Prescription rates for folic acid were associated with suicide mortality in young adult men but not in women, a new study suggests.

In a national analysis of Swedish data, higher prescription rates for the vitamin B₉ supplement were associated with lower suicide mortality among men aged 25-29 years but higher suicide mortality among men aged 20-24 years. There was no association in women.

While the researchers say the findings don’t contradict a 2022 study covered by Medscape Medical News that showed a link between folic acid and a significant decrease in suicidal behavior, they do raise new questions.

“I think that the previous study made some clinicians think that maybe add-on folic acid could have a protective effect. It’s quite cheap and easy to use. Our results maybe dampen a little bit of this enthusiasm,” lead author Jussi Jokinen, MD, professor of psychiatry and head of academic discipline at Umeå University, Umeå, Sweden, and researcher at the Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News.

“Suicidal behaviors are extremely complex and very few add-on treatments have shown really robust evidence for suicide prevention,” Jokinen added.

The findings were presented on October 11 at the European College of Neuropsychopharmacology (ECNP) Congress in Munich, Germany.

Probing a Promising Signal

In the US, suicide is the second leading cause of death among teens and young adults. Following publication of a US study on folic acid and suicidal behavior, folic acid emerged as a supplement of interest for potential protective effects.

That research, which included data on more than 800,000 adults, showed that folic acid prescriptions were associated with a 44% lower risk for suicide events. In a follow-up study by the same group, folic acid was also tied to a lower risk for suicidal behavior among people with a psychiatric diagnosis and among those receiving psychotropic drugs.

The findings pointed to a potential tool to reduce suicide risk that is inexpensive, safe, and relatively easy to access. But questions about the link between folic acid and suicide remain.

To further explore those questions, investigators studied folic acid prescriptions and suicidality among young adults from 2006 to 2021 using national Swedish registry data. There were 3463 suicide-related deaths among this age group. Of these, 2693 were classified as suicide and 770 as events of undetermined intent.

Dispensations for folic acid were identified using Anatomical Therapeutic Chemical drug classification codes. Excess suicide mortality (ESM) was defined as the regional yearly proportion of suicide-related deaths in adults aged 20-24 years compared to the total of these deaths among those aged 20-29 years.

Sex-stratified generalized linear mixed-effects models were used to evaluate associations between regional ESM each year and folic acid dispensation rates. Dispensation rates in both age groups were treated as fixed variables, while the year and region were treated as random effects.

Not A Clear Picture

During 2006-2021, the median population-adjusted regional prescription rates of folic acid among 20- to 24-year-olds varied from the national median in both men (factor range, 0.47-2.00) and women (0.55-1.73).

Annual folic acid dispensing rates in the younger male group were associated with an increase in suicide-related deaths (P = .0104), but a decrease in suicide-related deaths in men aged 25-29 years (P = .0017). The associations remained significant after adjusting for dispensing rates in the two age groups.

There were no statistically significant associations observed among women, which Jokinen said might be explained by known gender differences in suicidal behaviors.

“Women make more suicide attempts, but men commit more often suicide. So the number of suicides among men was higher here so that may also play a role,” he said. “But why we did not see any association among women needs to be studied further.”

Since concluding the current study, Jokinen said that the investigators have repeated the analysis and included 3 more years of registry data, with associations remaining the same. Researchers are also planning to submit the full findings for publication.

More Data Needed

Joseph John Mann, MD, principal investigator of the 2022 JAMA study, said it’s difficult to compare the two studies as they had different designs and looked at different suicidal outcomes.

While the Swedish study is not yet published, Mann noted that the study he led used a more statistically powerful method and had less unknowns, such as the reasons why people received a prescription for folic acid.

“This might be why there are some hard-to-explain results,” Mann, professor of translational neuroscience in psychiatry and radiology at Columbia University, and director of the Molecular Imaging and Neuropathology Division at the New York State Psychiatric Institute in New York City, told Medscape Medical News. “How could you switch from a drug being helpful in males in one 5-year period of life to potentially being harmful in males and nothing in females?”

Still, the result is interesting, he noted, and a clinical trial that is currently in progress might shed more clarity on folic acid’s effects on suicide risk.

Limitations of the current study include its observational design and the lack of individual-level data. Researchers also lacked information on the indications for which folic acid may have been prescribed, some of which may also influence suicide risk.

Further lines of investigation Jokinen wants to pursue are longitudinal studies assessing this link that incorporate measurements of plasma folate levels alongside clinical data on psychiatric and medical conditions.

“Before folic acid can be discussed as a suicide-prevention strategy, we need individual-level longitudinal studies that can account for why it was prescribed and for patients’ clinical characteristics. It means the jury is still out,” Jokinen said in the statement.

Mann and Jokinen declared no relevant disclosures. The research was funded by the Swedish Research Council.