Research

JAMA Psychiatry | Original Investigation

Association Between Folic Acid Prescription Fills and Suicide Attempts

and Intentional Self-harm Among Privately Insured US Adults
Robert D. Gibbons, PhD; Kwan Hur, PhD; Jill E. Lavigne, PhD; J. John Mann, MD

Supplemental content
IMPORTANCE Suicide is a leading cause of death in the United States, having increased more
than 30% from 2000 to 2018. An inexpensive, safe, widely available treatment for
preventing suicidal behavior could reverse this trend.

OBJECTIVE To confirm a previous signal for decreased risk of suicide attempt following
prescription fills for folic acid in a national pharmacoepidemiologic study of patients treated
with folic acid.

DESIGN, SETTING, AND PARTICIPANTS A within-person exposure-only cohort design was used
to study the dynamic association between folic acid (vitamin B9) prescription fills over a
24-month period and suicide attempts and intentional self-harm. Data were collected from a
pharmacoepidemiologic database of US medical claims (MarketScan) for patients with private
health insurance who filled a folic acid prescription between 2012 and 2017. The same
analysis was repeated with a control supplement (cyanocobalamin, vitamin B12).
Data were analyzed from August 2021 to June 2022.

EXPOSURE Folic acid prescription fills.

MAIN OUTCOME AND MEASURE Suicide attempt or intentional self-harm resulting in an

outpatient visit or inpatient admission as identified by codes from the International Statistical
Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification.

RESULTS Data on 866 586 patients were collected; 704 514 (81.30%) were female,
and 90 296 (10.42%) were 60 years and older. Overall, there were 261 suicidal events
during months covered by a folic acid prescription (5 521 597 person-months) for a rate of
4.73 per 100 000 person-months, compared with 895 suicidal events during months
without folic acid (8 432 340) for a rate of 10.61 per 100 000 person-months. Adjusting for
age and sex, diagnoses related to suicidal behavior, diagnoses related to folic acid deficiency,
folate-reducing medications, history of folate-reducing medications, and history of suicidal
events, the hazard ratio (HR) for folic acid for suicide events was 0.56 (95% CI, 0.48-0.65),
with similar results for the modal dosage of 1 mg of folic acid per day (HR, 0.57; 95% CI,
0.48-0.69) and women of childbearing age (HR, 0.60; 95% CI, 0.50-0.73).
A duration-response analysis (1-mg dosage) revealed a 5% decrease in suicidal events per
month of additional treatment (HR, 0.95; 95% CI, 0.93-0.97). The same analysis for the
negative control, cyanocobalamin, found no association with suicide attempt (HR, 1.01;
95% CI, 0.80-1.27).

CONCLUSIONS AND RELEVANCE This large-scale pharmacoepidemiologic study of folic acid

found a beneficial association in terms of lower rates of suicide attempts. The results warrant
the conduct of a randomized clinical trial with suicidal ideation and behavior as outcomes of
interest. If confirmed, folic acid may be a safe, inexpensive, and widely available treatment for Author Affiliations: University of
suicidal ideation and behavior. Chicago, Chicago, Illinois (Gibbons,
Hur); Center of Excellence for Suicide
Prevention, Department of Veterans
Affairs, Canandaigua, New York
(Lavigne); Wegmans School of
Pharmacy, St John Fisher College,
Rochester, New York (Lavigne);
Columbia University, New York,
New York (Mann).
Corresponding Author: Robert D.
Gibbons, PhD, Center for Health
Statistics, University of Chicago,
5841 S Maryland Ave, Room W260,
JAMA Psychiatry. 2022;79(11):1118-1123. doi:10.1001/jamapsychiatry.2022.2990 MC2000, Chicago, IL 60637
Published online September 28, 2022. (rdg@uchicago.edu).

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 Folic Acid and Suicide Attempts and Intentional Self-harm
W
e developed a novel statistical drug safety signal-
generation algorithm known as iDEAS (High Dimen-
sional Empirical Bayes Screening) and illustrated its
use by examining the association of suicide attempt with all
922 drugs on the market that had 3000 or more prescriptions
in 2014.1 We found 10 drugs associated with greater suicide at-
tempt risk and 44 drugs associated with decreased suicide at-
tempt risk. The strongest associations with increased risk were
for alprazolam, butalbital, hydrocodone, and the combina-
tion codeine/promethazine. The strongest associations with
decreased risk were for folic acid, mirtazapine, hydroxyzine,
disulfiram, and naltrexone.
The decreased risk of suicidal events in patients taking fo-
lic acid was not predicted.1 Although many people who take
folic acid purchase it over the counter (OTC), the population
receiving it via prescription may be different. In the original
article,1 we found that 52% of patients receiving prescrip-
tions for folic acid had a diagnosis of pain, 16% had a mood dis-
order diagnosis, 31% filled a prescription for methotrexate, and
approximately 60% received anti-inflammatories or analge-
sics. Only 8% received antidepressants. We noted that metho-
trexate is commonly prescribed for rheumatoid arthritis pain,
and methotrexate depletes folate,2 so folic acid is often pre-
scribed to prevent folic acid deficiency. We hypothesized that
low folate levels produced by methotrexate may increase sui-
cide risk, which is then decreased after folic acid supplemen-
tation. 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.
In terms of mechanism, folate deficiency predicts poorer
clinical response to selective serotonin reuptake inhibitors,3 and
folate may enhance effects of antidepressants acting via mono-
amine neurotransmitter systems by its involvement in meth-
ylation pathways in the 1-carbon cycle.4 Folate levels are re-
portedly low in blood and red cells in future suicide decedents5
but not in cerebrospinal fluid.6 Improvement with folinic acid
treatment in treatment-resistant depression was associated with
cerebrospinal fluid evidence of brain folate deficiency.7 More
broadly, folate is a member of the vitamin B family and pre-
vents neural tube and heart defects in the fetus during
pregnancy8 and may prevent strokes9 and reduce age-related
hearing loss in adults.10 It is essential for neurogenesis, nucleo-
tide synthesis, and methylation of homocysteine.
We previously proposed that signals related to individual
drugs identified by iDEAS should be tested using more rigor-
ous pharmacoepidemiologic studies and, if confirmed, fur-
ther studied in randomized clinical trials (RCTs). Given the pos-
sibility of suicide prevention properties of folic acid, and its
potential as a new, safe, and inexpensive preventive, we fur-
ther explored this association in a well-controlled large-scale
pharmacoepidemiologic study using cyanocobalamin (vita-
min B12) as a negative control supplement. A meta-analysis of
35 prospective studies including more than 14 000 adults did
not find an association between vitamin B12 and cognitive im-
pairment or dementia,11 and our iDEAS study did not detect
an association with suicidal events.1
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Original Investigation Research
Key Points
Question Is folic acid associated with decreased suicide attempts
and intentional self-harm?
Findings In this cohort study, a within-person pharmacoepidemiologic
study that included 866 586 adults, folic acid treatment was associated
with a significantly reduced rate of suicidal events. This large-scale
observational study confirmed results of an earlier signal-generation
study.
Meaning Folic acid may be an inexpensive and widely available
suicide prevention tool; a large-scale randomized clinical trial
is warranted.
Methods
Patients
This study was reviewed and deemed exempt from review by
the University of Chicago institutional review board. Data were
obtained from the MarketScan Commercial Claims and En-
counters databases 12 distributed by IBM Watson and in-
cluded inpatient, outpatient, and prescription claims from
more than 100 insurers in the United States (164 million unique
enrollee observations between 2005 and 2017). Codes from the
International Statistical Classification of Diseases, Ninth and
Tenth Revisions, Clinical Modification (ICD-9-CM and ICD-10-
CM), were used to identify suicide attempt and intentional
self-harm (including deaths by suicide after a medical claim),
as well as other diagnoses relevant to suicide risk or folate
deficiency, from service claims (eTable in the Supplement).
Diagnoses relevant to suicide risk included depression, anxi-
ety, attention-deficit/hyperactivity disorder, bipolar disor-
der, schizophrenia, sleep disorders, and pain.13,14
The data were extracted for the period of 2010 to 2018. The
cohort was restricted to patients filling a folic acid prescrip-
tion in 2012 to 2017, and the first folic acid prescription was
considered the index date. The 2018 data were not used in de-
fining the cohort so that all patients would have at least 1 year
of follow-up. The sample was restricted to adults 18 years and
older. The baseline period data (2 years before the index date)
were used to identify folate-reducing medications (Table 115-17)
and identify previous users of folic acid, which were used to
define an incident-user cohort. Patients with private health in-
surance who filled a folic acid prescription between 2012 and
2017 were followed up until disenrollment (including death)
or suicide attempt or intentional self-harm. The entire pro-
cess (including identification of the index prescription) was re-
peated for the negative control, cyanocobalamin. Data were
analyzed from August 2021 to June 2022.
Folic Acid Exposure
Analyses were restricted to folic acid products, including mul-
tivitamins, prescribed by a health care professional. As previ-
ously noted, the majority of patients prescribed folic acid had
a pain disorder.1 In this study, 48.0% of folic acid prescrip-
tions were single agent at a dosage of 1 mg/d. Other single-
agent daily dosages ranging from 0.4 mg to 5 mg accounted
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 Research Original Investigation
Table 1. Indications for Folate Prescribing and Folate Drug Interactions
Medication group Generic name
Antimetabolite Methotrexate
Proton pump Dexlansoprazole, esomeprazole, lansoprazole,
inhibitor lansoprazole/naproxen, omeprazole, omeprazole/sodium
bicarbonate, pantoprazole, rabeprazole
Antihistamine and Cimetidine, cimetidine/dextrose, cimetidine/sodium chloride,
antacid famotidine, nizatidine, ranitidine, ranitidine/sodium chloride
Antidiabetes Metformin
Antirheumatic Sulfasalazine
Antimicrobial Sulfamethizole/trimethoprim,
sulfamethoxazole/trimethoprim
Antibiotic Trimethoprim
Antidepressant Citalopram, escitalopram, fluoxetine, olanzapine,
fluvoxamine, paroxetine, sertraline, desvenlafaxine,
venlafaxine, levomilnacipran, duloxetine, doxepin, trazodone,
isocarboxazid, phenelzine, tranylcypromine, amitriptyline,
bupropion, fluoxetine, mirtazapine, nefazodone, vilazodone,
vortioxetine, amitriptyline, amoxapine, clomipramine,
desipramine, imipramine, maprotiline, nortriptyline,
protriptyline, trimipramine
Antiepileptic Acetazolamide, carbamazepine, divalproex, eslicarbazepine
acetate, ethanol/phenobarbital, ethosuximide, ethotoin,
felbamate, fosphenytoin, lacosamide, levetiracetam,
methsuximide, oxcarbazepine, perampanel, phenobarbital,
phenytoin, primidone, rufinamide, tiagabine, topiramate,
valproate sodium, valproic acid, vigabatrin, zonisamide
for 0.11% of all prescriptions, and the remainder were multi-
vitamins. To have a negative control, we selected the supple-
ment cyanocobalamin (vitamin B12). Cyanocobalamin is a man-
made form of vitamin B12 that is essential for metabolism, blood
cell synthesis, and the nervous system. It is also available both
OTC and by prescription. It does not contain folic acid and is
commonly used to treat anemia.
Outcomes
Our primary end point was suicide attempt or intentional self-
harm resulting in an outpatient visit or inpatient admission as
identified by the ICD-9-CM and ICD-10-CM codes listed in the
eTable in the Supplement. We refer to these as suicidal events
in the rest of the article.
Statistical Analysis
The primary analysis used a discrete-time survival model,18
based on a logistic regression with complementary log-log link
function, so that the exponential of the estimated regression
coefficient is a hazard ratio (HR). Patients were followed up for
24 months after the index folic acid prescription month, which
was designated as month zero and not used in the analysis. We
selected a 24-month follow-up period because patients change
insurance carriers or discontinue service on average every 2
years. Month was the unit of analysis and treated as a categori-
cal variable. Folic acid is a time-varying treatment variable, so
we compared suicidal events during months with and with-
out folic acid prescription coverage within individuals.
This is a proportional hazards model in that the effect of
folic acid is assumed to be constant over time. We tested this
assumption by adding folic acid × month interactions to the
model, which allows the effect of folic acid on the hazard func-
tion to take on month-specific values. In our view, the target
trial19 is a sequential randomized trial with rerandomization
to treatment and control on a monthly basis. In this connection,
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Folic Acid and Suicide Attempts and Intentional Self-harm
Folic acid indication
Rheumatoid arthritis,15,16
psoriasis.
Any use. May reduce folate, but a
folate may also impede Effects are not well understood.
mechanism of action.a The prescriber may use discretion in
supplementation with folic acid
when prescribing antiepileptic
drugs.17
the non–proportional hazard model can be used to assess pe-
riod and carryover effects, in which the folic acid × month in-
teraction allows the effect of treatment to vary over time.
Models were adjusted for age, sex, baseline use of folate-
reducing drugs (eg, methotrexate), prior suicidal events, di-
agnoses related to suicide attempt (depression, anxiety,
attention-deficit/hyperactivity disorder, bipolar disorder,
schizophrenia, sleep disorders, pain) and diagnoses related to
intestinal folate absorption (Crohn disease and celiac dis-
ease) or both (substance use disorder), and any other use of
folate-reducing drugs (antimetabolites, proton pump inhibi-
tors, antihistamines and antacids, antidiabetics, antirheumat-
ics, antimicrobials, antibiotics, antiepileptics, and antidepres-
sants) (Table 1). Diagnostic covariates were assessed at baseline,
but pharmacologic covariates were treated as time-varying
covariates. As such, covariation between folic acid prescrip-
tion and antidepressant and antimanic (antiepileptic) drug
prescriptions were adjusted for in the analysis.
To determine if the association between folic acid and sui-
cidal events was moderated by folate-reducing drugs, a sepa-
rate model with interactions between folic acid and folate-
reducing drugs was also fit to these data. A model with
interactions between folic acid and sex and age was used to
determine if the effects were different in women and/or el-
derly individuals. Sex and age have large effects on suicide
and suicide attempt rates, and women frequently take folic acid
during pregnancy. These 2 variables were specifically exam-
ined in our original article1 and were included here based on
that prespecification and to determine whether any identi-
fied association was restricted to pregnant women. Age was
dichotomized at younger than 60 years.
As sensitivity analyses, we first repeated the main analy-
sis in patients taking the modal 1-mg dosage and second in
women of childbearing age. Third, a duration-response analy-
sis was conducted in patients taking the modal 1-mg dosage
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 Folic Acid and Suicide Attempts and Intentional Self-harm
by treating the cumulative number of months on treatment as
a time-varying covariate. Fourth, we restricted the analysis to
enrollment from 2015 to 2017 so that there was no overlap with
the original signal-generation study. Fifth, we conducted an
incident-user analysis by eliminating data for patients with pre-
vious use (past 2 years) of folic acid. Sixth, we eliminated data
for patients with a history of suicide attempt and reanalyzed
both using the primary analysis and the incident-user cohort.
In terms of multiplicity, we designate the primary analy-
sis as the only hypothesis test of the association between fo-
lic acid and suicide attempts, and all of the other analyses as
secondary/sensitivity analyses to test the robustness and gen-
eralizability of our conclusions. Furthermore, to have a nega-
tive control, we performed comparable analyses in patients pre-
scribed cyanocobalamin (vitamin B12), excluding those also
taking folic acid.
Results
Data on 866 586 patients were collected; 704 514 (81.30%) were
female, and 90 296 (10.42%) were 60 years and older. Table 2
provides characteristics of the sample in terms of diagnoses,
concomitant medications, and demographic data. Most folic
acid doses were for the upper tolerable limit for adults (in-
cluding in pregnancy and lactation) of 1 mg/d.
Overall, there were 261 suicidal events during months cov-
ered by a folic acid prescription (5 521 597 person-months) for
a rate of 4.73 per 100 000 person-months, and 895 suicidal
events during months without folic acid (8 432 340) for a rate
of 10.61 per 100 000 person-months. The observed relative risk
is 0.45, which is comparable with the previously reported
iDEAS odds ratio (OR) of 0.40 (95% CI, 0.28-0.59), and within
its 95% CI.1 The total number of patients in this data set is
866 586 for an overall suicidal event rate of 133 per 100 000
population. This rate is lower than the reported national rate
of 600 per 100 000.20
The adjusted estimated HR for folic acid for suicide events
was 0.56 (95% CI, 0.48-0.65) (Figure). The unadjusted esti-
mated HR for folic acid for suicide events was 0.39 (95% CI,
0.34-0.45).
Tests of the moderating effects of folate-reducing drugs
were all nonsignificant. Two- and 3-way interactions be-
tween age, sex, and folic acid were also nonsignificant. In-
cluding folic acid × month interactions in the model to test for
nonproportional hazards did not significantly improve the fit
of the model to the data (χ 223 = 28.21, P = .21), which also sug-
gests that there were no period or crossover effects.
A duration-response analysis restricted to patients tak-
ing the 1-mg/d dosage revealed a steady 5% decrease in sui-
cidal event rates for each additional month of treatment (HR,
0.95; 95% CI, 0.93-0.97). The median (IQR) number of months
of treatment was 6 months (2-13).
A total of 259 600 individuals took cyanocobalamin, the
negative control, during the study period. After excluding those
who also took folic acid, 236 610 individuals remained, with
1 460 534 person-months of cyanocobalamin use (128 suicide
attempts) and 2 440 834 months of no use (206 suicide
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Original Investigation Research
attempts), for suicide event rates of 8.76 and 8.44 per 100 000
person-months, respectively. No association was found be-
tween cyanocobalamin and suicidal events in the adjusted
analysis (HR, 1.01; 95% CI, 0.80-1.27) or unadjusted analysis
(HR, 1.02; 95% CI, 0.80-1.28).
Discussion
This large-scale pharmacoepidemiologic study showed an as-
sociation with the signal originally detected using the iDEAS
methodology.1 The unadjusted HR of 0.39 was comparable with
the iDEAS OR of 0.40. These estimates are not unbiased, and
the adjusted estimated HR, 0.56, was associated with a 44%
reduction in suicidal events. Although both studies used Mar-
ketScan claims data, eliminating any overlap in years yielded
virtually identical results (HR, 0.55; 95% CI, 0.45-0.66). Our
hypothesis that folic acid decreases suicidal event risk by in-
creasing folate levels in people taking folate-reducing drugs
was not confirmed in this study. Age and sex did not moderate
the association, and a similar association was found in women
of childbearing age. No association was found for our nega-
tive control supplement, cyanocobalamin.
Adding to the validity of our findings was the demonstra-
tion of a significant inverse duration-response association (1-mg
dosage subcohort). Every additional month of treatment was
associated with a 5% reduction in the suicidal event rate. The
validity is also supported by lack of an association between our
negative control supplement, cyanocobalamin, and suicidal
events. The HR of 1.01 found in our analysis of cyanocobala-
min is also similar to that found in our previous study, iDEAS,
in an all-drug screening analysis (HR, 0.98; 95% CI, 0.53-
1.81), which was based on 301 188 individuals.1
Several studies have found associations between folate lev-
els and folic acid supplementation and depression and suicid-
ality. In a case-control study involving 110 patients with de-
pression and 220 matched controls, a healthy dietary pattern
was associated with a 25% reduced risk of depression, and the
effect was mediated by folate levels.21 In a meta-analysis of 43
studies including 8519 individuals with depression and 27 282
individuals without depression, individuals with depression
had lower folate levels than those without depression (effect
size = 0.24 SD units).22 In an RCT of folic acid augmentation
therapy for depression in patients treated with lithium for 1
year,23 patients who achieved folate levels of 13 ng/mL or above
at the end point had a 40% greater reduction in Affective Mor-
bidity Index scores relative to placebo augmentation. A re-
cent study in South Korea24 found an association between se-
rum folate levels and fatal and nonfatal suicide attempts during
follow-up (area under the curve, 0.77). Using a cutpoint of 6
ng/mL, an adjusted OR of 2.69 (95% CI, 1.27-5.69) was found
for dichotomized serum folate levels and OR 2.84 (95% CI, 1.19-
6.77) for folate deficiency defined as less than 3 ng/mL. A case-
control study7 found cerebral folate deficiency in 36% of pa-
tients with refractory depression. All individuals with cerebral
folate deficiency and depression were treated with folinic acid
(leucovorin calcium) for at least 6 weeks, and 83.3% showed
improvement at follow-up (including reduction in suicidal
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 Research Original Investigation Folic Acid and Suicide Attempts and Intentional Self-harm

Table 2. Baseline Characteristics of Study Cohort (N = 866 586) Figure. Hazard Function for Suicide Attempts for Folic Acid vs Control:
Proportional Hazards Model
Variable No. (%)
Age, y 100
18-29 223 294 (25.77)
30-39 236 551 (27.30)

Rate per 100 000 person-years

80
40-49 144 852 (16.72)
50-59 171 593 (19.80)
≥60 90 296 (10.42) 60

Female 704 514 (81.30) Control

Male 162 072 (18.70) 40

Prior suicide attempt and intentional self-harm 1283 (0.15)
Medication
20
Folic acid 125 870 (14.52)
Folic acid
Antimetabolite (methotrexate) 161 789 (18.67)
Proton pump inhibitor 151 295 (17.46) 0
0 4 8 12 16 20 24
Antihistamine and antacid 33 046 (3.81)
Month
Antidiabetic 60 913 (7.03)
Antirheumatic 15 992 (1.85)
Antimicrobial 76 298 (8.80) in a population of US veterans.29 In the Veterans Affairs study,
Antibiotic 5565 (0.64) the baseline suicide attempt rate over the past 3 months was
Antidepressant 208 804 (24.10) 6%. To detect a 50% reduction in suicide attempt rate with
Antiepileptic 47 016 (5.43) power of 0.8 (6% vs 4%) would require 4000 participants.
Any of above drugs excluding folic acid 464 541 (53.61) Sample size requirements for the CAT-SS would be in the hun-
Comorbidity or other diagnosis dreds for a moderate effect size.
Substance use disorder 41 019 (4.73)
Depression 103 954 (12.00) Limitations
Anxiety 126 425 (14.59) There are several limitations of this study. First, it is an obser-
Attention-deficit/hyperactivity disorder 17 680 (2.04) vational study, and selection effects may be present. How-
Bipolar disorder 21 234 (2.45) ever, because all members of the cohort filled a folic acid pre-
Schizophrenia 7301 (0.84) scription in the month before the start of the study period, if
Sleep disorder 82 004 (9.46) confounding does exist, it is dynamic and related to the pro-
Crohn disease 10 369 (1.20)
gression of a disease and increased use of folic acid and sui-
Celiac disease 3177 (0.37)
cidal events. Second, claims data (ICD-9-CM and ICD-10-CM)
Pain 399 019 (46.04)
likely underrepresent the number of suicidal events because
of incomplete reporting. Indeed, our rate of suicidal events is
ideation). However, an RCT that randomized 475 patients to one-fourth of the national rate reported by the National Insti-
receive either 5 mg of folic acid daily (223 patients) or placebo tutes of Health. Third, the association between folic acid and
(217 patients) as an adjunct to antidepressant treatment for 12 suicidal events may be explained by healthy user bias. While
weeks found no significant difference between groups on sui- this is likely for OTC folic acid use, it is less true for filled pre-
cide ratings.25 scriptions, where more than half of these prescriptions were
The role of folate in depression and cognition has been rec- associated with pain disorders. The within-person nature of
ognized for more than a decade, leading to recommenda- our design and analysis further insulates the treatment effect
tions for folate augmentation in patients with low or normal from this bias. Fourth, in addition to OTC, folate may be pro-
levels at the start of any depression treatment.4 Polymor- vided as leucovorin calcium (folinic acid) as in Pan et al7 or as
phisms have been hypothesized to account for individual 5-MTHF (levomefolate calcium). However, this would lead us
differences in response to antidepressants, including to underestimate the association because some of our non-
treatment-resistant depression; however, in 1 study, no asso- use periods might actually be use periods. Fifth, while we con-
ciation between MTHFR polymorphisms and fluoxetine treat- ducted a sensitivity analysis in women of childbearing age, we
ment response were found.26 did not have data on women actively planning for pregnancy.
We believe that these results justify advocating for an RCT Nevertheless, we found the same association in men and
to study the effect of folic acid on suicidality. That study could women and no evidence of a sex × age × folic acid interac-
be conducted in a high-risk population, which would maxi- tion, making confounding unlikely.
mize the number of suicidal events, and could also use longi-
tudinal assessments of suicidal events using previously vali-
dated adaptive tests for suicidality. 27 The Computerized
Adaptive Test Suicide Scale (CAT-SS)27 has recently been dem-
Conclusions
onstrated to be feasible in a group-level intervention (n = 1485) This large-scale well-controlled pharmacoepidemiologic study
in the US Air Force Wingman Connect Study28 and validated of folic acid found a beneficial association in terms of lowering

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 Folic Acid and Suicide Attempts and Intentional Self-harm
rates of suicide attempts. These results warrant the conduct of
an RCT with suicidal ideation and behavior as outcomes of in-
ARTICLE INFORMATION
Accepted for Publication: August 3, 2022.
Published Online: September 28, 2022.
doi:10.1001/jamapsychiatry.2022.2990
Author Contributions: Dr Gibbons had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Gibbons, Lavigne.
Acquisition, analysis, or interpretation of data:
Gibbons, Hur, Mann.
Drafting of the manuscript: Gibbons, Lavigne.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Gibbons, Hur.
Supervision: Gibbons, Mann.
Conflict of Interest Disclosures: Dr Gibbons
reported serving as an expert witness in cases for
the US Department of Justice; receiving expert
witness fees from Merck, GlaxoSmithKline, Pfizer,
and Wyeth; and having founded the company
Adaptive Testing Technologies, which distributes
the Computerized Adaptive Test Suicide Scale
(CAT-SS), outside the submitted work. Dr Lavigne
reported serving as a consultant for CVS Health
outside the submitted work. Dr Mann reported
royalties from the Research Foundation for Mental
Hygeine Royalties outside the submitted work.
No other disclosures were reported.
Funding/Support: This research was supported by
National Institutes of Health grant R01 MH080122,
by Agency for Healthcare Research and Quality
(CERT) grant U18HS016973, and by resources from
the Center of Excellence for Suicide Prevention,
Department of Veterans Affairs.
Role of the Funder/Sponsor: The National
Institutes of Health and Center of Excellence for
Suicide Prevention had a role in the design and
conduct of the study, and the Agency for
Healthcare Research and Quality had a role in the
collection, management, analysis, and
interpretation of the data. The funders had no role
in the preparation, review, or approval of the
manuscript and decision to submit the manuscript
for publication.
REFERENCES
1. Gibbons RD, Hur K, Lavigne J, Wang J, Mann JJ.
Medications and suicide: high dimensional
empirical Bayes screening (iDEAS). Harvard Data
Science Review. Published November 1, 2019.
https://doi.org/10.1162/99608f92.6fdaa9de
2. Selhub J, Seyoum E, Pomfret EA, Zeisel SH.
Effects of choline deficiency and methotrexate
treatment upon liver folate content and
distribution. Cancer Res. 1991;51(1):16-21.
3. Miller AL. The methylation, neurotransmitter,
and antioxidant connections between folate and
depression. Altern Med Rev. 2008;13(3):216-226.
4. Fava M, Mischoulon D. Folate in depression:
efficacy, safety, differences in formulations, and
jamapsychiatry.com
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Mexico | Access Provided by JAMA User on 11/03/2022
terest. If confirmed, folic acid may be a safe, inexpensive, and
widely available treatment for suicidal ideation and behavior.
clinical issues. J Clin Psychiatry. 2009;70(suppl 5):
12-17. doi:10.4088/JCP.8157su1c.03
5. Wolfersdorf M, Keller F, Maier V, Fröscher W,
Kaschka WP. Red-cell and serum folate levels in
depressed inpatients who commit violent suicide:
a comparison with control groups.
Pharmacopsychiatry. 1995;28(3):77-79. doi:10.1055/
s-2007-979594
6. Engström G, Träskman-Bendz L. Blood folate,
vitamin B12, and their relationships with
cerebrospinal fluid monoamine metabolites,
depression, and personality in suicide attempters.
Nord J Psychiatry. 1999;53:131-137. doi:10.1080/
080394899426837
7. Pan LA, Martin P, Zimmer T, et al.
Neurometabolic disorders: potentially treatable
abnormalities in patients with treatment-refractory
depression and suicidal behavior. Am J Psychiatry.
2017;174(1):42-50. doi:10.1176/appi.ajp.2016.15111500
8. Czeizel AE, Dudás I, Vereczkey A, Bánhidy F.
Folate deficiency and folic acid supplementation:
the prevention of neural-tube defects and
congenital heart defects. Nutrients. 2013;5(11):
4760-4775. doi:10.3390/nu5114760
9. Wang X, Qin X, Demirtas H, et al. Efficacy of folic
acid supplementation in stroke prevention:
a meta-analysis. Lancet. 2007;369(9576):1876-1882.
doi:10.1016/S0140-6736(07)60854-X
10. Durga J, Verhoef P, Anteunis LJ, Schouten E,
Kok FJ. Effects of folic acid supplementation on
hearing in older adults: a randomized, controlled
trial. Ann Intern Med. 2007;146(1):1-9. doi:10.7326/
0003-4819-146-1-200701020-00003
11. O’Leary F, Allman-Farinelli M, Samman S.
Vitamin B12 status, cognitive decline and dementia:
a systematic review of prospective cohort studies.
Br J Nutr. 2012;108(11):1948-1961. doi:10.1017/
S0007114512004175
12. Hansen L. The MarketScan databases for life
sciences researchers [MarketScan white paper].
Truven Health Analytics. Published 2016.
13. Nock MK, Hwang I, Sampson NA, Kessler RC.
Mental disorders, comorbidity and suicidal
behavior: results from the National Comorbidity
Survey Replication. Mol Psychiatry. 2010;15(8):
868-876. doi:10.1038/mp.2009.29
14. Baldessarini RJ, Tondo L. Suicidal risks in 12
DSM-5 psychiatric disorders. J Affect Disord. 2020;
271:66-73. doi:10.1016/j.jad.2020.03.083
15. Duhra P. Treatment of gastrointestinal
symptoms associated with methotrexate therapy
for psoriasis. J Am Acad Dermatol. 1993;28(3):
466-469. doi:10.1016/0190-9622(93)70069-6
16. Ortiz Z, Shea B, Suarez Almazor M, Moher D,
Wells G, Tugwell P. Folic acid and folinic acid for
reducing side effects in patients receiving
methotrexate for rheumatoid arthritis. Cochrane
Database Syst Rev. 2000;(2):CD000951.
17. Linnebank M, Moskau S, Semmler A, et al.
Antiepileptic drugs interact with folate and vitamin
(Reprinted) JAMA Psychiatry November 2022 Volume 79, Number 11
Original Investigation Research
B12 serum levels. Ann Neurol. 2011;69(2):352-359.
doi:10.1002/ana.22229
18. Efron B. Logistic regression, survival analysis,
and the Kaplan-Meier curve. J Am Stat Assoc. 1988;
83(402):414-425. doi:10.1080/01621459.1988.
10478612
19. Hernán MA, Robins JM. Using big data to
emulate a target trial when a randomized trial is not
available. Am J Epidemiol. 2016;183(8):758-764.
doi:10.1093/aje/kwv254
20. National Institute of Mental Health. Suicide.
Retrieved December 6, 2021. https://www.nimh.
nih.gov/health/statistics/suicide
21. Khosravi M, Sotoudeh G, Amini M, Raisi F,
Mansoori A, Hosseinzadeh M. The relationship
between dietary patterns and depression mediated
by serum levels of folate and vitamin B12. BMC
Psychiatry. 2020;20(1):63. doi:10.1186/s12888-020-
2455-2
22. Bender A, Hagan KE, Kingston N.
The association of folate and depression:
a meta-analysis. J Psychiatr Res. 2017;95:9-18.
doi:10.1016/j.jpsychires.2017.07.019
23. Coppen A, Chaudhry S, Swade C. Folic acid
enhances lithium prophylaxis. J Affect Disord. 1986;
10(1):9-13. doi:10.1016/0165-0327(86)90043-1
24. Kim JM, Kim HY, Lee HJ, et al. Prediction of
suicidality according to serum folate levels in
depressive patients receiving stepwise
pharmacotherapy. Front Psychiatry. 2021;12:747228.
doi:10.3389/fpsyt.2021.747228
25. Bedson E, Bell D, Carr D, et al. Folate
Augmentation of Treatment–Evaluation for
Depression (FolATED): randomised trial and
economic evaluation. Health Technol Assess. 2014;
18(48):vii-viii,1-159. doi:10.3310/hta18480
26. Mischoulon D, Lamon-Fava S, Selhub J, et al.
Prevalence of MTHFR C677T and MS A2756G
polymorphisms in major depressive disorder, and
their impact on response to fluoxetine treatment.
CNS Spectr. 2012;17(2):76-86. doi:10.1017/
S1092852912000430
27. Gibbons RD, Kupfer D, Frank E, Moore T,
Beiser DG, Boudreaux ED. Development of a
computerized adaptive test suicide scale: the
CAT-SS. J Clin Psychiatry. 2017;78(9):1376-1382.
doi:10.4088/JCP.16m10922
28. Wyman PA, Pisani AR, Brown CH, et al. Effect
of the Wingman-Connect upstream suicide
prevention program for Air Force personnel in
training: a cluster randomized clinical trial. JAMA
Netw Open. 2020;3(10):e2022532. doi:10.1001/
jamanetworkopen.2020.22532
29. Brenner LA, Betthauser LM, Penzenik M,
Bahraini N, Gibbons RD. Validation of a
computerized adaptive test suicide scale (CAT-SS)
among United States military veterans. PLoS One.
2022;17(1):e0261920. doi:10.1371/journal.pone.
0261920
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