert witness fees from GlaxoSmithKline; Merck & Co., Inc.; Pfizer Inc.; and Wyeth Pharmaceuticals Inc.; and having founded Adaptive Testing Technologies, which distributes the Computerized Adaptive Test Suicide Scale. Yen has reported no relevant financial relationships.

Clinical Implications

• A previous study by Gibbons and colleagues found that 10 drugs were associated with a higher risk for suicide after exposure, and the most prominent of these were alprazolam, butalbital, hydrocodone, and promethazine/codeine. A total of 44 drugs were associated with a lower risk for suicide, including mirtazapine, disulfiram, naltrexone, and hydroxyzine.
• In the current observational study by Gibbons and colleagues of adults, folic acid supplements were associated with a lower risk for suicide, but vitamin B12 supplements were not.
• Implications for the healthcare team: The healthcare team should await the evidence from clinical trials before providing education on or prescribing folic acid supplements to prevent suicide.

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