The association between vitamin D serum levels, supplementation, and suicide attempts and intentional self-harm

Jill E Lavigne; Jason B Gibbons

doi:10.1371/journal.pone.0279166

. 2023 Feb 1;18(2):e0279166. doi: 10.1371/journal.pone.0279166

The association between vitamin D serum levels, supplementation, and suicide attempts and intentional self-harm

Jill E Lavigne ^1,², Jason B Gibbons ^1,^3,^*

Editor: James D Clelland⁴

PMCID: PMC9891532 PMID: 36724169

Abstract

Objectives

The purpose of this study is to determine the associations between Vitamin D supplementation, 25(OH) blood serum levels, suicide attempts, and intentional self-harm in a population of veterans in the Department of Veterans Affairs (VA).

Methods

A retrospective cohort study of US Veterans supplemented with Vitamin D. Veterans with any Vitamin D₃ (cholecalciferol) or Vitamin D₂ (ergocalciferol) fill between 2010 and 2018 were matched 1:1 to untreated control veterans having similar demographics and medical histories. Cox proportional hazards regression was used to estimate the time from the first Vitamin D₃ (cholecalciferol) or Vitamin D₂ (ergocalciferol) prescription fill to the first suicide attempt or intentional self-harm. Analyses were repeated in stratified samples to measure associations by race (Black or White), gender (male or female), blood levels (0–19 ng/ml, 20–39 ng/ml, and 40+ ng/ml), and average daily dosage.

Results

Vitamin D3 and D2 supplementation were associated with a 45% and 48% lower risk of suicide attempt and self-harm ((D₂ Hazard Ratio (HR) = 0.512, [95% CI, 0.457, 0.574]; D₃ HR = 0.552, [95% CI, 0.511, 0.597])). Supplemented black veterans and veterans with 0–19 ng/ml vitamin D serum levels were at ~64% lower risk relative to controls (Black Veteran HR: 0.362 [95% CI: 0.298,0.440]; 0–19 ng/ml HR: 0.359 [95% CI: 0.215,0.598]). Supplementation with higher vitamin D dosages was associated with greater risk reductions than lower dosages (Log Average Dosage HR: 0.837 [95% CI: 0.779,0.900]).

Conclusions

Vitamin D supplementation was associated with a reduced risk of suicide attempt and self-harm in Veterans, especially in veterans with low blood serum levels and Black veterans.

Introduction

Serum vitamin D is derived from skin exposure to the sun or dietary Vitamin D, including supplements D₂ and D₃. Serum vitamin D supports bone health, immune function, and absorption of other micronutrients [1]. Vitamin D insufficiency and deficiency are prevalent in the US [2]. More than 30% of US military members have been shown to have 25-hydroxyvitamin D [25(OH)] levels below 20ng/ml [3], which is considered deficient [4]. Vitamin deficiency is particularly prevalent among service members of color and males [3]. Servicemembers and veterans also have elevated suicide attempt and suicide rates [5].

A growing body of evidence has identified associations between suicidal behavior [3, 6–13] or depressive symptoms [14–21] and low levels of serum 25-hydroxyvitamin D (serum Vitamin D). In a case-control study of 495 service members who had been deployed and later died by suicide, those with seasonally-adjusted Vitamin D serum levels [(25-hydroxyvitamin D [25(OH)]) less than 15.5 ng/mL had the highest risk of a suicide attempt [3]. In a study of 157,211 healthy Korean veterans, those with 25 (OH) levels below 10ng/mL were significantly more likely to have experienced suicidal ideation [22]. Vitamin D deficiency has previously been associated with symptoms similar to depression, including fatigue, mood changes (e.g., hopelessness and sadness), suicidal thoughts, anxiety, changes in appetite and weight, insomnia, and forgetfulness [1]. In addition, low Vitamin D serum levels have been associated with other mental and physical disorders with high rates of comorbid depression, including obesity, schizophrenia, and seasonal affective disorder [1].

A potential mechanism of action for vitamin D serum levels and suicide was found in a study of the post-mortem brain tissue from 15 depressed suicide decedents matched by age, sex, and death interval to 15 non-psychiatric controls [9]. Specifically, increased vitamin D receptor gene expression and decreased cathelicidin-related antimicrobial peptide expression were identified in the suicide decedents but not the matched controls. [9] However, randomized controlled trials of vitamin D supplementation and psychiatric outcomes have produced conflicting results, with trials reporting both positive [16, 17, 19–21, 23] and null or negative effects [14, 15, 18, 24–26]. The US Preventive Services Task Force reviewed 11 trials of Vitamin D supplementation and all-cause mortality but found no differences in mortality between the intervention and control groups in any study [27]. Notably, all of these trials, including those of mortality and incident depression, included subjects whose 25(OH) levels were above the level (<20ng/mL) defined by the National Academies of Medicine as deficient. Due to insufficient evidence [28–30], the US Preventive Services Task Force (USPSTF) was unable to make a recommendation for or against Vitamin D supplementation in the general adult population in 2021 [2]. The USPSTF has since called for research to more clearly define serum level cut-offs for insufficiency and deficiency as well as associations between vitamin D blood serum levels and diseases, including psychiatric disorders [2, 27, 29].

This study aimed to explore associations between 25(OH) levels, vitamin D₃ or D₂ supplementation, and suicide attempts or self-harm among U.S. veterans. We also evaluated the moderation of these associations by veteran race, vitamin D serum level, dosage, and gender.

Materials & methods

Study design

This retrospective cohort study included Department of Veterans Health Affairs (VHA) veterans represented in the national VHA Corporate Data Warehouse (CDW) with at least one electronic medical or pharmacy record between 2010–2018 linked at the individual level to Medicare inpatient, outpatient, professional (i.e., carrier), beneficiary summary (i.e., MBSF), and Part D (Drug) files for the same period. All veterans who received Vitamin D₂ (ergocalciferol) or Vitamin D₃ (cholecalciferol) fills between 2010 and 2018 were separately identified and matched 1:1 to untreated veterans on their propensity for supplementation (Table 1). After matching, Cox proportional hazards models were used to estimate the association between supplementation with Vitamin D₂ or D₃ (ergocalciferol or cholecalciferol) and suicide attempts. Veterans were followed from their index prescription for Vitamin D and censored at the first instance of a suicide attempt or self-harm, death, 24 months, or the end of the study period in December 2018. Analyses were repeated using stratified patient samples to see if patient race, gender, vitamin D dosage, and vitamin D blood serum levels modified the association between supplementation and suicide attempts and intentional self-harm.

Table 1. Characteristics of veterans receiving vitamin D and controls before and after 1-1- propensity score matching.

Covariate	Vitamin D₂				Vitamin D₃
	Pre-Matching		Post-Matching Restricted Sample		Pre-Matching		Post-Matching Restricted Sample
	Control	Treated	Control	Treated	Control	Treated	Control	Treated
N	1,764,309	176,403	169,241	169,241	1,907,720	538,442	490,885	490,885
Age	62	60	60	60	62	60	61	61
Gender
Female	8.4%	13.7%	13.3%	13.4%	8.6%	12.2%	11.5%	11.7%
Male	91.6%	86.3%	86.7%	86.6%	91.4%	87.8%	88.5%	88.3%
Race/Ethnicity
African American	14.2%	27.8%	26.8%	27.2%	14.3%	21.1%	20.0%	20.1%
Asian	1.7%	0.9%	0.9%	0.9%	1.3%	1.6%	1.5%	1.6%
Native American	1.8%	1.7%	1.7%	1.7%	1.8%	2.3%	2.2%	2.2%
Other Race	4.0%	4.0%	4.2%	4.1%	4.1%	4.8%	4.8%	4.8%
White	78.4%	65.6%	66.4%	66.1%	78.5%	70.2%	71.4%	71.4%
Mental Health Condition
Bipolar	2.9%	3.7%	4.0%	3.7%	3.0%	5.4%	5.2%	5.0%
Depression	27.0%	35.8%	36.3%	35.6%	28.2%	42.8%	41.9%	40.9%
Mood disorder	20.1%	28.1%	28.5%	27.8%	21.2%	34.8%	33.6%	32.8%
Personality Disorder	1.9%	2.6%	2.8%	2.6%	2.0%	3.6%	3.0%	2.9%
PTSD	17.3%	22.9%	23.5%	22.6%	18.5%	31.7%	30.1%	29.4%
Schizophrenia	0.9%	1.1%	1.3%	1.1%	1.0%	1.7%	1.7%	1.6%
Sleep Disorder	4.2%	5.2%	5.2%	5.1%	4.4%	6.7%	6.6%	6.4%
Substance Use Disorder	24.6%	33.7%	34.7%	33.6%	26.1%	35.6%	35.9%	34.7%
Physical Condition
Anemia	19.9%	21.0%	21.0%	20.9%	19.7%	22.0%	22.0%	21.9%
Congestive Heart Failure	11.0%	10.2%	9.7%	10.2%	10.7%	10.2%	9.9%	10.3%
Diabetes	25.2%	30.8%	31.4%	30.8%	25.3%	31.9%	32.4%	31.5%
Fatigue	21.9%	21.1%	21.3%	21.0%	21.6%	22.7%	23.3%	22.7%
Hypercholesterolemia	15.1%	13.9%	14.6%	13.8%	14.9%	15.0%	16.0%	15.1%
Hyperlipidemia	56.6%	63.0%	64.9%	63.0%	57.0%	66.0%	67.7%	65.5%
Hypertension	58.8%	65.4%	66.4%	65.4%	58.9%	66.1%	67.2%	65.7%
Hypothyroidism	12.2%	11.6%	16.4%	11.6%	12.2%	13.1%	13.5%	13.2%
Limb Pain	17.7%	20.4%	21.8%	20.3%	17.5%	21.4%	22.3%	20.9%
Long Term use of Medication	30.6%	33.0%	34.2%	32.9%	30.6%	35.3%	36.3%	34.9%
Needs Flu Shot	64.5%	71.8%	73.4%	71.7%	65.0%	75.0%	76.6%	74.5%
Reflux	33.6%	36.9%	38.0%	36.8%	33.8%	41.2%	41.9%	40.5%
Urinary Tract Infection	15.4%	16.0%	16.1%	15.8%	15.2%	16.9%	17.0%	16.8%
Vitamin D Deficiency	21.4%	54.0%	53.8%	54.3%	22.9%	52.4%	48.5%	50.2%

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Note: Treated beneficiaries include all beneficiaries that received one or more vitamin D prescriptions between January 1, 2010, and December 31, 2018. Conditions were measured based on the presence of one or more ICD-9 or ICD-10 codes during the entire study period.

Source: VA and Medicare Claims Data.

Study population

Data from the Department of Veterans Affairs Corporate Data Warehouse (CDW), including inpatient, outpatient, laboratory, prescription fill, and demographic data, were used to identify cohorts of veterans treated with and without Vitamin D supplementation in 2010–2018. Data were linked to Medicare claims at the individual patient level inside the VHA secure computing environment. Veterans with one or more filled prescriptions or medical claims between 2010–2018 were identified as having filled prescriptions for vitamin D₂, vitamin D_3, or neither (Table 1). We excluded veterans who filled both vitamin D₂ and D₃ and those with less than 90 days of supplementation in the two years following their index (i.e., first) vitamin D prescription. We also excluded veterans who had one or more prescriptions for vitamin D₂ between 2010–2018 from the vitamin D₃ control group and veterans who had one or more prescriptions for vitamin D₃ between 2010–2018 from the vitamin D₂ control group. This was done to prevent Vitamin D₃ and D₂ treated veterans from being used as controls for the D₂ and D₃ analyses. We used 1-to-1 propensity score matching from the remaining sample to identify a cohort of 169,241 vitamin D₂-treated veterans and 490,885 vitamin D₃-treated veterans, each matched to an equal number of controls (Table 1). Covariates (Table 1) used to generate propensity scores included common indications for vitamin D (e.g., vitamin D deficiency; see Table 1 for a complete list of conditions), demographic (i.e., age, race/ethnicity, and gender), and mental health comorbidities previously associated with suicide attempts in the academic literature (i.e., major depressive disorder, mood disorder, schizophrenia, bipolar disorder, substance use disorder, post-traumatic stress disorder, and personality disorder). Health conditions were identified using the presence of one or more ICD-9 or ICD-10 diagnoses on any medical claim for a veteran between 2010–2018. Propensity score matching was performed to help balance the treated and control populations across characteristics associated with vitamin D supplementation and suicidal and self-harm behaviors.

We also created subgroups for use in stratified analyses (Table 2). Subgroups were sampled from the initial vitamin D₂ and D₃ cohorts separately to determine subgroup heterogeneity in association with suicide attempts and self-harm rates by vitamin D₂ versus D₃. Subgroups included cohorts of individuals by race (black versus white), gender (male versus female), and vitamin D blood serum levels (i.e., 0–19 ng/ml, 20–39 ng/ml, and ≥ 40 ng/ml). Vitamin D blood serum levels were identified by the last 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D test before the index prescription of a vitamin D supplement for a patient in either the D2 or D3 treatment group or the corresponding treated pair’s index prescription for the untreated controls. Therefore, vitamin D blood serum levels reflect pre-treatment (or baseline) values. We provide counts of treated and control veterans in each subgroup in Table 2.

Table 2. Frequencies of suicide attempts and intentional self-harm by veteran cohort.

Veteran Cohort	Total Veterans N	Control N	Treated N	Suicide Attempt and Intentional Self-Harm by Control N (%)	Suicide Attempt and Intentional Self-Harm by Treated N (%)
Vitamin D ₂
All Veterans	338,482	169,241	169,241	878 (0.52%)	452 (0.27%)
Gender
Male	293,205	146,704	146,501	773 (0.50%)	376 (0.26%)
Female	45,277	22,537	22,740	145 (0.64%)	76 (0.33%)
Race
Black	91,446	45,362	46,084	243 (0.54%)	105 (0.23%)
White	211,655	104,724	106,931	553 (0.53%)	305 (0.29%)
0–19 Vitamin D Level Cohort	57,681	3,800	53,881	6 (0.16%)	77 (0.14%)
20–39 Vitamin D Level Cohort	37,356	14,335	23,021	20 (0.14%)	34 (0.15%)
40+ Vitamin D Level Cohort	5,377	4,591	786	5 (0.11%)	1 (0.13%)
Vitamin D ₃
All Veterans	981,770	490,885	490,885	1,786 (0.36%)	991 (0.20%)
Gender
Male	867,800	433,450	434,350	1,499 (0.35%)	833 (0.19%)
Female	113,970	56,535	57,435	287 (0.51%)	158 (0.28%)
Race
Black	196,732	98,164	98,568	383 (0.39%)	138 (0.14%)
White	666,322	329,024	337,298	1,209 (0.37%)	766 (0.23%)
0–19 Vitamin D Level Cohort	81,194	9,534	71,660	20 (0.21%)	55 (0.08%)
20–39 Vitamin D Level Cohort	153,887	41,678	112,209	51 (0.12%)	116 (0.10%)
40+ Vitamin D Level Cohort	20,940	14,327	6,613	5 (0.03%)	6 (0.09%)

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Exposure

The primary exposure was supplementation with vitamin D₃ (cholecalciferol) or vitamin D₂ (ergocalciferol), including multivitamins. Specifically, the association between suicide attempts and self-harm and supplementation was captured by the parameter estimates on an indicator variable equal to one (supplementation) or zero (control). We used the natural logarithm of average vitamin D dosage as a secondary exposure. The average vitamin D dosage was obtained by taking the average of the prescribed or administered dosages (which ranged from 40 UI to 50,000 UI) weighted by days supplied during the observation period during which the patient filled prescriptions for vitamin D (i.e., two years following index prescription). For veterans not taking vitamin D, we set the average daily dosage and its natural logarithm to be 0 to prevent constructing undefined values. Using the natural logarithm allowed us to relate percentage-point increases in average daily dosage to the associated probability of suicide attempt or self-harm in our statistical model. Single-unit increases in vitamin D dosage (i.e., 1 ng/ml) are unlikely to be related to changes in suicide and self-harm risk, which motivated our use of the natural logarithm of the average daily dosage. Vitamin D₃ and D₂ prescriptions and dosages were identified using National Drug Codes in the Department of Veterans Affairs Electronic Health Records data and the Medicare Part D claims data (i.e., Medicare prescription drug claims file).

Outcomes

The primary outcome identified in VHA and Medicare data was suicide attempt or intentional self-harm resulting in an emergency department (ED) or inpatient admission (from January 1, 2010) as identified by any mention at the first record (initial, subsequent or sequelae) of ICD–10–CM codes: X71–X83, T36–T50 with the 6^th character of 2 (except for T36.9, T37.9, T39.9, T41.4, T42.7, T43.9, T45.9, T47.9, and T49.9, which are included if the 5^th character is 2), T51–T65 with the 6^th character of 2 (except for T51.9, T52.9, T53.9, T54.9, T56.9, T57.9, T58.0, T58.1, T58.9, T59.9, T60.9, T61.0, T61.1, T61.9, T62.9, T63.9, T64.0, T64.8, and T65.9, which are included if the 5^th character is 2), T71 with the 6^th character of 2, and T14.91.) About 90% of all injury ED visits and hospitalizations were assigned an external cause of injury code by 2013.

Statistical analysis

We used a Cox proportional hazards model to compare vitamin D₂ and D₃ supplementation groups to matched controls on time to first suicide attempt or intentional self-harm. The only covariate in the model was an indicator representing vitamin D supplementation (i.e., “1” if supplemented and “0” if untreated control). The model was run separately for vitamin D₂ and D₃ treated veterans and their matched controls. Associations were estimated separately due to potential differences in outcomes between Vitamin D₂ and D₃ due to differences in metabolism. In both models, veterans were followed from their index prescription fill (or, for the matched treated pair’s control, the index prescription date) and were censored at the first instance of suicide attempt or self-harm, death, after two years, or the end of the study period in December 2018, whichever came first. The model was then estimated separately for each of the subgroups, which included race (black versus white), gender (female versus male), and vitamin D blood serum level (0–19 ng/ml, 20–39 ng/ml, and 40+ ng/ml). For the Vitamin D blood serum level subgroup analyses, we also included specifications that modeled the association between the natural logarithm of the average daily dosage across the entire treatment episode and suicide attempts and intentional self-harm.

This study (VA MIRB # 00701, PI Jill Lavigne) was reviewed and approved under Category 4 exempt determination by the Syracuse VA Medical Center Institutional Review Board in Syracuse, New York, and the VA’s VIREC Office for Medicare data. This research did not meet the criteria for human subjects research because the VA Corporate Warehouse Data and Medicare claims are de-identified, so informed consent was not required. All methods were performed in accordance with the relevant guidelines and regulations.

Results

Following matching, the vitamin D₂ and D₃ supplemented and control groups were similar across potential confounders (see Table 1). Moreover, most treated veterans in the D₂ and D₃ cohorts were successfully matched to an untreated control.

Patient frequencies by analytic cohort and suicide attempts by supplemented versus control veterans are presented in Table 2. In our entire Vitamin D₂ sample, we identified a total of 338,482 veterans, 169,241 treated and 169,241 controls, with a 0.52% unadjusted suicide attempt and self-harm rate in controls and a 0.27% rate amongst the treated. In our entire Vitamin D₃ sample, we identified 981,770 veterans; 490,885 treated and 490,885 controls. The unadjusted suicide attempt and self-harm rate was 0.36% in the control population and 0.20% in the treated. Attempt and self-harm rates by gender and race were similar to the entire sample for both Vitamin D₂ and D₃ subsamples. However, the serum level subsamples in both Vitamin D₂ and Vitamin D₃ demonstrated notably lower attempt and self-harm rates than the full sample. It may therefore be the case that those who have their vitamin D levels tested are characteristically different from those that did not receive testing. Finally, as vitamin D levels increased, the proportion of veterans experiencing suicide attempts and self-harm declined in the control groups for Vitamin D₂ and Vitamin D₃ and stayed relatively fixed in the treated groups.

Suicide attempts and intentional self-harm in the total sample

Estimates from the Cox proportional hazards models of the association between vitamin D₂ and D₃ supplementation and suicide attempts and self-harm appear in Table 3. Vitamin D₂ supplementation was associated with a 48.8% reduction in suicide attempt risk, and vitamin D₃ supplementation with a 44.8% reduction in suicide attempt and self-harm risk (D₂ Hazard Ratio (HR) = 0.512, [95% CI, 0.457, 0.574]; D₃ HR = 0.552, [95% CI, 0.511, 0.597]). Kaplan Meier curves are displayed in Figs 1 & 2.

Table 3. Estimated hazard ratios from a survival analysis comparing time-to-first-suicide-attempt or intentional self-harm between vitamin D supplemented veterans and matched control veterans.

Patient Cohort	Vitamin D₂ Treated versus Untreated Control (Hazard Ratio w/ 95% CI)	Vitamin D₃ Treated versus Untreated Control (Hazard Ratio w/ 95% CI)
All Veterans	0.512^***	0.552^***
All Veterans	(0.457, 0.574)	(0.511, 0.597)
Gender
Male	0.511^***	0.554^***
Male	(0.451, 0.579)	(0.509, 0.603)
Female	0.517^***	0.541^***
Female	(0.392, 0.683)	(0.446, 0.657)
Race
Black	0.421^***	0.362^***
Black	(0.335, 0.530)	(0.298, 0.440)
White	0.537^***	0.613^***
White	(0.467, 0.618)	(0.561, 0.672)
0–19 Vitamin D Level Cohort
All Dosages	0.887	0.359^***
All Dosages	(0.386, 2.034)	(0.215, 0.598)
Log Average Dosage	0.955	0.837^***
Log Average Dosage	(0.911, 1.000)	(0.779, 0.900)
20–39 Vitamin D Level Cohort
All Dosages	1.100	0.832
All Dosages	(0.628, 1.929)	(0.598, 1.15)
Log Average Dosage	0.957	0.904^***
Log Average Dosage	(0.893, 1.026)	(0.862, 0.948)
40+ Vitamin D Level Cohort
All Dosages	1.151	2.54
All Dosages	(0.135, 9.856)	(0.778, 8.35)
Log Average Dosage	0.971	1.045
Log Average Dosage	(0.805, 1.170)	(0.867, 1.260)

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Notes: Parameters expressed, except for cases where log average dosage are referenced, are for an indicator variable set to 1 if treated and 0 if control. Average dosage is measured as the logarithm of the weighted average prescription dosage (weighted by days supplied) during the patient follow-up period (i.e., two years following the index prescription). Blood levels were based on the last patient lab value preceding the index prescription date for the treated veterans and the matched treated pair’s index prescription date for the untreated controls. All Dosages analyses relate a supplementation indicator variable to suicide attempts and self-harm while the log-average dosages analyses relate the logarithm of the weighted average prescription dosage measure to suicide attempts and self-harm.

* P < .05

** P < .01

*** P < .001

Source: Veterans Affairs Chronic Data Warehouse Electronic Medical Records data and Medicare Claims Data.

Fig 1 — Source: Veterans Affairs Chronic Data Warehouse Electronic Medical Records data and Medicare Claims Data.

Fig 2 — Source: Veterans Affairs Chronic Data Warehouse Electronic Medical Records data and Medicare Claims Data.

Subgroup analyses

Gender

The association between supplementation and suicide attempts and self-harm was similar by gender for both vitamin D₂ and D₃ and was similar to the full sample estimates. Among veterans supplemented with vitamin D₂ (ergocalciferol), males had a 48.9% lower risk and females a 48.3% lower risk of suicide attempt (males HR = 0.511, [95% CI, 0.451, 0.579]; females HR = 0.517, [95% CI, 0.392, 0.683]). Similarly, among veterans supplemented with Vitamin D₃ (cholecalciferol), males were at 44.6% lower risk relative to 45.9% for females (males HR = 0.554, [95% CI, 0.509, 0.603]; females HR = 0.541, [95% CI, 0.446, 0.657]).

Race

The association between supplementation and suicide attempt and self-harm differed notably between Black and White veterans. Vitamin D₂ supplementation was associated with a 57.9% reduction in suicide attempt and self-harm risk for Black veterans compared to a 46.3% lower risk for White veterans (White veterans HR = 0.537, [95% CI, 0.467, 0.618]; Black veterans HR = 0.421, [95% CI, 0.335, 0.530]). Similarly, among veterans supplemented with vitamin D₃ (cholecalciferol), White veterans were at 38.7% lower risk relative to 63.8% lower risk for Black veterans (White veterans HR = 0.613, [95% CI, 0.561, 0.672]; Black veterans HR = 0.362, [95% CI, 0.298, 0.440]).

Vitamin D serum levels

The association between supplementation and suicide attempts and self-harm also differed by vitamin D blood serum level. In the 0–19 ng/ml blood serum cohort, Vitamin D₃ (cholecalciferol) supplementation was associated with a 64.1% reduction in risk relative to untreated controls (0–19 ng/ml HR = 0.359, [95% CI, 0.215, 0.598]). In this cohort of vitamin D deficient veterans, each additional percentage point increase in average daily dosage was associated with a 13.8% reduction in risk (0–19 ng/ml log average daily dosage HR = 0.837, [95% CI, 0.779, 0.900]). For veterans with blood levels between 20–39 ng/ml, while the overall association was not significant, Vitamin D₃ (cholecalciferol) supplementation was associated with a significant 9.6% reduction in suicide attempt and self-harm risk for each additional percentage point increase in average daily dosage (20–39 ng/ml log average daily dosage HR = 0.904, [95% CI, 0.862, 0.948]). No significant overall or dose-response associations were found for the 40+ ng/ml group. All results for Vitamin D₂ (ergocalciferol) by dosage and blood level were statistically insignificant.

Discussion

Our findings suggest that supplementation with vitamin D₂ (ergocalciferol) or vitamin D₃ (cholecalciferol) is associated with a 45%-48% reduced risk of suicide attempts and self-harm, on average, among veterans in the Department of Veterans Health Affairs. Subgroup analyses demonstrated the strongest associations among Black veterans and those with vitamin D deficiency (0–19 ng/ml serum levels). Only vitamin D₃ (cholecalciferol) demonstrated a dose-response effect in deficient veterans, with more significant reductions in suicide attempt and self-harm risk at higher doses of vitamin D₃ (cholecalciferol) supplementation. This finding is consistent with the pharmacology of the two D vitamins. When supplements are comprised of plant-based ingredients (D₂, ergocalciferol) rather than from animal-based ingredients (D_3, cholecalciferol), the inactive vitamin D storage form (25-hydroxyvitamin D2) has a shorter half-life. Cholecalciferol (D3) has been shown to increase serum 25(OH)D more efficiently than ergocalciferol (D2). Higher doses of vitamin D are more likely to achieve and maintain serum levels than low-dose prescriptions, which may explain the association between treatment intensity and suicide attempts and self-harm [31]. Moreover, those with the lowest blood levels may benefit the most from supplementation. The dose-response finding combined with more significant risk reductions in veterans with the lowest blood serum levels adds confidence to our primary finding of a general decrease in suicide attempt and self-harm risk for veterans receiving Vitamin D supplementation. However, additional research is required to determine the association between suicidal and self-harm behavior risk once sufficient vitamin D levels are obtained.

Low vitamin D serum levels may be prevalent among veterans and service members. An analysis of the Department of Defense Serum Repository found that more than 30% of subjects had 25(OH)D values below 20ng/ml [8]. No differences in mean 25(OH)D serum levels were found between those who died by suicide and those who did not, but those in the lowest season-adjusted octile had the highest risk of suicide. A secondary analysis of these data suggested the need for further research on vitamin D, including precision medicine approaches specifically for suicide prevention [32]. This need for precision medicine (i.e., focusing Vitamin D supplementation on those with deficient levels) approaches is further supported by twelve clinical trials of vitamin D supplementation and depression reported between January 2010 and May 2020 with overall negative results. Heterogenous designs may have contributed to divergent findings. The largest trial (Bertone-Johnson 2012) of 36,282 women did not include 25(OH)D levels and found no effect of vitamin D supplementation and depression after two years [26]. Similarly, a trial of 18,535 subjects aged 50 or older with a relatively high mean baseline 25(OH) level of 30.8ng/mL randomized to placebo or 2,000 IU/d of cholecalciferol (Vitamin D3) plus fish oil found no differences in the incidence of depression or mood scores after a mean of 5.3 years of follow-up [33]. However, suicidal ideation and behavior were not assessed. Two smaller trials with shorter follow-up periods found no effect of vitamin D supplementation versus placebo on depression measures [16, 34]. Other trials included subjects with relatively normal or high 25(OH)D levels [14–21]. Supplementation dosing ranged widely from daily doses of 400 IU to 4,800 IU over eight weeks to 12 months, weekly doses of 40,000 IU to 50,000 IU over eight weeks to six months, and annual doses of 50,000 IU over three to five years. Depression screening and assessment tools included 17 instruments, such as the PHQ-9, HMA-A, WHO-5, HAM-D17, and others.

Practice and policy implications

The Department of Veterans Health Affairs offers 25(OH)D testing to veterans, but the USPSTF does not support screening in asymptomatic adults as of 2021. Preventive services recommended by the USPSTF are required to be covered without patient cost-sharing by health plans under the Patient Protection and Affordable Care Act (2010). Although the USPSTF called for further research on Vitamin D screening in asymptomatic adults, screening may not be readily available to most US adults. However, screening may be indicated for veterans exhibiting warning signs of suicide or those with a history of suicidal behavior or ideation, particularly veterans whose suicide rates and vitamin D deficiency rates have been demonstrated to be higher than others.

The U.S. Recommended Dietary Allowance (RDA) for most adults is 600 IU of vitamin D per day. Pending confirmatory randomized controlled trials, providers may wish to initiate low-dose vitamin D supplementation, for example, at the US RDA level of 600 IU per day, without screening in patients with a history of suicidal behavior or ideation or who exhibit warning signs of suicidal behavior. Emerging evidence suggests a possible correlation between low vitamin D levels and depression [4]. Vitamin D receptors are located in areas of the brain involved in developing depression, including the hippocampus and hypothalamus [5, 6]. Adjuvant treatment of depression with vitamin D supplementation has been recommended [9]. Risk of toxicity can be managed by monitoring as toxicity is typically symptomatic, including nausea and gastrointestinal symptoms, before proceeding to urinary tract stones. However, toxicity has been shown to occur only at doses above 60,000 IU daily over several weeks, ten times the USRDA.

When recommending vitamin D supplementation, providers may wish to describe the potentially greater effectiveness of D₃, particularly because D₃ supplements are typically more expensive than D₂.

Limitations

Several limitations may affect the internal validity and generalizability of our study. While many disabled veterans and those with very high medication costs receive free care from the VA, including non-prescription products, for many veterans, the cost of vitamin D products may be the same or lower when purchased through retail outlets. Therefore, we suspect some of our untreated sample, especially those with vitamin D deficiency, received over-the-counter supplementation. However, unobserved supplementation in the control group would make our estimates of decreased suicide attempt risk conservative. Another limitation is that patients filling prescriptions for Vitamin D may engage in other health and mental health improving behaviors that we do not observe. Further, although we attempt to control for some characteristics likely to be associated with vitamin D supplementation and/or suicidal and self-harm behaviors, there are many unobservable characteristics (for example, traumatic brain injury common among veterans) that could confound our results. Our findings should therefore be interpreted as associations rather than causal effects. Concerning generalizability, the VA is primarily male and middle-aged, so our associations may not be generalizable to other populations.

Conclusion

Oral vitamin D is associated with a suicide attempt and intentional self-harm risk reduction of approximately 45%-48%. Supplementation with higher daily dosages of vitamin D₃ was associated with lower suicide attempt and self-harm risk than supplementation with lower dosages. Further, the associated risk reduction in suicide attempt and self-harm was more significant among Black veterans receiving supplementation with Vitamin D than white veterans, among whom low Vitamin D serum levels are more common than among White veterans. As a relatively safe, easily accessible, and affordable medication, supplementation with vitamin D in the VA may hold promise if confirmed in clinical trials to prevent suicide attempts and suicide.

Data Availability

The data that support the findings of this study are available from the United States Department of Veterans Affairs, but restrictions apply to the availability of these data, which were used for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of the United States Department of Veterans Affairs. You may contact Erika L. Trumble (erka.trumble@va.gov) to request data access information.

Funding Statement

This study was supported, in part, with resources from the Department of Veterans Affairs Center of Excellence for Suicide Prevention. Support for VA/CMS data was provided by the Department of Veterans Affairs, VA Health Services Research and Development Service, VA Information Resource Center (Project Numbers SDR 02-237 and 98-004), awarded to authors JG and JL. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

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PLoS One. doi: 10.1371/journal.pone.0279166.r001

Decision Letter 0

James D Clelland

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

20 Sep 2022

PONE-D-22-20954

The Association between Vitamin D Serum Levels, Supplementation, and Suicide Attempts or Intentional Self Harm

PLOS ONE

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Please address the questions and comments of both reviewers: Reviewer 1. " I was very glad to see the review of these studies in this paper revealing their inadequacies and emphasizing that suicidal ideation and behavior were not assessed. But I wonder if that review might be more appropriate in the introduction rather than the discussion.

This study looks at suicide attempts and intentional self-harm resulting in emergency room or in-patient admission, which are much more definite and specific than depression and have some different brain mechanisms. It is a retrospective study using Veterans Affairs and Medicare electronic data, from 2010 to 2018, with patients prescribed Vitamin D matched 1:1 to untreated controls. It uses a very large sample: over half a million treated, nearly two million not treated controls: or is it three and a half million not treated? (D2 Controls plus D3 Controls.) Why are the numbers of Pre-matching D3 controls not the same as Pre-matching D2 controls? If they are a different pool of controls how were the controls chosen for each pool? Some further explanation might be useful. And related: why are there only 9,534 D3 controls with 0-19 Vitamin D level when there are 53,881 D2 controls with that level?

The treated patients were included from the date of their prescription. Were the untreated matched by that starting date?

It is fortuitous (and surprising to me) that so many had Vitamin D blood levels, especially as many with low levels were not treated (see below)

The dose used is mentioned and analyzed using the natural logarithm of average dosage (why?). I think mention of the range of dose used would be useful – especially as there is discussion of the appropriate dose under Practical and Policy Implications – but not based on the results of this study.

I don’t understand Propensity Score matching despite reading several descriptions on line. I will accept that it is legitimate. Someone experienced with it should decide its appropriateness. Is everyone expected to know what it means? If not, some more explanation might help. For example, if I look at Depression can I presume that for each Treated person there is a Control of the same gender, race, age (how close?) and any other characteristic?

Typo Table 1, Post-Matching Restricted Sample Control column, Age ?61 not 6.

Table 1 does confirm that people with Bipolar, Depression and other psychiatric conditions were more likely to be given Vitamin D although a greater number with these conditions were not treated, but the matching brought the numbers and the treatment likelihood to the same. The same is true for Vitamin D deficiency. All good.

Table 2, typo: Suicide Attempt by Control column, 0-19 Vitamin D Level Cohort line, should be 86, not 6. And some of the numbers don’t add up; for example, Vitamin D2 females: if there are 45,277 total females the treated should be about 22,742 not 227,420. It does look as if, when Vitamin D levels were very low, D3 was used preferentially for treatment but still about 63,000 with levels 0-19 were untreated. That raises the question of why blood levels were taken.

The Vitamin D2 Level Cohorts Suicide Attempts are surprising (not much difference) given the big differences in race and gender cohorts. That makes it hard to understand the last sentence of the Results section: “However, models of the serum level subsamples demonstrated notably lower rates with increasing blood serum levels relative to the full sample.” Is that for D2 as well as D3 or just the latter? And is there a higher rate of suicide attempts with Vitamin D when the blood level was over 40. (Yes, the numbers are too small. Still it reminds me of the association between maternal (or cord) blood levels and schizophrenia in the offspring – a J-shaped curve.)

Presumably the mental health comorbidities were taken from any time during the two years of treatment (or control). It is interesting to me that the beneficial effects of treatment continue with little change for the two years (Figures 1 and 2) when blood levels of Vitamin D normalize with treatment in two to three months.

Under Discussion, second paragraph, line 4, typo: did should be died. In the sixth line the word “by” presumably should not be there. I think it would be useful to say exactly what is meant by “precision medicine” – presumably only treating those with low Vitamin D levels."

Reviewer 2. "Methods: It seems from Table 1 that the pre- and post-matched control groups for Vitamin D2 and D3 were independent of each other (as the starting numbers are different). Statistically speaking, this is a benefit and should be noted in the methods.

Line 86. The authors should specify the vitamin D assays employed for blood measures (e.g. 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D or both etc.)

Lines 132-135. For the vitamin D blood serum subgroups, the variable ln{average daily dosage)} is very confusing, as the natural log of 0 is undefined (those with no daily Vit D (thus ln{0}). In lines 99-102, the authors describe weighting the average dose by the numbers of days supplies during the observation period, but this would still not seem to amend an undefined value for those with no vitamin D (the control groups). In which case, how were the controls employed in the subgroup analysis? A better description of this variable and how it was employed in the models would be very helpful.

Results:

Did the authors consider the condition of TBI as a potential covariate, give that in this veteran population TBI may be frequent, may differ between exposure groups, and could impact the outcomes of interest?

Do the authors have access to vitamin D blood levels after the onset of supplementation? As if so, analysis by those that reached sufficient levels, versus those with continued insufficiency and/or deficiency may be interesting.

Discussion:

Sentence starting “ A secondary analysis of these data by suggested…….” A word is missing here.

Final paragraph: Reference should be included in this paragraph starting from the sentence “Other trials included subjects with…..”.

Conclusion: Second line of paragraph- it would be better for the authors refer to the veterans by another definition, rather than “Patients”.

Table 1: There are some mistakes in the tables: (e.g. Table 1 age of the D3 post-matched controls; Table 2, 0-19 D2 cohort numbers of control N and treated N, do no sum to the total patient N). Checking of the tables is advised."

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Reviewer #1: I found this study very interesting and very revealing. I was very enthusiastic about Vitamin D 10-15 years ago and did a small study in people with schizophrenia but became disenchanted with it after a succession of negative studies were published, mainly in depression. I was very glad to see the review of these studies in this paper revealing their inadequacies and emphasizing that suicidal ideation and behavior were not assessed. But I wonder if that review might be more appropriate in the introduction rather than the discussion.

The treated patients were included from the date of their prescription. Were the untreated matched by that starting date?

It is fortuitous (and surprising to me) that so many had Vitamin D blood levels, especially as many with low levels were not treated (see below)

Typo Table 1, Post-Matching Restricted Sample Control column, Age ?61 not 6.

Overall, I think it is a very good study, good methodology, with important findings.

Reviewer #2: In this interesting study, Lavigne & Gibbons set out to examine the benefits of exposure to Vitamin D, on the outcome of suicide. They performed a retrospective cohort study, using the extensive VA database of medical and pharmacy records, covering a period of approximately 8 years. Cox proportional hazards models were employed to estimate the association between vitamin D exposure (D2 or D3), on suicide attempt or death, with stratified analysis also included to assess the impact of race, gender, dosage and vitamin D blood serum levels.

The rationale behind the study is supported by the growing body of evidence cited in the Introduction, suggesting that low levels of vitamin D are associated with an increased risk of suicidal behavior. The methods are appropriate and the conclusions valid. There are only a few amendments that are suggested to improve clarity of the manuscript as currently written

Methods:

It seems from Table 1 that the pre- and post-matched control groups for Vitamin D2 and D3 were independent of each other (as the starting numbers are different). Statistically speaking, this is a benefit and should be noted in the methods.

Line 86. The authors should specify the vitamin D assays employed for blood measures (e.g. 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D or both etc.)

Results:

Discussion:

Sentence starting “ A secondary analysis of these data by suggested…….” A word is missing here.

Final paragraph: Reference should be included in this paragraph starting from the sentence “Other trials included subjects with…..”.

Conclusion: Second line of paragraph- it would be better for the authors refer to the veterans by another definition, rather than “Patients”.

**********

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Reviewer #1: Yes: Nigel Bark

Reviewer #2: No

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PLoS One. 2023 Feb 1;18(2):e0279166. doi: 10.1371/journal.pone.0279166.r002

Author response to Decision Letter 0

7 Nov 2022

Response to Editors

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Author Response: We have updated our formatting and file naming conventions to be consistent with journal requirements

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

Author Response: We have added language around the exempt determination status from the VA IRB in the last paragraph of the methods section.

3. Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

Author Response: We have updated or funding statement to include this sentence. See below.

Funding Statement: This study was supported, in part, with resources from the Department of Veterans Affairs Center of Excellence for Suicide Prevention in support of the 2020 call by the Department of Veterans Affairs for research to support the national response to the COVID-19 pandemic. This study does not represent the views of the Department of Veterans Affairs or the United States Government. Dr. Gibbons had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

4. Thank you for stating the following in the Acknowledgments Section of your manuscript. We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Author Response: See previous response for our funding statement. We have removed it from the text of our manuscript.

5. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability."Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter.

Author Response: See below for our data availability statement.

Data availability statement: The data that support the findings of this study are available from the United States Department of Veterans Affairs, but restrictions apply to the availability of these data, which were used for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of the United States Department of Veterans Affairs.

Author Response: We have updated the corresponding information on the title page.

Author Response: We have updated our ethics statement in the last paragraph of the methods section of the manuscript. See below:

“This study (VA MIRB # 00701, PI Jill Lavigne) was reviewed and approved under Category 4 exempt determination by the Syracuse VA Medical Center Institutional Review Board in Syracuse, New York, and the VA’s VIREC Office for Medicare data. This research did not meet the criteria for humans subjects research because the VA Corporate Warehouse Data and Medicare claims are de-identified, so informed consent was not required. All methods were performed in accordance with the relevant guidelines and regulations.”

Reviewer 1 Comments & Author Responses

I was very glad to see the review of these studies in this paper revealing their inadequacies and emphasizing that suicidal ideation and behavior were not assessed. But I wonder if that review might be more appropriate in the introduction rather than the discussion.

Author Response: We now review these studies in the third paragraph of the introduction section and discuss them further in the discussion section. The extension of this discussion is done to further contextualize our research findings in light of the previous literature.

Why are the numbers of Pre-matching D3 controls not the same as Pre-matching D2 controls? If they are a different pool of controls how were the controls chosen for each pool? Some further explanation might be useful.

Author Response: The number of controls for each supplement is different because D2 controls were dropped if they had taken D3 at any point in the study period, and D3 controls can’t have taken D2 at any point in the study period to clarify this point. We have added these details to the description in the study population section of the methods section:

“We also excluded patients who had one or more prescriptions for vitamin D2 between 2010-2020 from the vitamin D3 control group and patients who had one or more prescriptions for vitamin D3 between 2010-2020 from the vitamin D2 control group. This was done to prevent Vitamin D3 and D2 treated patients from being used as controls for the D2 and D3 analyses, respectively.”

And related: why are there only 9,534 D3 controls with 0-19 Vitamin D level when there are 53,881 D2 controls with that level?

Author Response: There was a typo during the construction of the table. The correct number for D2 controls is 3,800 and D2 treated is 53,881. The ratio of D2 untreated to treated at 0-19 ng/ml is similar to D3 after this correction. See table 2.

The treated patients were included from the date of their prescription. Were the untreated matched by that starting date?

Author Response: Matching was only done on included covariates. After matching, treated and control veterans were followed from the date of the treated pair’s index prescription, so yes, they were matched in terms of the index date in terms of the analysis of suicidal events. See the statistical analysis subsection of the methods section for clarification.

The dose used is mentioned and analyzed using the natural logarithm of average dosage (why?).

Author Response: This was done to give the parameter estimate interpretations of a percentage point change in dosage. Our motivation for this is now clarified in the exposure subsection of the methods section.

“Single unit increases in vitamin D dosage (i.e., 1 ng/ml) are unlikely to be related to changes in suicide and self-harm risk, which motivated our use of the natural logarithm of the average daily dosage.”

I think mention of the range of dose used would be useful – especially as there is discussion of the appropriate dose under Practical and Policy Implications – but not based on the results of this study.

Author Response: we have added the range of vitamin D dosages observed in the data in the first paragraph of the exposure section.

“The average vitamin D dosage was obtained by taking the average of the prescribed or administered dosages (which ranged from 40 UI to 50,000 UI) weighted by days supplied during the observation period during which the patient filled prescriptions for vitamin D (i.e., two years following index prescription).”

I don’t understand Propensity Score matching despite reading several descriptions online. I will accept that it is legitimate. Someone experienced with it should decide its appropriateness. Is everyone expected to know what it means? If not, some more explanation might help. For example, if I look at Depression can I presume that for each Treated person there is a Control of the same gender, race, age (how close?) and any other characteristic?

Author Response: We see in a comment below you resolved some of this confusion over the use of propensity score matching. Either way, we have added some additional language around the motivation in the last sentence of the first paragraph of the study population subsection of the methods section.

“Propensity score matching was performed to help balance the treated and control populations across characteristics known to be associated with both vitamin D supplementation and suicidal and self-harm behaviors.”

Typo Table 1, Post-Matching Restricted Sample Control column, Age ?61 not 6.

Author Response: We have fixed this typo. See table 1.

Author Response: The value of 6 is correct, but the number of controls with 0-19 ng/ml in the vitamin d2 population should be 3,800 instead of 53,881. We have fixed this issue and some other data entry typos in this table. See updated table 2.

It does look as if, when Vitamin D levels were very low, D3 was used preferentially for treatment but still about 63,000 with levels 0-19 were untreated. That raises the question of why blood levels were taken.

Author Response: D3 is generally more common than D2. It is also possible that some portion of the 63,000 that received a test were asked/decided to take vitamin D over the counter. This is mentioned as a possible limitation of the study but likely makes our results more conservative (as the controls may have been receiving treatment).

Author Response: We have rewritten the sentence for additional clarity. It is curious that those with testing had lower attempt rates than those that did not have a test, which we have called attention to. Our secondary point, which is now at the end of the sentence, is that the attempt and self-harm rates were generally lower in the control groups at higher blood levels.

“However, the serum level subsamples in both the Vitamin D2 and Vitamin D3 demonstrated notably lower attempt rates than the full sample. It may therefore be the case that those who have their vitamin D levels tested are characteristically different from those that did not receive testing. Finally, as vitamin D levels increased, the proportion of veterans experiencing suicide attempts and self-harm declined in the control groups for Vitamin D2 and Vitamin D3 and stayed relatively fixed in the treated groups.”

Presumably, the mental health comorbidities were taken from any time during the two years of treatment (or control).

Author Response: We have clarified that comorbidities span all possible medical claims for each veteran in the second to last sentence of the study population subsection of the methods section.

“Health conditions were identified using the presence of one or more ICD-9 or ICD-10 diagnoses on any medical claim for a veteran between 2010-2018.”

It is interesting to me that the beneficial effects of treatment continue with little change for the two years (Figures 1 and 2) when blood levels of Vitamin D normalize with treatment in two to three months.

Author Response: This is a good observation. The risk appears to be higher while blood levels are being established but continues to decrease over time, likely because those who were at high risk of an attempt have already been censored because they made an attempt (the same effect is observed in the controls but to a lesser degree). The intervention might also continue to be effective over time, even after levels have become more normal.

Under Discussion, second paragraph, line 4, typo: did should be died.

Author Response: We have fixed this typo

In the sixth line the word “by” presumably should not be there.

Author Response: We have fixed this typo

I think it would be useful to say exactly what is meant by “precision medicine” – presumably only treating those with low Vitamin D levels.

Author Response: We have added some context to this sentence as you suggest.

“This need for precision medicine (i.e., focusing Vitamin D supplementation on those with particularly low levels) approaches is further supported by twelve clinical trials of vitamin D supplementation and depression reported between January 2010 and May 2020 with overall negative results”

Reviewer 2 Comments & Author Responses

"Methods: It seems from Table 1 that the pre- and post-matched control groups for Vitamin D2 and D3 were independent of each other (as the starting numbers are different). Statistically speaking, this is a benefit and should be noted in the methods.

Author Response: To be clear, before matching, there were 1,764,309 possible controls in the D2 sample and 1,907,720 in the D3 control sample. Note that there is substantial overlap in these control groups, and the total number of unique controls is closer to 2 million. The number of controls for each supplement is different because D2 controls were dropped if they had taken D3 at any point in the study period, and D3 controls can’t have taken D2 at any point in the study period to clarify this point. We have added more description in the study population section of the methods section:

Line 86. The authors should specify the vitamin D assays employed for blood measures (e.g. 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D or both etc.)

Author Response: We have specified that this includes both. In the second paragraph of the study population subsection of the methods section.

“Vitamin D blood serum levels were identified by the last 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D test prior to the index prescription of a vitamin D supplement for a patient in either the D2 or D3 treatment group or the corresponding treated pair’s index prescription for the untreated controls.”

Lines 132-135. For the vitamin D blood serum subgroups, the variable ln{average daily dosage)} is very confusing, as the natural log of 0 is undefined (those with no daily Vit D (thus ln{0}). In lines 99-102, the authors describe weighting the average dose by the number of days supplies during the observation period, but this would still not seem to amend an undefined value for those with no vitamin D (the control groups). In which case, how were the controls employed in the subgroup analysis? A better description of this variable and how it was employed in the models would be very helpful.

Author Response: We have forced these values to be 0 manually. We have clarified this in in the first paragraph of the Exposure subsection of the Methods section.

“For patients not taking vitamin D, we set the average daily dosage and its natural logarithm to be 0 to prevent constructing undefined values..”

Results:

Did the authors consider the condition of TBI as a potential covariate, given that in this veteran population TBI may be frequent, may differ between exposure groups, and could impact the outcomes of interest?

Author Response: We did not control for TBI in our analyses. This is mentioned as a potential limitation in the limitations subsection of the discussion section.

“Further, although we attempt to control for some characteristics likely to be associated with vitamin D supplementation and/or suicidal and self-harm behaviors, there are many unobservable characteristics (for example, traumatic brain injury common among veterans) that could confound our results.”

Do the authors have access to vitamin D blood levels after the onset of supplementation?

As if so, analysis by those that reached sufficient levels, versus those with continued insufficiency and/or deficiency may be interesting.

Author Response: This is a potentially interesting extension of our work, unfortunately, our two-year follow-up period makes it difficult to study this, given the infrequent number of patients receiving regular lab tests. We have called for a prospective study where blood levels are routinely obtained to in the last sentence of the first paragraph of the discussion section.

“However, additional research is required to determine what happens to suicidal and self-harm behavior risk once sufficient levels of vitamin D are obtained and is left for future research.”

Discussion:

Sentence starting “A secondary analysis of these data by suggested…….” A word is missing here.

Author Response: We have revised this sentence.

“A secondary analysis of these data suggested the need for further research on vitamin D, including precision medicine approaches specifically for suicide prevention.34”

Final paragraph: Reference should be included in this paragraph starting from the sentence “Other trials included subjects with”.

Author Response: We have added some references to this sentence.

“Other trials included subjects with relatively normal or high 25(OH)D levels.14-21“

Conclusion: The second line of the paragraph- it would be better for the authors to refer to the veterans by another definition, rather than “Patients”.

Author Response: We have revised this sentence. We have also replaced all instances of the word “patients” with “veterans” throughout the manuscript.

“Veterans receiving higher prescription daily dosages were associated with lower risk or suicide attempt than veterans receiving lower dosages, and the associated risk reduction was more significant among Black veterans, among whom low Vitamin D serum levels are more common than among White veterans.”

Table 1: There are some mistakes in the tables: (e.g., Table 1 age of the D3 post-matched controls; Table 2, 0-19 D2 cohort numbers of control N and treated N, do no sum to the total patient N). Checking of the tables is advised."

Author Response: We have reviewed all tables and updated them with the correct numbers. Thank you for flagging these typos.

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PLoS One. doi: 10.1371/journal.pone.0279166.r003

Decision Letter 1

James D Clelland

1 Dec 2022

The Association between Vitamin D Serum Levels, Supplementation, and Suicide Attempts and Intentional Self-Harm

PONE-D-22-20954R1

Dear Dr. Gibbons,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: I appreciate the authors' responses to my comments and alterations or corrections where appropriate. All were addressed.

Reviewer #2: The authors have been very responsive to the previous reviewers comments. This manuscript is now ready to be published.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Nigel Bark

Reviewer #2: No

**********

PLoS One. doi: 10.1371/journal.pone.0279166.r004

Acceptance letter

James D Clelland

5 Jan 2023

PONE-D-22-20954R1

The Association between Vitamin D Serum Levels, Supplementation, and Suicide Attempts and Intentional Self-Harm

Dear Dr. Gibbons:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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Data Availability Statement

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PERMALINK

The association between vitamin D serum levels, supplementation, and suicide attempts and intentional self-harm

Jill E Lavigne

Jason B Gibbons

Roles

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Materials & methods

Study design

Table 1. Characteristics of veterans receiving vitamin D and controls before and after 1-1- propensity score matching.

Study population

Table 2. Frequencies of suicide attempts and intentional self-harm by veteran cohort.

Exposure

Outcomes

Statistical analysis

Results

Suicide attempts and intentional self-harm in the total sample

Table 3. Estimated hazard ratios from a survival analysis comparing time-to-first-suicide-attempt or intentional self-harm between vitamin D supplemented veterans and matched control veterans.

Fig 1. Cumulative survival curves comparing vitamin D2 treated against matched controls on time to first suicide attempt or intentional self harm.

Fig 2. Cumulative survival curves comparing vitamin D3 treated against matched controls on time to first suicide attempt or intentional self harm.

Subgroup analyses

Gender

Race

Vitamin D serum levels

Discussion

Practice and policy implications

Limitations

Conclusion

Data Availability

Funding Statement

References

Decision Letter 0

James D Clelland

Roles

Transfer Alert

Author response to Decision Letter 0

Decision Letter 1

James D Clelland

Roles

Acceptance letter

James D Clelland

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Fig 1. Cumulative survival curves comparing vitamin D₂ treated against matched controls on time to first suicide attempt or intentional self harm.

Fig 2. Cumulative survival curves comparing vitamin D₃ treated against matched controls on time to first suicide attempt or intentional self harm.