CNS Drugs (2019) 33:619–637

https://doi.org/10.1007/s40263-019-00640-4

LEADING ARTICLE

Potential Role of Vitamin D for the Management of Depression

and Anxiety
Gleicilaine A. S. Casseb1 · Manuella P. Kaster1 · Ana Lúcia S. Rodrigues1 

Published online: 15 May 2019

© Springer Nature Switzerland AG 2019

Abstract
Vitamin D, a fat-soluble vitamin, plays a role not only in calcium and phosphate homeostasis but also in several other
functions, including cell growth and neuromuscular and immune function. The deficiency of vitamin D is highly prevalent
throughout the world and has been suggested to be associated with an enhanced risk of major depressive disorder (MDD)
and anxiety disorders. Therefore, vitamin D supplementation has been investigated for the prevention and treatment of these
disorders. This review presents preclinical and clinical evidence of the effects of vitamin D supplementation in these disor-
ders. Although preclinical studies provide limited evidence on the possible mechanisms underlying the beneficial effects of
vitamin D for the management of these disorders, most of the clinical studies have indicated that vitamin D supplementation
is associated with the reduction of symptoms of depression and anxiety, particularly when the supplementation was car-
ried out in individuals with an MDD diagnosis (of the 13 studies in which MDD diagnosis was established, 12 had positive
results with vitamin supplementation). However, some heterogeneity in the outcomes was observed and might be associated
with an absence of overt psychiatric symptoms in several studies, genetic polymorphisms that alter vitamin D metabolism
and bioavailability, differences in the supplementation regimen (monotherapy, adjunctive therapy, or large bolus dosing),
and levels of 25-hydroxyvitamin ­D3 (25(OH)D) at baseline (individuals with low vitamin D status may respond better) and
attained after supplementation. Additionally, factors such as sex, age, and symptom severity also need to be further explored
in relation to the effects of vitamin D. Therefore, although vitamin D may hold significant potential for mental health, further
preclinical and clinical studies are clearly necessary to better understand its role on mood/affect modulation.

Key Points 
Major depressive disorder (MDD) and anxiety disor-
ders are highly prevalent, representing a public health
problem.
Vitamin D plays a role in immunomodulation, oxidative
stress and neuroplasticity.
Some clinical studies have indicated that vitamin D may
be useful for the management of symptoms of depression
and anxiety disorders. However, data vary widely, so
more investigation is needed.
* Ana Lúcia S. Rodrigues
alsrodri@gmail.com; ana.l.rodrigues@ufsc.br
1
Department of Biochemistry, Center for Biological
Sciences, Universidade Federal de Santa Catarina,
88040‑900 Florianópolis, SC, Brazil
1 Introduction
Major depressive disorder (MDD) and anxiety disorders are
among the most prevalent psychiatric disorders worldwide.
Symptoms of depression and anxiety frequently overlap in
patients, and comorbid MDD and anxiety disorders is com-
mon in healthcare settings and constitutes a great mental
health burden; however, the treatment of these disorders
remains a challenge [1]. Given that mood and anxiety dis-
orders are relatively common and are associated with con-
siderable health impairment and that current treatments are
limited, novel compounds exhibiting antidepressant and
anxiolytic properties are needed. In this context, vitamin D
has been investigated as a promising strategy for the man-
agement of these disorders. Therefore, this narrative review
provides a summary of the existing preclinical and clinical
data regarding the potential antidepressant and anxiolytic
benefits of vitamin D. It presents the available evidence
indicating that vitamin D supplementation may afford ben-
eficial effects for individuals with symptoms of anxiety and

Vol.:(0123456789)

620
depression and the possible cellular and molecular targets
modulated by this vitamin that may be relevant for its effects
on the pathophysiology of MDD and anxiety disorders. The
lack of effects observed in some studies and populations is
also presented and discussed.
1.1 Vitamin D: Metabolism and Biological Effects
Vitamin D may be obtained via the diet (vitamin ­D2 or ergo-
calciferol derived from plants, fungi, and yeast; vitamin D ­ 3
or cholecalciferol, from both plants and animal sources, but
extremely abundant in cold-water fish), but diet sources con-
tribute to only a small fraction of the vitamin D available
to be metabolized [2, 3]. Vitamin D ­ 3 is mainly produced in
the skin from 7-dehydrocholesterol following exposure to
ultraviolet radiation in the 260–320 nm wavelength (range
of ultraviolet B [UVB] radiation). This process causes the
rearrangement of the double bonds, opening up the B ring
of the molecule to form the seco-steroid previtamin D ­ 3 [4].
Previtamin ­D3, in turn, is converted into vitamin ­D3 by ther-
mal isomerization [4, 5]. Vitamin D ­ 3 itself is not biologi-
cally active – it undergoes two hydroxylations to become
biologically active; the first hydroxylation, at the C-25 site,
occurs in the liver, and the second hydroxylation, at the C-1α
site, occurs mainly in the kidney. In hepatic cells, vitamin
­D3 is hydroxylated into its major circulating metabolite,
25-hydroxyvitamin ­D3 (25(OH)D), mainly by the enzyme
25-hydroxylase (CYP2R1). In the kidney, 25-hydroxyvita-
min ­D3 1α-hydroxylase (mitochondrial CYP27B1) converts
25(OH)D into its active form, 1,25-dihydroxyvitamin D ­ 3
Fig. 1  Synthesis of the active form of vitamin D. Previtamin D ­ 3 is
synthesized in the skin from 7-dehydrocholesterol by the action of
ultraviolet light. In a subsequent nonenzymatic step, previtamin ­D3 is
converted into vitamin D ­ 3 (cholecalciferol). In the liver, cholecalcif-
G. A. S. Casseb et al.
(1,25(OH)D), also known as calcitriol [6]. The synthesis of
the active form of vitamin D is illustrated in Fig. 1.
The biological actions of 1,25(OH)D are mediated by the
vitamin D receptor (VDR), which belongs to the steroid-
thyroid-retinoid receptor superfamily of ligand-activated
transcription factors, controlling 3–5% of human genes [6].
Serum level of 25(OH)D has served as a biomarker of vita-
min D status and deficiency [7, 8]. The transport of vitamin
D and its metabolites in the circulation is dependent on its
binding to vitamin D binding protein (DBP) and to a lesser
extent (about 15%) to albumin [9]. A summary of vitamin
D metabolism is depicted in Fig. 2.
It is important to highlight that the levels of vitamin D
synthesis after sunlight exposure are strongly influenced by
different factors, including skin pigmentation, use of sun-
screen, latitude, season, and age. On the other hand, the
contribution of diet intake and supplementation to serum
25(OH)D levels appears nonlinear and can also be influ-
enced by several factors, including baseline levels of vitamin
D, body mass index and percentage of body fat, age, and
calcium intake, among others [10, 11].
Vitamin D deficiency is prevalent throughout the world
[12–14]. It is estimated that over 50% of the world’s popu-
lation have low vitamin D levels (i.e., hypovitaminosis D;
serum levels of 25(OH)D < 30 ng/mL or 75 nmol/L) [13].
However, a single cutoff value to define vitamin D defi-
ciency or insufficiency is a matter of debate. The establish-
ment of desirable serum 25(OH)D levels generally relies
on the required vitamin D levels to maintain skeletal and
mineral homeostasis [13, 15].
erol is converted into 25(OH)D (calcidiol) by the enzyme CYP2R1.
In the kidney, calcidiol is converted into 1,25(OH)D (calcitriol), the
active form of vitamin D, by the enzyme CYP27B1. CYP cytochrome
P450
Vitamin D for Depression and Anxiety Disorders
Regarding vitamin D toxicity, serum 25(OH)D lev-
els > 150 ng/mL are likely to be associated with life-threat-
ing hypercalcemia. As a result of the hypercalcemia, individ-
uals can experience nausea, vomiting, weakness, polyuria,
nephrocalcinosis, and even renal failure [16]. The highest
daily intake of vitamin D that will pose no risk of adverse
effects is not well-established and is dependent on several
factors [16]. However, intake of vitamin D 5000 IU/day is
generally considered as the safe daily upper limit of supple-
mentation [13], but the upper intake for long-term supple-
mentation of vitamin D is proposed to be 2000 IU/day [16].
Doses > 50,000 IU/day raise serum concentrations above
150 ng/mL, leading to hypercalcemia [16].
Although 1,25(OH)D is well-known to regulate calcium
and phosphate homeostasis, it also has pleiotropic actions
[6]. A growing body of evidence suggests that low vitamin
D levels also play a role in the pathogenesis of a wide range
of non-skeletal, age-associated diseases, including cancer,
heart disease, metabolic syndrome, type 2 diabetes mellitus,
stroke, and neurodegenerative and neuropsychiatric diseases
[17–25].
Over the past three decades, an intricate interaction
between peripheral immune activation, neuroinflamma-
tion, and changes in brain circuits related to depression and
Fig. 2  Vitamin D metabolism. Vitamin D is produced by cutaneous
synthesis (vitamin D
­ 3 or cholecalciferol) or may be obtained via the
diet (vitamin ­D2 or ergocalciferol from plant, fungi and yeast, and
­D3 or cholecalciferol mainly from animal sources). Dietary vitamin
D is absorbed in the small intestine and packed into chylomicrons to
reach the systemic circulation. In the circulation, vitamin ­D2 and D
­3
are transported by DBP or albumin. Vitamin D is transported to the
621
anxiety has been described [26]. In this regard, vitamin D is
a well-known regulator of innate immunity, acting as both
a transcription and a growth factor, as well as by interacting
with surface receptors in different immune cells [27]. Thus,
many of the positive effects of vitamin D on behavior might
be associated with its ability to regulate both peripheral and
central nervous system (CNS) immune responses.
In the periphery, VDR are widely expressed in immune
cells, including B and T lymphocytes, monocytes/mac-
rophages, dendritic cells, and natural killer cells [28–32].
Moreover, most of the immune cells also possess the enzyme
1α-hydroxylase, responsible for metabolizing 25(OH)D into
its active metabolite, 1,25(OH)D, and different immune
cells—including B cells and monocytes—also express
24α-hydroxylase, the enzyme that degrades 1,25(OH)D
[27, 30]. The first immune-related properties described for
vitamin D were antimicrobial properties, but vitamin D
is involved in the modulation of both innate and adaptive
immune responses [27]. In this context, depression and anxi-
ety are frequently associated with a low-grade inflammatory
status and peripheral increase in acute-phase proteins and
inflammatory cytokines [33–35].
Vitamin D induces T cell polarization to a type 2 T-helper
(Th2) cell phenotype, attenuating pro-inflammatory type 1
liver, where it undergoes hydroxylation at C25 mainly by the enzyme
CYP2R1, forming 25(OH)D (calcidiol). This metabolite is trans-
ported by DBP to the kidneys for another hydroxylation, catalyzed by
the enzyme CYP27B1, forming 1,25(OH)D (calcitriol). The active
metabolite 1,25(OH)D circulates through the body in order to pro-
duce different biological functions. CYP cytochrome P450, DBP vita-
min D-binding protein, Vit D vitamin D, UVB ultraviolet B

622
T-helper (Th1) cells and stimulating anti-inflammatory Th2-
cell responses. Vitamin D can inhibit the secretion of Th1
cells’ pro-inflammatory cytokines such as interleukin (IL)-
1, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and
induced those of Th2-cell anti-inflammatory cytokines such
as IL-4 and IL-10 [36].
Moreover, 1,25(OH)D is a potent downregulator of
Toll-like receptor (TLR)-2 and TLR4 in monocytes,
decreasing inflammatory responses [37]. Peripheral
blood mononuclear cells of patients with depression were
reported to express higher levels of TLR4, but this param-
eter was normalized following antidepressant treatment
[38]. VDR expression is considerably enhanced in mac-
rophages, monocytes, and lymphocytes after inflammatory
and immunological stimuli, and vitamin D can modulate
the innate immune system, either by increasing the phago-
cytic ability of immune cells or by reinforcing the physi-
cal barrier function of epithelial cells [39]. In particular,
1,25(OH)D can enhance intestinal epithelial barrier func-
tion and modulate the bowel immune system. In fact, gut
epithelial VDR signaling controls mucosal inflammation,
mucosal barrier permeability, and gut microbiota com-
position [40, 41]. This function is of particular interest
since disruption in the gut–brain axis and dysbiosis have
been associated with psychiatric symptoms [42]. Specifi-
cally, a leaking gut allows translocation of lipopolysaccha-
rides (LPS) into the circulation, causing the activation of
various immune cells, which leads to systemic low-grade
inflammation. Moreover, some recent reports suggest that
microbiota, per se, influences systemic levels of vitamin
D [43].
The association of vitamin D and the immune system
does not occur only in the periphery. In fact, in the CNS,
microglia cells stimulated with IFN-γ or LPS increased the
expression of VDR and cytochrome P450 (CYP)27B1 and
decreased the expression of CYP24A1, which degrades
the active form of vitamin D ­ 3, 1,25(OH)D, leading to
increased levels of 1,25(OH)D [44]. Thus, microglia
cells have an intracrine system whereby the cells convert
25(OH)D to 1,25(OH)D, which can then bind to VDR in
the cell. These observations suggest that vitamin D can
alter the immune activation of microglia, which may have
implications in the immune response in the CNS during
disease states [44].
Taken together, these data point to a role for vitamin D
in the immune system, in both innate and adaptive immune
responses. Although a causal link between vitamin D,
immune modulation, and symptoms of depression or anxi-
ety has not yet been proven, some of the beneficial effects
of vitamin D in psychiatric symptoms might be associated
with neuroimmune interactions.
G. A. S. Casseb et al.
1.2 Vitamin D and the Central Nervous System
(CNS)
In the CNS, VDR and the enzyme 25-hydroxyvitamin ­D3
1α-hydroxylase are found in both neurons and glial cells in
rodents and humans [45]. The distribution of the VDR in the
human brain was similar to that reported in rodents. In the
human brain, the strongest immunohistochemical staining
for both the receptor and the enzyme was in the hypothala-
mus (supraoptic nucleus and paraventricular nucleus) and in
the large neurons within the substantia nigra, but an intense
immunoreactivity was also found in the prefrontal cortex
(external granule), cingulate gyrus (external and internal
granule), hippocampus (pyramidal layer of CA1 and CA2),
fimbria, dentate gyrus (granule cell layer), and caudate-
putamen [45].
Although evidence from a transport study with 1,25(OH)
D and 25(OH)D indicated their restricted transport by the
blood–brain barrier (BBB) in rats [46], there is evidence
that 25(OH)D may be converted into 1,25(OH)D within
the human brain parenchyma [45]. In the CNS, 1,25(OH)D
is frequently associated with neuroprotective properties. It
modulates the production and release of neurotrophic factors
[47], cell proliferation and apoptosis [48], biosynthesis of
monoamines through the increase of tyrosine hydroxylase
and tryptophan hydroxylase 2 expression [49, 50], calcium
and redox homeostasis [51, 52], and mitochondrial func-
tion [53]. Moreover, antioxidant and anti-inflammatory
properties were also described for 1,25(OH)D in the brain
in preclinical studies [54–56]. A recent study reported that
1,25(OH)D is able to inhibit serotonin reuptake transport
and the gene expression of monoamine oxidase-A (MAO-A;
enzyme responsible for monoamine degradation) in cultured
rat serotonergic neuronal cell lines, suggesting that calcitriol
may act in a way similar to antidepressants [57].
The importance of vitamin D to many brain processes,
including neuroimmunomodulation, oxidative stress, and
neuroplasticity suggests a potential role in psychiatric dis-
orders. This review summarizes the main findings regard-
ing the possible role of vitamin D in the pathophysiology
of MDD and anxiety disorders. The preclinical studies
that focused on this issue have been carried out in models
of depression and anxiety in rodents subjected to vitamin
D supplementation/depletion as well as in transgenic mice
not expressing VDR. Clinical studies that were designed
to assess the impact of vitamin D supplementation on
MDD or anxiety risk or symptoms are also presented and
discussed. The data reviewed were identified in a compre-
hensive literature search in PubMed using the following
search terms: vitamin D or cholecalciferol and depression,
depressive symptoms, major depression, MDD, anxiety,
anxiety disorders. Articles published up to December
Vitamin D for Depression and Anxiety Disorders
2018 were considered. No language limit was applied to
the search.
2 The Possible Role of Vitamin D
in the Pathophysiology of Major
Depressive Disorder (MDD)
MDD is a neuropsychiatric disorder characterized by low
mood, reduced self-esteem, loss of interest or pleasure in
normally enjoyable activities (anhedonia), and fatigue,
among other symptoms. It is a highly debilitating and
prevalent disorder that is approximately twice as preva-
lent in women compared with men [58].
Although the pathophysiology of MDD is complex,
several mechanisms have been postulated to exert a key
role in the development of the depressive symptoms,
namely impairment in neurotrophic support and neuro-
genesis, neuroinflammation, disruption of bioenergetic
signaling, oxidative stress, and excitotoxicity [59–62]. All
these alterations may be triggered by chronic stress, a
condition that may cause the activation of the peripheral
macrophages and central microglia, dysfunction of the
hypothalamus–pituitary–adrenal (HPA) axis and hyper-
cortisolemia, and a consequent impairment of synaptic
plasticity, dendritic spine growth, and synaptic commu-
nication [61]. Considering that vitamin D plays a role
in neuroimmunomodulation and neuroplasticity and may
reduce oxidative stress [52, 54], it has been investigated
as a potential strategy for the prevention and/or treatment
of depressive symptoms. This approach is particularly rel-
evant because the treatment of MDD has several draw-
backs related to the limited efficacy and side effects of
conventional antidepressants [63, 64].
2.1 Preclinical Studies
The preclinical studies that have investigated the possible
beneficial effects of vitamin D in animal models are lim-
ited, and most of them do not deal with the mechanisms
underlying vitamin D effects.
The levels of 25(OH)D and VDR expression in the hip-
pocampus were significantly increased after 4 weeks of
chronic unpredictable mild stress in rats that exhibited
a depressive-like behavior, maybe as a compensatory
mechanism [65]. Alterations in the expression of brain
VDR were also reported following the repeated admin-
istration of dexamethasone in rats, a protocol associated
with a depressive-like behavior [66]. A decreased expres-
sion of both VDR and CYP27B1 and CYP24A1 (enzymes
involved in vitamin D catabolism) in the prefrontal cortex
and hippocampus of rats exposed to a high dose of this
623
glucocorticoid, as well as increased expression of VDR in
the prefrontal cortex and decreased CYP27B1/CYP24A1/
VDR expression in the hippocampus of animals exposed
to a low dose of dexamethasone, were reported [66]. These
studies suggest that vitamin D signaling could be regu-
lated in the brain in response to stress, one of the major
environmental factors associated with the occurrence of
MDD episodes.
The intragastric administration of vitamin D 1 µg/kg to
mice (24, 3 and 1 h before the test) was reported to produce
a reduction in the immobility time in the forced swim test
without causing alterations in locomotor activity, a finding
consistent with antidepressant-like effect [67]. Additionally,
a study by Fedotova et al. [68] showed that chronic vitamin
D administration for 14 days caused antidepressant-like
behavior in the forced swim test in ovariectomized rats. In
this same study, the coadministration of subcutaneous vita-
min D (high dose, 5 mg/kg/day) and 17beta-estradiol also
exerted an antidepressant-like effect in ovariectomized rats.
In line with these findings, vitamin D deficiency in dams
produced anhedonia (a key symptom of depression), anxiety,
and cognitive impairment in male pups [69]. In addition, a
recent study reported that, although the acute administration
of vitamin D ­ 3 failed to cause significant effects in the forced
swim test and tail suspension test, repeated administration
of this vitamin (2.5, 7.5, and 25 µg/kg) for 7 days effectively
counteracted the depressive-like behavior and brain oxida-
tive stress induced by chronic administration of corticoster-
one (21 days) in mice, suggesting that the antidepressant-like
effect of vitamin D may be related to its ability to modulate
oxidative stress [70].
It was reported that klotho-deficient mice that present
excessive plasma 1,25(OH)D have a lower floating time
when submitted to the forced swim test as compared with
wild-type mice, an effect reversed when animals were sub-
jected to a low vitamin D diet, suggesting that excessive
levels of calcitriol are associated with antidepressant-like
effects [71].
Further reinforcing the notion that vitamin D may afford
antidepressant effects, a recent study showed that intraperi-
toneal treatment with 1,25(OH) vitamin ­D3 (5, 10 µg/kg,
twice weekly) for 5 weeks along with chronic mild stress
effectively improved anhedonia-like symptoms in rats sub-
jected to stress [72].
Although the above-mentioned studies have suggested
that vitamin D has an antidepressant profile, some results
about this issue are also contradictory. A study that inves-
tigated the behavioral response of male Sprague–Dawley
rats deficient in vitamin D ­ 3 (6 weeks exposure to vitamin
D-deficient diet) found no alteration in the forced swim test
compared with control rats [73]. Similarly, Groves et al.
[74] found no behavioral alterations in the forced swim
test of C57BL/6J and BALB/c mice subjected to a vitamin

624
D-deficient diet for 10 weeks. However, another study from
the same group showed that BALB/c mice, subjected to the
same protocol of vitamin D-deficient diet, presented lower
immobility time in the forced swim test than mice receiv-
ing a standard diet, suggesting an antidepressant-like effect
afforded by vitamin D deficiency [75]. In this study, vitamin
D deficiency did not affect proliferation or survival of adult
hippocampal neurons in the dentate gyrus at baseline or after
voluntary wheel running in mice.
2.2 Epidemiological and Clinical Studies
Associating Vitamin D Supplementation
and Depressive Symptoms
The majority of the clinical literature that deal with the
possible role of vitamin D in MDD are cross-sectional and
cohort studies that have established an inverse association
between serum 25(OH)D levels and depressive symptoms [8,
76–83] as well as the risk of MDD [84–86]. Although most
of the human studies have shown an association between
serum 25(OH)D and depressive symptoms and/or MDD
risk, some failed to find significant associations [87–92].
Studies in which vitamin D supplementation was used as
a treatment for MDD, either as a unique therapeutic strat-
egy or as an adjuvant to classical pharmacotherapy, have
also been reported. These studies, which are presented in
chronological order in Table 1, show either positive effects
or an absence of effects of vitamin D supplementation. Most
report a beneficial effect of vitamin D on depression when
supplemented alone [93–106] or in combination with fluox-
etine [107] or probiotics [108]. Despite the positive results,
the vitamin D supplementation in several studies was car-
ried out not in individuals primarily diagnosed with MDD
but in those in whom depressive symptoms were associated
with different clinical conditions, such as obesity [94], mul-
tiple sclerosis [109], Crohn’s disease [101], type 2 diabetes
mellitus [103], and ulcerative colitis [105]. Considering that
vitamin D possesses anti-inflammatory effects and exerts an
important role in glucose homeostasis [110], a relationship
might exist between the positive effects of supplementation
and the occurrence of metabolic and/or inflammatory clini-
cal conditions. However, more studies are necessary to char-
acterize whether vitamin D is particularly effective against
depressive symptoms accompanied by systemic inflamma-
tory conditions. Indeed, several factors may have contrib-
uted to the contradictory results, such as the heterogeneity
of the study participants, including the severity of depres-
sive symptoms, the presence of comorbidities, the baseline
25(OH)D level and that attained after supplementation, and
the vitamin D supplementation regimen (dose and duration
of supplementation).
Vitamin D status has also been investigated in the etiol-
ogy of seasonal affective disorder (SAD), a type of recurring
G. A. S. Casseb et al.
major depression with a seasonal pattern. The symptoms
usually occur during the fall and winter months when there
is less sunlight and usually improve with the arrival of
spring [111]. Given the contribution of sunlight to vitamin
D synthesis, some studies have evaluated the relationship
between vitamin D levels and SAD. However, despite the
intuitive appeal, only a few studies have evaluated the topic
and most involved very small samples or health cohorts. Two
longitudinal studies evaluated vitamin D levels and symp-
toms of depression according to seasonality. Kerr et al. [112]
found variation in vitamin D levels and depression scores in
different seasons, in a group of 185 healthy females. Addi-
tionally, Premkumar et al. [113] found that lower vitamin
D levels were associated with symptoms of depression dur-
ing 1 year of Antarctic residence. However, a case–control
study including 15 subjects with a SAD diagnosis and 15
controls failed to find a similar association [114]. Clinical
trials were also planned to test this hypothesis. These stud-
ies are included in Table 1. Although some studies found
positive outcomes with vitamin D supplementation [93,
115, 116], most failed to find a positive effect for vitamin
D supplementation and SAD or mood changes according to
seasonality. In a sample of 250 females, vitamin D 400 IU
for 1 year did not change mood scores during different sea-
sons [117]. Similarly, Dumville et al. [118] did not observe
mood improvements in 1621 women randomized to vitamin
D 800 IU for 6 months. Additionally, in two randomized
controlled trials (RCTs), one involving 34 subjects with SAD
and the other including 243 individuals with low levels of
vitamin D, supplementation for 3 or 6 months, respectively,
was not associated with a reduction in symptoms [78, 119].
Taken together, there is only modest evidence that vitamin
D is effective for the treatment of SAD symptoms, but most
of the studies were conducted in small samples, using dif-
ferent scales to access mood and different vitamin D doses
and administration schedules. Therefore, although vitamin D
levels fluctuate in direct relation to seasonally available sun-
light, and VDR are found throughout the hypothalamus, the
brain region that controls circadian rhythms, further studies
are necessary to better establish the role of vitamin D in
SAD development, prevention, and/or treatment.
3 Possible Role of Vitamin D
in the Pathophysiology of Anxiety
Disorders
Anxiety is defined as a negative, vague, and unpleasant
emotional state derived from the anticipation of a potential
hazard and generates hypervigilance and alertness, even in
the absence of immediate danger [130]. When occasional,
anxiety represents a normal aspect of emotional behavior
Table 1  Clinical trial studies associating vitamin D supplementation and depressive symptoms
Study Study design Study participants Vitamin D supplementation Assessment scale Results

Harris and Dawson- Prospective 250 females (aged 43–72 years) healthy Calcium 377 mg + vitamin ­D3 POMS questionnaire on Supplementation with vitamin
Hughes [117] individuals (1% in treatment for cur- 400 IU QD for 1 year four visits (summer, D did not change mood scores
rent depression) autumn, winter, spring)
Lansdowne and Provost Randomized placebo- 44 male and female healthy students 400 or 800 IU vitamin ­D3 per day Positive and Negative Vitamin ­D3 enhanced positive
[93] controlled double-blind (mean age 22 years)—no MDD for 5 days during late winter Affect Schedule as a affect; some evidence of
diagnosis self-report measure reduction in negative affect
Gloth et al. [115] Prospective, RCT​ 15 SAD subjects Vitamin D 100,000 IU as a single HDRS; SIGH-SAD, SAD Vitamin D improved mood
dose (n = 8) or phototherapy measures 1 month after treat-
(n = 7) ment; phototherapy showed
no significant changes
Vitamin D for Depression and Anxiety Disorders

Vieth et al. [116] Blinded randomized 82 adults with vitamin D deficiency—no Vitamin ­D3 600 or 4000 IU QD Well-being questionnaire Higher dose of vitamin D asso-
MDD diagnosis for 3 months over 2 consecutive ciated with improvements in
winters well-being vs. lower dose
Dumville et al. [118] Randomized 1621 elderly women—no MDD diag- Calcium 1000 mg + vitamin D SF-12 questionnaire to No improvement in mental
nosis 800 IU supplementation QD evaluate subjective health scores
or no supplementation for psychological well-being
6 months
Jorde et al. [94] Randomized placebo- 441 obese subjects (159 men; 282 Vitamin ­D3 20,000 or 40,000 IU/ BDI Inverse relation between
controlled women) aged 21–70 years from out- week supplementation for serum levels of 25(OH)D
patient clinic (BMI 28–47 kg/m2)—no 1 year (1 capsule 20,000 IU + 1 and symptoms of depression
depression, median BDI scores of 4.5 placebo or 2 capsules for subjects with 25(OH)
(0.0–28.0) 20,000 IU per week, respec- D < 40 nmol/L. Supplementa-
tively) tion ameliorated depressive
symptoms
Arvold et al. [120] Randomized placebo- 100 mild to moderate vitamin D-defi- Vitamin ­D3 50,000 IU/week for Depressed mood, and sea- Severely deficient participants
controlled cient adults (10–25 ng/mL)—no MDD 8 weeks sonal (winter) depressed reported depressive symp-
diagnosis mood assessed by FIQ toms. Mood symptoms did
not change after supplementa-
tion
Zanetidou et al. [95] Longitudinal, non­‑ 39 women aged ≥ 65 years with MDD Vitamin ­D3 300,000 IU as a HDRS Significant improvement in
randomized design, (DSM-IV criteria, ascertained via single dose orally (evaluation at depressive symptomatology
not placebo-controlled clinical interview with experienced baseline and after 4 weeks)
psychiatrist), and taking antidepres-
sants
Dean et al. [121] Randomized placebo- 128 male and female young healthy Vitamin ­D3 5000 IU QD for BDI Supplementation did not influ-
controlled volunteers—mood disorders were an 6 weeks ence cognitive or emotional
exclusion criterion functioning
Sanders et al. [122] Double-blind, ran‑ Women aged ≥ 70 years (n = 1015 vita- Vitamin ­D3 500,000 IU or GHQ, SF-12, Patient Lack of improvement in indices
domized, placebo- min D; n = 1016 placebo) – no MDD matched placebo once each Global Impression- of mental well-being in the
controlled diagnosis year for 3–5 years Improvement scale and vitamin D-treated group
WHO Well-being Index
625


Table 1  (continued)
626

Study Study design Study participants Vitamin D supplementation Assessment scale Results

Bertone-Johnson et al. Cross-sectional and 81,189 women (aged 50–79 years at
[123] prospective analysis baseline) – 9.4% in supplementation
of vitamin D intake group; 9.9% in control group with
from food and supple- depressive disorders
ments and depressive
symptoms
Bertone-Johnson et al. Randomized placebo- 36,282 postmenopausal women (2263
[124] controlled completed the study); 8952 women
(11.0%) met criteria for depressive
symptoms
Kjaergaard et al. [78] Randomized placebo- 243 adults (aged 30–75 years) with
controlled serum 25(OH)D < 55 nmol/L
or > 70 nmol/L (110 placebo and
120 vitamin D group completed the
study)—no to mild depressive symp-
toms, median BDI scores = 4
Högberg et al. [96] Clinical trial 54 Swedish depressed adolescents (37
girls, 17 boys) with vitamin D defi-
ciency—19 with moderate depression
and 35 with severe depression assessed
by clinicians
Yalamanchili and Gal- Randomized placebo- 489 older postmenopausal women—
lagher [125] controlled absence of depression, average GDS-
LF30 scores of 3.8 in Caucasian and
3.0 in African American
Khoraminya et al. [107] Placebo-controlled 42 individuals with diagnosis of MDD
(score ≥ 15 on the HDRS, DSM-IV
criteria)
Mozaffari-Khosravi Clinical trial 120 depressive patients with BDI
et al. [97] scores > 17
Frandsen et al. [119] Randomized, double- 34 subjects with SAD (mean age
blind, placebo- 44 years, indoor workers who had
controlled experienced winter depressive symp-
toms in the past)
Vitamin D intake from food or Burnam scale Lower risk of depressive
supplements (groups: < 100 IU/ symptoms at year 3 in non-
day; 200 to < 400 IU/day; 400 depressive women who had a
to < 800 IU/day; > 800 IU/day) higher vitamin D intake from
food. No relationship between
vitamin ­D3 supplementation
and depression
Vitamin ­D3 400 IU QD + elemen- Burnam scale No relation between vitamin
tal calcium 1000 mg for 2 years ­D3 supplementation and
depression
Vitamin ­D3 40,000 IU/week for BDI; HADS; SPAQ Low levels of serum 25(OH)
6 months (for SAD symptoms); D associated with depressive
MADRS symptoms, but no effect with
vitamin D supplementation
Vitamin ­D3 4000 IU QD for WHO-5; MFQ-S Vitamin D supplementation
1 month and 2000 IU QD for improved symptoms of
2 months depression
0.25 g BID conjugated with GDS-LF30 No effect of vitamin D sup-
estrogens or medroxyproges- plementation on depressive
terone acetate (compliance at symptoms. Vitamin D recep-
36 months 92–94%) tor polymorphisms were not
associated with depression or
response to intervention
Vitamin ­D3 1500 IU QD plus HDRS (24-item scale); Vitamin D and fluoxetine com-
fluoxetine 20 mg or fluoxetine BDI bination superior to fluoxetine
alone for 8 weeks alone in controlling depres-
sive symptoms
Single IM dose of vitamin ­D3 BDI Higher dose of vitamin D­ 3
150,000 or 300,000 IU improved depression symp-
toms after 3 months
Daily dose of vitamin D 70 μg or HDRS, SIGH-SAD, Well- No effect of vitamin D on SAD
placebo for 3 months Being Index symptoms
G. A. S. Casseb et al.
Table 1  (continued)
Study Study design Study participants Vitamin D supplementation Assessment scale Results

Wang et al. [126] Prospective, randomized, 746 dialysis patients with depression; Vitamin ­D3 50,000 IU/week or Chinese version of BDI-II No improvement in depressive
double-blind cutoff value of 16 in BDI-II placebo for 52 weeks symptoms in total dialysis
population, but a beneficial
effect on vascular depression
was found
Sepehrmanesh et al. [98] Randomized, double- 40 patients (aged 18–65 years) with Vitamin ­D3 50,000 IU/week HDRS; BDI Improvement in BDI score and
blind, placebo- MDD-HDRS score ≥ 15 (n = 20) or placebo (n = 20) for indicators of glucose homeo-
controlled clinical trial 8 weeks stasis, and oxidative stress
Stokes et al. [99] Cross-sectional analysis 111 patients with chronic liver diseases: 77 patients with inadequate vita- BDI-II Vitamin D levels correlated
31% with depressive symptoms (BDI- min D concentrations received with BDI-II scores, and
II score ≥ 14) vitamin ­D3 20,000 IU/week for vitamin D supplementation
Vitamin D for Depression and Anxiety Disorders

6 months improved depressive symp-

toms in women
Vaziri et al. [100] RCT​ 169 pregnant women assigned to placebo Vitamin D group received vita- EPDS Supplementation decreased
or vitamin D (no depression, EPDS min ­D3 2000 IU QD from 26 perinatal symptoms of
scores < 13) to 28 weeks of gestation until depression
childbirth. Maternal serum
25(OH)D levels measured at
baseline and childbirth
Rolf et al. [109] RCT​ 40 patients with MS (aged Vitamin ­D3 supplementation HADS-D No evidence for reduction of
18–55 years)—no depression diagno- (n = 20: 7000 IU/day in the depressive symptoms
sis, HADS-D scores < 8 first 4 weeks, followed by
14,000 IU/day up to week
48) or placebo (n = 20) for
48 weeks
Narula et al. [101] Randomized, double- 34 patients with CD (aged 18–70 years); Vitamin ­D3 10,000 IU QD HADS Improvement in depression
blind placebo- 11 with clinical depression HADS (n = 18) vs. 1000 IU QD scores and a good safety
controlled scores > 10 (n = 16) for 12 months profile in both groups treated
with vitamin D ­ 3
Ghaderi et al. [102] Randomized, double- 68 methadone-treatment patients: 34 Vitamin ­D3 50,000 IU (n = 34) or BDI; PSQI Improvement in depression
blind, placebo- controls, 34 intervention (moder- placebo (n = 34) every 2 weeks scores, sleep quality and
controlled, clinical trial ate depression, average BDI scores for 12 weeks metabolic parameters such
23.0 ± 6.9 in placebo and 22.3 ± 6.1 in as homeostasis model of
vitamin D group) assessment-insulin resistance
Penckofer et al. [103] Open label, proof of 50 women with T2DM with elevated Vitamin ­D2 50,000 IU (ergocal- CES-D, PHQ-9 (depres- Improvement in depressive
concept depressive symptoms measured by ciferol) QW for 6 months sion questionnaire used symptoms even after control-
CES-D to validate CES-D) ling for race, season of enroll-
ment, baseline vitamin D,
baseline depression, and BMI
Hongell et al. [127]. Pooled data from fingoli- Vitamin D use was defined as “non- Lack of data about the dose of Expanded Disability Trend of less depression in
mod phase III trials in users” (n = 562), “casual users” vitamin D obtained from the Status Scale “daily users” of vitamin D
patients with RRMS (n = 157) and “daily users” (n = 110) supplements supplement
627


Table 1  (continued)
628

Study Study design Study participants Vitamin D supplementation Assessment scale Results

Raygan et al. [108] Randomized, double- 60 patients with diabetes aged
blind, placebo- 45–85 years with coronary heart dis-
controlled ease—(moderate depression, average
BDI scores 21.5  ±  3.9 for placebo and
23.2  ±  4.6 for vitamin D)
Bahrami et al. [104] Longitudinal clinical 940 adolescent girls: 15.8% mild, 12.4% Vitamin D ­ 3 50,000 IU/week for
moderate, 4.3% severe depression
Sharifi et al. [105] Double-blind RCT​ 86 patients with UC—mild depression,
average BDI scores of 12.8 ± 5.6 for
placebo and 13.9 ± 7.4 for vitamin D
Choukri et al. [128] Double-blind RCT​ 152 healthy women (aged 18–40 years)
Alavi et al. [106] Double-blind RCT​ 78 adults aged > 60 years with moderate
to severe depression (n = 39 in each
group) assessed by GDS-15
Jorde and Kubiak [129] RCT​ Vitamin D (n = 206), placebo (n = 202)
(few subjects [11%] clinically
depressed as assessed by BDI-II)
Vitamin D 50,000 IU Q2 W plus BDI Vitamin D and probiotic
probiotics (n  =  30) or placebo cosupplementation resulted in
(n  =  30) for 12 weeks significant improvements in
depression score
BDI-II Significant reduction on mild,
9 weeks moderate, and severe depres-
sion score
Vitamin ­D3 300,000 IU injection BDI Significant reduction in BDI
or placebo score 3 months after supple-
mentation
Vitamin ­D3 50,000 IU or placebo CES-D No evidence of any beneficial
once monthly for 6 months effect of supplementation on
depressive symptoms
Vitamin ­D3 50,000 IU or placebo GDS-15 Decrease in depression score in
per week for 8 weeks supplemented individuals
Vitamin D 100,000 IU as bolus BDI-II No significant effect of vitamin
dose followed by 20,000 IU D supplementation on depres-
QW for 4 months sive symptoms

25(OH)D calcidiol, BDI Beck Depression Inventory, BDI-II Beck Depression Inventory second edition, BID twice daily, BMI body mass index, CD Crohn’s disease, CES-D Center for Epide-
miologic Studies Depression Scale, DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, EPDS Edinburgh Postnatal Depression Scale, FIQ Fibromyalgia Impact
Questionnaire, GDS-15 15-item Geriatric Depression Scale, GDS-LF30 Geriatric Depression Scale-Long Form 30, GHQ General Health Questionnaire, HADS Hospital Scale of Anxiety and
Depression, HADS-D Hospital Anxiety and Depression Scale—Depression, HDRS Hamilton Depression Rating Scale, IM intramuscular, MADRS Montgomery–Åsberg Depression Rating
Scale, MDD major depressive disorder, MFQ-S Mood and Feelings Questionnaire, MS multiple sclerosis, PHQ-9 9-item Patient Health Questionnaire, POMS Profile of Mood States, PSQI
Pittsburgh Sleep Quality Index, Q2 W every 2 weeks, QD every day, QW every week, RCT​ randomized controlled trial, RRMS relapsing–remitting muscular sclerosis, SAD Seasonal Affective
Disorder, SF-12 12-Item Short Form Health Survey, SIGH-SAD Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders, SPAQ Seasonal Pattern
Assessment Questionnaire, T2DM type 2 diabetes mellitus, UC ulcerative colitis, WHO World Health Organization, WHO-5 5-item WHO Well-Being Index
G. A. S. Casseb et al.
Vitamin D for Depression and Anxiety Disorders
and has a key role in the adaption and survival of organisms,
allowing a rapid defensive response to possible threats [130].
Although healthy individuals may present some signs of
anxiety, persistent or disproportionate anxiety may be con-
sidered pathological. Anxiety disorders include separation
anxiety disorder, selective mutism, specific phobia, social
phobia, panic disorder, agoraphobia, and generalized anxi-
ety disorder [131]. The clinical characteristics differ in most
of these categories, but, in all cases, the somatic, cognitive,
and behavioral manifestations of anxiety affect the normal
functioning of the individual.
Anxiety disorders are common psychiatric conditions
that have a global current prevalence ranging from 5.3% in
African cultures to 10.4% in European/Anglo-Saxon cultures
[132]. A considerable proportion of individuals considered
pathologically anxious do not receive adequate treatment,
and few therapeutic targets have been identified. The most
commonly used treatments for anxiety disorders are phar-
macotherapy and psychotherapy. Since the mid-1950s, the
drugs developed and approved for the treatment of most anx-
iety disorders have been benzodiazepines. Although they are
generally well-tolerated, they present a risk of dependence
after chronic use as well as adverse and sedative effects.
For these reasons, current clinical practice recommends the
use of antidepressants, particularly tricyclic antidepressants,
selective serotonin reuptake inhibitors (SSRIs), and dual ser-
otonin and noradrenaline reuptake inhibitors (SNRIs), which
have been extended to treat anxiety disorders [133]. Despite
this therapeutic arsenal, the treatment of anxiety disorders
remains ineffective as the available drugs are not effective in
all patients or in all types of disorders and present a series of
adverse effects, reducing adherence to treatment [134]. To
improve the therapeutic strategies used in the treatment of
anxiety disorders, a better understanding of the biological
basis of the disease and the neural circuits regulating the
emotional states is necessary.
Stress and high trait anxiety are major risk factors for
MDD and anxiety disorders. Individuals presenting high
trait anxiety are particularly vulnerable to developing
depression when facing stress and adversity [135]. Anxi-
ety disorders share many biological substrates with MDD,
including alterations in emotion-processing brain structures,
the influence of both genetic and environmental factors, and
a variety of neuroendocrine, neurotransmitter, and neuroana-
tomical disruptions [136]. In general, anxiety is frequently
associated with hyperarousal, caused by decreased inhibi-
tory signaling by γ-aminobutyric-acid (GABA) or increased
excitatory glutamatergic neurotransmission. Additionally,
the well-documented anxiolytic properties of antidepressant
compounds that act primarily on monoaminergic systems
have implicated serotonin, norepinephrine, and dopamine in
the pathogenesis of anxiety disorders. Other neurotransmit-
ters are also considered to be involved in the pathogenesis
629
of anxiety disorders, including the neuropeptides cholecys-
tokinin, galanin, neuropeptide Y, oxytocin, vasopressin, and
corticotrophin-releasing factor [136].
A role for oxidative stress and inflammation in the patho-
physiology of anxiety disorders has been reported [137,
138]. A recent review highlighted that compounds capable
of counteracting oxidative stress and neuroinflammation
may be promising candidates for the treatment of anxiety
[139]. As such, vitamin D—with its antioxidant and anti-
inflammatory properties—stands out as a candidate that has
been investigated for the management of anxiety disorders.
3.1 Preclinical Studies Associating Vitamin D
and Anxiety
Only a few studies have investigated the ability of vitamin D
to cause anxiolytic effects in animal models. Chronic vita-
min ­D3 administration was shown to elicit anxiolytic-like
effects in female ovariectomized rats and ovariectomized
rats treated with 17β-estradiol in the elevated plus maze
and in the light–dark tests [140, 141], accompanied by an
increase in dopamine and serotonin levels in the hippocam-
pus [140]. In addition, klotho-deficient mice with excessive
plasma 1,25(OH)D levels exhibited anxiolytic-like behavior,
indicated by a higher number of entries and time spent in
the center area of the open field, as well as more visits to the
light area of the light–dark box than wild-type mice. These
behavioral alterations observed in klotho-deficient mice
were reversed when animals received a low vitamin D diet,
a finding that reinforced the notion that enhanced 1,25(OH)
D levels may be associated with anxiolytic-like behavior
[71]. However, the administration of intraperitoneal vitamin
D 18.75–37.5 µg/kg to the mice failed to cause an anxiolytic
effect in the elevated plus maze [142]. Another study [72]
also showed no anxiolytic effect of intraperitoneal vitamin
D at 5 and 10 µg/kg twice weekly in the open field in rats
subjected to chronic mild stress for 3 weeks [72].
The effects of vitamin D diet on the behavioral response of
rodents in the elevated plus maze are contradictory. Compared
with controls, mice receiving a vitamin D-deficient diet for
10 weeks spent a significantly longer time in the open arms of
the elevated plus maze. These behavioral observations were
associated with higher brain levels of GABA, suggesting an
anxiolytic-like behavior in this group of animals [74]. On the
other hand, mice with reduced serum 25(OH)D levels due to
a vitamin D-deficient diet exhibited anxiety-related behavior
in the elevated plus maze, indicated by an increased latency of
the first entry into the open arms [69]. Additionally, no altera-
tion in the elevated plus maze performance in mice exposed
to a vitamin D-deficient diet was also reported, suggesting no
changes in anxiety-related behavior [143, 144].
A study carried out with VDR knockout mice subjected
to behavioral tests of anxiety concluded that these animals

630
present musculoskeletal impairments that may confound the
interpretation of the results and the observation of the anxious
phenotype [145], as previously suggested [146]. However, it
was reported that VDR knockout mice exhibited increased
grooming, a finding that did not correlate with unaltered gen-
eral activity level and anxiety-like behaviors [147].
Pan et al. [148] reported a trend to anxiety-related behav-
ior, characterized by increased grooming activity in juvenile
rat offspring after maternal vitamin ­D3 deficiency. However,
a recent study evaluating the effects of postnatal vitamin D
deficiency and overdose in adult life reported that abnor-
malities in postnatal vitamin D intake impaired hippocampal
learning and memory in adults but failed to affect anxiety-
related behaviors assessed in the open field and light–dark
tests or depressive-related behavior assessed in the tail sus-
pension test and forced swim test [149].
In conclusion, although several studies have indicated
the possible anxiolytic profile of vitamin D, others failed
to clearly demonstrate a relationship between vitamin D
levels and anxiety-related behaviors in rodents. Therefore,
additional studies are needed to better establish the role of
vitamin D in animal models of anxiety as well as the pos-
sible mechanisms underlying its effects.
3.2 Clinical Studies Associating Vitamin D
and Anxiety Disorders
Most studies evaluating anxiety-related symptoms in differ-
ent populations indicate an association between low levels of
vitamin D and anxiety [82, 150–152], although an absence
of association between anxiety symptoms and serum vitamin
D has also been reported [87, 91, 153].
This review describes the clinical studies that were designed
to establish a relationship between vitamin D supplementation
and anxiety symptoms, as presented in Table 2. Some reported
that vitamin D supplementation is associated with lower anxi-
ety symptoms [101, 103, 108, 154]. However, others failed to
find an association between vitamin D supplementation and
reduction of anxiety symptoms [78, 155, 156]. It is important
to highlight that most of the studies were designed to evaluate
anxiety symptoms associated with different clinical conditions.
So far, no clinical trials have been conducted in patients with
anxiety disorders (generalized anxiety disorder, phobia, panic
disorder, and others) and vitamin D supplementation.
4 Genetic and Environmental
Factors Affecting Vitamin D Levels
and Metabolism
An important factor that should be considered in human
studies is the presence of genetic polymorphisms in vita-
min D, VDR, and its metabolizing enzymes. Despite the
G. A. S. Casseb et al.
increasing number of studies designed to verify associations
between these genetic variations and several diseases [158],
as yet, only a few studies have considered psychiatric disor-
ders and VDR polymorphisms.
VDR contains a different set of genetic polymorphisms,
including ApaI (rs7975232), BsmI (rs1544410), TaqI
(rs731236), and FokI (rs2228570), which have been reported
to be associated with several diseases. The FokI polymor-
phism is the only known VDR gene polymorphism asso-
ciated with an altered protein. In fact, carriers of the GG
VDR genotype are thus expected to have more VDR activity
than carriers of the GA or AA genotypes [159]. In a study
of 101 elderly individuals, a significantly lower prevalence
of depression was seen in carriers of the GG VDR geno-
type than in those with the AA and GA genotypes [160].
On the other hand, a study including 86 patients with MDD
and 89 healthy volunteers found no relationship between
depression, anxiety symptoms, vitamin D levels, and FokI
polymorphism of VDR [91]. Additionally, a study evaluat-
ing polymorphisms in FokI, BsmI, ApaI, and TaqI in 563
participants found that only carriers of ApaI variant-alleles
had fewer depressive symptoms [161].
Additionally, the relationship between 25(OH)D lev-
els and vitamin D supplementation can be influenced by
a large number of environmental and demographic factors
[11, 162]. Zittermann et al. [163] conducted a systematic
review and demonstrated that 34.5% of the variation in cir-
culating 25(OH)D after supplementation was explained by
body weight, 9.8% by the type of supplement ­(D2 or ­D3),
3.7% by age, 2.4% by levels of calcium intake, and 1.9%
by basal 25(OH)D levels. Individuals with lower levels of
25(OH)D gain more benefits from supplementation, prob-
ably because hepatic hydroxylation of vitamin D may be a
saturable process [162, 164]. On the other hand, higher body
fat or higher body mass index (BMI), particularly > 30 kg/
m2, have been associated with smaller increases in 25(OH)
D levels after supplementation, probably because vitamin
D is a fat-soluble vitamin and can accumulate in body fat
stores. Aging has frequently been reported to be associated
with lower levels of 25(OH)D, mainly due to a decrease in
the precursor 7-dehydrocholesterol and the expression of
vitamin DBP. However, it seems that aging has little or no
effect on response to supplementation [11]. Other factors,
including ethnicity, season, and calcium intake, have been
less explored in the literature [11]. Thus, the wide interin-
dividual variations affecting the response to vitamin D sup-
plements must be carefully addressed in future clinical stud-
ies to determine the potential of supplementation to mood
regulation.
The potential role of vitamin D in the pathophysiology of
MDD and anxiety disorders, and the exact biological mecha-
nisms underlying this association, remain largely unknown,
but some plausible hypotheses have been presented.
Table 2  Clinical trial studies associating vitamin D supplementation and anxiety symptoms
References Study design Study participants Vitamin D supplementation Assessment scale Results

Kjaergaard et al. [78] Randomized placebo-controlled 230 individuals aged
30–75 years with high serum
25(OH)D levels and 114
nested controls
Slow et al. [156] RCT​ 322 healthy adults (241 women, Vitamin D
81 men, aged 18–67 years)
Vitamin ­D3 40,000 IU QW for HADS-A No effect on anxiety symptoms
6 months
­ 3 200,000 IU/month Self-reported adverse effects Number of psychological adverse
for 2 months then 100,000 IU/ due to earthquakes events, including anxiety, was
month (n = 161) or placebo higher after earthquake but did
(n = 161) for 18 months not differ between treatment
Vitamin D for Depression and Anxiety Disorders

Wepner et al. [155] RCT​
Hansen et al. [157] Clinical trial
Tartagni et al. [154] Clinical trial
Penckofer et al. [103] Open label, proof of concept
Narula et al. [101] Randomized, double-blind
placebo-controlled
Raygan et al. [108] Randomized, double-blind,
placebo-controlled
Choukri et al. [128] Double-blind RCT​
groups
30 women with fibromyalgia Vitamin ­D3 1200 or 2400 IU HADS No significant differences
(mean age 48.37 years) QD for 20 weeks between groups or over time
95 male subjects (fish, n = 48;Diet containing salmon STAI Salmon consumption had benefi-
control, n = 47) (3 × weekly) for 23 weeks or cial effects on state anxiety
meal with the same nutritional
value (control group)
158 females (aged 15–21 years) Vitamin D for 4 months Daily symptoms rating form Vitamin D therapy was effective
with PMS-related severe (200,000 IU followed by assessing presence and sever- for improving anxiety
symptoms of the emotional 25,000 IU Q2 W [n = 80]) or ity of anxiety, irritability,
and cognitive domains and placebo (n = 78) crying easily and disturbed
serum 25(OH)D lev- relationships
els < 10 ng/mL
50 women with T2DM with Vitamin ­D2 50,000 IU QW for STAI Improvement in anxiety
elevated depressive symptoms 6 months (state and trait)
measured by CES-D (mean
age 54.32 ± 10.64 years)
34 patients with CD (aged Vitamin ­D3 10,000 IU QD HADS Anxiety scores improved in both
18–70 years) (n = 18) vs. 1000 IU QD groups treated with vitamin D
­ 3
(n = 16) for 12 months
60 patients with diabetes with Vitamin D 50,000 IU Q2 W BAI Vitamin D and probiotic cosup-
coronary heart disease (aged plus probiotics (n  =   30) plementation improved anxiety
45–85 years) or placebo (n  =  30) for scores
12 weeks
152 healthy women (aged Vitamin ­D3 50,000 IU or HADS No effect of supplementation on
18–40 years) placebo once monthly for anxiety symptoms
6 months

25(OH)D calcidiol, BAI Beck Anxiety Inventory, CD Crohn’s disease, CES-D Center for Epidemiologic Studies Depression Scale, HADS Hospital Anxiety and Depression Scale, HADS-A Hos-
pital Anxiety and Depression Scale—anxiety subscale, PMS premenstrual syndrome, Q2 W every 2 weeks, QD every day, QW every week, RCT​ randomized controlled trial, STAI State-Trait
Anxiety Inventory, T2DM type 2 diabetes mellitus
631

632
Fig. 3  Descriptive scheme of the possible mechanism that may
account for the beneficial effects of vitamin D on major depressive
disorder and anxiety. Vitamin D exerts several biological effects in
the central nervous system that may contribute to its possible antide-
pressant and anxiolytic effects. Moreover, it is important to note that
Growing evidence from animal and human studies suggest
that vitamin D exhibits potent immunosuppressant activ-
ity and may influence proinflammatory cytokines, such as
IL-6, in the brain [165]. Vitamin D may also be neuropro-
tective against oxidative stress through its influence on the
expression of γ-glutamyl transpeptidase, which is necessary
for the synthesis of glutathione, one of the most important
antioxidants in the brain and previously reported to elicit
antidepressant-like effects in mice [166]. Moreover, as men-
tioned in this review, vitamin D has several effects on the
CNS that may account for its ability to act as a mood modu-
lator, besides the wide distribution of VDR receptors and
CYP27B1 in brain regions closely implicated in MDD and
anxiety disorders pathophysiology, as indicated in Fig. 3.
However, further studies are needed to clarify which of these
mechanisms might be associated with mood improvement
and which groups of patients might benefit from vitamin D
supplementation.
5 Conclusion and Perspectives
Besides the well-established role of vitamin D for calcium
and phosphate homeostasis and bone health [13, 167], sev-
eral preclinical and clinical studies have suggested that vita-
min D may also have beneficial effects on mental health.
G. A. S. Casseb et al.
brain areas expressing the enzyme CYP27B1 and VDR are relevant
for mood modulation. aMCC anterior medial cingulate cortex, Amyg
amygdala, BF basal forebrain, CYP cytochrome P450, Hy hippocam-
pus, lHyp lateral hypothalamus, PFC prefrontal cortex, VDR vitamin
D receptor, vmPFC ventromedial prefrontal cortex
However, although several preclinical studies have indicated
that vitamin D administration may afford antidepressant and
anxiolytic-like effects, most do not establish the mecha-
nisms underlying the neuroprotective effects of vitamin D
against the development of depressive and anxiety-related
symptoms.
The majority of clinical studies have indicated that vita-
min D supplementation may hold significant potential as a
prophylactic strategy for reducing the risk of both depres-
sive and anxiety symptoms in different populations and as
an adjunctive therapy for these disorders. However, to date,
no appropriately controlled trials of vitamin D supplemen-
tation in the treatment of anxiety disorders or MDD have
been conducted. Furthermore, other studies have failed to
show positive effects of vitamin D for risk reduction and/
or reduction of depressive and anxiety symptoms. The cur-
rent lack of knowledge about genetic polymorphisms that
alter the metabolism, availability, and biological actions of
vitamin D may account for some heterogeneity in clinical
studies. Other factors, such as sex, age, BMI, basal levels of
vitamin D, severity and chronicity of psychiatric symptoms,
and presence of psychiatric symptoms associated with dif-
ferent clinical diseases, also need to be explored in relation
to the disparate effects seen with vitamin D. Until the results
of such trials (particularly those involving a large number
of individuals) are available, any conclusion regarding the
therapeutic value of vitamin D may be premature. Despite
Vitamin D for Depression and Anxiety Disorders
this, vitamin D supplementation may be an interesting
therapeutic strategy to be further investigated in efforts to
improve mood, given its neuroprotective effects and benefi-
cial effects for general health, including its beneficial role in
glucose homeostasis and lipid profile, and anti-inflammatory
and anticancer effects, not to mention its low cost and safety
profile [2, 110].
Compliance with Ethical Standards  Circulation. 2008;117(4):503–11.
Funding  Dr. Rodrigues and Dr Manuella P. Kaster are “National Coun-
sel of Technological and Scientific Development (CNPq)” research
fellows. Their studies are supported by grants from CNPq and Coorde-
nação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES).
Conflict of interest  Gleicilaine A. S. Casseb, Manuella P. Kaster and
Ana Lúcia S. Rodrigues have received no financial support or com-
pensation from any individual or corporate entity over the past 3 years
for research or professional service and have no personal financial
holdings that could be perceived as constituting a potential conflict
of interest.
References
1. Vermani M, Marcus M, Katzman MA. Rates of detection of
mood and anxiety disorders in primary care: a descriptive,
cross-sectional study. Prim Care Companion CNS Disord.
2011;13(2):e1–10.
2. Hossein-Nezhad A, Holick MF. Vitamin D for health: a global
perspective. Mayo Clin Proc. 2013;88(7):720–55.
3. Japelt RB, Jakobsen J. Vitamin D in plants: a review of occur-
rence, analysis, and biosynthesis. Front Plant Sci. 2013;4:136.
4. Holick MF, Ultraviolet B. Radiation: the vitamin D connection.
Adv Exp Med Biol. 2017;996:137–54.
5. Wacker M, Holick MF. Sunlight and Vitamin D: a global per-
spective for health. Dermatoeendocrinology. 2013;5(1):51–108.
6. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G.
Vitamin D: metabolism, molecular mechanism of action, and
pleiotropic effects. Physiol Rev. 2016;96(1):365–408.
7. Holick MF. Vitamin D deficiency. N Engl J Med.
2007;357(3):266–81.
8. Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT, Pen-
ninx BW. Depression is associated with decreased 25-hydroxy-
vitamin D and increased parathyroid hormone levels in older
adults. Arch Gen Psychiatry. 2008;65(5):508–12.
9. Haddad JG, Cooke NE. Vitamin D transport—the nature of the
interaction between plasma DBP and tissue protein. Progr Bio-
chem Pharmacol. 1980;17:168–72.
10. Tsiaras WG, Weinstock MA. Factors influencing vitamin D sta-
tus. Acta Derm Venereol. 2011;91(2):115–24.
11. Mazahery H, von Hurst PR. Factors affecting 25-hydroxyvita-
min D concentration in response to vitamin D supplementation.
Nutrients. 2015;7(7):5111–42.
12. van Schoor NM, Lips P. Worldwide vitamin D status. Best Pract
Res Clin Endocrinol Metab. 2011;25(4):671–80.
13. Wimalawansa SJ, Razzaque MS, Al-Daghri NM. Calcium and
vitamin D in human health: hype or real? J Steroid Biochem Mol
Biol. 2018;180:4–14.
633
14. Holick MF, Chen TC. Vitamin D deficiency: a world-
wide problem with health consequences. Am J Clin Nutr.
2008;87(4):1080S–6S.
15. Alshahrani F, Aljohani N. Vitamin D: deficiency, sufficiency and
toxicity. Nutrients. 2013;5(9):3605–16.
16. Galior K, Grebe S, Singh R. Development of vitamin D toxicity
from overcorrection of vitamin D deficiency: a review of case
reports. Nutrients. 2018. https​://doi.org/10.3390/nu100​80953​.
17. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier
K, et al. Vitamin D deficiency and risk of cardiovascular disease.
18. Kayaniyil S, Vieth R, Retnakaran R, Knight JA, Qi Y, Gerstein
HC, et al. Association of vitamin D with insulin resistance and
beta-cell dysfunction in subjects at risk for type 2 diabetes. Dia-
betes Care. 2010;33(6):1379–81.
19. Maki KC, Fulgoni VL 3rd, Keast DR, Rains TM, Park KM,
Rubin MR. Vitamin D intake and status are associated with
lower prevalence of metabolic syndrome in U.S. adults: National
Health and Nutrition Examination Surveys 2003–2006. Metab
Syndr Relat Disord. 2012;10(5):363–72.
20. Song Y, Wang L, Pittas AG, Del Gobbo LC, Zhang C, Manson
JE, et al. Blood 25-hydroxy vitamin D levels and incident type 2
diabetes: a meta-analysis of prospective studies. Diabetes Care.
2013;36(5):1422–8.
21. Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain
development, adult brain function and the links between low lev-
els of vitamin D and neuropsychiatric disease. Front Neuroendo-
crinol. 2013;34(1):47–64.
22. Berridge MJ. Vitamin D deficiency accelerates ageing
and age-related diseases: a novel hypothesis. J Physiol.
2017;595(22):6825–36.
23. Zhao J, Wang H, Zhang Z, Zhou X, Yao J, Zhang R, et al. Vita-
min D deficiency as a risk factor for thyroid cancer: a meta-
analysis of case-control studies. Nutrition. 2018;57:5–11.
24. Zhou R, Wang M, Huang H, Li W, Hu Y, Wu T. Lower Vitamin
D status is associated with an increased risk of ischemic stroke:
a systematic review and meta-analysis. Nutrients. 2018. https​://
doi.org/10.3390/nu100​30277​.
25. Ferrer-Mayorga G, Larriba MJ, Crespo P, Munoz A. Mechanisms
of action of vitamin D in colon cancer. J Steroid Biochem Mol
Biol. 2019;185:1–6.
26. Lopez RB, Denny BT, Fagundes CP. Neural mechanisms of
emotion regulation and their role in endocrine and immune
functioning: a review with implications for treatment of affec-
tive disorders. Neurosci Biobehav Rev. 2018;95:508–14.
27. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin
D: modulator of the immune system. Curr Opin Pharmacol.
2010;10(4):482–96.
28. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC.
1,25-dihydroxyvitamin D3 receptors in human leukocytes.
Science. 1983;221(4616):1181–3.
29. Lemire JM, Adams JS, Sakai R, Jordan SC. 1 alpha,25-dihy-
droxyvitamin D3 suppresses proliferation and immunoglobulin
production by normal human peripheral blood mononuclear
cells. J Clin Invest. 1984;74(2):657–61.
30. Rolf L, Muris AH, Hupperts R, Damoiseaux J. Vitamin D
effects on B cell function in autoimmunity. Ann N Y Acad
Sci. 2014;1317:84–91.
31. Sarkar S, Hewison M, Studzinski GP, Li YC, Kalia V. Role of
vitamin D in cytotoxic T lymphocyte immunity to pathogens
and cancer. Crit Rev Clin Lab Sci. 2016;53(2):132–45.
32. Barragan M, Good M, Kolls JK. Regulation of dendritic cell
function by vitamin D. Nutrients. 2015;7(9):8127–51.
33. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim
EK, et al. A meta-analysis of cytokines in major depression.
Biol Psychiatry. 2010;67(5):446–57.

634
34. Miller AH, Raison CL. The role of inflammation in depression:
from evolutionary imperative to modern treatment target. Nat
Rev Immunol. 2016;16(1):22–34.
35. Vogelzangs N, Beekman AT, de Jonge P, Penninx BW. Anxi-
ety disorders and inflammation in a large adult cohort. Transl
Psychiatry. 2013;3:e249.
36. Ros-Soto J, Anthias C, Madrigal A, Snowden JA. Vitamin D:
is it important in haematopoietic stem cell transplantation?
A review. Bone marrow transplantation. 2018. https​: //doi.
org/10.1038/s4140​9-018-0377-0.
37. Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D,
Friedl J, et  al. Vitamin D3 down-regulates monocyte TLR
expression and triggers hyporesponsiveness to pathogen-asso-
ciated molecular patterns. Eur J Immunol. 2006;36(2):361–70.
38. Keri S, Szabo C, Kelemen O. Expression of toll-like recep-
tors in peripheral blood mononuclear cells and response to
cognitive-behavioral therapy in major depressive disorder.
Brain Behav Immun. 2014;40:235–43.
39. Di Rosa M, Malaguarnera M, Nicoletti F, Malaguarnera L.
Vitamin D3: a helpful immuno-modulator. Immunology.
2011;134(2):123–39.
40. Kong J, Zhang Z, Musch MW, Ning G, Sun J, Hart J, et al.
Novel role of the vitamin D receptor in maintaining the integ-
rity of the intestinal mucosal barrier. Am J Physiol Gastrointest
Liver Physiol. 2008;294(1):G208–16.
41. He L, Liu T, Shi Y, Tian F, Hu H, Deb DK, et al. Gut epithelial
vitamin D receptor regulates microbiota-dependent mucosal
inflammation by suppressing intestinal epithelial cell apopto-
sis. Endocrinology. 2018;159(2):967–79.
42. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland
NP. Breaking down the barriers: the gut microbiome, intesti-
nal permeability and stress-related psychiatric disorders. Front
Cell Neurosci. 2015;9:392.
43. Tabatabaeizadeh SA, Tafazoli N, Ferns GA, Avan A, Ghayour-
Mobarhan M. Vitamin D, the gut microbiome and inflamma-
tory bowel disease. J Res Med Sci. 2018;23:75.
44. Boontanrart M, Hall SD, Spanier JA, Hayes CE, Olson JK. Vita-
min D3 alters microglia immune activation by an IL-10 depend-
ent SOCS3 mechanism. J Neuroimmunol. 2016;292:126–36.
45. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Dis-
tribution of the vitamin D receptor and 1 alpha-hydroxylase in
human brain. J Chem Neuroanat. 2005;29(1):21–30.
46. Pardridge WM, Sakiyama R, Coty WA. Restricted transport
of vitamin D and A derivatives through the rat blood-brain
barrier. J Neurochem. 1985;44(4):1138–41.
47. Naveilhan P, Neveu I, Wion D, Brachet P. 1,25-Dihydroxyvi-
tamin D3, an inducer of glial cell line-derived neurotrophic
factor. NeuroReport. 1996;7(13):2171–5.
48. Ko P, Burkert R, McGrath J, Eyles D. Maternal vitamin D3
deprivation and the regulation of apoptosis and cell cycle dur-
ing rat brain development. Dev Brain Res. 2004;153(1):61–8.
49. Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK. Vita-
min D increases expression of the tyrosine hydroxylase gene in
adrenal medullary cells. Mol Brain Res. 1996;36(1):193–6.
50. Jiang P, Zhang LH, Cai HL, Li HD, Liu YP, Tang MM, et al.
Neurochemical effects of chronic administration of calcitriol
in rats. Nutrients. 2014;6(12):6048–59.
51. Alexianu ME, Robbins E, Carswell S, Appel SH. 1Alpha,
25 dihydroxyvitamin D3-dependent up-regulation of cal-
cium-binding proteins in motoneuron cells. J Neurosci Res.
1998;51(1):58–66.
52. Berridge MJ. Vitamin D, reactive oxygen species and calcium
signalling in ageing and disease. Philos Trans R Soc Lond B
Biol Sci. 2016. https​://doi.org/10.1098/rstb.2015.0434.
53. Ricca C, Aillon A, Bergandi L, Alotto D, Castagnoli C, Sil-
vagno F. Vitamin D receptor is necessary for mitochondrial
G. A. S. Casseb et al.
function and cell health. Int J Mol Sci. 2018. https​: //doi.
org/10.3390/ijms1​90616​72.
54. Moore ME, Piazza A, McCartney Y, Lynch MA. Evidence that
vitamin D3 reverses age-related inflammatory changes in the
rat hippocampus. Biochem Soc Trans. 2005;33(Pt 4):573–7.
55. Huang YN, Ho YJ, Lai CC, Chiu CT, Wang JY. 1,25-Dihy-
droxyvitamin D3 attenuates endotoxin-induced production
of inflammatory mediators by inhibiting MAPK activation
in primary cortical neuron-glia cultures. J Neuroinflamm.
2015;12:147.
56. Yamini P, Ray RS, Chopra K. Vitamin D3 attenuates cogni-
tive deficits and neuroinflammatory responses in ICV-STZ
induced sporadic Alzheimer’s disease. Inflammopharmacology.
2018;26(1):39–55.
57. Sabir MS, Haussler MR, Mallick S, Kaneko I, Lucas DA,
Haussler CA, et  al. Optimal vitamin D spurs serotonin:
1,25-dihydroxyvitamin D represses serotonin reuptake transport
(SERT) and degradation (MAO-A) gene expression in cultured
rat serotonergic neuronal cell lines. Genes Nutr. 2018;13:19.
58. Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava
M, et  al. Major depressive disorder. Nat Rev Dis Primers.
2016;2:16065.
59. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW.
From inflammation to sickness and depression: when the immune
system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46–56.
60. Kim HK, Nunes PV, Oliveira KC, Young LT, Lafer B. Neuro-
pathological relationship between major depression and demen-
tia: a hypothetical model and review. Progr Neuropsychophar-
macol Biol Psychiatry. 2016;67:51–7.
61. Price JB, Bronars C, Erhardt S, Cullen KR, Schwieler L, Berk
M, et al. Bioenergetics and synaptic plasticity as potential targets
for individualizing treatment for depression. Neurosci Biobehav
Rev. 2018;90:212–20.
62. Dey A, Hankey Giblin PA. Insights into Macrophage Heterogene-
ity and Cytokine-Induced Neuroinflammation in Major Depres-
sive Disorder. Pharmaceuticals. 2018. https​://doi.org/10.3390/
ph110​30064​.
63. Wang SM, Han C, Bahk WM, Lee SJ, Patkar AA, Masand
PS, et  al. Addressing the side effects of contemporary anti-
depressant drugs: a comprehensive review. Chonnam Med J.
2018;54(2):101–12.
64. Artigas F, Bortolozzi A, Celada P. Can we increase speed and
efficacy of antidepressant treatments? Part I: general aspects
and monoamine-based strategies. Eur Neuropsychopharmacol.
2018;28(4):445–56.
65. Jiang P, Zhang WY, Li HD, Cai HL, Liu YP, Chen LY.
Stress and vitamin D: altered vitamin D metabolism in both
the hippocampus and myocardium of chronic unpredict-
able mild stress exposed rats. Psychoneuroendocrinology.
2013;38(10):2091–8.
66. Jiang P, Xue Y, Li HD, Liu YP, Cai HL, Tang MM, et al. Dys-
regulation of vitamin D metabolism in the brain and myocar-
dium of rats following prolonged exposure to dexamethasone.
Psychopharmacology. 2014;231(17):3445–51.
67. Kawaura A, Kitamura Y, Tanida N, Akiyama J, Mizutani M,
Harada K, et al. Antidepressant-like effect of 1alpha-hydrox-
yvitamin D3 on mice in the forced swimming test. J Nutr Sci
Vitaminol. 2017;63(1):81–4.
68. Fedotova J, Dudnichenko T, Kruzliak P, Puchavskaya Z. Dif-
ferent effects of vitamin D hormone treatment on depression-
like behavior in the adult ovariectomized female rats. Biomed
Pharmacother. 2016;84:1865–72.
69. Fu L, Chen YH, Chen X, Xu S, Yu Z, Xu DX. Vitamin D
deficiency impairs neurobehavioral development in male mice.
Physiol Behav. 2017;179:333–9.
Vitamin D for Depression and Anxiety Disorders
70. Camargo A, Dalmagro AP, Rikel L, da Silva EB, Simao da
Silva KAB, Bertarello Zeni AL. Cholecalciferol counteracts
depressive-like behavior and oxidative stress induced by
repeated corticosterone treatment in mice. Eur J Pharmacol.
2018;833:451–61.
71. Leibrock CB, Voelkl J, Kuro OM, Lang F, Lang UE.
1,25(OH)2D3 dependent overt hyperactivity phenotype in
klotho-hypomorphic mice. Sci Rep. 2016;6:24879.
72. Sedaghat K, Yousefian Z, Vafaei AA, Rashidy-Pour A, Parsaei H,
Khaleghian A, et al. Mesolimbic dopamine system and its modu-
lation by vitamin D in a chronic mild stress model of depression
in the rat. Behav Brain Res. 2019;356:156–69.
73. Byrne JH, Voogt M, Turner KM, Eyles DW, McGrath JJ, Burne
TH. The impact of adult vitamin D deficiency on behaviour
and brain function in male Sprague-Dawley rats. PLoS One.
2013;8(8):e71593.
74. Groves NJ, Kesby JP, Eyles DW, McGrath JJ, Mackay-Sim A,
Burne TH. Adult vitamin D deficiency leads to behavioural and
brain neurochemical alterations in C57BL/6J and BALB/c mice.
Behav Brain Res. 2013;241:120–31.
75. Groves NJ, Bradford D, Sullivan RK, Conn KA, Aljelaify RF,
McGrath JJ, et al. Behavioural effects of adult vitamin D defi-
ciency in BALB/c mice are not associated with proliferation
or survival of neurons in the adult hippocampus. PLoS One.
2016;11(4):e0152328.
76. Lee DM, Tajar A, O’Neill TW, O’Connor DB, Bartfai G, Boonen
S, et al. Lower vitamin D levels are associated with depression
among community-dwelling European men. J Psychopharmacol.
2011;25(10):1320–8.
77. Knippenberg S, Bol Y, Damoiseaux J, Hupperts R, Smolders
J. Vitamin D status in patients with MS is negatively corre-
lated with depression, but not with fatigue. Acta Neurol Scand.
2011;124(3):171–5.
78. Kjaergaard M, Waterloo K, Wang CE, Almas B, Figenschau Y,
Hutchinson MS, et al. Effect of vitamin D supplement on depres-
sion scores in people with low levels of serum 25-hydroxyvita-
min D: nested case-control study and randomised clinical trial.
Brit J Psychiatry. 2012;201(5):360–8.
79. Milaneschi Y, Hoogendijk W, Lips P, Heijboer AC, Schoevers
R, van Hemert AM, et al. The association between low vitamin
D and depressive disorders. Mol Psychiatry. 2014;19(4):444–51.
https​://doi.org/10.1038/mp.2013.36.
80. Naqvi SH, Moore A, Bevilacqua K, Lathief S, Williams J, Naqvi
N, et al. Predictors of depression in women with polycystic ovary
syndrome. Arch Women’s Ment Health. 2015;18(1):95–101.
81. Song BM, Kim HC, Rhee Y, Youm Y, Kim CO. Association
between serum 25-hydroxyvitamin D concentrations and depres-
sive symptoms in an older Korean population: a cross-sectional
study. J Affec Disord. 2016;189:357–64.
82. Pu D, Luo J, Wang Y, Ju B, Lv X, Fan P, et al. Prevalence of
depression and anxiety in rheumatoid arthritis patients and
their associations with serum vitamin D level. Clin Rheumatol.
2018;37(1):179–84.
83. Sherchand O, Sapkota N, Chaudhari RK, Khan SA, Baran-
wal JK, Pokhrel T, et al. Association between vitamin D defi-
ciency and depression in Nepalese population. Psychiatry Res.
2018;267:266–71.
84. Jaaskelainen T, Knekt P, Suvisaari J, Mannisto S, Partonen T,
Saaksjarvi K, et al. Higher serum 25-hydroxyvitamin D con-
centrations are related to a reduced risk of depression. Br J Nutr.
2015;113(9):1418–26.
85. Vidgren M, Virtanen JK, Tolmunen T, Nurmi T, Tuomainen TP,
Voutilainen S, et al. Serum concentrations of 25-hydroxyvitamin
D and depression in a general middle-aged to elderly population
in Finland. J Nutr Health Aging. 2018;22(1):159–64.
635
86. Briggs R, McCarroll K, O’Halloran A, Healy M, Kenny RA,
Laird E. Vitamin D deficiency is associated with an increased
likelihood of incident depression in community-dwelling older
adults. J Am Med Dir Assoc. 2018. https​://doi.org/10.1016/j.
jamda​.2018.10.006.
87. Bossola M, Ciciarelli C, Di Stasio E, Conte GL, Vulpio C,
Luciani G, et  al. Correlates of symptoms of depression and
anxiety in chronic hemodialysis patients. Gen Hosp Psychiatry.
2010;32(2):125–31.
88. Zhao G, Ford ES, Li C, Balluz LS. No associations between
serum concentrations of 25-hydroxyvitamin D and parathy-
roid hormone and depression among US adults. Br J Nutr.
2010;104(11):1696–702.
89. Kwasky AN, Groh CJ. Vitamin d, depression and coping self-
efficacy in young women: longitudinal study. Arch Psychiatric
Nur. 2014;28(6):362–7.
90. Almeida OP, Hankey GJ, Yeap BB, Golledge J, Flicker L. Vita-
min D concentration and its association with past, current and
future depression in older men: the health in men study. Maturi-
tas. 2015;81(1):36–41.
91. Can MS, Baykan H, Baykan O, Erensoy N, Karlidere T. Vitamin
D levels and vitamin D receptor gene polymorphism in major
depression. Psychiatr Danub. 2017;29(2):179–85.
92. Michaelsson K, Melhus H, Larsson SC. Serum 25-hydroxyvitamin
D concentrations and major depression: a mendelian randomiza-
tion study. Nutrients. 2018. https​://doi.org/10.3390/nu101​21987​.
93. Lansdowne AT, Provost SC. Vitamin D3 enhances mood
in healthy subjects during winter. Psychopharmacology.
1998;135(4):319–23.
94. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K.
Effects of vitamin D supplementation on symptoms of depres-
sion in overweight and obese subjects: randomized double blind
trial. J Int Med. 2008;264(6):599–609.
95. Zanetidou S, Belvederi Murri M, Buffa A, Malavolta N, Anzivino
F, Bertakis K. Vitamin D supplements in geriatric major depres-
sion. Int J Geriatr Psychiatry. 2011;26(11):1209–10.
96. Hogberg G, Gustafsson SA, Hallstrom T, Gustafsson T, Klawit-
ter B, Petersson M. Depressed adolescents in a case-series were
low in vitamin D and depression was ameliorated by vitamin D
supplementation. Acta Paediatr. 2012;101(7):779–83.
97. Mozaffari-Khosravi H, Nabizade L, Yassini-Ardakani SM,
Hadinedoushan H, Barzegar K. The effect of 2 different
single injections of high dose of vitamin D on improving
the depression in depressed patients with vitamin D defi-
ciency: a randomized clinical trial. J Clin Psychopharmacol.
2013;33(3):378–85.
98. Sepehrmanesh Z, Kolahdooz F, Abedi F, Mazroii N, Assarian
A, Asemi Z, et al. Vitamin D supplementation affects the beck
depression inventory, insulin resistance, and biomarkers of oxi-
dative stress in patients with major depressive disorder: a rand-
omized. Controlled Clin Trial J Nutr. 2016;146(2):243–8.
99. Stokes CS, Grunhage F, Baus C, Volmer DA, Wagenpfeil S,
Riemenschneider M, et al. Vitamin D supplementation reduces
depressive symptoms in patients with chronic liver disease. Clin
Nutr. 2016;35(4):950–7.
100. Vaziri F, Nasiri S, Tavana Z, Dabbaghmanesh MH, Sharif F,
Jafari P. A randomized controlled trial of vitamin D supplemen-
tation on perinatal depression: in Iranian pregnant mothers. BMC
Pregnancy Child. 2016;16:239.
101. Narula N, Cooray M, Anglin R, Muqtadir Z, Narula A, Marshall
JK. Impact of high-dose vitamin D3 supplementation in patients
with crohn’s disease in remission: a pilot randomized double-
blind controlled study. Dig Dis Sci. 2017;62(2):448–55.
102. Ghaderi A, Banafshe HR, Motmaen M, Rasouli-Azad M, Bahm-
ani F, Asemi Z. Clinical trial of the effects of vitamin D supple-
mentation on psychological symptoms and metabolic profiles in

636
maintenance methadone treatment patients. Prog Neuropsychop-
harmacol Biol Psychiatry. 2017;79(Pt B):84–9.
103. Penckofer S, Byrn M, Adams W, Emanuele MA, Mumby P,
Kouba J, et al. Vitamin D supplementation improves mood in
women with type 2 diabetes. J Diabetes Res. 2017;2017:8232863.
104. Bahrami A, Mazloum SR, Maghsoudi S, Soleimani D, Khayy-
atzadeh SS, Arekhi S, et al. High dose vitamin D supplementa-
tion is associated with a reduction in depression score among
adolescent girls: a nine-week follow-up study. J Dietary Suppl.
2018;15(2):173–82.
105. Sharifi A, Vahedi H, Nedjat S, Mohamadkhani A, Hosseinzadeh
Attar MJ. Vitamin D Decreases Beck Depression Inventory Score
in Patients with Mild to Moderate Ulcerative Colitis: A Double-
Blind Randomized Placebo-Controlled Trial. J Dietary Suppl.
2019. https​://doi.org/10.1080/19390​211.2018.14721​68.
106. Alavi NM, Khademalhoseini S, Vakili Z. Assarian F. Clin Nutr:
Effect of vitamin D supplementation on depression in elderly
patients. A randomized clinical trial; 2018. p. 19.
107. Khoraminya N, Tehrani-Doost M, Jazayeri S, Hosseini A,
Djazayery A. Therapeutic effects of vitamin D as adjunctive
therapy to fluoxetine in patients with major depressive disorder.
Aust N Z J Psychiatry. 2013;47(3):271–5.
108. Raygan F, Ostadmohammadi V, Bahmani F, Asemi Z. The effects
of vitamin D and probiotic co-supplementation on mental health
parameters and metabolic status in type 2 diabetic patients with
coronary heart disease: a randomized, double-blind, placebo-
controlled trial. Prog Neuropsychopharmacol Biol Psychiatry.
2018;84(Pt A):50–5.
109. Rolf L, Muris AH, Bol Y, Damoiseaux J, Smolders J, Hupperts
R. Vitamin D3 supplementation in multiple sclerosis: symptoms
and biomarkers of depression. J Neurol Sci. 2017;378:30–5.
110. Van Belle TL, Gysemans C, Mathieu C. Vitamin D and diabetes:
the odd couple. Trends Endocrinol Metab. 2013;24(11):561–8.
111. Wirz-Justice A. Seasonality in affective disorders. Gen Comp
Endocrinol. 2018;258:244–9.
112. Kerr DC, Zava DT, Piper WT, Saturn SR, Frei B, Gombart
AF. Associations between vitamin D levels and depressive
symptoms in healthy young adult women. Psychiatry Res.
2015;227(1):46–51.
113. Premkumar M, Sable T, Dhanwal D, Dewan R. Vitamin D
homeostasis, bone mineral metabolism, and seasonal affective
disorder during 1 year of Antarctic residence. Arch Osteoporos.
2013;8:129.
114. Oren DA, Schulkin J, Rosenthal NE. 1,25 (OH)2 vitamin D3
levels in seasonal affective disorder: effects of light. Psychop-
harmacology. 1994;116(4):515–6.
115. Gloth FM 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum
phototherapy in the treatment of seasonal affective disorder. J
Nutr Health Aging. 1999;3(1):5–7.
116. Vieth R, Kimball S, Hu A, Walfish PG. Randomized com-
parison of the effects of the vitamin D3 adequate intake versus
100 mcg (4000 IU) per day on biochemical responses and the
wellbeing of patients. Nutr J. 2004;3:8.
117. Harris S, Dawson-Hughes B. Seasonal mood changes in 250
normal women. Psychiatry Res. 1993;49(1):77–87.
118. Dumville JC, Miles JN, Porthouse J, Cockayne S, Saxon L,
King C. Can vitamin D supplementation prevent winter-time
blues? A randomised trial among older women. J Nutr Health
Aging. 2006;10(2):151–3.
119. Frandsen TB, Pareek M, Hansen JP, Nielsen CT. Vitamin D
supplementation for treatment of seasonal affective symptoms
in healthcare professionals: a double-blind randomised pla-
cebo-controlled trial. BMC Res Notes. 2014;7:528.
120. Arvold DS, Odean MJ, Dornfeld MP, Regal RR, Arvold JG,
Karwoski GC, et  al. Correlation of symptoms with vita-
min D deficiency and symptom response to cholecalciferol
G. A. S. Casseb et al.
treatment: a randomized controlled trial. Endocr Pract.
2009;15(3):203–12.
121. Dean AJ, Bellgrove MA, Hall T, Phan WM, Eyles DW,
Kvaskoff D, et al. Effects of vitamin D supplementation on
cognitive and emotional functioning in young adults–a ran-
domised controlled trial. PLoS One. 2011;6(11):e25966.
122. Sanders KM, Stuart AL, Williamson EJ, Jacka FN, Dodd S,
Nicholson G, et al. Annual high-dose vitamin D3 and men-
tal well-being: randomised controlled trial. Br J Psychiatry.
2011;198(5):357–64.
123. Bertone-Johnson ER, Powers SI, Spangler L, Brunner RL,
Michael YL, Larson JC, et al. Vitamin D intake from foods and
supplements and depressive symptoms in a diverse population
of older women. Am J Clin Nutr. 2011;94(4):1104–12.
124. Bertone-Johnson ER, Powers SI, Spangler L, Larson J, Michael
YL, Millen AE, et al. Vitamin D supplementation and depres-
sion in the women’s health initiative calcium and vitamin D
trial. Am J Epidemiol. 2012;176(1):1–13.
125. Yalamanchili V, Gallagher JC. Treatment with hormone therapy
and calcitriol did not affect depression in older postmenopausal
women: no interaction with estrogen and vitamin D receptor
genotype polymorphisms. Menopause. 2012;19(6):697–703.
126. Wang Y, Liu Y, Lian Y, Li N, Liu H, Li G. Efficacy of high-
dose supplementation with oral vitamin D3 on depressive
symptoms in dialysis patients with vitamin D3 insufficiency:
a prospective, randomized. Double-Blind Study. J Clin Psy-
chopharmacol. 2016;36(3):229–35.
127. Hongell K, Silva DG, Ritter S, Meier DP, Soilu-Hanninen M.
Efficacy and safety outcomes in vitamin D supplement users in
the fingolimod phase 3 trials. J Neurol. 2018;265(2):348–55.
128. Choukri MA, Conner TS, Haszard JJ, Harper MJ, Houghton
LA. Effect of vitamin D supplementation on depressive symp-
toms and psychological wellbeing in healthy adult women: a
double-blind randomised controlled clinical trial. J Nutr Sci.
2018;7:e23.
129. Jorde R, Kubiak J. No improvement in depressive symptoms by
vitamin D supplementation: results from a randomised controlled
trial. J Nutr Sci. 2018;7:e30.
130. Davis M, Walker DL, Miles L, Grillon C. Phasic vs sustained
fear in rats and humans: role of the extended amygdala in fear vs
anxiety. Neuropsychopharmacology. 2010;35(1):105–35.
131. Kupfer DJ. Anxiety and DSM-5. Dialogues Clin Neurosci.
2015;17(3):245–6.
132. Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence
of anxiety disorders: a systematic review and meta-regression.
Psychol Med. 2013;43(5):897–910.
133. Hoffman EJ, Mathew SJ. Anxiety disorders: a compre-
hensive review of pharmacotherapies. Mt Sinai J Med.
2008;75(3):248–62.
134. Farach FJ, Pruitt LD, Jun JJ, Jerud AB, Zoellner LA, Roy-
Byrne PP. Pharmacological treatment of anxiety disorders:
current treatments and future directions. J Anxiety Disord.
2012;26(8):833–43.
135. Sandi C, Richter-Levin G. From high anxiety trait to depression: a
neurocognitive hypothesis. Trends Neurosci. 2009;32(6):312–20.
136. Martin EI, Ressler KJ, Binder E, Nemeroff CB. The neuro-
biology of anxiety disorders: brain imaging, genetics, and
psychoneuroendocrinology. Psychiatric Clin North Am.
2009;32(3):549–75.
137. Bouayed J, Rammal H, Soulimani R. Oxidative stress and anxi-
ety: relationship and cellular pathways. Oxid Med Cell Longev.
2009;2(2):63–7.
138. Hassan W, Silva CE, Mohammadzai IU, da Rocha JB, J LF. Asso-
ciation of oxidative stress to the genesis of anxiety: implications
for possible therapeutic interventions. Curr Neuropharmacol.
2014;12(2):120–39.
Vitamin D for Depression and Anxiety Disorders
139. Santos P, Herrmann AP, Elisabetsky E, Piato A. Anxiolytic
properties of compounds that counteract oxidative stress, neu-
roinflammation, and glutamatergic dysfunction: a review. Braz J
Psychiatry. 2019;41(2):168–78.
140. Fedotova J, Zarembo D, Dragasek J, Caprnda M, Kruzliak P,
Dudnichenko T. Modulating effects of cholecalciferol treatment
on estrogen deficiency-induced anxiety-like behavior of adult
female rats. Folia Med. 2017;59(2):139–58.
141. Fedotova J, Pivina S, Sushko A. Effects of chronic vitamin D3
hormone administration on anxiety-like behavior in adult female
rats after long-term ovariectomy. Nutrients. 2017. https​://doi.
org/10.3390/nu901​0028.
142. Borowicz KK, Morawska D, Morawska M. Effect of cholecal-
ciferol on the anticonvulsant action of some second generation
antiepileptic drugs in the mouse model of maximal electroshock.
Pharmacol Rep. 2015;67(5):875–80.
143. Brouwer-Brolsma EM, Schuurman T, de Groot LC, Feskens EJ,
Lute C, Naninck EF, et al. No role for vitamin D or a moderate fat
diet in aging induced cognitive decline and emotional reactivity
in C57BL/6 mice. Behav Brain Res. 2014;267:133–43.
144. Burne TH, Becker A, Brown J, Eyles DW, Mackay-Sim A,
McGrath JJ. Transient prenatal Vitamin D deficiency is asso-
ciated with hyperlocomotion in adult rats. Behav Brain Res.
2004;154(2):549–55.
145. Burne TH, McGrath JJ, Eyles DW, Mackay-Sim A. Behavioural
characterization of vitamin D receptor knockout mice. Behav
Brain Res. 2005;157(2):299–308.
146. Kalueff AV, Lou YR, Laaksi I, Tuohimaa P. Increased anxi-
ety in mice lacking vitamin D receptor gene. NeuroReport.
2004;15(8):1271–4.
147. Kalueff AV, Lou YR, Laaksi I, Tuohimaa P. Increased grooming
behavior in mice lacking vitamin D receptors. Physiol Behav.
2004;82(2–3):405–9.
148. Pan P, Jin DH, Chatterjee-Chakraborty M, Halievski K, Lawson
D, Remedios D, et al. The effects of vitamin D3 during preg-
nancy and lactation on offspring physiology and behavior in
sprague-dawley rats. Dev Psychobiol. 2014;56(1):12–22.
149. Liang Q, Cai C, Duan D, Hu X, Hua W, Jiang P, et al. Postnatal
vitamin D intake modulates hippocampal learning and memory
in adult mice. Front Neurosci. 2018;12:141.
150. Karonova TL, Andreeva AT, Beljaeva OD, Bazhenova EA, Globa
PJ, Vasil’eva EJ, et al. Anxiety/depressive disorders and vitamin
D status. Zhurnal nevrologii i psikhiatrii imeni SS Korsakova.
2015;115(10 Pt 2):55–8.
151. Bicikova M, Duskova M, Vitku J, Kalvachova B, Ripova D, Mohr
P, et al. Vitamin D in anxiety and affective disorders. Physiol
Res. 2015;64(Suppl 2):S101–3.
152. Han B, Zhu FX, Yu HF, Liu S, Zhou JL. Low serum levels of
vitamin D are associated with anxiety in children and adolescents
with dialysis. Sci Rep. 2018;8(1):5956.
153. Huang JY, Arnold D, Qiu CF, Miller RS, Williams MA,
Enquobahrie DA. Association of serum vitamin D with
637
symptoms of depression and anxiety in early pregnancy. J Wom-
en’s Health. 2014;23(7):588–95.
154. Tartagni M, Cicinelli MV, Tartagni MV, Alrasheed H, Mat-
teo M, Baldini D, et al. Vitamin D supplementation for pre-
menstrual syndrome-related mood disorders in adolescents
with severe hypovitaminosis D. J Pediatr Adolesc Gynecol.
2016;29(4):357–61.
155. Wepner F, Scheuer R, Schuetz-Wieser B, Machacek P, Pieler-
Bruha E, Cross HS, et al. Effects of vitamin D on patients with
fibromyalgia syndrome: a randomized placebo-controlled trial.
Pain. 2014;155(2):261–8.
156. Slow S, Florkowski CM, Chambers ST, Priest PC, Stewart AW,
Jennings LC, et al. Effect of monthly vitamin D3 supplementa-
tion in healthy adults on adverse effects of earthquakes: ran-
domised controlled trial. BMJ. 2014;349:g7260.
157. Hansen AL, Olson G, Dahl L, Thornton D, Grung B, Graff
IE, et  al. Reduced anxiety in forensic inpatients after a
long-term intervention with Atlantic salmon. Nutrients.
2014;6(12):5405–18.
158. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen
JP. Genetics and biology of vitamin D receptor polymorphisms.
Gene. 2004;338(2):143–56.
159. Neela VS, Suryadevara NC, Shinde VG, Pydi SS, Jain S, Jon-
nalagada S, et al. Association of Taq I, Fok I and Apa I polymor-
phisms in Vitamin D Receptor (VDR) gene with leprosy. Hum
Immunol. 2015;76(6):402–5.
160. Glocke M, Lang F, Schaeffeler E, Lang T, Schwab M, Lang UE.
Impact of vitamin D receptor VDR rs2228570 polymorphism in
oldest old. Kidney Blood Press Res. 2013;37(4–5):311–22.
161. Kuningas M, Mooijaart SP, Jolles J, Slagboom PE, Westendorp
RG, van Heemst D. VDR gene variants associate with cognitive
function and depressive symptoms in old age. Neurobiol Aging.
2009;30(3):466–73.
162. Stokes CS, Lammert F. Vitamin D supplementation: less con-
troversy, more guidance needed. F1000Res. 2016. https​://doi.
org/10.12688​/f1000​resea​rch.8863.1
163. Zittermann A, Ernst JB, Gummert JF, Borgermann J. Vita-
min D supplementation, body weight and human serum
25-hydroxyvitamin D response: a systematic review. Eur J Nutr.
2014;53(2):367–74.
164. Aloia JF, Patel M, Dimaano R, Li-Ng M, Talwar SA, Mikhail M,
et al. Vitamin D intake to attain a desired serum 25-hydroxyvita-
min D concentration. Am J Clin Nutr. 2008;87(6):1952–8.
165. van Etten E, Mathieu C. Immunoregulation by 1,25-dihy-
droxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol.
2005;97(1–2):93–101.
166. Rosa JM, Dafre AL, Rodrigues AL. Antidepressant-like
responses in the forced swimming test elicited by glutathione
and redox modulation. Behav Brain Res. 2013;253:165–72.
167. Goltzman D. Functions of vitamin D in bone. Histochem Cell
Biol. 2018;149(4):305–12.