Vitamin D and depression: mechanisms, determination and application

Abstract

Depression is the most common debilitating psychiatric disease, the pathological mechanisms of which are associated with multiple aspects of neural function. While recent evidence has consistently suggested that a suboptimal vitamin D status is frequently observed in patients with depression, the results concerning whether vitamin D insufficiency is a causal factor of depression or is secondary to depressive behavior are conflicting; additionally, the lack of consistency of the method of vitamin D determination between labs has further worsened this confusion. Herein, we reviewed the neuroactivities of vitamin D that may be associated with depression and the current studies and clinical investigations to provide a full overview on the use of vitamin D in the treatment and prevention of depression.

Full text

Asia Pac J Clin Nutr 2019;28(4):689-694 689
Review Article
Vitamin D and depression: mechanisms, determination
and application
Chunmei Geng MD1, Abdul Sami Shaikh MD, PhD2, Wenxiu Han MD1, Dan Chen MD1,
Yujin Guo MD1, Pei Jiang MD, PhD1
1Institute of Clinical Pharmacy & Pharmacology, Jining First People’s Hospital, Jining Medical University,
Jining, China
2Department of Pharmacy, Shah Abdul Latif University, Khairpur, Pakistan
Depression is the most common debilitating psychiatric disease, the pathological mechanisms of which are asso-
ciated with multiple aspects of neural function. While recent evidence has consistently suggested that a subopti-
mal vitamin D status is frequently observed in patients with depression, the results concerning whether vitamin D
insufficiency is a causal factor of depression or is secondary to depressive behavior are conflicting; additionally,
the lack of consistency of the method of vitamin D determination between labs has further worsened this confu-
sion. Herein, we reviewed the neuroactivities of vitamin D that may be associated with depression and the current
studies and clinical investigations to provide a full overview on the use of vitamin D in the treatment and preven-
tion of depression.
Key Words: depression, vitamin D, pathological mechanisms, neuroactivities, determination
Depression is a public health concern with no current
effective treatment, and approximately 1 out of 10 people
are currently suffering from depression worldwide. De-
pression is also called major depressive disorder or clini-
cal depression, and it is a common debilitating psychiatric
illness that is marked by sadness, worthlessness, hope-
lessness, a loss of interest, and sometimes, feeling as if
life is not worth living.1,2 Depression is more than just
about of the blues, depression is not a weakness and you
cannot simply “snap out” of it. Depression may require
long-term treatment. However, do not get discouraged.
Most people with depression feel better with medication,
psychological counseling or both. Unfortunately, it is not
known what exactly causes depression, and as with many
mental disorders, a variety of factors may be involved,
such as biological differences, brain chemistry, hormones
and inherited traits. Because of these uncertainties, re-
searchers are trying to find the underlying mechanism
involved in depression.
Recently, researchers found that there is a slight link
between vitamin D and depression; however, the link is
not completely understood.3 Additionally, this link does
not prove whether a low level of vitamin D causes de-
pression or if depression causes a low level of vitamin D.
The only certainty is that the risk of depression may be
further exacerbated by low serum levels of vitamin D.
Vitamin D is a fat-soluble vitamin, which is also
known as the “sunshine” vitamin. Vitamin D3 (cholecal-
ciferol) and D2 (ergocalciferol) are the main precursors of
the active vitamin D hormones. Vitamin D3 can either be
obtained from the diet, or it can be synthesized from 7-
dehydrocholesterol upon sun exposure of the skin. Both
vitamin D3 and D2 can enter the blood circulation and
can bind to the vitamin D binding protein (VDBP). Ini-
tially, vitamin D is transported to the liver, where it is
hydroxylated at C-25 by the cytochrome P450 enzyme
(CYP2R). In the kidneys, a second hydroxylation at the
C1-position by cytochrome P450 [5(OH)D-1α-
hydroxylase; CYP27B1] occurs. Then, the best nutritional
status indicator of vitamin D, 25-hydroxyvitamin D
(25(OH)D2 or 25(OH)D3), is produced. Next, 25(OH)D3
is metabolized to 1, 25-dihydroxyvitamin D (1,
25(OH)2D3), which is the most active form of vitamin D,
and it is then transported to the target tissues.4,5 The
whole vitamin D metabolic process is shown in Figure 1.
An accumulating number of studies have indicated that
vitamin D also acts as a neuroactive steroid,6 ,7 which
plays a key role in the expression of neurotransmitters,
the regulation of neurotrophic factors, neuroimmuno-
modulation, the production of antioxidants and neuro-
tropic factors , making it biologically plausible that vita-
min D might be associated with depression. Currently, the
results concerning whether vitamin D insufficiency is a
causal factor of depression or secondary to depressive
behavior are conflicting, and the lack of consistency in
the vitamin D determination methods between labs has
Corresponding Author: Dr Pei Jiang, Jining First People’s
Hospital, Jining Medical University, No. 6 Jiankang Road,
Jining 272000, Shandong Province, People’s Republic of China.
Tel: 86-537-2106209; Fax: 86- 537- 2106209
Email: jiangpeicsu@sina.com
Manuscript received 21 March 2019. Initial review completed
and accepted 23 July 2019.
doi: 10.6133/apjcn.201912_28(4).0003

690 C Geng, AS Shaikh, W Han, D Chen, Y Guo and P Jiang
further worsened this confusion. Herein, we reviewed the
neuroactivities of vitamin D that may be associated with
depression as well as the current studies and clinical in-
vestigations to provide a full overview of the use of vita-
min D in the treatment and prevention of depression.
METHODS
Depression: Underlying mechanisms involving Vitamin
Although the underlying pathophysiology of vitamin D in
depression is still not fully understood, the main mecha-
nisms of depression that are associated with vitamin D are
as follows.
Vitamin D and neurotrophic hypothesis
Vitamin D receptors (VDRs) were initially found in the
central nervous system (CNS) by immunohistochemical
studies, providing the first real clue that vitamin D might
have a role in brain function. The VDR and vitamin D
activating enzyme 1-alpha-hydroxylase are widely dis-
tributed in multiple brain regions and in many different
types of cells, particularly in the neurons in the amygdala
and the glial cells in the hypothalamus,8,9 thus adding fur-
ther support for the hypothesis that vitamin D signaling
might be involved in the pathophysiology of neuropsy-
chiatric disease. VDR is widely distributed throughout the
brain, particularly in the neuroepithelium and proliferat-
ing zones, whereas expression is not confined to these
regions. Previous studies have indicated that
1,25(OH)2D3 could cross the blood-brain barrier to bind
to VDR in specific brain regions, including the hippo-
campus, which raises the possibility that vitamin D is
either directly or indirectly involved in brain and cogni-
tive function.10 Meanwhile, hippocampal structure could
control memory, the emotional function of other brain
regions, and the atrophy of the hippocampus and other
limbic structures. In addition, hippocampal structure ab-
normalities have also been validated to take place in hu-
mans when they are suffering from chronic depression.
The hippocampus plays a key role in the mechanisms of
depression, and therefore, the discovery of VDR within
the hippocampus has prompted many researchers to study
the effects of vitamin D on hippocampal structure or
function in rodents.11 Numerous studies have also been
conducted with the in vitro culturing of hippocampal cells,
and even on the brains of adult rodents in vivo, and the
results have shown that vitamin D deficiency could
change the structure or function during hippocampal de-
velopment.
Increasing evidence has revealed that vitamin D is a
potent modulator of the expression of neurotrophic agents,
such as nerve growth factor (NGF), brain-derived neuro-
trophin factor (BDNF) and neurotrophin (NT)-3. Neu-
rotrophic factors are essential for the survival, growth and
migration of neurons, which exert their biological func-
tion by combining with their cognate tropomyosin-related
kinase (Trk) receptors, including NGF/TrkA,
BDNF/TrkB, NT-3/ TrkC and the common neurotrophin
receptor p75 (p75NTR).12 An extensive body of research
has demonstrated that 1,25(OH)2D could increase the
expression of BDNF, NGF and NT-3, whereas NT-4 is
downregulated in astrocytes in the brain,13,14 thus provid-
ing further evidence that vitamin D could modulate neu-
ronal survival and differentiation during development.
BDNF plays an important role in the long-term survival,
differentiation, and function of newborn neurons in the
adult hippocampus. Therefore, restoring the levels of
BDNF might be beneficial for the treatment of depression.
Neurogenesis is also important for depression, suggesting
that the discovery of TrkB ligands might open new ave-
nues for the treatment of this disorder. NT-3 and NT-4 are
vital to the survival of developing neurons, including the
proliferation and differentiation of neural progenitor cells,
thereby directly or indirectly influencing depression.
Therefore, vitamin D could modulate neurotrophic agents,
the abnormal function of which is believed to be associat-
ed with various psychiatric diseases.
Vitamin D and monoamine neurotransmission hy-
pothesis
The classic monoamine neurotransmission hypothesis
suggests that monoamine deficiency may be a cause of
depression; more precisely, depression is related to sero-
tonin (5-HT), dopamine (DA) and norepinephrine (NE).
The common clinical antidepressant drugs, such as tricy-
clic drugs, function by inhibiting the 5-HT and NE trans-
porters. 5-HT, a monoamine neurotransmitter, is synthe-
Figure 1. The process of vitamin D metabolism.

The association between vitamin D and depression 691
sized from the amino acid tryptophan, and the hypotheses
regarding the role that 5-HT plays in the pathophysiology
of depression were formed as early as the 1960s. Some
evidence has verified that 5-HT plays an important role in
the brain functions that are involved with the regulation
of mood.15 However, a lack of vitamin D could affect the
synthesis of 5-HT, leading to the abnormal development
of the brain and serotonergic neurons. Additionally, 5-HT
also acts on the hippocampus, where the generation of
new neurons and synaptic plasticity has been implicated
as possible factors in the development and treatment of
depression. The VDR is expressed in dopaminergic neu-
rons in the human and rat hippocampus, substantia nigra
and prefrontal cortex, which are involved in depression.16
VDR expression in the substantia nigra could delay DA
cell differentiation and could cause DA-mediated behav-
ioral deficits upon vitamin D deficiency,17 and it further
indicates that vitamin D deficiency could affect the de-
velopment of dopaminergic neurons and has serious im-
plications for the development of depression. Therefore,
vitamin D might be involved in depression by directly or
indirectly influencing the levels of 5-HT, DA and NE.
Vitamin D and neuroimmunomodulation
With a renewed interest in vitamin D, new pharmacologi-
cal effects of vitamin D in autoimmune diseases and in-
flammation have been discovered. Accumulating evi-
dence has suggested that 1, 25(OH)2D3, a key transcrip-
tional regulator of components of the immune system, can
inhibit the abnormal activation of the immune system,
thereby having a neuroprotective effect.18 Our previous
basic research and that of others have shown that vitamin
D insufficiency could elevate inflammatory markers in
chronic mild stress (CMS)-induced depressive rats, spe-
cifically interleukin (IL)-1βand IL-6.19 Thus, vitamin D
insufficiency might contribute to inflammation. However,
the underlying mechanisms are not clearly understood
and are topics of ongoing investigation. Vitamin D sup-
plementation could reduce elevated [Ca2+]i via the CRAC
and P2X7 channels and could decrease the expression of
the cell surface P2X7 receptors in early chronic kidney
disease (CKD).20 As we and others previous researchers
have shown,21 vitamin D insufficiency exacerbated the
depressive symptoms caused by P2X7R/NLRP3 activa-
tion; therefore, we think vitamin D may play a neuroim-
munological role by regulating the activity and expression
of P2X7R, thus preventing the excessive activation of the
immune system that is caused by long-term stress, pro-
tecting nerve cells and producing antidepressant effects.
Therefore, more researches related to this important po-
tential mechanism is highly warranted.
Serum vitamin D concentrations and depression
Increasing attention has been paid to the levels of serum
vitamin D; in the mid- to late-1980s, total serum
25(OH)D concentrations were usually used to character-
ize the vitamin D levels, as circulating 25(OH)D was
deemed the best nutritional status indicator for vitamin D.
Accumulating studies have shown that the levels of
25(OH)D are related to many diseases, such as cardiovas-
cular disease, cancer, diabetes, obesity, and asthma.22 It
should be noted that vitamin D could regulate the expres-
sion of neurotrophic factors and interleukins. Thus, the
role of vitamin D in the prevention and treatment of de-
pression has gained more attention. Several studies still
have not achieved a general consensus regarding whether
lower levels of serum 25(OH)D are significantly associat-
ed with depression.23,24 In contrast, recent studies have
failed to demonstrate a correlation between serum
25(OH)D levels and depression in female subjects25 or in
older subjects.26 The small numbers of subjects, and soci-
odemographic factors, including sex differences, genetics,
body-mass index, residence, family affluence, parental
education levels, subjective academic achievement, diet,
drinking and smoking, have not been comprehensively
considered, resulting in discrepancies arising when vali-
dating the previously observed correlations. There is no
doubt that lowered serum vitamin D levels present a non-
significant but increased risk of depression (OR 1.31,
95% CI 1.00-1.71).27 Thus, the most important thing that
we can do currently is to summarize the best available
evidence to date to clarify the mechanism of vitamin D in
the prevention and treatment of depression.
Vitamin D determination
Currently, for the diagnosis of vitamin D deficiency, a
doctor or health professional will ask about your diet and
the time spent in the sun. After this, the doctor will order
a 25(OH)D blood test to check the level of vitamin D in
your body. A number of hospitals and laboratories al-
ready include vitamin D testing as a part of clinical rou-
tine testing, and vitamin D levels are also a testing item
for therapeutic drug monitoring (TDM). There are a va-
riety of assays used to measure 25(OH)D, such as immu-
noassays (e.g., radio-labeled, enzyme, or chemilumines-
cent),28 electrochemistry assays and chromatographic
assays that use different detectors, e.g., ultraviolet
(HPLC-UV) or tandem mass spectrometry (LC-
MS/MS).29,30 The immunoassays, such as the Siemens
ADVIA Centaur Vitamin D total assay and Roche El-
ecsys Vitamin D total assay, cannot distinguish 25(OH)D
from its analogue or its metabolites, indicating that these
assays lack specificity. Chromatographic assays, such as
LC-MS/MS, are considered to be the gold standard with
the advantage of having high sensitivity and specificity
and the ability to simultaneously measure 25(OH)D2 and
25(OH)D3. The concentration measurements are accurate,
but LC-MS/MS is a very complicated assay, and thus, it
is not suitable for routine clinical use by hospitals or la-
boratories for serum samples. Therefore, the inconsisten-
cy among the various conclusions regarding whether vit-
amin D deficiency is a cause of depression may be due to
the inconsistencies in the quantitative methods, which
make it hard to make sense of the data.
The inadequate accuracy or the cumber some tech-
niques of the methods used to measure 25(OH)D not only
hamper the ability to interpret data in patient care and
public health research but also the diagnosis and treat-
ment of hypovitaminosis D. To solve the problem of inter
laboratory and inter assay discrepancies, vitamin D stand-
ardization efforts are ongoing, and the Vitamin D Stand-
ardization Program (VDSP) was established in 2011.31,32
Due to these efforts, the National Institute of Standards
and Technology (NIST), in collaboration with the US

692 C Geng, AS Shaikh, W Han, D Chen, Y Guo and P Jiang
Office of Dietary Supplements (ODS), has developed
Standard Reference Materials (SRM 2972 and 972), and
these materials have been certified by the Reference Ma-
terials Procedures (RMPs) for 25(OH)D testing in human
serum.33 Based on a method evaluation study on the new
follow-up version of a chemiluminescence immunoassay
(CLIA) and a new enzyme-linked immunosorbent assay
(ELISA), both methods are aligned with the NIST SRM
2972, and the LC-MS/MS method is aligned with the new
NIST SRM 972a.34 Both the 25(OH)D2 and 25(OH)D3
concentrations are measured, with the sum gives the total
serum 25(OH)D concentration. Even if the new NIST
SRM 972a Standard is a relatively accurate measurement
and assessment method, various discrepancies (e.g., re-
gion, ethnicity and diet) can make it difficult to determine
whether the vitamin D level is normal. Despite the many
shortcomings in the determination methods that remain,
their use can still provide an idea of the 25(OH)D level,
which is beneficial for the prevention and treatment of
depression in some individuals.
Vitamin D supplementation for depression treatment
There is no absolute agreement as to whether there is in-
ter human and inter region diversity in the ranges of the
serum 25(OH)D concentration. Recent reviews have re-
ported that children, young, middle-aged, and older adults
worldwide, especially depressed individuals, are all at
risk for having vitamin D deficiency.35 Based on all of the
information that has been collected, most experts now
agree that a 25(OH)D level of <20 ng/mL indicates vita-
min D deficiency and vitamin D insufficiency is now rec-
ognized as a 25(OH)D level of 21-29 ng/mL. Many ex-
perts now say that the ideal levels for 25(OH)D are >30
ng/mL. With aging, the skin’s ability to synthesize vita-
min D significantly decreases. A study indicated that the
capacity of the skin to synthesize vitamin D at 70 years of
age is reduced by more than 50% compared to at 20 years
of age. However, aging does not affect the intestinal ab-
sorption of vitamin D,36,37 and another study revealed that
approximately two-thirds of the population in northern
climates are considered deficient for vitamin D, with av-
erage serum 25(OH)D levels of 30 ng/mL;38 thus, vitamin
D supplementation is urgently required to reduce the risk
of vitamin-related disease, to improve the quality of life
and to prolong the lifetime of humans.
Vitamin D supplementation in combination with fluox-
etine is more effective than fluoxetine alone in reducing
depressive symptoms of patients with depression in the
general population; therefore, the efficacy of vitamin D
supplementation in depression has raised much interest.
In three small pilot studies, vitamin D supplementation
had a positive effect on the well-being, and the symptoms
of depression were improved when high doses of vitamin
D (≥100 µg D3 daily) were given for 1 to 3 months.39 A
study with a large sample size (n=441) demonstrated a
similar significant improvement in the Beck Depression
Inventory (BDI) scores in the treatment groups receiving
70 μg and 140 μg vitamin D supplementation compared
to those of the placebo group during a 1-year period.40 In
addition, several studies have also shown that vitamin D
supplementation is more effective and relevant in high-
risk participants who have low serum 25(OH)D and have
apparent depressive symptoms or reduced physical func-
tioning.41-43 In conclusion, the treatment of depression
with vitamin D supplementation could have a profound
influence, as vitamin D is not only an effective antide-
pressant but is also a cost-effective treatment for depres-
sion. However, while people with very low levels of vit-
amin D could benefit from vitamin D supplementation,
people with a sufficient amount of vitamin D in the blood
would not benefit from vitamin D supplementation and
would not experience a decrease in depression. A serum
25(OH)D level >150 ng/mL is associated with hyper-
calcemia, hypercalciuria and hyperphosphatemia, which
is called vitamin D intoxication. Therefore, the relation-
ship between vitamin D supplementation and depression
is complicated for the following reasons. First, different
doses of vitamin D have been used for supplementation
for different lengths of time in different studies. Second,
different parameters are used to define vitamin D suffi-
ciency and the efficacy of treatment. Third, different tools
are used to evaluate mental health and depression. Finally,
previous studies have administered vitamin D at different
frequencies. Furthermore, serum 25(OH)D concentrations
should be determined first, and then, according to the
serum 25(OH)D concentrations, depressed patients might
be treated with vitamin D supplementation in combina-
tion with other therapeutic schedules. To verify whether
vitamin D supplementation improves depressive symp-
toms, large, randomized and controlled clinical trials are
highly warranted.
Conclusion
In our paper, we reviewed the current underlying mecha-
nisms of depression that are involving vitamin D, as well
as vitamin D determination, supplementation and applica-
tion. Although the data regarding the relationship be-
tween vitamin D and depression are conflicting, lower
serum 25(OH)D levels are associated with an increased
risk for depression, and depressive symptoms could be
eased in people with very low levels of vitamin D through
vitamin D supplementation. Additionally, in some cases,
monitoring serum 25(OH)D concentrations can help us to
learn about health status and can provide new insights
into depression. Furthermore, we have structured our
thoughts into the review and believe that the effective and
safe protocols for dealing with depression will be devel-
oped. We hope that every depressed patient will receive
personalized treatment.
EDITORS’ NOTE
The Editors wish readers of this paper to be aware that serum
vitamin D’s association with affective disorders like depression
may be as an indicator of sunlight (UV) exposure in its own
right or in association wit UV-dependent cutaneous vitamin D
synthesis. Similarly, the association may be attributable to par-
ticipant food intake or food pattern from which vitamin D is
derived.
AUTHOR DISCLOSURES
All authors declare no conflict of interest, financial or otherwise.
The study was supported by the Taishan Scholar Program of
Shandong Province (tsqn201812159) and The Foundation of
Clinical Pharmacy of the Chinese Medical Association (LCYX-
M008).

The association between vitamin D and depression 693
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