Abstract

While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D3 combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995–2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D3 along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.

Ample evidence suggests that vitamin D has important functions in the human brain and may play a role in depression (1–3). Vitamin D receptors are present in multiple brain regions associated with depressive disorders, including the prefrontal cortex and hippocampus (2), and cells in many of these regions are capable of metabolizing 25-hydroxyvitamin D to the biologically active metabolite 1,25-dihydroxyvitamin D (2, 4). Animal studies have suggested that vitamin D may increase the synthesis and/or metabolism of neurotransmitters, including dopamine and norepinephrine, though results have been inconsistent (1, 5, 6).

Relatively few epidemiologic studies have assessed whether vitamin D plays a role in depression (7). In most (but not all) cross-sectional (8–16) and prospective (17, 18) analyses, investigators have observed an inverse relation between blood 25-hydroxyvitamin D levels and prevalent or incident depression. However, these studies were limited by potential confounding by physical activity, body mass index, and other factors that influence 25-hydroxyvitamin D levels (19) and that may be independently associated with depression (20–22).

Randomized trials of vitamin D supplementation and depression are needed to determine whether vitamin D may hold promise for preventing or treating depression. To date, few trials have been conducted (23–30); they have had mixed results, and many have focused on seasonal depression alone. Thus, we evaluated the association between daily supplementation with 400 IU of vitamin D3, along with 1,000 mg of elemental calcium, and the occurrence of depression and antidepressant use in a randomized, double-blinded trial.

MATERIALS AND METHODS

Study design

The Women’s Health Initiative (WHI) Calcium and Vitamin D (CaD) Trial included women previously enrolled in the WHI Dietary Modification (DM) Trial and/or Hormone Therapy (HT) Trial. Establishment of the DM and HT trials has been described previously (31–33). Briefly, between 1993 and 1998, postmenopausal women aged 50–79 years were recruited through direct mailing campaigns and media awareness programs. Recruitment was conducted at 40 clinical centers throughout the United States. Major ineligibility criteria included a history of cancer (other than nonmelanoma skin cancer) within the previous 10 years, medical conditions likely to result in death within 3 years, and conditions likely to interfere with study retention. Women were also excluded if they had a history of hypercalcemia, kidney stones, or corticosteroid or calcitriol use.

DM and HT trial participants were invited to join the CaD Trial at their first or second annual follow-up clinic visit (Figure 1). The CaD Trial was designed to test calcium and vitamin D supplementation for the prevention of fracture and colorectal cancer, and has been described in detail previously (34). Of 68,132 women enrolled in the HT Trial or the DM Trial, 36,282 women were eligible and willing to participate in the CaD Trial. More than 95% of participants joining the CaD Trial did so at their first follow-up visit (hereafter referred to as “year 1”).

Figure 1.

Derivation of the cohort for analysis of the relation between vitamin D and calcium supplementation and depressive symptoms at year 3, Women’s Health Initiative (WHI) Calcium and Vitamin D (CaD) Trial, 1995–2000. While all participants were invited to complete the Burnam scale (37) at year 1, only a subset were invited to complete the Burnam scale at year 3. (AD, antidepressant; DM, Dietary Modification; HT, Hormone Therapy).

Figure 1.

Derivation of the cohort for analysis of the relation between vitamin D and calcium supplementation and depressive symptoms at year 3, Women’s Health Initiative (WHI) Calcium and Vitamin D (CaD) Trial, 1995–2000. While all participants were invited to complete the Burnam scale (37) at year 1, only a subset were invited to complete the Burnam scale at year 3. (AD, antidepressant; DM, Dietary Modification; HT, Hormone Therapy).

Women were randomized to receive a calcium-and-vitamin D supplement or an identical-appearing placebo using a permuted block algorithm. The total daily dose was 1,000 mg of elemental calcium (as calcium carbonate) and 400 IU of vitamin D3, given in 2 divided doses. Women were allowed to continue personal use of calcium and vitamin D supplements, with an initial cutoff for the latter of 600 IU/day, which later was increased to 1,000 IU/day. Supplementation was terminated if women reported kidney stones, kidney dialysis, hypercalcemia, calcitriol use, or personal use of vitamin D supplements at dosages higher than 600 IU/day (later 1,000 IU/day).

Participants were contacted after 4 weeks and then twice per year for assessment of safety, adherence, and clinical outcomes. Adherence was defined as taking 80% or more of study medication. In the first 3 years of follow-up, adherence ranged from 60% to 63% (35). An additional 13%–21% of participants took at least half of their medications. At baseline, the mean 25-hydroxyvitamin D level in a subset of 898 CaD Trial participants was 52.0 nmol/L (standard deviation, 21.1) (35). In a substudy of 448 trial participants, after 2 years 25-hydroxyvitamin D levels were 28% higher in women assigned to receive supplements than in women assigned to receive placebo (36).

The study protocol was approved by institutional review boards at all participating institutions and registered at clinicaltrials.gov. An independent data and safety monitoring board reviewed all clinical outcomes. Supplementation and clinic visits continued until final planned visits were conducted from October 1, 2004, to March 31, 2005. The average duration of participant follow-up was 7.0 years (36).

Study outcome

Among all CaD participants, we assessed the prevalence of depressive symptoms at year 1 with the Burnam 8-item scale for depressive disorders (37). A subset of study participants (n = 2,263) also completed the Burnam scale at their year 3 follow-up visit, which took place approximately 2 years after CaD randomization for most women. The Burnam scale includes 6 items from the Center for Epidemiologic Studies Depression Scale and 2 items from the Diagnostic Interview Schedule. Questions from the Center for Epidemiologic Studies Depression Scale asked women to report how often, in the past week, they had felt depressed (“blue or down”); their sleep had been restless; they had enjoyed life; they had had crying spells; they had felt sad; and they had felt that people disliked them. Response options were: “rarely or none of the time (<1 day)”; “some or a little of the time (1–2 days)”; “occasionally or a moderate amount of time (3–4 days)”; and “most or all of the time (5–7 days).” Questions from the Diagnostic Interview Schedule were: “In the past year, have you had 2 weeks or more during which you felt sad, blue, or depressed, or lost pleasure in things that you usually cared about or enjoyed?”; “Have you had 2 years or more in your life when you felt depressed or sad most days, even if you felt okay sometimes?”; and “If yes, have you felt depressed or sad much of the time in the past year?”.

We calculated the Burnam score using questionnaire responses and a logistic regression-based algorithm (37). Values for this scale range from 0 to 0.99, with higher scores indicating greater depressive symptomatology. For our main analysis, we dichotomized continuous Burnam scores at the standard threshold of 0.06 to identify women experiencing symptoms consistent with depressive disorders, including major depression and dysthymia, as in previous studies in the WHI (38–40). In analyses testing the validity of the Burnam scale in relation to the gold standard of psychiatric interview using the Diagnostic Interview Schedule, the cutoff value of 0.06 was determined to maximize sensitivity, specificity, and positive predictive value in both primary care and general populations (37). As discussed previously (41), this threshold score is not itself a measure of clinically diagnosed depression but is well correlated with clinical depression. An ancillary study evaluating the reliability of the Burnam algorithm versus clinical diagnosis in the WHI found a sensitivity of 74% and a specificity of 87% (42). Furthermore, depressive symptoms assessed with the Burnam scale have been predictive of cardiovascular disease and heart rate variability in the WHI (38, 41).

Among all CaD participants, we assessed use of antidepressant medications as a proxy for previously clinically diagnosed depression at year 1 and again at year 3. We included this outcome to enhance our statistical power, since only a subset of WHI participants were invited to complete the Burnam scale at year 3. Participants were asked to bring all current medications to their clinic visits, including selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, modified cyclic agents, tricyclic agents, and other medications classified as antidepressants. The names of medications used regularly (i.e., for more than 2 weeks) were recorded, along with information on dose and duration of use.

Dietary vitamin D intake and other factors

At an HT or DM enrollment clinic visit (i.e., in “year 0”), participants were asked to complete a semiquantitative food frequency questionnaire designed and validated for use in the WHI (43). Participants reported their usual intake and portion size of 122 foods or food groups in the previous 3 months. Intakes of vitamin D and calcium from food sources were calculated by multiplying the nutrient content of the specified portion size of each food (University of Minnesota Nutrition Coordinating Center nutrient database) by its frequency of consumption and summing the contributions of all foods. At clinic visits in year 0 and year 1, intakes of vitamin D and calcium from supplemental sources were assessed by trained interviewers using a standard questionnaire that measured dose, frequency (pills per week), and duration (months and years) of use of multivitamins, multivitamin-mineral supplements, and single-nutrient supplements (44). Total nutrient intakes were determined by summing intakes from food sources and supplemental sources. In a validation study in the WHI, vitamin D and calcium intakes measured by food frequency questionnaire correlated well with intakes measured with 4 days of diet recalls plus 4 days of food records (for total vitamin D, deattenuated r = 0.73; for total calcium, deattenuated r = 0.78) (43).

At year 0, women completed questionnaires assessing demographic, behavioral, and health-related factors, including age, race/ethnicity, education, previous use of hormone therapy and oral contraceptives, alcohol intake, history of smoking, and participation in physical activity. Weight and height were measured directly and used to calculate body mass index (weight (kg)/height (m)2). Annual level of solar irradiance in Langleys (gram-calories) per cm2 at each clinical center was estimated using measurements from the National Weather Service and adapted for use in the WHI (45). The extent to which health conditions limited physical function was measured with the RAND Short Form 36 (46).

Statistical analysis

We followed intention-to-treat principles for our main analyses. Descriptive statistics are presented with frequencies and percentages. Categorical variables were compared across supplement groups using chi-square statistics, while for continuous variables we used t tests. All P values are 2-sided.

Continuous change in Burnam score (year 3 – year 1) was modeled using continuous linear regression, with change as a function of assigned supplementation group (vitamin D + calcium or placebo). We used logistic regression to calculate odds ratios and 95% confidence intervals for the relation between supplementation and depressive symptoms above the threshold (Burnam score ≥0.06) at year 3 and antidepressant use at year 3. To assess whether vitamin D and calcium supplementation differently affected risk of “new” depression at year 3 among women without evidence of depression at year 1, we repeated these analyses excluding women who at year 1 had had a Burnam score greater than or equal to 0.06 or had reported current antidepressant use.

To determine whether the effect of supplements varied by background level of vitamin D or calcium intake, we conducted a series of logistic regression analyses modeling each outcome as a function of randomized supplementation group, background nutrient intake, and the interaction of the two. Contrasts were used to calculate odds ratios within each subgroup of total vitamin D or calcium intake, and P values for interaction were calculated. In this analysis, we evaluated interactions with vitamin D and calcium intakes from all sources (i.e., total intake), from food sources only, and from supplemental sources only. We used this same approach to evaluate whether other factors such as age, body mass index, or race/ethnicity modified the effect of supplementation on antidepressant use at year 3.

In all models, results were adjusted for age and HT or DM trial treatment assignment. Furthermore, analyses using the dichotomized Burnam scale endpoint were adjusted for this variable at year 1, while analyses of antidepressant use at the year 3 endpoint were adjusted for year 1 antidepressant use.

RESULTS

Characteristics of CaD Trial participants by randomization group are presented in Table 1. The intervention groups did not differ significantly by any factor evaluated except antidepressant use at year 1, which was reported by 6.5% of women assigned to receive supplements and 7.1% of women assigned to receive the placebo (P = 0.03). A depressive symptom score above the threshold value (Burnam score ≥0.06) was reported by 9.4% of women randomized to supplement use and 9.9% randomized to placebo (P = 0.25). Women assigned to supplement use did not differ from those assigned to placebo in terms of total vitamin D or calcium intake or intake of these nutrients from foods or self-administered supplements. Overall, total vitamin D intake was low (mean = 366 IU/day), with 42% of study participants consuming at least 400 IU of vitamin D per day and fewer than 6% consuming at least 800 IU/day.

Table 1.

Characteristics of Participants in the Women’s Health Initiative (WHI) Calcium and Vitamin D Trial at the Time of WHI Screening (i.e., Year 0), by Supplementation Group, 1995–2000

Characteristic Supplementation Group Placebo Group P Value 
No. %a No. %a 
Age, years     >0.99 
    50–59 6,726 37.0 6,696 37.0  
    60–69 8,276 45.5 8,243 45.5  
    70–79 3,174 17.5 3,167 17.5  
Race/ethnicity     0.45 
    White 15,051 82.8 15,104 83.4  
    Black 1,680 9.2 1,635 9.0  
    Hispanic 785 4.3 717 4.0  
    American Indian 77 0.4 72 0.4  
    Asian/Pacific Islander 370 2.0 351 1.9  
Annual income, dollars     0.68 
    <20,000 2,942 16.2 2,876 15.9  
    20,000–49,999 8,122 44.7 8,092 44.7  
    ≥50,000 6,205 34.1 6,192 34.2  
Marital status     0.96 
    Never married 725 4.0 712 3.9  
    Divorced/separated 2,850 15.7 2,875 15.9  
    Widowed 3,004 16.5 3,008 16.6  
    Married/living as married 11,522 63.4 11,442 63.2  
Regional solar irradiance, Langleys     >0.99 
    475–500 3,861 21.2 3,852 21.3  
    400–430 3,016 16.6 3,012 16.7  
    75–380 2,009 11.1 2,009 11.1  
    350 3,924 21.6 3,879 21.4  
    300–325 5,366 29.5 5,354 29.6  
Smoking status     0.50 
    Never smoker 9,325 51.3 9,428 52.1  
    Past smoker 7,255 39.9 7,133 39.4  
    Current smoker 1,405 7.7 1,356 7.5  
Alcohol intake, drinks/day     0.63 
    0 5,055 27.8 5,100 28.2  
    >0–<1 11,065 60.9 10,977 60.6  
    ≥1 1,908 10.5 1,900 10.5  
Hormone useb     0.24 
    Never use 5,810 32.0 5,685 31.4  
    Past use 3,007 16.5 2,937 16.2  
    Current use 9,359 51.5 9,484 52.4  
Body mass indexc     0.17 
    <25 4,745 26.1 4,834 26.7  
    25–<30 6,476 35.6 6,487 35.8  
    ≥30 6,870 37.8 6,692 37.0  
Physical activity, MET-hours/week     0.60 
    <3.00 5,405 29.7 5,340 29.5  
    3.00–9.99 4,642 25.5 4,648 25.7  
    10.00–19.99 3,647 20.1 3,569 19.7  
    ≥20.00 2,852 15.7 2,891 16.0  
Total vitamin D intake, IU/day     0.32 
    <100 2,750 15.1 2,653 14.7  
    100–<200 4,092 22.5 4,025 22.2  
    200–<400 3,373 18.6 3,419 18.9  
    400–<600 4,180 23.0 4,293 23.7  
    ≥600 3,426 18.8 3,363 18.6  
Dietary vitamin D intake, IU/day     0.47 
    <100 4,893 26.9 4,747 26.2  
    100–<200 7,434 40.9 7,496 41.4  
    200–<400 4,651 25.6 4,651 25.7  
    ≥400 843 4.6 859 4.7  
Supplemental vitamin D intake, IU/day     0.41 
    None 9,639 53.0 9,507 52.5  
    <400 1,795 9.9 1,780 9.8  
    400–<800 6,339 34.9 6,401 35.4  
    ≥800 403 2.2 418 2.3  
Meeting IOM guidelines for vitamin D intaked     0.99 
    No 15,379 84.6 15,430 85.2  
    Yes 2,374 13.1 2,391 13.2  
Total calcium intake, mg/day     0.44 
    <400 1,318 7.3 1,273 7.0  
    400–<800 4,790 26.4 4,732 26.1  
    800–<1,000 2,514 13.8 2,459 13.6  
    1,000–<1,200 2,198 12.1 2,195 12.1  
    ≥1,200 7,001 38.5 7,094 39.2  
Dietary calcium intake, IU/day     0.52 
    <400 2,406 13.2 2,378 13.1  
    400–<800 7,629 42.0 7,603 42.0  
    800–<1,000 2,906 16.0 2,878 15.9  
    1,000–<1,200 1,868 10.3 1,853 10.2  
    ≥1,200 3,012 16.6 3,041 16.8  
Supplemental calcium intake, IU/day     0.55 
    None 8,027 44.2 7,885 43.5  
    <400 4,289 23.6 4,295 23.7  
    400–<800 3,358 18.5 3,406 18.8  
    ≥800 2,502 13.8 2,520 13.9  
Total saturated fat intake, g/day     0.79 
    <15.1 4,469 24.6 4,415 24.4  
    15.1–21.4 4,463 24.6 4,479 24.7  
    21.5–29.7 4,505 24.8 4,367 24.1  
    ≥29.8 4,384 24.1 4,492 24.8  
Use of antidepressant medicationb     0.03 
    No 16,992 93.5 16,820 92.9  
    Yes 1,184 6.5 1,286 7.1  
Burnam depression scale (37) scoreb     0.25 
    <0.06 16,401 90.2 16,244 89.7  
    ≥0.06 1,708 9.4 1,790 9.9  
WHI Hormone Trial assignment     0.74 
    Not randomized 10,122 55.7 10,071 55.6  
    Active 4,039 22.2 4,078 22.5  
    Placebo 4,015 22.1 3,957 21.9  
WHI Dietary Modification Trial assignment     0.30 
    Not randomized 5,582 30.7 5,490 30.3  
    Intervention 4,767 26.2 4,878 26.9  
    Comparison 7,827 43.1 7,738 42.7  
Characteristic Supplementation Group Placebo Group P Value 
No. %a No. %a 
Age, years     >0.99 
    50–59 6,726 37.0 6,696 37.0  
    60–69 8,276 45.5 8,243 45.5  
    70–79 3,174 17.5 3,167 17.5  
Race/ethnicity     0.45 
    White 15,051 82.8 15,104 83.4  
    Black 1,680 9.2 1,635 9.0  
    Hispanic 785 4.3 717 4.0  
    American Indian 77 0.4 72 0.4  
    Asian/Pacific Islander 370 2.0 351 1.9  
Annual income, dollars     0.68 
    <20,000 2,942 16.2 2,876 15.9  
    20,000–49,999 8,122 44.7 8,092 44.7  
    ≥50,000 6,205 34.1 6,192 34.2  
Marital status     0.96 
    Never married 725 4.0 712 3.9  
    Divorced/separated 2,850 15.7 2,875 15.9  
    Widowed 3,004 16.5 3,008 16.6  
    Married/living as married 11,522 63.4 11,442 63.2  
Regional solar irradiance, Langleys     >0.99 
    475–500 3,861 21.2 3,852 21.3  
    400–430 3,016 16.6 3,012 16.7  
    75–380 2,009 11.1 2,009 11.1  
    350 3,924 21.6 3,879 21.4  
    300–325 5,366 29.5 5,354 29.6  
Smoking status     0.50 
    Never smoker 9,325 51.3 9,428 52.1  
    Past smoker 7,255 39.9 7,133 39.4  
    Current smoker 1,405 7.7 1,356 7.5  
Alcohol intake, drinks/day     0.63 
    0 5,055 27.8 5,100 28.2  
    >0–<1 11,065 60.9 10,977 60.6  
    ≥1 1,908 10.5 1,900 10.5  
Hormone useb     0.24 
    Never use 5,810 32.0 5,685 31.4  
    Past use 3,007 16.5 2,937 16.2  
    Current use 9,359 51.5 9,484 52.4  
Body mass indexc     0.17 
    <25 4,745 26.1 4,834 26.7  
    25–<30 6,476 35.6 6,487 35.8  
    ≥30 6,870 37.8 6,692 37.0  
Physical activity, MET-hours/week     0.60 
    <3.00 5,405 29.7 5,340 29.5  
    3.00–9.99 4,642 25.5 4,648 25.7  
    10.00–19.99 3,647 20.1 3,569 19.7  
    ≥20.00 2,852 15.7 2,891 16.0  
Total vitamin D intake, IU/day     0.32 
    <100 2,750 15.1 2,653 14.7  
    100–<200 4,092 22.5 4,025 22.2  
    200–<400 3,373 18.6 3,419 18.9  
    400–<600 4,180 23.0 4,293 23.7  
    ≥600 3,426 18.8 3,363 18.6  
Dietary vitamin D intake, IU/day     0.47 
    <100 4,893 26.9 4,747 26.2  
    100–<200 7,434 40.9 7,496 41.4  
    200–<400 4,651 25.6 4,651 25.7  
    ≥400 843 4.6 859 4.7  
Supplemental vitamin D intake, IU/day     0.41 
    None 9,639 53.0 9,507 52.5  
    <400 1,795 9.9 1,780 9.8  
    400–<800 6,339 34.9 6,401 35.4  
    ≥800 403 2.2 418 2.3  
Meeting IOM guidelines for vitamin D intaked     0.99 
    No 15,379 84.6 15,430 85.2  
    Yes 2,374 13.1 2,391 13.2  
Total calcium intake, mg/day     0.44 
    <400 1,318 7.3 1,273 7.0  
    400–<800 4,790 26.4 4,732 26.1  
    800–<1,000 2,514 13.8 2,459 13.6  
    1,000–<1,200 2,198 12.1 2,195 12.1  
    ≥1,200 7,001 38.5 7,094 39.2  
Dietary calcium intake, IU/day     0.52 
    <400 2,406 13.2 2,378 13.1  
    400–<800 7,629 42.0 7,603 42.0  
    800–<1,000 2,906 16.0 2,878 15.9  
    1,000–<1,200 1,868 10.3 1,853 10.2  
    ≥1,200 3,012 16.6 3,041 16.8  
Supplemental calcium intake, IU/day     0.55 
    None 8,027 44.2 7,885 43.5  
    <400 4,289 23.6 4,295 23.7  
    400–<800 3,358 18.5 3,406 18.8  
    ≥800 2,502 13.8 2,520 13.9  
Total saturated fat intake, g/day     0.79 
    <15.1 4,469 24.6 4,415 24.4  
    15.1–21.4 4,463 24.6 4,479 24.7  
    21.5–29.7 4,505 24.8 4,367 24.1  
    ≥29.8 4,384 24.1 4,492 24.8  
Use of antidepressant medicationb     0.03 
    No 16,992 93.5 16,820 92.9  
    Yes 1,184 6.5 1,286 7.1  
Burnam depression scale (37) scoreb     0.25 
    <0.06 16,401 90.2 16,244 89.7  
    ≥0.06 1,708 9.4 1,790 9.9  
WHI Hormone Trial assignment     0.74 
    Not randomized 10,122 55.7 10,071 55.6  
    Active 4,039 22.2 4,078 22.5  
    Placebo 4,015 22.1 3,957 21.9  
WHI Dietary Modification Trial assignment     0.30 
    Not randomized 5,582 30.7 5,490 30.3  
    Intervention 4,767 26.2 4,878 26.9  
    Comparison 7,827 43.1 7,738 42.7  

Abbreviations: IOM, Institute of Medicine; MET, metabolic equivalent task; WHI, Women’s Health Initiative.

a

Percentages may not sum to 100 because of missing data.

b

Measured at year 1.

c

Weight (kg)/height (m)2.

d

The IOM guidelines for vitamin D intake are ≥600 IU/day for women aged 50–70 years and ≥800 IU/day for women aged ≥70 years (42).

We did not find supplementation with vitamin D and calcium to be associated with a significant change in continuous Burnam score from baseline to year 3, as compared with placebo (Table 2). Among women without evidence of depression at year 1, depressive symptom score was modestly but significantly higher in women assigned to the supplementation group than in those assigned to the placebo group (for supplementation vs. placebo, multivariable-adjusted mean change = 0.009; 95% confidence interval (CI): 0.002, 0.017).

Table 2.

Association of Calcium and Vitamin D Supplementation With Change in Mean Burnam Scale Score Between Year 1 and Year 3 of Follow-up, Women’s Health Initiative Calcium and Vitamin D Trial, 1995–2003

 All Participants Participants Without Evidence of Depression at Year 1a 
 No. of Women Mean Changeb (SD) (Year 3 – Year 1) Multivariable-Adjusted Mean Changec 95% CI No. of Women Mean Changeb (SD) (Year 3 – Year 1) Multivariable-Adjusted Mean Changed 95% CI 
Supplementation group 1,109 0.004 (0.143) 0.007 −0.003, 0.017 956 0.020 (0.099) 0.009 0.002, 0.017 
Placebo group 1,143 −0.002 (0.113) Referent 1,001 0.010 (0.061) Referent 
 All Participants Participants Without Evidence of Depression at Year 1a 
 No. of Women Mean Changeb (SD) (Year 3 – Year 1) Multivariable-Adjusted Mean Changec 95% CI No. of Women Mean Changeb (SD) (Year 3 – Year 1) Multivariable-Adjusted Mean Changed 95% CI 
Supplementation group 1,109 0.004 (0.143) 0.007 −0.003, 0.017 956 0.020 (0.099) 0.009 0.002, 0.017 
Placebo group 1,143 −0.002 (0.113) Referent 1,001 0.010 (0.061) Referent 

Abbreviations: CI, confidence interval; SD, standard deviation; WHI, Women’s Health Initiative.

a

Analysis excluded women with depressive symptoms above the threshold level (Burnam score ≥0.06) or antidepressant use at baseline.

b

Positive change reflects a higher Burnam score at year 3 versus baseline; negative change reflects a lower Burnam score at year 3 versus baseline.

c

Multivariable models adjusted for age, race/ethnicity, WHI Hormone Trial intervention, WHI Dietary Modification Trial intervention, and depressive symptoms above the threshold level (Burnam score ≥0.06) at year 1.

d

Multivariable models adjusted for age, race/ethnicity, WHI Hormone Trial intervention, and WHI Dietary Modification Trial intervention.

Furthermore, as shown in Table 3, compared with those randomized to placebo, women randomized to supplement use had an odds ratio of 1.16 (95% CI: 0.86, 1.56) for experiencing depressive symptoms above the threshold level. Supplementation was not associated with the likelihood of antidepressant use at year 3; compared with women assigned to placebo, women assigned to supplements had an odds ratio of 1.01 (95% CI: 0.92, 1.12) for antidepressant use. In analyses limited to women without evidence of depression at year 1, those randomized to supplement use had an odds ratio of 1.41 (95% CI: 0.97, 2.05) compared with women assigned to placebo.

Table 3.

Association of Calcium and Vitamin D Supplementation With Risk of Depressive Symptoms Above the Threshold Level at Year 3 and Risk of Antidepressant Medication Use at Year 3, Women’s Health Initiative Calcium and Vitamin D Trial, 1995–2003

 All Participants Participants Without Evidence of Depression at Year 1a 
 No. of Cases No. of Noncases Multivariate ORb 95% CI No. of Cases No. of Noncases Multivariate ORc 95% CI 
Depressive symptoms above threshold level (Burnam score ≥0.06) at year 3         
    Supplementation group 119 997 1.16 0.86, 1.56 70 886 1.41 0.97, 2.05 
    Placebo group 108 1,039 Referent 52 949 Referent 
Use of antidepressant medication at year 3         
    Supplementation group 1,326 15,732 1.01 0.92, 1.12 419 14,248 0.96 0.84, 1.10 
    Placebo group 1,380 15,597 Referent 428 14,001 Referent 
 All Participants Participants Without Evidence of Depression at Year 1a 
 No. of Cases No. of Noncases Multivariate ORb 95% CI No. of Cases No. of Noncases Multivariate ORc 95% CI 
Depressive symptoms above threshold level (Burnam score ≥0.06) at year 3         
    Supplementation group 119 997 1.16 0.86, 1.56 70 886 1.41 0.97, 2.05 
    Placebo group 108 1,039 Referent 52 949 Referent 
Use of antidepressant medication at year 3         
    Supplementation group 1,326 15,732 1.01 0.92, 1.12 419 14,248 0.96 0.84, 1.10 
    Placebo group 1,380 15,597 Referent 428 14,001 Referent 

Abbreviations: CI, confidence interval; OR, odds ratio; WHI, Women’s Health Initiative.

a

Analysis excluded women with depressive symptoms above the threshold level (Burnam score ≥0.06) or antidepressant use at baseline.

b

Multivariable models adjusted for age, race/ethnicity, WHI Hormone Trial intervention, and WHI Dietary Modification Trial intervention. The analysis of risk of depressive symptoms above the threshold level (Burnam score ≥0.06) included adjustment for this variable at baseline. The analysis of risk of antidepressant use included adjustment for antidepressant use at baseline.

c

Multivariable models adjusted for age, race/ethnicity, WHI Hormone Trial intervention, and WHI Dietary Modification Trial intervention.

Overall, we found inconclusive evidence that baseline vitamin D and calcium intakes modified the association between supplementation and risk of either depressive symptoms above the threshold level or antidepressant use (Table 4). We observed a statistically significant interaction between supplementation assignment and total vitamin D intake as related to the occurrence of depressive symptoms above the threshold level (P = 0.03) but not as related to antidepressant use. Supplementation was unrelated to risk of either outcome when we stratified the results by level of vitamin D intake from foods only, vitamin D intake from supplements only, or calcium intake.

Table 4.

Association of Calcium and Vitamin D Supplementation With Measures of Depression at Year 3, According to Vitamin D and Calcium Intake at Baseline, Women’s Health Initiative Calcium and Vitamin D Trial, 1995–2003

 Depressive Symptoms (Burnam Score ≥0.06) Use of Antidepressant Medication 
 No. of Cases Total No. ORa for Supplementation vs. Placebo 95% CI No. of Users Total No. ORa for Supplementation vs. Placebo 95% CI 
Total vitamin D intake, IU/dayb         
    <100 46 418 0.61 0.30, 1.22 350 4,965 0.89 0.68, 1.16 
    100–<200 49 487 2.84 1.38, 5.83 550 7,570 1.20 0.96, 1.49 
    200–<400 34 390 1.80 0.82, 3.97 509 6,382 0.96 0.76, 1.21 
    400–<600 53 520 0.91 0.49, 1.70 683 8,018 0.92 0.76, 1.13 
    ≥600 37 379 0.99 0.47, 2.05 574 6,468 1.09 0.87, 1.36 
        Pinteraction    0.03    0.32 
Dietary vitamin D intake, IU/day         
    <100 70 687 0.88 0.51, 1.52 668 8,989 0.91 0.75, 1.11 
    100–<200 76 876 1.46 0.87, 2.44 1,127 14,039 1.10 0.94, 1.28 
    200–<400 59 529 1.39 0.76, 2.53 725 8,782 0.96 0.79, 1.17 
    ≥400 14 102 0.99 0.29, 3.35 146 1,593 1.13 0.73, 1.76 
        Pinteraction    0.55    0.45 
Supplemental vitamin D intake, IU/day         
    None 127 1,201 1.38 0.91, 2.07 1,296 17,367 1.02 0.89, 1.18 
    <400 20 207 1.15 0.43, 3.11 272 3,383 1.04 0.76, 1.43 
    400–<800 68 733 1.04 0.61, 1.78 1,038 11,882 0.99 0.84, 1.17 
    ≥800 53 0.22 0.02, 2.63 60 771 0.86 0.44, 1.69 
        Pinteraction    0.48    0.96 
Total calcium intake, mg/dayb         
    <400 29 221 0.50 0.20, 1.24 146 2,358 0.87 0.58, 1.31 
    400–<800 65 655 1.76 0.98, 3.17 661 8,831 1.00 0.82, 1.22 
    800–<1,000 24 293 1.81 0.73, 4.48 403 4,682 1.24 0.96, 1.61 
    1,000–<1,200 19 244 1.16 0.43, 3.19 301 4,154 0.98 0.73, 1.32 
    ≥1,200 82 781 1.05 0.63, 1.73 1,155 13,378 0.97 0.83, 1.14 
        Pinteraction    0.18    0.52 
Dietary calcium intake, mg/day         
    <400 39 380 0.61 0.29, 1.29 318 4,429 0.94 0.71, 1.25 
    400–<800 96 932 1.28 0.80, 2.04 1,098 14,298 0.98 0.84, 1.14 
    800–<1,000 24 328 2.57 1.01, 6.55 450 5,448 1.15 0.90, 1.47 
    1,000–<1,200 24 231 1.03 0.41, 2.60 270 3,526 1.26 0.92, 1.73 
    ≥1,200 36 323 1.27 0.59, 2.73 530 5,702 0.90 0.71, 1.13 
        Pinteraction    0.21    0.37 
Supplemental calcium intake, mg/day         
    None 114 1,024 1.28 0.83, 1.99 1,070 14,334 1.00 0.85, 1.17 
    <400 47 528 1.47 0.77, 2.82 697 7,987 1.13 0.92, 1.38 
    400–<800 29 382 0.97 0.43, 2.19 516 6,342 0.93 0.74, 1.17 
    ≥800 29 260 0.80 0.34, 1.88 383 4,740 0.96 0.74, 1.26 
        Pinteraction    0.66    0.63 
 Depressive Symptoms (Burnam Score ≥0.06) Use of Antidepressant Medication 
 No. of Cases Total No. ORa for Supplementation vs. Placebo 95% CI No. of Users Total No. ORa for Supplementation vs. Placebo 95% CI 
Total vitamin D intake, IU/dayb         
    <100 46 418 0.61 0.30, 1.22 350 4,965 0.89 0.68, 1.16 
    100–<200 49 487 2.84 1.38, 5.83 550 7,570 1.20 0.96, 1.49 
    200–<400 34 390 1.80 0.82, 3.97 509 6,382 0.96 0.76, 1.21 
    400–<600 53 520 0.91 0.49, 1.70 683 8,018 0.92 0.76, 1.13 
    ≥600 37 379 0.99 0.47, 2.05 574 6,468 1.09 0.87, 1.36 
        Pinteraction    0.03    0.32 
Dietary vitamin D intake, IU/day         
    <100 70 687 0.88 0.51, 1.52 668 8,989 0.91 0.75, 1.11 
    100–<200 76 876 1.46 0.87, 2.44 1,127 14,039 1.10 0.94, 1.28 
    200–<400 59 529 1.39 0.76, 2.53 725 8,782 0.96 0.79, 1.17 
    ≥400 14 102 0.99 0.29, 3.35 146 1,593 1.13 0.73, 1.76 
        Pinteraction    0.55    0.45 
Supplemental vitamin D intake, IU/day         
    None 127 1,201 1.38 0.91, 2.07 1,296 17,367 1.02 0.89, 1.18 
    <400 20 207 1.15 0.43, 3.11 272 3,383 1.04 0.76, 1.43 
    400–<800 68 733 1.04 0.61, 1.78 1,038 11,882 0.99 0.84, 1.17 
    ≥800 53 0.22 0.02, 2.63 60 771 0.86 0.44, 1.69 
        Pinteraction    0.48    0.96 
Total calcium intake, mg/dayb         
    <400 29 221 0.50 0.20, 1.24 146 2,358 0.87 0.58, 1.31 
    400–<800 65 655 1.76 0.98, 3.17 661 8,831 1.00 0.82, 1.22 
    800–<1,000 24 293 1.81 0.73, 4.48 403 4,682 1.24 0.96, 1.61 
    1,000–<1,200 19 244 1.16 0.43, 3.19 301 4,154 0.98 0.73, 1.32 
    ≥1,200 82 781 1.05 0.63, 1.73 1,155 13,378 0.97 0.83, 1.14 
        Pinteraction    0.18    0.52 
Dietary calcium intake, mg/day         
    <400 39 380 0.61 0.29, 1.29 318 4,429 0.94 0.71, 1.25 
    400–<800 96 932 1.28 0.80, 2.04 1,098 14,298 0.98 0.84, 1.14 
    800–<1,000 24 328 2.57 1.01, 6.55 450 5,448 1.15 0.90, 1.47 
    1,000–<1,200 24 231 1.03 0.41, 2.60 270 3,526 1.26 0.92, 1.73 
    ≥1,200 36 323 1.27 0.59, 2.73 530 5,702 0.90 0.71, 1.13 
        Pinteraction    0.21    0.37 
Supplemental calcium intake, mg/day         
    None 114 1,024 1.28 0.83, 1.99 1,070 14,334 1.00 0.85, 1.17 
    <400 47 528 1.47 0.77, 2.82 697 7,987 1.13 0.92, 1.38 
    400–<800 29 382 0.97 0.43, 2.19 516 6,342 0.93 0.74, 1.17 
    ≥800 29 260 0.80 0.34, 1.88 383 4,740 0.96 0.74, 1.26 
        Pinteraction    0.66    0.63 

Abbreviations: AD, antidepressant; CI, confidence interval; OR, odds ratio.

a

Multivariable models adjusted for age, race/ethnicity, WHI Hormone Trial intervention, and WHI Dietary Modification Trial intervention. The analysis of risk of depressive symptoms above the threshold level (Burnam score ≥0.06) included adjustment for this variable at year 1. The analysis of risk of antidepressant use included adjustment for antidepressant use at year 1.

b

Total nutrient intake = dietary nutrient intake (assessed at year 0) + supplemental nutrient intake (assessed at year 1).

Results did not suggest that the relation between supplementation and antidepressant use at year 3 varied by such factors as solar irradiance, physical activity, or current smoking (Table 5). The likelihood of antidepressant use was significantly modified by educational level (P = 0.007); among women with no education after high school, women randomized to supplements had an odds ratio of 0.78 (95% CI: 0.63, 0.96) compared with those randomized to placebo. Supplementation was associated with a nonsignificant reduced risk of antidepressant use in women with a normal body mass index (odds ratio = 0.82, 95% CI: 0.67, 1.00) but not in heavier women, although the test for interaction did not reach statistical significance (P = 0.06). Risk did not vary according to the presence of depression symptoms at year 1.

Table 5.

Odds Ratios for Use of Antidepressant Medication at Year 3 by Randomization Group, According to Participant Characteristics, Women’s Health Initiative Calcium and Vitamin D Trial, 1995–2003

Characteristic Supplementation Group Placebo Group Multivariate Odds Ratioa for Supplementation vs. Placebo 95% Confidence Interval P for Interaction 
No. of AD Users Total No. No. of AD Users Total No. 
Age, years       0.98 
    50–59 554 6,221 557 6,186 1.02 0.87, 1.19  
    60–69 581 7,842 614 7,820 1.00 0.86, 1.16  
    70–79 191 2,995 209 2,971 1.01 0.79, 1.29  
Post-high-school education       0.007 
    No 274 4,010 339 4,025 0.78 0.63, 0.96  
    Yes 1,040 12,941 1,031 12,845 1.08 0.97, 1.22  
Body mass indexb       0.06 
    <25 283 4,513 322 4,584 0.82 0.67, 1.00  
    25–<30 431 6,102 452 6,120 1.02 0.86, 1.21  
    ≥30 603 6,360 597 6,185 1.12 0.96, 1.30  
Race/ethnicity       0.19 
    White 1,169 14,231 1,260 14,248 0.98 0.88, 1.09  
    Black 78 1,513 66 1,474 1.12 0.76, 1.66  
    Hispanic 47 699 37 647 1.31 0.77, 2.24  
    Other/unknown 32 615 17 608 1.89 0.94, 3.80  
Current smoking       0.30 
    No 1,181 15,617 1,228 15,583 1.01 0.91, 1.12  
    Yes 139 1,272 125 1,218 1.22 0.87, 1.70  
Alcohol intake, drinks/day       0.70 
    0 429 4,717 467 4,733 0.96 0.80, 1.15  
    >0–<1 785 10,407 778 10,319 1.04 0.92, 1.19  
    ≥1 105 1,798 122 1,805 0.95 0.68, 1.32  
Physical activity, MET-hours/week       0.47 
    <3.00 474 5,014 508 4,935 0.99 0.84, 1.18  
    3.00–9.99 325 4,349 354 4,382 0.99 0.82, 1.21  
    10.00–19.99 266 3,465 242 3,379 1.12 0.89, 1.40  
    ≥20.0 157 2,694 181 2,734 0.84 0.64, 1.10  
Physical function (RAND Short Form 36 score)       0.88 
    ≤50 251 1,701 288 1,725 0.97 0.75, 1.25  
    51–90 742 8,701 775 8,725 1.00 0.88, 1.15  
    >90 329 6,614 316 6,488 1.05 0.87, 1.26  
History of cardiovascular disease       0.63 
    No 1,208 16,111 1,247 16,012 1.02 0.92, 1.13  
    Yes 118 947 133 965 0.93 0.65, 1.32  
Solar irradiance, Langleys       0.42 
    <350 432 5,127 413 5,082 1.11 0.93, 1.33  
    350–<400 415 5,597 445 5,544 0.97 0.81, 1.15  
    ≥400 479 6,334 522 6,351 0.96 0.82, 1.13  
Total saturated fat intake, g/day        
    <15.1 277 4,203 298 4,130 0.91 0.74, 1.12 0.11 
    15.1–<21.5 303 4,197 342 4,228 0.87 0.71, 1.07  
    21.5–<29.8 359 4,240 334 4,114 1.10 0.90, 1.34  
    ≥29.8 372 4,101 381 4,190 1.17 0.96, 1.42  
Characteristic Supplementation Group Placebo Group Multivariate Odds Ratioa for Supplementation vs. Placebo 95% Confidence Interval P for Interaction 
No. of AD Users Total No. No. of AD Users Total No. 
Age, years       0.98 
    50–59 554 6,221 557 6,186 1.02 0.87, 1.19  
    60–69 581 7,842 614 7,820 1.00 0.86, 1.16  
    70–79 191 2,995 209 2,971 1.01 0.79, 1.29  
Post-high-school education       0.007 
    No 274 4,010 339 4,025 0.78 0.63, 0.96  
    Yes 1,040 12,941 1,031 12,845 1.08 0.97, 1.22  
Body mass indexb       0.06 
    <25 283 4,513 322 4,584 0.82 0.67, 1.00  
    25–<30 431 6,102 452 6,120 1.02 0.86, 1.21  
    ≥30 603 6,360 597 6,185 1.12 0.96, 1.30  
Race/ethnicity       0.19 
    White 1,169 14,231 1,260 14,248 0.98 0.88, 1.09  
    Black 78 1,513 66 1,474 1.12 0.76, 1.66  
    Hispanic 47 699 37 647 1.31 0.77, 2.24  
    Other/unknown 32 615 17 608 1.89 0.94, 3.80  
Current smoking       0.30 
    No 1,181 15,617 1,228 15,583 1.01 0.91, 1.12  
    Yes 139 1,272 125 1,218 1.22 0.87, 1.70  
Alcohol intake, drinks/day       0.70 
    0 429 4,717 467 4,733 0.96 0.80, 1.15  
    >0–<1 785 10,407 778 10,319 1.04 0.92, 1.19  
    ≥1 105 1,798 122 1,805 0.95 0.68, 1.32  
Physical activity, MET-hours/week       0.47 
    <3.00 474 5,014 508 4,935 0.99 0.84, 1.18  
    3.00–9.99 325 4,349 354 4,382 0.99 0.82, 1.21  
    10.00–19.99 266 3,465 242 3,379 1.12 0.89, 1.40  
    ≥20.0 157 2,694 181 2,734 0.84 0.64, 1.10  
Physical function (RAND Short Form 36 score)       0.88 
    ≤50 251 1,701 288 1,725 0.97 0.75, 1.25  
    51–90 742 8,701 775 8,725 1.00 0.88, 1.15  
    >90 329 6,614 316 6,488 1.05 0.87, 1.26  
History of cardiovascular disease       0.63 
    No 1,208 16,111 1,247 16,012 1.02 0.92, 1.13  
    Yes 118 947 133 965 0.93 0.65, 1.32  
Solar irradiance, Langleys       0.42 
    <350 432 5,127 413 5,082 1.11 0.93, 1.33  
    350–<400 415 5,597 445 5,544 0.97 0.81, 1.15  
    ≥400 479 6,334 522 6,351 0.96 0.82, 1.13  
Total saturated fat intake, g/day        
    <15.1 277 4,203 298 4,130 0.91 0.74, 1.12 0.11 
    15.1–<21.5 303 4,197 342 4,228 0.87 0.71, 1.07  
    21.5–<29.8 359 4,240 334 4,114 1.10 0.90, 1.34  
    ≥29.8 372 4,101 381 4,190 1.17 0.96, 1.42  

Abbreviations: AD, antidepressant; MET, metabolic equivalent task; WHI, Women's Health Initiative.

a

Adjusted for age, WHI Hormone Trial intervention, WHI Dietary Modification Trial intervention, and use of antidepressant medication at year 1.

b

Weight (kg)/height (m)2.

In subanalyses limited to participants who were adherent with the treatment protocol, results were similar (results not shown).

DISCUSSION

In this randomized clinical trial, we did not find that 2 years of supplementation with 400 IU/day of vitamin D3, combined with 1,000 mg/day of elemental calcium, influenced the risk of depression. The effect of supplementation did not vary meaningfully by levels of vitamin D and calcium intake from diet and supplemental sources or by other participant characteristics.

Few intervention trials have evaluated the association of vitamin D supplementation with risk of depression (23–30). Results from these trials are difficult to compare because they differ substantially in terms of vitamin D doses tested, assessment of depression, duration of participant follow-up, use of placebo controls, sample size, and participant characteristics, including age and menopausal status. Jorde et al. (28) observed a modest but significant improvement in depressive symptom score after 1 year of supplementation in 334 Norwegians (mean age = 47 years) randomized to either 40,000 IU/week or 20,000 IU/week as compared with placebo. However, mean depressive symptom scores in this population were low, suggesting that few participants were experiencing clinically significant depression. In 3 other small trials (15–88 participants), investigators observed some improvement in mood symptoms during winter in young and middle-aged persons taking supplemental vitamin D (22–24). In these studies, supplementation doses ranged from 400 IU/day to 100,000 IU/week, and follow-up periods ranged from 5 days to 3 months. However, in 4 other clinical trials of vitamin D at doses of 800 IU/day (23), 5,000 IU/day (29), 50,000 IU/week (27), and 500,000 IU once annually (30), no effect of vitamin D on depressive symptoms was found.

The dose of vitamin D we tested (400 IU/day) may not have been sufficient to affect the occurrence of depression, although this dosage (combined with personal intake) is consistent with recent recommendations from the Institute of Medicine (47). Vitamin D intake among our participants was comparable to that among women in the WHI Observational Study, which found that intake of vitamin D from food sources at the start of follow-up was inversely associated with risk of depression 3 years later (for ≥400 IU/day vs. <100 IU/day, odds ratio = 0.80, 95% CI: 0.67, 0.96; P for trend = 0.002) (40). We did not find evidence that supplementation with 400 IU/day affected risk of depressive symptoms either among women likely to be vitamin D-deficient due to low dietary intake, high body mass index, or high latitude of residence or among women reporting high dietary intake and/or vitamin D supplement use at baseline.

It is possible that vitamin D is truly unrelated to depression and that the beneficial effects reported in observational studies are largely due to residual confounding by lifestyle and dietary behaviors. For example, fatty fish are major sources of both marine omega-3 fatty acids and vitamin D, and omega-3 fatty acid intake has been inversely associated with risk of depression in multiple studies (48, 49); most observational studies of vitamin D status and depression have not accounted for omega-3 fatty acid intake.

Alternatively, if vitamin D is truly related to depression, results from our study may have been confounded by calcium supplementation. Some evidence suggests that high long-term calcium intake may increase the risk of arterial calcification (50), which has been associated with depression, and may increase the number and size of brain lesions (51–54). We did not find supplementation to be associated with higher risk of depression in women with high background calcium intakes in our study. However, it is possible that supplemental vitamin D combined with calcium is related to depression differently than vitamin D alone, especially in older women with some degree of existing arterial calcification. Further evaluation of vitamin D alone or of this relation in younger persons without preclinical cardiovascular disease may shed light on this issue.

A limitation of our study was our reliance on self-reported symptoms to assess depression, instead of the use of psychiatric interviews. The Burnam scale primarily measures depressive symptoms experienced in the year prior to completion, as opposed to clinical diagnoses of depression made during the entire follow-up period. Thus, women who developed depression prior to their year 3 clinic visit but whose symptoms remitted either naturally or after treatment would not have been classified as cases. Only a subset of WHI participants were asked to complete the Burnam scale at year 3, thus limiting our statistical power for this analysis. For this reason, we also considered antidepressant use at year 3 to be a proxy for depression. However, women may be prescribed antidepressants for reasons other than depression, such as fibromyalgia, migraine headache, or panic disorder. This misclassification could have attenuated our findings to some extent.

To our knowledge, our study is among the first large randomized trials to have evaluated the relation of vitamin D supplementation with depressive symptoms. Additional strengths of our study include the diversity of our population, allowing us to evaluate effect modification of a possible vitamin D-depression association by a variety of characteristics, including background vitamin D and calcium intakes, race/ethnicity, body mass index, smoking status, and physical activity. Supplementation was associated with a lower risk of antidepressant use in year 3 among women with a high school education or less and was marginally significantly associated with lower risk in normal-weight women. We also observed significant interaction with total vitamin D intake, but odds ratios for the effect of supplementation did not vary across intake categories in a meaningful pattern. Given the large number of subgroups examined, these findings were probably attributable to chance. The randomized trial design of our study should have precluded the likelihood of confounding by sun exposure and 25-hydroxyvitamin D status, which may be a concern in observational studies.

In summary, we did not observe a relation between 2 years of daily supplementation with 400 IU of vitamin D3 and 1,000 mg of elemental calcium and measures of depression status. Additional trials testing higher supplemental doses of vitamin D are needed to determine whether this nutrient may be beneficial in preventing or treating depression among specific populations.

Abbreviations

    Abbreviations
  • CaD

    Calcium and Vitamin D

  • CI

    confidence interval

  • DM

    Dietary Modification

  • HT

    Hormone Therapy

  • WHI

    Women’s Health Initiative

Author affiliations: Division of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts (Elizabeth R. Bertone-Johnson); Department of Psychology, College of Natural Sciences, University of Massachusetts, Amherst, Massachusetts (Sally I. Powers); Group Health Research Institute, Seattle, Washington (Leslie Spangler); Department of Family and Community Medicine, School of Medicine, University of Nevada, Reno, Nevada (Robert L. Brunner); Department of Epidemiology and Biostatistics, School of Public Health, Drexel University, Philadelphia, Pennsylvania (Yvonne L. Michael); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington (Joseph Larson); Department of Social and Preventive Medicine, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, New York (Amy E. Millen); Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Maria N. Bueche, JoAnn E. Manson); Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts (Elena Salmoirago-Blotcher, Ira Ockene); Division of Preventive and Behavioral Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts (Judith K. Ockene); Department of Medicine, School of Public Health, University of California, Los Angeles, Los Angeles, California (Simin Liu); and Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York (Sylvia Wassertheil-Smoller).

The Women’s Health Initiative (WHI) is funded by the National Heart, Lung, and Blood Institute through contracts N01WH22110, N01WH24152, N01WH 32100-2, N01WH 32105-6, N01WH 32108-9, N01WH 32111-13, 32115, N01WH 32118-32119, N01WH 32122, N01WH 42107-26, N01WH 42129-32, and N01WH 44221.

The WHI Investigators—Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Joan McGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, Washington) Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles L. Kooperberg; (Medical Research Labs, Highland Heights, Kentucky) Evan Stein; (University of California, San Francisco, San Francisco, California) Steven Cummings; Clinical Centers: (Albert Einstein College of Medicine, Bronx, New York) Sylvia Wassertheil-Smoller; (Baylor College of Medicine, Houston, Texas) Haleh Sangi-Haghpeykar; (Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts) JoAnn E. Manson; (Brown University, Providence, Rhode Island) Charles B. Eaton; (Emory University, Atlanta, Georgia) Lawrence S. Phillips; (Fred Hutchinson Cancer Research Center, Seattle, Washington) Shirley Beresford; (George Washington University Medical Center, Washington, DC) Lisa Martin; (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California) Rowan Chlebowski; (Kaiser Permanente Center for Health Research, Portland, Oregon) Erin LeBlanc; (Kaiser Permanente Division of Research, Oakland, California) Bette Caan; (Medical College of Wisconsin, Milwaukee, Wisconsin) Jane Morley Kotchen; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Northwestern University, Chicago/Evanston, Illinois) Linda Van Horn; (Rush Medical Center, Chicago, Illinois) Henry Black; (Stanford Prevention Research Center, Stanford, California) Marcia L. Stefanick; (State University of New York at Stony Brook, Stony Brook, New York) Dorothy Lane; (Ohio State University, Columbus, Ohio) Rebecca Jackson; (University of Alabama at Birmingham, Birmingham, Alabama) Cora E. Lewis; (University of Arizona, Phoenix, Arizona) Cynthia A. Thomson; (State University of New York at Buffalo, Buffalo, New York) Jean Wactawski-Wende; (University of California, Davis, Sacramento, California) John Robbins; (University of California, Irvine, Irvine, California) F. Allan Hubbell; (University of California, Los Angeles, Los Angeles, California) Lauren Nathan; (University of California, San Diego, La Jolla, California) Robert D. Langer; (University of Cincinnati, Cincinnati, Ohio) Margery Gass; (University of Florida, Gainesville, Florida) Marian Limacher; (University of Hawaii, Honolulu, Hawaii) J. David Curb; (University of Iowa, Iowa City, Iowa) Robert Wallace; (University of Massachusetts/Fallon Clinic, Worcester, Massachusetts) Judith Ockene; (University of Medicine and Dentistry of New Jersey, Newark, New Jersey) Norman Lasser; (University of Miami, Miami, Florida) Mary Jo O’Sullivan; (University of Minnesota, Minneapolis, Minnesota) Karen Margolis; (University of Nevada, Reno, Nevada) Robert Brunner; (University of North Carolina at Chapel Hill, Chapel Hill, North Carolina) Gerardo Heiss; (University of Pittsburgh, Pittsburgh, Pennsylvania) Lewis Kuller; (University of Tennessee Health Science Center, Memphis, Tennessee) Karen C. Johnson; (University of Texas Health Science Center, San Antonio, Texas) Robert Brzyski; (University of Wisconsin, Madison, Wisconsin) Gloria E. Sarto; (Wake Forest University School of Medicine, Winston-Salem, North Carolina) Mara Vitolins; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, Michigan) Michael S. Simon; WHI Memory Study: (Wake Forest University School of Medicine, Winston-Salem, North Carolina) Sally Shumaker.

The funding organization was independent of the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, and approval of the manuscript.

Dr. JoAnn E. Manson and colleagues at Brigham and Women’s Hospital, Harvard Medical School, are recipients of funding from the National Institutes of Health to conduct the Vitamin D and Omega-3 Trial, a large-scale randomized trial of the role of vitamin D and omega-3 fatty acids in the prevention of cancer and cardiovascular disease.

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