International Journal of

Molecular Sciences

Review
Molecular Basis Underlying the Therapeutic Potential of
Vitamin D for the Treatment of Depression and Anxiety
Bruna R. Kouba 1 , Anderson Camargo 1 , Joana Gil-Mohapel 2,3, * and Ana Lúcia S. Rodrigues 1, *

1 Center of Biological Sciences, Department of Biochemistry, Federal University of Santa Catarina,

Florianópolis 88040-900, SC, Brazil; [email protected] (B.R.K.); [email protected] (A.C.)
2 Island Medical Program, Faculty of Medicine, University of British Columbia, Victoria, BC V8P 5C2, Canada
3 Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada
* Correspondence: [email protected] (J.G.-M.); [email protected] (A.L.S.R.); Tel.: +1-250-721-6586 (J.G.-M.);
+55-(48)-3721-5043 (A.L.S.R.)

Abstract: Major depressive disorder and anxiety disorders are common and disabling conditions that
affect millions of people worldwide. Despite being different disorders, symptoms of depression and
anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately.
Therefore, compounds capable of exerting beneficial effects against both disorders are of special
interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of devel-
oping depression and anxiety, and individuals with these psychiatric conditions have low serum
levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many
functions that go beyond its effects on calcium–phosphorus metabolism. Particularly, antioxidant,
anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its an-
tidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms
that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we
Citation: Kouba, B.R.; Camargo, A.; discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the
Gil-Mohapel, J.; Rodrigues, A.L.S. management of these disorders.
Molecular Basis Underlying the
Therapeutic Potential of Vitamin D Keywords: anti-inflammatory effect; anxiety; depression; neuromodulator; pro-neurogenic effect;
for the Treatment of Depression and
vitamin D
Anxiety. Int. J. Mol. Sci. 2022, 23, 7077.
https://doi.org/10.3390/
ijms23137077

Academic Editors: Irena Nalepa and 1. Introduction

Agnieszka Zelek-Molik Major depressive disorder (MDD) and anxiety disorders, which in this review will be
referred to as depression and anxiety, are devastating and highly prevalent clinical entities
Received: 31 May 2022
Accepted: 24 June 2022
that constitute one of the leading causes of disability worldwide [1,2]. These disorders
Published: 25 June 2022
often occur concomitantly and their symptoms frequently overlap in individuals, and
patients with these two comorbidities often present with a higher severity and duration of
Publisher’s Note: MDPI stays neutral symptoms [3]. Therefore, the diagnosis and treatment of these disorders remain a challenge
with regard to jurisdictional claims in
in the clinical setting [1,4]. Despite being different disorders, the etiology of depression
published maps and institutional affil-
and anxiety involves similar factors, such as genetic predispositions, environmental as-
iations.
pects, and several biological mechanisms [1,2,5]. Among the main biological mechanisms
implicated in the pathophysiology of these disorders, compelling evidence has pointed
to neuroinflammation as a key factor in the onset and progression of these disorders [6].
Copyright: © 2022 by the authors.
Notably, other biological mechanisms that have been implicated in depression and anxi-
Licensee MDPI, Basel, Switzerland.
ety, such as gut dysbiosis, impaired neurogenesis, and monoaminergic dysfunction, may
This article is an open access article be triggered by a neuroinflammatory process, opening new perspectives for studying
distributed under the terms and molecular targets and neuroprotective agents against these mood disturbances [4,7–9].
conditions of the Creative Commons In this regard, in recent years, vitamin D has gained prominence due to its antioxidant,
Attribution (CC BY) license (https:// anti-inflammatory, pro-neurogenic, and neuromodulatory properties that appear to be
creativecommons.org/licenses/by/ fundamental to its antidepressant and anxiolytic effects [10–13]. Given this background,
4.0/).

Int. J. Mol. Sci. 2022, 23, 7077. https://doi.org/10.3390/ijms23137077 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022, 23, 7077 2 of 14

in this review, we highlight the main mechanisms that may underlie the potential antide-
pressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical
studies that support the therapeutic potential of this vitamin for the management of these
mood disorders.

2. Literature Data Searching

This review presents a mechanistic overview of the clinical and preclinical research
regarding the effects of vitamin D on depression and anxiety. The search included original
manuscripts and contemporary reviews published in English, assessed by specific search
terms in the title or abstract of the manuscripts available through PubMed. The search terms
used were “vitamin D”, “calcitriol”, “cholecalciferol”, “calcidiol”, “anxiety”, “depression”,
“major depressive disorder”, “neuroinflammation”, “inflammation” “neurogenesis”, and
“monoaminergic system”. We performed a specific screening of the clinical and preclinical
studies that investigated the role of vitamin D in anxiety and depression. To review the
molecular basis underlying the therapeutic potential of vitamin D for the treatment of
depression and anxiety, we selected preclinical and clinical studies published over a 28-year
period (1994 to 2022).

3. Neuroinflammation as a Key Pathophysiological Mechanism Related to

Mood Disorders
Neuroinflammation is a complex process that comprises a defense mechanism in
the central nervous system (CNS), protecting and restoring the structure and function of
the brain against infection and injury, through the modulation of neurogenesis, axonal
regeneration, and remyelination of neural cells [14]. However, chronic and exacerbated
inflammatory responses can produce harmful effects in the brain. These inflammatory
processes may involve inflammation-related signaling molecules, microbiota, as well as
immune and brain cells [7,15].
Microglia, nervous-system-specific immune cells, are of special interest to neuroin-
flammatory responses. Under normal conditions, microglia assume a phenotype defined
by a ramified morphology and highly motile processes for constant monitoring of the
brain parenchyma (M2 phenotype). After an insult, promoted by pathogen-associated
molecular patterns and/or damage-associated molecular patterns that interact with pattern
recognition receptors (PRRs), such as Toll-like receptors (TLRs), microglia retract their pro-
cesses and adopt an ameboid form (M1 phenotype) [16–19]. In addition to morphological
changes, the binding of these molecular patterns to these receptors induces the priming of
NLRP3 [nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeats (LRR)-
and pyrin domain-containing protein 3] and pro-interleukin (IL)-1β expression via nu-
clear factor kappa B (NF-kB) and myeloid differentiation primary response 88 (Myd88)
pathways [17,20,21]. Noteworthily, the expression of NLRP3 may be inhibited under cer-
tain conditions, particularly upon activation of nuclear factor erythroid 2-related factor
2 (Nrf2), the main regulator of the antioxidant response [22,23]. Subsequently, different
stimuli capable of promoting mitochondrial dysfunction, calcium and potassium ion flux,
reactive oxygen species (ROS) production, and lysosomal damage activate the NLRP3
inflammasome, promoting the autoproteolytic activation of pro-caspase-1 [20]. Caspase-1
can subsequently cleave pro-interleukin-1β and pro-interleukin-18 into their active forms,
interleukin-1β (IL-1β) and interleukin-18 (IL-18), respectively [17,24]. In addition, acti-
vation of NLRP3 can lead to gasdermin D-mediated formation of membrane pores and
subsequently pyroptosis [17].
Mediators released by activated microglia induce astrocyte polarization [25]. This
polarization contributes to the impairment of signaling pathways that play a crucial role
in neuronal survival and synaptic plasticity, such as the brain-derived neurotrophic factor
(BDNF)/tropomyosin-related kinase B (TrkB) signaling pathway [26]. Chronic activation
of astrocytes also results in increased levels of chemokines, such as chemokine ligand 2,
which interact with peripheral immune cell receptors to induce infiltration of macrophages
Int. J. Mol. Sci. 2022, 23, 7077 3 of 14

and monocytes from the circulation into the CNS and resulting in increased blood–brain
barrier permeability [27,28].
Interestingly, neuroinflammatory-process-derived pro-inflammatory cytokines, such
as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), cause an increase
in the activity of the enzyme indoleamine 2,3-dioxygenase in astrocytes, microglia, and
inflammatory cells. The activation of this enzyme increases the formation of quinolinic
acid, an N-methyl-D-aspartate (NMDA) receptor agonist, through the kynurenine pathway,
contributing to glutamatergic system disturbance and compromising the synthesis of sero-
tonin by depleting tryptophan [8,29–31]. Within this scenario, it is worth noting that more
than 90% of the body’s serotonin is produced in the gut, particularly by enterochromaffin
cells, and alterations in the intestinal microbiota triggered by inflammatory processes have
been shown to directly compromise the synthesis of this monoamine [32,33]. Indeed, it is
important to note that changes in gut microbiota have been reported to impair the efficacy
of antidepressants, such as fluoxetine [34].
In summary, neuroinflammation results from intrinsic communication among pe-
ripheral immune cells, gut microbiota, and immune cells present in the brain, and these
interactions culminate in glutamatergic dysregulation, as well as reduced synaptic plasticity
and monoamine synthesis. Together, these factors contribute to the atrophy and neuronal
loss seen in patients with chronic depression and anxiety disorders [35]. In this regard,
compounds with anti-inflammatory, pro-neurogenic, and neuromodulatory properties,
such as vitamin D, are of special interest for the treatment of these mood disorders.

4. Metabolism and Biological Functions of Vitamin D

Vitamin D is a steroid hormone that can be obtained from the diet in two forms: (i) vi-
tamin D2 (ergocalciferol) found in yeast, mushrooms, as well as plants, and (ii) vitamin D3
(cholecalciferol) found in foods of animal origin, such as cod liver oil and oily fish [36]. How-
ever, the main source of vitamin D is cholecalciferol synthesized endogenously through
solar ultraviolet B (UVB) radiation at wavelengths of 290–315 nm [36,37]. Through this
process, UVB photons penetrate into the dermis and are absorbed by 7-dehydrocholesterol,
which is then converted into previtamin D3 [37]. Previtamin D3 subsequently isomerizes
into vitamin D3 , which is then transported in the circulation by vitamin D-binding protein
(DBP) [37]. In the liver, vitamin D3 is hydroxylated at C-25 by 25-hydroxylase, mainly by cy-
tochrome P450 Family 2 Subfamily R Member 1 (CYP2R1), to produce 25-hydroxyvitamin
D3 (25(OH)D3 ) [38,39]. Following this, 25(OH)D3 can be stored or can undergo a sec-
ond hydroxylation in the kidneys by 25-hydroxyvitamin D-1α-hydroxylase (Cytochrome
P450 Family 27 Subfamily B Member 1; CYP27B1), forming its biologically active form,
1α,25-dihydroxyvitamin D (1,25(OH)2 D3 ), also known as calcitriol [40]. It is estimated
that humans can synthesize quantities equivalent to the oral intake of 20,000 IU of this
vitamin [38].
Vitamin D is widely known to play critical roles in calcium–phosphorus metabolism,
acting in the maintenance of bone homeostasis [38]. In addition, vitamin D also exerts
pleiotropic functions that have gained increased attention in the last few years [41]. These
biological actions of calcitriol are mediated by vitamin D receptors (VDRs) [42]. The
interaction between calcitriol and VDR allows other transcription factors, such as the
retinoid X receptor (RXR), to interact with this complex, forming a heterodimer [42]. This
heterodimer can then bind to vitamin D-responsive elements (VDREs), and by recruiting
complexes of either co-activators or co-repressors, it can modulate gene expression [42,43].
It is estimated that 200 to 2000 genes are modulated directly or indirectly by vitamin
D [42]. Due to the numerous biological actions mediated by vitamin D, the measurement
of its serum concentration becomes indispensable. In this regard, the Endocrine Society’s
Clinical Practice Guideline defines vitamin D deficiency as values <20 ng/mL; insufficiency
between 21–29 ng/mL; and sufficiency between 30–100 ng/mL [36,40]. However, reference
values for vitamin D remain a matter of debate [44].
Int. J. Mol. Sci. 2022, 23, 7077 4 of 14

4.1. Antioxidant and Anti-Inflammatory Properties of Vitamin D

Neurons and glial cells express VDR and vitamin D-metabolizing enzymes in various
regions, such as the prefrontal cortex and hippocampus, suggesting a possible role for
vitamin D in depression and anxiety disorders [45]. In line with this, several studies
have suggested an inverse association between serum vitamin D levels and symptoms
related to depression and anxiety [46–48]. In addition to glial cells, VDRs and CYP27B1
are also expressed in several other immune cells, such as CD4+ and CD8+ T cells, B cells,
macrophages, neutrophils, and dendritic cells [49]. Notably, it has been shown that calcitriol
is capable of modulating innate and adaptive immune responses [49]. Furthermore, the
positive modulation of antioxidant enzymes by calcitriol is known to contribute to redox
homeostasis and, consequently, to the attenuation of the neuroinflammatory process [50,51].
For example, calcitriol has been shown to inhibit the synthesis of interleukin interleukin-6
(IL-6), TNF-α, and nitric oxide (NO) by activated microglia [12]. Likewise, it has been
shown to decrease the expression of IL-1β, TNF-α, and inducible nitric oxide synthase
(iNOS), the enzyme responsible for the synthesis of NO under inflammatory conditions, in
the prefrontal cortex of rats [52].
In addition to IL-6 and TNF-α, vitamin D3 has also been shown to reduce the ex-
pression of interleukin-12 (IL-12) and increase the expression of the anti-inflammatory
cytokine interleukin-10 (IL-10) [53]. Furthermore, vitamin D was shown to up-regulate
the expression of other anti-inflammatory cytokines, including interleukin-14 (IL-4), and
transforming growth factor-beta (TGF-β) [54]. Calcitriol is also capable of up-regulating
TLR10 while down-regulating TLR2 and TLR4, reinforcing its role in attenuating microglial
activation [55,56].
In this context, it has been reported that vitamin D mitigates the activation of the
NLRP3 inflammasome [57,58]. Although a study by Camargo et al. (2020) did not find
changes in NLRP3 expression in mice treated for 7 days with cholecalciferol, this treat-
ment reduced the immunocontent of other inflammasome-related proteins, including ASC
(apoptosis-associated speck-like protein containing a caspase recruitment domain), TXNIP
(thioredoxin interacting protein), and caspase-1 in the hippocampus of mice. However,
Xin et al. (2019) showed that calcitriol attenuated NLRP3 expression by inhibiting the
NF-kB pathway in human bronchial epithelial cells. Likewise, treatment with a VDR ago-
nist (paricalcitol) was able to attenuate the expression of NLRP3, gasdermin D, caspase-1,
and IL-1β, proteins related to the NF-kB-mediated pyroptosis process in cisplatin-induced
acute kidney injury models [59]. One of the possible mechanisms by which vitamin D may
reduce the activation of NF-kB is by up-regulating the NF-kB inhibitor IkBα (nuclear factor
of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) [60]. In addition, it has
been reported that VDR can bind NLRP3, inhibiting the activation of this complex [61,62].
Calcitriol is also able of suppressing NLRP1 inflammasome activation by up-regulating
the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway [50]. Indeed,
the ability of calcitriol to activate Nrf2 signaling seems to be directly associated with its
neuroprotective properties [63]. Once activated, Nrf2 promotes the transcription of several
antioxidant enzymes [64]. In line with this, studies have shown that vitamin D is able to
induce the expression of heme oxygenase-1 (HO-1), catalase, superoxide dismutase (SOD),
and glutamate-cysteine ligase (the rate-limiting enzyme in the synthesis of glutathione, an
endogenous antioxidant), thereby inhibiting ROS accumulation in the brain [51,65–67].

4.2. Pro-Neurogenic and Neuromodulatory Properties of Vitamin D

Vitamin D deficiency during pregnancy has been demonstrated to directly affect brain
development in the offspring [68–70]. Vitamin D-deficient offspring exhibit a thinner
cortex, reduced expression of genes and proteins related to cytoskeleton maintenance,
synaptic plasticity, neurotransmission, cell proliferation, and growth, as well as decreased
levels of nerve growth factor (NGF) [70–73]. Although no alterations in BDNF and glial
cell line-derived neurotrophic factor (GDNF) levels were found in vitamin D-deficient
offspring, different lines of evidence have shown that this vitamin is effective in inducing
Int. J. Mol. Sci. 2022, 23, 7077 5 of 14

the synthesis of these neurotrophins [74,75]. In addition, vitamin D also participates in the
synthesis of the neurotrophin NT-3, a key regulator of survival, growth, and differentiation
of neurons [76,77].
Indeed, neurotrophins bind to receptor tyrosine kinases (Trk), which, in turn, con-
tribute to promoting the survival and growth of neurons as well as synaptogenesis [78]. In
this regard, a study by Atif et al. showed that a combined treatment with progesterone and
vitamin D was effective in activating the BDNF/TrkB signaling pathway [79]. Although
this study did not explore the mechanisms underlying this, it is known that activated
TrkB can phosphorylate and activate the mammalian target of rapamycin (mTOR), result-
ing in the translation of synaptic proteins, including postsynaptic density protein-95 kDa
(PSD-95), glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) re-
ceptor subunit 1 (GluA1), and synapsin [80,81]. Noteworthily, synapsins can increase
neurotransmitter release in the synaptic cleft [82]. Interestingly, vitamin D supplemen-
tation has been shown to promote an increase in serum serotonin in individuals suffer-
ing from depression [83] as well as serum dopamine levels in children with attention-
deficit/hyperactivity disorder (ADHD) [84]. Within this scenario, it has been shown
that vitamin D can directly increase the biosynthesis of monoamines by augmenting the
expression of the enzymes tyrosine hydroxylase and tryptophan hydroxylase, which me-
diate the synthesis of dopamine/noradrenaline and serotonin, respectively, particularly
in the prefrontal cortex [85]. In addition, VDR overexpression has been shown to in-
crease dopaminergic neuron differentiation, and consequently, dopamine production [86].
Moreover, Morello et al. (2018) showed that calcitriol can cause neuronal proliferation in
primary cultures of murine neural progenitor cells and improve neurogenesis in transgenic
Alzheimer’s disease (AD)-like mice [5XFAD model, which expresses human amyloid pre-
cursor protein (APP) and presenilin 1 (PSEN1) transgenes with a total of five AD-linked
mutations: the Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations
in APP, and the M146L and L286V mutations in PSEN1). Finally, calcitriol was also able
to inhibit serotonin reuptake transport and the expression of the monoamine oxidase-A
(MAO-A) gene, suggesting that this vitamin and antidepressants may share common
mechanisms of action [87].

4.3. Vitamin D: Modulation of Gut Microbiota

The immunological and neuromodulatory role of vitamin D occurs, in part, through its
interaction with the gut microbiota [88]. Indeed, serum vitamin D concentration may con-
tribute to changes in the composition of gut microbiota. Furthermore, vitamin D deficiency,
VDR, or CYP27B1 depletion have been shown to result in an increase in the Bacteroidetes
and Proteobacteria phyla, triggering epithelial barrier dysfunction and intestinal inflamma-
tion [89,90]. Interestingly, VDR has been shown to negatively regulate bacteria-induced
intestinal NF-kB activation, attenuating inflammatory responses. Therefore, VDR is an
important contributor to intestinal homeostasis and bacterial infection protection [91]. The
main neuromodulatory, anti-inflammatory, and antioxidant properties of vitamin D are
illustrated in Figure 1.
Int.
Int. J.
J. Mol. Sci. 2022,
Mol. Sci. 23, x
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FOR PEER REVIEW 66of
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15

Figure 1. Antioxidant, anti-inflammatory, and neuromodulatory properties of vitamin D. Neurons

Figure Antioxidant,
1. cells
and glial are able toanti-inflammatory,
express VDR in regionsand neuromodulatory properties
such as the prefrontal cortexofand
vitamin D. Neurons
hippocampus. In
and glial cells are able to express VDR in regions such as the prefrontal
these regions, the positive modulation of antioxidant enzymes, such as HO-1, CAT, and SOD, bycortex and hippocampus.
In these regions,
calcitriol the positive
contributes to redoxmodulation
homeostasisofand, antioxidant enzymes,
consequently, to thesuch as HO-1,ofCAT,
attenuation and SOD, by
the neuroinflam-
calcitriol contributes to redox homeostasis and, consequently, to the attenuation of
matory process. Calcitriol is also able to increase the expression of IkBα, thus, inhibiting the nuclearthe neuroinflam-
translocation
matory process.of Calcitriol
NF-kB. As a consequence,
is also less the
able to increase synthesis, oligomerization,
expression of IkBα, thus, and activation
inhibiting of the
the nuclear
NLRP3 inflammasome occurs, resulting in attenuation of pro-inflammatory
translocation of NF-kB. As a consequence, less synthesis, oligomerization, and activation of cytokines (such as the
IL-
1β and TNF-α) and an increase in anti-inflammatory cytokines (such as IL-10
NLRP3 inflammasome occurs, resulting in attenuation of pro-inflammatory cytokines (such as IL-1β and IL-4) (A). In ad-
dition, vitamin D has also been shown to modulate the intestinal microbiota (C). Finally, vitamin D
and TNF-α) and an increase in anti-inflammatory cytokines (such as IL-10 and IL-4) (A). In addition,
actively regulates the synthesis of monoamines and BDNF, thus, favoring the process of synaptic
vitamin D has also been shown to modulate the intestinal microbiota (C). Finally, vitamin D actively
plasticity (B). Abbreviations: ↓: decreased; ↑: increased; BDNF: brain-derived neurotrophic factor;
regulates the synthesis
CAT: catalase; of monoamines
HO-1: heme oxygenase-1; and IL-1β:
BDNF,interleukin-1β;
thus, favoring the process
IL-4: of synaptic
interleukin-4; plasticity
IL-10: (B).
interleu-
Abbreviations: ↓ : decreased; ↑ : increased; BDNF: brain-derived neurotrophic
kin-10; IkBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; factor; CAT: catalase;
HO-1: heme oxygenase-1;
MAO: monoamine oxidase; IL-1β:
NF-kB:interleukin-1β; IL-4: interleukin-4;
nuclear factor kappa B; NLRP3: NOD-likeIL-10: receptor
interleukin-10; IkBα:
family pyrin
nuclear factor of kappa
domain-containing lightreactive
3; ROS: polypeptide
oxygengene enhancer
species; in B-cells
SERT: inhibitor,
serotonin alpha; MAO:
transporters; SOD:monoamine
superoxide
dismutase;
oxidase; TNF-α:
NF-kB: tumor
nuclear necrosis
factor kappa factor-alpha; VDR: vitamin
B; NLRP3: NOD-like D receptor.
receptor family pyrin domain-containing
3; ROS: reactive oxygen species; SERT: serotonin transporters; SOD: superoxide dismutase; TNF-α:
5. Preclinical
tumor necrosis Studies:
factor-alpha;Effects
VDR:of Vitamin
vitamin D in Models of Depression and Anxiety
D receptor.
In recent years, several preclinical studies have been conducted to investigate the
5. Preclinical Studies: Effects of Vitamin D in Models of Depression and Anxiety
possible antidepressant and anxiolytic effects of vitamin D (Table 1).
In recent years, several preclinical studies have been conducted to investigate the
possible antidepressant
Table 1. Preclinical studiesand anxiolytic
on effects effects
of vitamin D of
in vitamin
models ofDdepression
(Table 1). and anxiety.
Of note, chronic administration of cholecalciferol [5 mg/kg for 14 days; subcutaneous
Study Animal Model
(s.c.) Treatment
administration] Behavioral Alterations
elicited an antidepressant-like effect in theBiochemical
forced swim Alterations
test in ovariec-
tomized Wistar Cholecalciferol (5
rats [92]. In addition, cholecalciferol supplementation (5 mg/kg for 14 days;
Fedotova et al. 2016 Ovariectomized Antidepressant-like effect
mg/kgoffor
s.c.) was capable 14 days; anxiety-like behaviors in the elevated
attenuating Not evaluated
plus-maze and
[92] Wistar rats in the FST
the light–dark box tests s.c.) in ovariectomized Wistar rats [10,93]. Based on these findings,
further studies Cholecalciferol
have been conducted to better understand the mechanisms underlying the
Fedotova et al. 2017 Ovariectomized
anxiolytic and (5 antidepressant Anxiolytic-like effect in
mg/kg for 14 effects of vitamin D in animal modelsNot [94,98].
evaluated
[10] Wistar ratsCamargo et days;
al. (2018) reported EPM
that and LDT
cholecalciferol [2.5 µg/kg, orally by mouth
s.c.)
(p.o.)], administered once a day in the last 7 days of chronic corticosterone administration
Cholecalciferol
Ovariectomized
(20 mg/kg, p.o., for 21 days), exerted Anxiolytic-like effect in effect in male mice subjected to
an antidepressant-like
Fedotova 2019 [93] (5 mg/kg for 14 Not evaluated
the splash
Wistar rats test and tail suspension test. EPM and LDTin this study, cholecalciferol treatment
Additionally,
days; s.c.)
attenuated the increase in protein carbonyl and nitrite levels induced by corticosterone in
the brain, suggesting that vitamin D3 has an antidepressant-like effect by, in part, modulat-
Int. J. Mol. Sci. 2022, 23, 7077 7 of 14

ing oxidative stress [94]. The administration of cholecalciferol (100 IU/kg, p.o.) for 7 days
also abolished the depressive-like behavior in the tail suspension test induced by chronic
corticosterone administration in female mice [95]. In this study, a significant decrease in
ROS production in the hippocampus was observed after treatment with cholecalciferol, both
in control and corticosterone-exposed mice, reinforcing the notion that the antidepressant-
like effect of this vitamin may involve the modulation of oxidative stress [95]. More recently,
a study by Neis et al. (2022) showed that repeated administration of cholecalciferol for
7 days (2.5 µg/kg, p.o.) abolished chronic unpredictable stress-induced depressive-like be-
havior in the tail suspension test, as well as a reduction in serotonin levels in the prefrontal
cortex of female mice. Moreover, reinforcing the involvement of the serotonergic system
in the antidepressant-like effect of cholecalciferol, in this study, the administration of the
serotonin synthesis inhibitor p-chlorophenylalanine methyl ester was effective in abolishing
the reduction in immobility time in the tail suspension test elicited by cholecalciferol [96].

Table 1. Preclinical studies on effects of vitamin D in models of depression and anxiety.

Study Animal Model Treatment Behavioral Alterations Biochemical Alterations

Cholecalciferol (5 mg/kg for Antidepressant-like effect in
Fedotova et al., 2016 [92] Ovariectomized Wistar rats Not evaluated
14 days; s.c.) the FST
Cholecalciferol (5 mg/kg for Anxiolytic-like effect in EPM
Fedotova et al., 2017 [10] Ovariectomized Wistar rats Not evaluated
14 days; s.c.) and LDT
Cholecalciferol (5 mg/kg for Anxiolytic-like effect in EPM
Fedotova 2019 [93] Ovariectomized Wistar rats Not evaluated
14 days; s.c.) and LDT
Corticosterone (21 days) in Cholecalciferol (2.5 µg/kg, Antidepressant-like effect in ↓ Protein carbonyl and
Camargo et al., 2018 [94]
male Swiss mice for 7 days; p.o.) the splash test and TST nitrite levels
Corticosterone (21days) in Cholecalciferol (100 IU/kg, Antidepressant-like effect in
da Silva Souza et al., 2020 [95] ↓ ROS
female Swiss mice p.o.) for 7 days the TST
Corticosterone (21 days) in Cholecalciferol (2.5 µg/kg, Antidepressant-like effect in
Camargo et al., 2020 [57] ↓ ASC, caspase-1, and TXNIP
male Swiss mice p.o.) for 7 days the TST and splash test
Cholecalciferol (2.5 µg/kg, Antidepressant-like effect in ↑ serotonin levels in the
Neis et al., 2022 [96] CUMS in female Swiss mice
p.o.) for 7 days the TST prefrontal cortex
Antidepressant-like effect in
Ovariectomized female Calcitriol (100 ng/kg, p.o.) for the FST and ↓ IL-1β, IL-6, and TNF-α,
Zhang et al., 2020 [97]
Sprague-Dawley rats 10 weeks novelty-suppressed feeding iNOS and COX-2
test
Anxiolytic and
Bakhtiari-Dovvombaygi et al., Vitamin D3 (10,000 IU/kg) for ↓ Malondialdehyde and IL-6
CUMS in male Wistar rats antidepressant-like effect in
2021 [98] 28 days ↑ Total thiols, SOD, and CAT
EPM and FST
CUMS (4 weeks) in male Depressive-like behavior in
Jiang et al., 2013 [99] Without treatment ↑ 1,25(OH)2 D and VDR
Sprague-Dawley rats sucrose preference test
Antidepressant-like effect in
CUMS in ovariectomized Vitamin D3 (5 mg/kg for
Koshkina et al., 2019 [76] FST and sucrose preference ↑BDNF and NT-3/NT-4
Wistar rat 4 weeks; s.c.)
test
Antidepressant-like effect in
post-stroke depression model Calcitriol (25 µg/kg/day for
Xu and Liang 2021 [75] FST and sucrose preference ↑ VDR and BDNF
(male C57BL/6 mice) 4 weeks; i.c.v.)
test
↓ decreased; ↑ increased; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain
(CARD); BDNF: brain-derived neurotrophic factor; CAT: catalase; COX-2: cyclooxygenase-2; CUMS: chronic
unpredictable mild stress; EPM: elevated plus maze; FST: forced swimming test; i.c.v.: intracerebroventricular;
IL-1β: interleukin-1β; IL-6: interleukin-6; iNOS: inducible nitric oxide synthase; LTD: light–dark box test; p.o.:
by mouth (orally); ROS, reactive oxygen species; s.c.: subcutaneous; SOD: superoxide dismutase; TNF-α: tumor
necrosis factor-alpha; TST: tail suspension test; TXNIP: thioredoxin-interacting protein; VDR: vitamin D receptor.

The repeated administration of a low dose of cholecalciferol (2.5 µg/kg, p.o.) also
caused an antidepressant-like effect and was effective in reducing the immunocontent of
proteins that form the NLRP3 inflammasome, such as ASC [apoptosis-associated speck-like
protein containing a caspase recruitment domain (CARD)], caspase-1, and thioredoxin-
interacting protein (TXNIP) in the hippocampus of male mice [57]. Calcitriol treatment
(100 ng/kg, p.o.) for 10 weeks in ovariectomized female Sprague–Dawley rats was also
effective in producing neuroprotective effects by regulating the adenosine monophosphate
(AMP)-activated protein kinase (AMPK)/NF-kB signaling pathway. Moreover, calcitriol
treatment reduced the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as iNOS
Int. J. Mol. Sci. 2022, 23, 7077 8 of 14

and cyclooxygenase-2 (COX-2) levels in the hippocampus [97]. This suggests that the
modulation of the NLRP3 inflammasome-driven pathway may underlie, at least in part,
the antidepressant-like effect of this vitamin.
More recently, Bakhtiari-Dovvombaygi et al. (2021) also reported that the anti-inflammatory
and antioxidant effects displayed by pretreatment with vitamin D3 (10,000 IU/kg for 28 days)
in male rats underlie the ability of this vitamin to abrogate anxiety- and depressive-like
behaviors induced by chronic unpredictable mild stress (CUMS) in the elevated plus-maze
and forced swimming test. Indeed, these protective effects of vitamin D were accompanied
by a decrease in cortical malondialdehyde and IL-6 levels, as well as an increase in total
thiol levels and enhanced SOD and catalase activity [98]. Interestingly, another study
observed that following 4 weeks of CUMS, the occurrence of depressive-like behaviors
was associated with an increase in 1,25(OH)2 D and VDR expression in the hippocampus of
rats, suggesting a compensatory mechanism, by which vitamin D may protect against the
development of depressive-like behaviors [99].
In addition to attenuating depressive- and anxiety-like behaviors through its anti-
inflammatory and antioxidant properties, the modulation of neurotrophic factors has also
been shown to contribute to the protective properties of vitamin D [76]. Xu et al. used
male C57BL/6 mice to show that calcitriol (25 µg/kg/day for 4 weeks; i.c.v.) is effective in
acting as an antidepressant in a post-stroke depression model by up-regulating VDR and
BDNF expression [75]. In an ovariectomized Wistar rat model of depression induced by
CUMS, vitamin D3 (5 mg/kg for 4 weeks; s.c.) treatment was able to reverse depression-
like behaviors in the sucrose preference test and the forced swimming test by increasing
BDNF and NT-3/NT-4 levels in the hippocampus [76]. Although these studies showed that
vitamin D supplementation results in an increase in pro-neurogenic neurotrophins, such as
BDNF, Groves et al. observed that vitamin D deficiency in BALB/c mice was associated
with depressive-like behaviors without compromising hippocampal neurogenesis [100].
Therefore, further studies are needed to elucidate whether neurogenesis is critical for the
anxiolytic and antidepressant effects of this vitamin.

6. Clinical Studies: Effects of Vitamin D in Depression and Anxiety

Several studies have reported that vitamin D supplementation improves symptoms
of depression and anxiety associated with various medical conditions, including type II
diabetes, Crohn’s disease, ulcerative colitis, and obesity [101–105].
However, the potential therapeutic effects of vitamin D in individuals primarily
diagnosed with depression or anxiety remain controversial. For example, vitamin D supple-
mentation (1600 IU for 6 months) was shown to significantly improve anxiety symptoms,
but not depressive symptoms, in patients with vitamin D deficiency [106]. Likewise, sup-
plementation with 2800 IU of vitamin D in patients with depression did not promote a
significant reduction in Hamilton D-17 scores [107]. On the other hand, supplementation
with 50,000 IU of vitamin D for 2 weeks was able to improve depression severity, as assessed
with the Beck Depression Inventory-II (BDI-II), although no changes in serotonin levels
were detected [108]. However, in another study, cholecalciferol treatment (50,000 IU for
3 months) significantly increased serum serotonin levels, while decreasing BDI scores in
women with moderate, severe, and extreme depression. Interestingly, among men, an
improvement in the severity of depressive symptoms with vitamin D supplementation
was only observed in those diagnosed with severe depression [83]. Beneficial effects of
vitamin D (50,000 IU for 8 weeks) supplementation have also been observed in older
adults (over 60 years of age) with depression [109]. However, lower doses of vitamin D
(400 IU daily for 2 years) were not able to improve depressive symptoms [110]. Finally, a
single dose of vitamin D (300,000 IU) was reported as an effective and safe intervention
in MDD with concurrent vitamin D deficiency [111,112]. In patients with depression, the
daily administration of 1500 IU vitamin D3 plus 20 mg fluoxetine for 8 weeks was supe-
rior to fluoxetine alone [113]. Another study reported that vitamin D supplementation
(50,000 IU once/week for 3 months) in combination with standard of care improved the
Int. J. Mol. Sci. 2022, 23, 7077 9 of 14

severity of anxiety in individuals diagnosed with Generalized Anxiety Disorder by in-

creasing serotonin concentrations and decreasing the levels of the inflammatory biomarker
neopterin [114]. Overall, although there is compelling clinical evidence pointing to the
benefits of vitamin D for the management of depression and anxiety, it is important to note
that divergent results have also been obtained [46]. Multiple factors may contribute to
these discrepant results, including differences in the doses of vitamin D used, treatment
time, serum 25-hydroxyvitamin D levels at baseline, nutritional condition at the onset of
the treatment, age and sex of the individuals, as well as the presence of comorbidities that
may influence the efficacy of vitamin D supplementation. Additionally, the heterogeneity
observed in clinical studies may also be associated with genetic polymorphisms that may
affect vitamin D efficacy [115–117].

7. Conclusions and Future Directions

In this review, we discussed the main evidence underlining the therapeutic potential of
vitamin D in the management of depression and anxiety disorders. Of particular relevance,
compelling evidence suggests that vitamin D possesses antioxidant, anti-inflammatory,
pro-neurogenic, and neuromodulatory properties, and, thus, may act in a similar manner
to classic antidepressants. In support, several preclinical studies have shown the beneficial
effects of vitamin D supplementation in animal models of these mood disorders. Given
this, some studies have investigated the possible synergistic or additive beneficial effects of
vitamin D and current pharmacotherapy for the management of anxiety and depression.
However, the clinical studies that assess the efficacy of vitamin D supplementation in
the treatment of depression and anxiety are still scarce and their results are, at times,
controversial. The discrepant results from clinical trials call for the need to conduct future
studies, so as to establish a protocol for vitamin D supplementation that is effective in
preventing or attenuating depressive and anxiety symptoms. Therefore, appropriately
randomized clinical trials assessing the potential of vitamin D as co-adjuvant for the
treatment of these mood disorders are warranted, so as to ascertain the true therapeutic
value of this vitamin in the context of depression and anxiety.

Author Contributions: B.R.K.: conceptualization and writing of original manuscript draft. A.C.:
writing of original manuscript draft. J.G.-M.: review and editing of the manuscript and funding
acquisition for manuscript publication. A.L.S.R.: conceptualization, supervision, review and editing
of the manuscript, and funding acquisition. All authors have read and agreed to the published
version of the manuscript.
Funding: The authors acknowledge funding from Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq; #421143/2018-5 and #312215/2021-5) and Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (CAPES). J.G.M. acknowledges funding from the University of Victoria
(UVic, Victoria, BC, Canada)—São Paulo Research Foundation (FAPESP, São Paulo, SP, Brazil) SPRINT
partnership (UVic-FAPESP SPRINT 1/2018 Grant). A.L.S.R. is CNPq Research Fellow.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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