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Original Contribution
Vitamin D Supplementation and Depression in the Womens Health Initiative
Calcium and Vitamin D Trial
* Correspondence to Dr. Elizabeth R. Bertone-Johnson, Division of Biostatistics and Epidemiology, School of Public Health and
Health Sciences, University of Massachusetts, 409 Arnold House, 715 North Pleasant Street, Amherst, MA 01003-9304
(e-mail: ebertone@schoolph.umass.edu).
Initially submitted August 19, 2011; accepted for publication November 29, 2011.
While observational studies have suggested that vitamin D deciency 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 (19952000). 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% condence interval: 0.86,
1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use
(odds ratio 1.01, 95% condence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratied
by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The ndings 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.
antidepressive agents; calcium; clinical trial; depression; dietary supplements; postmenopause; vitamin D; women
Abbreviations: CaD, Calcium and Vitamin D; CI, condence interval; DM, Dietary Modication; HT, Hormone Therapy; WHI,
Womens Health Initiative.
Am J Epidemiol. 2012;176(1):113
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Bertone-Johnson et al.
Figure 1. Derivation of the cohort for analysis of the relation between vitamin D and calcium supplementation and depressive symptoms at year 3,
Womens Health Initiative (WHI) Calcium and Vitamin D (CaD) Trial, 19952000. 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 Modication; HT, Hormone
Therapy).
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Am J Epidemiol. 2012;176(1):113
Statistical analysis
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Study outcome
Bertone-Johnson et al.
Table 1. Characteristics of Participants in the Womens Health Initiative (WHI) Calcium and Vitamin D Trial at the Time of WHI Screening
(i.e., Year 0), by Supplementation Group, 19952000
Supplementation Group
Characteristic
No.
%a
Placebo Group
%a
No.
Age, years
>0.99
5059
6,726
37.0
6,696
37.0
6069
8,276
45.5
8,243
45.5
7079
3,174
17.5
3,167
17.5
White
15,051
82.8
15,104
83.4
Black
1,680
9.2
1,635
9.0
785
4.3
717
4.0
77
0.4
72
0.4
370
2.0
351
1.9
<20,000
2,942
16.2
2,876
15.9
20,00049,999
8,122
44.7
8,092
44.7
50,000
6,205
34.1
6,192
34.2
725
4.0
712
3.9
2,850
15.7
2,875
15.9
Race/ethnicity
American Indian
Asian/Pacic Islander
0.45
0.68
Marital status
Never married
Divorced/separated
Widowed
0.96
3,004
16.5
3,008
16.6
11,522
63.4
11,442
63.2
475500
3,861
21.2
3,852
21.3
400430
3,016
16.6
3,012
16.7
75380
2,009
11.1
2,009
11.1
350
3,924
21.6
3,879
21.4
300325
5,366
29.5
5,354
29.6
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
Married/living as married
Regional solar irradiance, Langleys
>0.99
Smoking status
0.50
0.63
5,055
27.8
5,100
28.2
11,065
60.9
10,977
60.6
1,908
10.5
1,900
10.5
Table continues
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
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Hispanic
P Value
Table 1. Continued
Supplementation Group
Characteristic
No.
Placebo Group
No.
%a
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
0.17
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
<3.00
5,405
29.7
5,340
29.5
3.009.99
4,642
25.5
4,648
25.7
10.0019.99
3,647
20.1
3,569
19.7
20.00
2,852
15.7
2,891
16.0
0.60
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
<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
843
4.6
859
4.7
9,639
53.0
9,507
52.5
0.47
0.41
<400
1,795
9.9
1,780
9.8
400<800
6,339
34.9
6,401
35.4
403
2.2
418
2.3
No
15,379
84.6
15,430
85.2
Yes
2,374
13.1
2,391
13.2
800
Meeting IOM guidelines for vitamin D intaked
0.99
Table continues
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<25
400
P Value
Bertone-Johnson et al.
Table 1. Continued
Supplementation Group
Characteristic
No.
Placebo Group
%a
No.
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
2,406
13.2
2,378
13.1
0.52
<400
7,629
42.0
7,603
42.0
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
8,027
44.2
7,885
43.5
0.55
<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
0.79
<15.1
4,469
24.6
4,415
24.4
15.121.4
4,463
24.6
4,479
24.7
21.529.7
4,505
24.8
4,367
24.1
29.8
4,384
24.1
4,492
24.8
No
16,992
93.5
16,820
92.9
Yes
1,184
6.5
1,286
7.1
0.03
0.25
<0.06
16,401
90.2
16,244
89.7
0.06
1,708
9.4
1,790
9.9
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
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
0.74
0.30
Abbreviations: IOM, Institute of Medicine; MET, metabolic equivalent task; WHI, Womens Health Initiative.
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 5070 years and 800 IU/day for women aged 70 years (42).
a
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400<800
800<1,000
P Value
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, Womens Health Initiative Calcium and Vitamin D Trial, 19952003
Participants Without Evidence of Depression at Year 1a
All Participants
b
No. of
Women
Mean Change
(SD)
(Year 3 Year 1)
Supplementation
group
1,109
0.004 (0.143)
Placebo group
1,143
0.002 (0.113)
MultivariableAdjusted
Mean Changec
95% CI
0.007
0.003, 0.017
Mean Changeb
(SD)
(Year 3 Year 1)
MultivariableAdjusted
Mean Changed
95% CI
956
0.020 (0.099)
0.009
0.002, 0.017
1,001
0.010 (0.061)
No. of
Women
Referent
Referent
Abbreviations: CI, condence interval; SD, standard deviation; WHI, Womens Health Initiative.
Analysis excluded women with depressive symptoms above the threshold level (Burnam score 0.06) or antidepressant use at baseline.
b
Positive change reects a higher Burnam score at year 3 versus baseline; negative change reects a lower Burnam score at year 3 versus
baseline.
c
Multivariable models adjusted for age, race/ethnicity, WHI Hormone Trial intervention, WHI Dietary Modication 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 Modication Trial intervention.
a
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.
In subanalyses limited to participants who were adherent
with the treatment protocol, results were similar (results not
shown).
DISCUSSION
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, Womens Health Initiative Calcium and Vitamin D Trial, 19952003
Participants Without Evidence of
Depression at Year 1a
All Participants
No. of
Cases
No. of
Noncases
No. of
Cases
Multivariate
ORb
95% CI
1.16
0.86, 1.56
70
Referent
52
No. of
Noncases
Multivariate
ORc
95% CI
886
1.41
0.97, 2.05
949
119
997
Placebo group
108
1,039
Supplementation group
1,326
15,732
1.01
Placebo group
1,380
15,597
Referent
Use of antidepressant
medication at year 3
0.92, 1.12
419
14,248
0.96
Referent
428
14,001
0.84, 1.10
Referent
Abbreviations: CI, condence interval; OR, odds ratio; WHI, Womens Health Initiative.
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 Modication 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 Modication Trial intervention.
a
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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.
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.
Bertone-Johnson et al.
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, Womens Health Initiative Calcium and Vitamin D Trial, 19952003
Depressive Symptoms (Burnam Score 0.06)
No. of
Cases
Total
No.
ORa for
Supplementation
vs. Placebo
95% CI
Total
No.
ORa for
Supplementation
vs. Placebo
95% CI
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
0.03
0.32
<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
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
53
0.22
0.02, 2.63
60
771
0.86
0.44, 1.69
800
Pinteraction
0.48
0.96
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
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
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
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Pinteraction
Dietary vitamin D intake, IU/day
Table 5. Odds Ratios for Use of Antidepressant Medication at Year 3 by Randomization Group, According to Participant Characteristics,
Womens Health Initiative Calcium and Vitamin D Trial, 19952003
Supplementation
Group
Placebo Group
Characteristic
No. of
AD Users
Total
No.
No. of
AD Users
Total No.
Multivariate
Odds Ratioa for
Supplementation
vs. Placebo
95%
Condence
Interval
Age, years
0.98
5059
554
6,221
557
6,186
1.02
0.87, 1.19
6069
581
7,842
614
7,820
1.00
0.86, 1.16
7079
191
2,995
209
2,971
1.01
0.79, 1.29
274
4,010
339
4,025
0.78
0.63, 0.96
1,040
12,941
1,031
12,845
1.08
0.97, 1.22
<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
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
Post-high-school education
No
0.007
0.06
Race/ethnicity
0.19
Current smoking
No
0.30
1,181
15,617
1,228
15,583
1.01
0.91, 1.12
139
1,272
125
1,218
1.22
0.87, 1.70
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
Yes
Alcohol intake, drinks/day
0.70
0.47
<3.00
474
5,014
508
4,935
0.99
0.84, 1.18
3.009.99
325
4,349
354
4,382
0.99
0.82, 1.21
10.0019.99
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
50
251
1,701
288
1,725
0.97
0.75, 1.25
5190
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
1,208
16,111
1,247
16,012
1.02
0.92, 1.13
118
947
133
965
0.93
0.65, 1.32
432
5,127
413
5,082
1.11
0.93, 1.33
0.88
0.63
0.42
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
<15.1
277
4,203
298
4,130
0.91
0.74, 1.12
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
0.11
Abbreviations: AD, antidepressant; MET, metabolic equivalent task; WHI, Womens Health Initiative.
Adjusted for age, WHI Hormone Trial intervention, WHI Dietary Modication Trial intervention, and use of antidepressant medication at year 1.
b
Weight (kg)/height (m)2.
a
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Yes
P for
Interaction
10
Bertone-Johnson et al.
ACKNOWLEDGMENTS
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,
Am J Epidemiol. 2012;176(1):113
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Am J Epidemiol. 2012;176(1):113
REFERENCES
1. Garcion E, Wion-Barbot N, Montero-Menei CN, et al. New
clues about vitamin D functions in the nervous system. Trends
Endocrinol Metab. 2002;13(3):100105.
2. Eyles DW, Smith S, Kinobe R, et al. Distribution of the
vitamin D receptor and 1 alpha-hydroxylase in human brain.
J Chem Neuroanat. 2005;29(1):2130.
3. McCann JC, Ames BN. Is there convincing biological or
behavioral evidence linking vitamin D deficiency to brain
dysfunction? FASEB J. 2008;22(4):9821001.
4. Zehnder D, Bland R, Williams MC, et al. Extrarenal expression
of 25-hydroxyvitamin D3-1a-hydroxylase. J Clin Endocrinol
Metab. 2001;86(2):888894.
Downloaded from http://aje.oxfordjournals.org/ at Biblioteca Centrala Universitaradin Iasi on May 28, 2015
11
12
Bertone-Johnson et al.
Downloaded from http://aje.oxfordjournals.org/ at Biblioteca Centrala Universitaradin Iasi on May 28, 2015
43.
44.
45.
46.
47.
Am J Epidemiol. 2012;176(1):113
Downloaded from http://aje.oxfordjournals.org/ at Biblioteca Centrala Universitaradin Iasi on May 28, 2015
48.
13