The use of folic acid reduces the risk of suicide attempts

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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.


Suicide is a major public health problem worldwide. Approximately 800,000 people die by suicide annually, comprising 1.5% of all deaths (1). Non-fatal suicidal behavior, such as suicidal ideation or attempt, is considerably more common than fatal suicide (2). Biomarkers reflecting or predicting suicidal behavior would be helpful for establishment of suicide prevention strategies.

Peripheral blood biomarkers for suicidal behavior risk may have several advantages in terms of convenience and cost-effectiveness. However, studies of potential targets (e.g., monoamines, neurotrophins, hypothalamic-pituitary-adrenal axis, and inflammatory markers) have failed to provide consistent results (3, 4).

Folate is involved in one-carbon transfer (methylation) reactions necessary for the production of monoamine neurotransmitters, phospholipids, and nucleotides (5). Folate deficiency, which causes impaired methylation reactions in the central nervous system, has been associated with depressive and neuropsychiatric illnesses (6–8). In contrast, folate intake has been associated with augmentation of antidepressant effects (9, 10).

Suicidal behavior is strongly associated with depressive disorder and suicidal ideation is one of the diagnostic criteria for depressive disorders, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (11). Folate thus might be associated with suicidal behavior.

A previous small study with 18 depressed inpatients reported no difference in serum folate levels between those with and without violent suicide (12). However, to our knowledge, there have been no studies regarding the relationship between folate and various suicidal behaviors in a real world depressive outpatients setting.

Using data from a prospective study of Korean patients with depressive disorders who were receiving stepwise antidepressant treatment strategies, this study investigated the associations of serum folate levels with suicidal behavior in patients with depressive disorders.

Discussion
In this study of depressive patients receiving a stepwise pharmacotherapy intervention in a real-world clinical setting, reduced serum folate levels were significantly associated with previous suicide attempt history, baseline suicidal severity, and prospective worsening of suicidality and actual suicide attempt or death during the 12-month follow-up period. These findings remained statistically significant following adjustment for multiple relevant covariates.

There are several possible explanations for these findings. First, folate is a B vitamin and an important dietary nutrient. There is increasing observational evidence that nutritional deficits such as low body weight (26) and low levels of cholesterol (27) and docosahexaenoic acid (28) are associated with suicidal behavior.

Second, nutritional deficits (i.e., fatty acid deficiency) had negative effects on function with respect to neurotransmitters, the hypothalamic-pituitary-adrenal axis, and limbic and cortical brain areas (29, 30). Folate deficiency also caused impaired methylation reactions and thus impaired the production of neurotransmitters, phospholipids, and nucleotides (5).

This dysfunction may lead to suicidal behavior, rather than healthy adaptive behavior, under stressful situations. Third, nutritional deficits such as folate deficiency have been associated with risks of depressive disorders (6, 8, 31), and nutritional intake (including folate intake) has augmented antidepressant effects (9, 32). Suicidal behavior could have similar associations because it is strongly related to depressive disorders (11).

Reduced serum folate level (<6.0 ng/mL) and folate deficiency (<3.0 ng/mL) were both significantly associated with suicidal behavior. These findings are consistent with previous observations concerning associations of reduced serum folate levels (but not folate deficiency) with depressive disorders (6, 33). Similarly, low and high levels of docosahexaenoic acid (stratified according to the median value) influenced suicide risk (28).

With respect to the strengths of the associations, lower serum folate levels were significantly associated with all four suicidal behaviors evaluated in this study, while folate deficiency was not associated with increased suicidal severity during the 12-month pharmacotherapy period. These results were presumably influenced by the low statistical power related to the low number of participants in the folate deficiency group (N = 65) compared to the lower serum folate levels group (N = 335) (see Tables 4, ​,5).5). The low prevalence of folate deficiency is likely to be due to the high intake of folate-containing green vegetables in Korean populations, compared with Caucasian populations (34).

According to AUROC curve analyses, discriminant or prognostic values of reduced serum folate levels (<6.0 ng/mL) were fair for fatal/non-fatal suicide attempts during follow-up, but modest for previous suicide attempt, baseline suicidal severity, and increased suicidal severity (Table 3). This stronger association with actual prospective suicide attempts was consistent with previous findings concerning other nutrients: low cholesterol was associated with violent (rather than non-violent) suicide attempt (35), while lower docosahexaenoic acid levels were predictive of suicide attempt over a 2-year period (28).

The associations of reduced serum folate levels with previous suicide attempt and baseline suicidal severity might be obscured by selection bias because people with both nutritional deficiency and higher suicidality are more likely to be hospitalized (or die of suicide) and therefore under-represented in an outpatient treatment setting (36). When applying the folate deficiency criteria, the biomarker values became unbalanced with respect to sensitivities and specificities.

Based on these observations, lower folate levels (rather than folate deficiency) could be recommended to distinguish between previous suicide attempt or present suicidal severity, as well as for prediction of suicidal behaviors during the treatment period. With respect to predictive values, positive predictive values were obvious low, while negative predictive values were considerably high. The low positive predictive values probably due to the low prevalence or incidence of suicidal behavior, particularly in actual retrospective and prospective suicidal attempt. On the other hand, the high negative predictive values might be related to higher sensitivity than specificity (37). Summing up, the serum folate level could be used as an adjunct rather than a substitute for prediction of suicidal behavior considering its low positive predictive values.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674940/


Original Research: Closed access.
Association Between Folic Acid Prescription Fills and Suicide Attempts and Intentional Self-harm Among Privately Insured US Adults” by Robert D. Gibbons et al. JAMA Psychiatry

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