Study finds folic acid treatment is associated with decreased risk of suicide attempts
Patients who filled prescriptions for folic acid, also known as vitamin B9, experienced a 44% reduction in suicidal events (suicide attempts and intentional self-harm).
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In US adults, prescription of folic acid supplements was linked with a 44% reduction in suicide attempts and/or deliberate self-harm, according to new research using data from a large medical insurance database.As this was a purely observational study, these findings cannot be taken as evidence for a cause-and effect relationship. To find out if supplementation might help will require clinical trials, as both the authors and independent commentators acknowledge. (See: expert reaction to US study looking at folic acid prescription fills, suicide attempts and intentional self-harm)
However, previous studies have often linked depression and other mental health problems with low intakes and/or levels of Vitamn B9. Folate is the natural form of this nutrient, while folic acid is the form most commonly used in supplements or fortified foods.
There is also some clinical trial evidence that supplementation with Vitamin B9 may benefit patients with depression, schizophrenia or other mental health disorders - but findings suggest that a more absorbable form (methylfolate) may be more effective than folic acid for these populations. (For details, see: Firth et al 2019 - The efficacy and safety of nutrient supplements in the treatment of mental disorders).
Fortification of basic foodstuffs with folic acid is already a public health policy in the US and many other countries, because low folate intakes are common, and a lack of this nutrient in early pregnancy can permanently harm brain development, but widespread fortification is only now being adopted in the UK and EU.
For brain health, folate works in synergy with other nutrients - notably other B vitamins, particularly B12 and B6 (often supplemented together with folic acid), as well as choline and betaine; but also with the long-chain omega-3 fatty acids, EPA and DHA. (See Omega 3 Oils and Vitamin B Supplements: A Winning Combination)
Furthermore, deficiencies of long-chain omega-3 have long been linked with increased risks for both depression and suicide - and clinical trials have already led to evidence-based treatment guidelines for the use of omega-3 (particularly EPA) as an adjunctive treatment for clinical depression.
Real food provides multiple nutrients in combination, so where possible, dietary interventions, or multinutrient supplementation, may prove more effective than any single nutrients for improving mood, behaviour or cognition in ways that may reduce self-harm and suicide.
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Suicide is one of the leading causes of death in the US, with more than 45,000 people dying by suicide in 2020. Experts recommend many strategies and treatments to decrease the risk of suicide, including psychotherapy, peer support, economic support, and medications like antidepressants. Few if any would be likely to put folic acid supplements on that list, but a recent study done at the University of Chicago may change that.
The study, published in JAMA Psychiatry on September 28th, used data from the health insurance claims of 866,586 patients and looked at the relationship between folic acid treatment and suicide attempts over a two-year period. They found that patients who filled prescriptions for folic acid, also known as vitamin B9, experienced a 44% reduction in suicidal events (suicide attempts and intentional self-harm). Robert Gibbons, Ph.D., the Blum-Riese Professor of Biostatistics and Medicine at the University of Chicago, the lead author of the study, is hopeful that these findings could improve suicide prevention efforts, especially because of how accessible folic acid is.
"There are no real side effects, it doesn't cost a lot of money, you can get it without a prescription," Gibbons said. "This could potentially save tens of thousands of lives."
Gibbons initially became interested in folic acid in the context of suicide because of a previous study in which his group looked for relationships between risk of attempting suicide and 922 different prescribed drugs. The study simultaneously screened each drug for associations with increases and decreases in suicide attempts. Surprisingly, folic acid was associated with a decreased risk of suicide attempt, along with drugs expected to be associated with risk of suicide, like antidepressants, anxiolytics, and antipsychotics.
One of the challenges of this earlier study was to analyze the effects of many drugs in a large-scale data set, which is difficult. Many people take more than one drug, and drugs can have different effects when taken together than when taken alone. It can also be difficult to get meaningful results from studies like these that look for relationships in large data sets because of confounding factors, which can cause two variables in a study, like suicide and a drug, to seem to have a direct causal relationship with each other. Sometimes, these are actually both related to a confounding factor, such as socioeconomic status or health-conscious attitudes, or because they are prescribed for a condition that is associated with suicide (e.g. depression). But Gibbons and his group were able to partially eliminate these complications by comparing subjects to themselves before and after being prescribed a drug, instead of comparing subjects who did and did not take the drug to one another.
In fact, they initially thought folic acid had only shown up in their study because of a simple explanation, but that turned out not to be the case. "When we first saw this result, we thought it was pregnancy. Pregnant women take folic acid, and pregnant women tend to have a low suicide rate, so it's just a false association. So, we just did a quick analysis to restrict it to men. But we saw exactly the same effect in men," Gibbons said.
To investigate and further confirm the relationship between folic acid and suicide risk, Gibbons and his co-authors did this new study and focused specifically on folic acid, and accounted for many possible confounding factors, including age, sex, mental health diagnoses, other central nervous system drugs, conditions that affect folic acid metabolism, and more. Even after adjusting for all these factors, filling a prescription for folic acid was still associated with a decreased risk of attempting suicide.
They even found that the longer a person took folic acid, the lower their risk of suicide attempt tended to be. Each month of being prescribed folic acid was associated with an additional 5% decrease in risk of suicide attempt during the 24-month follow-up period of their study.
It also occurred to the authors that maybe people who take vitamin supplements in general want to improve their health and would thus be less likely to attempt suicide. To address this possibility, they did a similar analysis with another supplement, vitamin B12, as a negative control. But unlike folic acid, there didn't seem to be any relationship between vitamin B12 and risk of suicide.
Although Gibbons and his co-authors were careful to adjust for confounding factors, they cannot yet say for sure whether the relationship between folic acid and suicidal events is causal; that is, they don't yet know if taking folic acid will directly cause a person's risk of suicide to become lower. To know for sure, the authors are following up this study with a large-scale randomized controlled trial (RCT) to test whether folic acid directly lowers the risk of suicidal events, including ideation, attempts and completion. This will involve randomly splitting subjects into two groups, giving a placebo to one group and folic acid to the other and comparing the rate of suicidal events over time.
If their findings are confirmed in the new research, folic acid would be a safe, inexpensive, and widely available suicide prevention strategy, and potentially help save thousands of lives.
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