Vitamin D and Depression: A Potential Relationship?

Marissa Sherman
FN 463
Fall 2015

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Proper nutrition is an established component of a healthy lifestyle but remains
unclear regarding mental health. In particular, research suggests based on vitamin Ds
role in the brain, it could be beneficial for people diagnosed with depression. Depression
is a complex, chronic mental illness that involves multifaceted treatments (i.e. a
combination of antidepressants, antipsychotics, mood stabilizers and/or
psychotherapies) with a compliance rate of 60-80%. 1-2 Due to fear of addiction, cost
concerns, and unwanted side effects, patients often discontinue medication. 2
Complementary medicine has become a popular alternative with therapy options
including but not limited to yoga, tai-chi, massage and herbal as well as dietary
supplements like vitamin D.1 With upcoming research involving the various roles of
vitamin D in the body, particularly in the brain, it is conjectured that increased
consumption of the vitamin could benefit depressed individuals.
Depression
Depression affects 350 million people worldwide marking it as the leading cause
of disability.3 The typical onset of the disease begins in the mid 20s and affects both
genders with the majority as women (10-25%).4 Symptoms include depressed mood,
loss of interest in daily activities, decreased energy, and changes in appetite, sleep and
psychomotor function along with feelings of hopelessness, guilt, worthlessness and
suicidal ideation and/or action.4 Currently, causes of depression as well as the
pathophysiology is not completely understood. Besides genetic and environmental
factors, theories suggest that alterations in neurotransmitters, neuroendocrine
processes, and pro-inflammatory biological values are possible causes. 1. Current
literature on the etiology of depression suggests the alteration or lack of monoamine

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neurotransmitters could be involved because they support the use of monoamine,
serotonin and norepinephrine neurotransmitters in antidepressant medication. 4
Depression is complex to treat because it has a variety of drug classifications that
perform and/or target different mechanisms in the brain. For example, some
medications will work to increase serotonin and norepinephrine in synapses. 4 This will
result in an increase in postsynaptic neuron firing in the brain which will improve
depression symptoms.4 Currently, there is not enough evidence to support these
hypotheses, as even with medication and therapy, for many, depression is still a
struggle to cope with. For this reason, patients may seek out additional selfmanagement options including vitamin D supplementation.
Vitamin D
Vitamin D is a fat soluble vitamin and a prohormone that contributes to numerous
biological functions.5 Typically, the vitamin is linked to calcium homeostasis, and is
required for adequate dietary absorption of calcium and phosphorous. 1,6 Furthermore,
vitamin D is thought to play a role in chronic illnesses including osteoporosis, cancer,
diabetes and cardiovascular diseases.7-8 Current research is substantiating the
vitamins other beneficial roles specific to the brain including cognitive function,
development, detoxification, sleep, neurochemistry and protection. 1
Vitamin D is obtained through plant and animal sources although fortified foods
including orange juice, yogurt and cheese are examples of the most common source for
the majority of the worlds population.4-6 Sun exposure is the greatest method for
acquiring the vitamin, and endogenous synthesis of vitamin D is dependent on several
factors such as duration of exposure, latitude/location, season, age, gender, skin

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pigmentation and genetics.1,5-6 After exposure, ultra violet radiation converts 7dehydrocholesterol on the epidermis into vitamin D 3 (cholecalciferol) in the dermis.4,6 In
the liver, both sources of the vitamin are converted into 25-hydroxyvitamin D and
hydroxylated in the kidney into the biologically active metabolite 1,25-dihydroxyvitamin
D where it has the ability to bind to vitamin D receptors (VDRs) located all over the
body.6
Relative to depression, the metabolite can bind to VDRs in the areas of the brain
associated with depression such as the prefrontal cortex, hippocampus, thalamus,
hypothalamus, cingulate gyrus and substantia nygria. 4 1-25 dihydroxyvitamin D with the
VDRs (which are responsible for gene transcription) also contribute to the expression of
tyrosine hydroxylase; an enzyme involved in the synthesis of norepinephrine and
dopamine, two of the neurotransmitters responsible for mood regulation and
depression.4,7 In addition, the 1 alpha-hydroxylase enzymes in the hippocampus of the
brain are capable of converting 25-hydroxyvitamin D into 1-25 dihydroxyvitamin D for its
local use.4 With deficiency, these processes cannot effectively continue to occur
because of the lack of available vitamin D. With 1 billion people classified as vitamin D
deficient (25-hydroxyvitamin d levels under 10 ng/ml), along with the emerging evidence
of vitamin Ds beneficial role in the brain, it is suggested in current research that a
potential link exists between depression incidence and vitamin D status. 1,3
Evident Conclusions in Current Literature
Among young adults, 26% of the population suffers from a mental disorder.7
Ganji et al7 examined a potential relationship between the vitamin D concentrations and
depression incidence of individuals aged 15-39 years old using the Third National

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Health and Nutrition Examination Survey (NHANES III). The results reflected several
diverse variables observed in the US population. Vitamin D deficiency was observed
more often in women versus men as well as non-Hispanic black populations compared
to non-Hispanic white and Mexican Americans/Hispanics, individuals with a higher BMI,
and those who did not consume a vitamin/mineral supplement. 7 Based on geographic
location, individuals living in the South, West, and urban regions of the United States
had higher rates of deficiency versus those living in the Northeast, Midwest and rural
settings. Poverty status suggested those below the poverty line (an income ratio of less
than 1) were more deficient than those above.
Data concerning the length of time an individual is diagnosed suggested people
with depression for more than two years were more deficient than those who had the
disorder less than two years. Participants who were experiencing current episodes of
depression had 8.4% lower vitamin D concentrations than those who did not report
having depression.7 The study concluded that those who are vitamin D deficient were
significantly more likely to have depression compared to those who had sufficient
vitamin D levels. An important observation noted in the analysis of the survey is that it is
unclear whether vitamin D deficiency leads to depression or vice versa. 7
The younger adult population was examined by Milaneschi et al 9, although his
analysis consisted of participants in a cohort study comparing depressed patients,
remitted depressed patients and healthy controls. Patients were categorized as
depressed if they had an episode within the past six months and remitted depressed if
they had an episode within their lifetime but not currently. Healthy controls were
classified if never had an episode and scored below a 14 on the Inventory of Depressive

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Symptomatology scale. After two years, a follow-up assessment gathered 66.6% of the
population were female with the majority of these women described in the demographic
data as older, less educated and classified as either remitted depression or current
depression.9 The least favorable outcomes in the health and lifestyle characteristics
(smoking status, BMI, physical activity, alcohol use and vitamin D supplementation)
were the current depression group and were less likely to live in urban areas;
corresponding to the findings of Ganji et al.7 Both studies yield similar results but involve
varied study populations and factors. Ganji et al 7 had a larger group with additional
deficiency considerations while Milaneschi et al9 focused on symptoms and deficiency
status in particular depressed, remitted depressed and healthy subjects.
Milaneschi et al9 discovered increasingly lower levels of plasma vitamin D
starting from the healthy controls to the significantly lower levels observed in the
remitted and currently depressed subjects. The research depicted a relationship
between the severity of the symptoms and the level of plasma hydroxyvitamin D. With
an increase in the severity of the symptoms, the lower the level of plasma 25hydroxyvitamin D was present. Compared to the other two test groups, depressed
individuals had a higher risk of developing vitamin D insufficiency and deficiency. As a
whole, 33.6% of the participants were classified as vitamin D insufficient and 7% as
deficient. Within the deficient population, the classification of the groups showed that the
current depressed had the highest rate (9.0%), followed by remitted (5.8%) and the
controls (4.7%).9 This examination suggested that lower vitamin D serum levels were
associated with the occurrence and severity of depression.

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Black et al10 approached the younger male population by collecting data from the
Western Australia Pregnancy Cohort at a 20 year follow-up. The Depression Anxiety
Stress Scales (DASS-21) scores indicated males averaged a score of 12 and females a
score of 18; detecting higher stress, anxiety and depression in the female population.
Vitamin D status showed a significant variance between the genders with 18% of males
and 12% of females classified as deficient. 10
In data analyses focusing specifically on the males, higher serum levels were
linked to lower DASS-21 scores in all 3 categories. It was indicated every 10 nmol/L
increment of serum decreased the overall DASS-21 scores by 9% and sub category
depression scores by 12%.10 This finding associates less depressive symptoms
amongst males with higher serum levels of vitamin D. However, there was no
substantial evidence associated with serum concentrations for the stress and anxiety
categories. Black and colleagues10 concluded that substantial evidence supports a
relationship between vitamin D concentrations and indicators of depression. Black et
als10 findings are comparable to Milaneschi et als9 as they both unanimously confirmed
a relationship between higher serum levels associated with less occurrence and
severity of depression.
Studies with Unsubstantiated Outcomes
Similar to Ganji et al7, NHANES data was utilized by Zhao et al11, but the
distinctions concern the indicated criteria and variables. Zhao et al 11 specifically
examined adults aged 20 years and older investigating the relationship between
parathyroid levels, vitamin D and depression status. Of the 7,970 participants, 239
subjects were classified as having moderate to severe depression with a score of 10 or

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above in the Patient Health Questionnaire-9 (PHQ-9). 11 Those without depression
versus minor depression did not vary significantly in vitamin D concentrations.
Participants with moderate to severe and major depression had considerably lower
levels of vitamin D versus healthy subjects; corresponding to the findings of Ganji et al 7.
However, Ganji and colleagues7 supported outcomes focused on deficiency severity
and depression status whereas Zhao et als11 unsupported findings negatively
established the link between severity of depressive symptoms, parathyroid and
concentration levels.
Kwasky et al12 studied the relationship between vitamin D status and depression
in young adult African American and Caucasian women aged 18 to 24 years old from a
mid-western college in the United States. Researchers hypothesized African American
women would produce lower serum levels compared to Caucasians. Their results
confirmed their hypothesis as African American participants graded lower on the Beck
Depression Inventory II (BDI-II), a questionnaire that measures depression severity.
Compared to Caucasian subjects, African American participants had drastically lower
serum levels. These findings were statistically significant; an equivalent outcome to
Ganji et al.7
Of the study participants, 88.4% of the population scored below 20 (minimal to
mild depression) on the BDI-II. Of the10.7% in the moderate to severe depression
population, 8.4% were African American and 14.2% were Caucasian. Higher serum
levels were observed in the moderate and severe depression group versus the minimal
and mild depression group; although this unexpected outcome was statistically
insignificant.12 The study contributes a mixed conclusion, signifying there was no link

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between depression and vitamin D. These results contrast to Ganji et al 7 who examined
the relationship in both genders and concluded strong evidence.
Older adults are a subject of study for vitamin D and depression status as it
affects 5-15% of this specific population worldwide.13 As a component of The Health in
Men Study, Almeida et al13 investigated whether serum concentrations of vitamin D
were linked to past, present and future depression in men ages 71-88 years old. The
results among the three groups were varied with significantly lower plasma
concentrations in the current depression group compared to the no history of or past
depression populations. An increasing regression was observed in vitamin D levels from
no depression to past and current depression subjects. Greater probabilities of vitamin
D deficiency (<50nmol/L or 20ng/ML) was related to current but not past depression. 13
As for incident depression, 81% of the men without history of the mental illness went
through substantial depressive symptoms during the six years of the study.13
Almeida et al13 concluded that vitamin D deficiency as a factor is unlikely to be a
significant source of the depressive symptoms in older men. Ganji et al 7 and Milaneschi
et al9 compared to Almeida and colleagues13 may have different conclusions and
populations, but these studies commonly found an increased risk of deficiency as well
as lower plasma levels in depressed individuals. The end results of Almeida et al 13 do
not identify a relationship between depression and vitamin D levels and vitamin D
supplementation is not a valid treatment for the disorder.
Bertone-Johnson et al. Studies
Bertone-Johnson et al14-15 conducted two separate studies examining vitamin D
intake in older women. The first study14 examined 50-79 year old post-menopausal

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women by investigating vitamin D intake through diet and supplementation and the
prevalence of depressive symptoms. The data gathered was obtained from 81,189
women enrolled in the Womens Health Initiative (WHI)16, a clinical trial program
established by the National Institutes of Health to study post-menopausal women and
the common causes of death, disability and diminished quality of life. After 3 years, 11%
of the women met the criteria for depressive symptoms based on the Burnam 8-item
scale. However amongst these women differences were observed considering a variety
of factors including age, antidepressant use, income, exercise, marital status, and
physical function. It was found that high vitamin D intake from food sources was
correlated with a 20% lower occurrence of depression. 14 Women who did not show
signs of depression at baseline, but those who consumed a higher intake of dietary
vitamin D also had a lower possibility of depressive symptoms by the 3 rd year of the
study.
Furthermore, vitamin D supplementation (400 to <800IU/d) was related to a lower
chance of depression although an intake higher than 800IU was not. The research
suggested intakes of 100-800IU/d of vitamin D were significantly associated with the
less likelihood of depressive symptoms compared to those who consumed less. 14
Despite these findings, overall vitamin D intake (including supplements) was not directly
connected to risk.14 Supplementation use was not a reliable measure as it could not be
linked to depressive symptoms, including in those who were taking antidepressants.
However, the research gathered evident support for the inverse relationship between
vitamin D intake and depressive symptoms in older women.

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Bertone-Johnson et al15 further examined vitamin D status through the WHI in a
randomized, double-blinded trial investigating the incidence of depression and
antidepressant use in women supplemented with 400IU of vitamin D and 1,000mg of
calcium or a placebo daily. Overall, vitamin D intake was classified as low for both trial
groups with 42% consuming at least 400IU daily and less than 6% consuming 800IU
daily. 9.4% of the women in the supplement group and 9.9% on the placebo were
classified with depressive symptoms based on the Burnam Scale. 15 Neither groups
differed in vitamin D and calcium intake from dietary or supplemental sources. After 3
years, supplementation did not significantly change the Burnam scores as compared to
placebo. Supplemented women who were not classified as depressed after the first year
had significantly higher scores for depressive symptoms than women in the placebo
group.
Depression status, as well as the population examined, was a similar factor for
the studies with Bertone-Johnson et al14-15 but focus varies between the two trials. One
study14 examined typical vitamin D intake and depressive symptoms while the other 15
controlled vitamin D and calcium versus placebo consumption with the occurrence of
antidepressant use and incidence of depression. The findings in the latter study 15
indicate the probability of antidepressant use and supplementation were not related.
Supplementation was not related to depression status in both trials, yet they draw
different conclusions, an indicator of mixed results. The results do not support but rather
indicate that vitamin D and calcium intake did not have an effect on the relationship
between supplementation and diet for the risk of depressive symptoms.
Conclusion

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Inconsistent findings in the research suggest numerous explanations. The
abundant amount of variables investigated in each study contributed to the mixed
outcomes. Varying populations, ages, genders, measurement tools, and factors
examined such as dietary and supplemental intake, deficiency as well as depression
status, and antidepressant use could alter results that explain the differences in the
outcomes of current research. It is important to distinguish the risk of depression and
diagnosed depression when discussing findings as the terms do not entail equivalent
meanings. In application to an analysis of the research, differentiating between
depression status and deficiency status can make a significant difference when drawing
conclusions. Both sides of the studies have strong evidence to support or disprove their
findings which can further suggest need for additional research. Consistent protocol
when testing for replication purposes will create more concrete evidence to be able to
settle on a final conclusion. This review established that the current research does not
support the relationship between depression and vitamin D.
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6. U.S. Department of Health and Human Services. Vitamin D Fact Sheet for Health
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