US scientists have shown that folic acid supplements may reduce the risk of suicidal thoughts.
The team from the University of Chicago looked at health records for 866,586 patients, including records of supplement prescriptions, and compared those who were prescribed folic acid with people who were prescribed another ‘control’ supplement, vitamin B12.
Overall, they found there were 261 suicides among those on a current folic acid prescription, compared with 895 suicides during months without any folic acid, with further analysis revealing a 5% decrease in suicidal events per month of additional folic acid supplementation (HR, 0.95; 95% CI, 0.93-0.97).
Lead author Dr Robert Gibbons from the University of Chicago’s Centre for Health Statistics, explained that the role of folate in depression and cognition has been recognized for more than a decade, leading to recommendations for folate augmentation in patients with low or normal levels at the start of any depression treatment.
“In terms of mechanism, folate deficiency predicts poorer clinical response to selective serotonin reuptake inhibitors, and folate may enhance effects of antidepressants acting via monoamine neurotransmitter systems by its involvement in methylation pathways in the 1-carbon cycle,” Dr Gibbons said.
“Given the possibility of suicide prevention properties of folic acid, and its potential as a new, safe, and inexpensive preventive, we further explored this association in a well-controlled large-scale pharmacoepidemiologic study.
“The adjusted estimated HR for folic acid for suicide events was 0.56 (95% CI, 0.48-0.65)… [and] we found the same association in men and women and no evidence of a sex × age × folic acid interaction.”
The study, published 29 September 2022 in Jama Psychiatry, built on the team’s previous work in 2014, where they developed a novel statistical drug safety signal-generation algorithm, iDEAS (High Dimensional Empirical Bayes Screening), to examine the association of suicide attempt with all 922 drugs on the market that had 3,000 or more prescriptions.
The strongest association with decreased risk was for folic acid.
“We previously proposed that signals related to individual drugs identified by iDEAS should be tested using more rigorous pharmacoepidemiologic studies and, if confirmed, further studied in randomized clinical trials (RCTs),” Dr Gibbons explained.
“In the original article, we found that 52% of patients receiving prescriptions for folic acid had a diagnosis of pain, 16% had a mood disorder diagnosis, 31% filled a prescription for methotrexate, and approximately 60% received anti-inflammatories or analgesics – [but] only 8% received antidepressants.”
The researchers also noted that methotrexate was commonly prescribed for rheumatoid arthritis pain, and as methotrexate depletes folate, folic acid was often prescribed to prevent deficiency.
“We hypothesized that low folate levels produced by methotrexate may increase suicide risk, which is then decreased after folic acid supplementation,” Dr Gibbons said.
“In addition, prednisone (21%) and hydrocodone (20%) were also commonly prescribed in the year before a folic acid prescription is filled. Both drugs were associated with higher risk of suicide attempts, and we hypothesized that folic acid may reverse this increased risk.”
While the current study could not establish cause and effect, the team says that if the findings are confirmed in further trials, folic acid may be a safe, inexpensive, and widely available treatment for suicidal thoughts and attempts.
“We believe that these results justify advocating for an RCT to study the effect of folic acid on suicidality,” Dr Gibbons said.
“That study could be conducted in a high-risk population, which would maximize the number of suicidal events, and could also use longitudinal assessments of suicidal events using previously validated adaptive tests for suicidality.”
Suicide is a leading cause of death in the US, having increased more than 30% from 2000 to 2018, and similar trends have been seen in Australia, with the Infant, Child, and Adolescent (ICA) Taskforce Report, released in March 2022, indicating that the rate of suicide amongst young West Australians has increased by 50% in the last four years.