Depression and Vitamin D: A Peculiar Relationship

Abstract

Depression is a psychiatric disorder characterized by various symptoms that can impact one's quality of life. Vitamin D, a fat-soluble vitamin, is well-known for its role in bone health, and research on its effects on mental health has only recently emerged. Vitamin D deficiency is widespread worldwide, and it has been linked to an increased risk of depression. In this article, we have discussed different hypotheses that explain the role of vitamin D in gene expression and its effects on neurotransmitters and different brain functions. We have reviewed literature that shows us that Vitamin D deficiency is a risk factor for depression and explored studies that show us the effects of using or supplementing Vitamin D in preventing depression among various populations.

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Review began 04/08/2022
Review ended 04/21/2022
Published 04/21/2022
© Copyright 2022
Saji Parel et al. This is an open access
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Depression and Vitamin D: A Peculiar
Relationship
Nisha Saji Parel , Parimi Vamsi Krishna , Anuradha Gupta , Kamsika Uthayaseelan , Kivonika
Uthayaseelan , Monika Kadari , Muhammad Subhan , Sripada Preetham Kasire
1. Family Medicine, Tbilisi State Medical University, Tbilisi, GEO 2. Internal Medicine, Jagadguru Jayadeva
Murugarajendra Medical College, Davanagere, IND 3. Research, Government Medical College Nagpur, Nagpur, IND 4.
Internal Medicine, All Saints University College of Medicine, Saint Vincent and the Grenadines, Kingstown, VCT 5.
Internal Medicine, All Saints University School of Medicine, Dominica, Roseau, DMA 6. Internal Medicine, Bhaskar
Medical College, Hyderabad, IND 7. Internal Medicine, Jinnah Hospital, Lahore - Allama Iqbal Medical College, Lahore,
PAK 8. Internal Medicine, Mamata Medical College, Hyderabad, IND
Corresponding author: Nisha Saji Parel, nishaparel@gmail.com
Abstract
Depression is a psychiatric disorder characterized by various symptoms that can impact one's quality of life.
Vitamin D, a fat-soluble vitamin, is well-known for its role in bone health, and research on its effects on
mental health has only recently emerged. Vitamin D deficiency is widespread worldwide, and it has been
linked to an increased risk of depression. In this article, we have discussed different hypotheses that explain
the role of vitamin D in gene expression and its effects on neurotransmitters and different brain functions.
We have reviewed literature that shows us that Vitamin D deficiency is a risk factor for depression and
explored studies that show us the effects of using or supplementing Vitamin D in preventing depression
among various populations.
Categories: Family/General Practice, Internal Medicine, Psychiatry
Keywords: age and depression, serum vitamin d levels, serum 25-hydroxy vitamin d level, depression in elderly, post
partum depression, depression, depression prevention, vitamin d supplementation, vitamin-d deficiency, vitamin d &
depression
Introduction And Background
Major depressive disorder (MDD) is a psychiatric illness marked by various symptoms that can harm one's
quality of life [1]. The earliest recorded reports of what is now considered depression were seen in the second
millennium B.C.E in Mesopotamia, where depression was considered a spiritual affliction rather than a
mental disorder [2]. During the 1970s, physicians in the United States coined the term major depressive
disorder [3]. In 1980, it officially became a part of the Diagnostic and Statistical Manual of Mental Disorders-
III (DSM) [3]. In 2008, WHO ranked MDD as the third cause of burden of disease and has estimated that by
2030 this disorder will rank first [4]. MDD is two times more prevalent in women than men [5]. People with
comorbid psychiatric disorders such as social anxiety and panic disorders or substance use have a higher risk
of suicide when diagnosed with MDD [6]. Genetic and environmental factors contribute to the etiology of
depression, and some studies report that genetic factors mainly play a role in early-onset depression [7]. In
the elderly, strokes, seizure disorders, neurodegenerative diseases, and chronic pain have been implicated
with greater risk for developing depression [7]. Other environmental factors such as financial problems,
traumatic experiences, death of a loved one, conflicts, and lack of social support are other examples that
could trigger depression in an individual [7]. The underlying pathophysiology has not been clearly
understood; however, earlier evidence shows that there are abnormalities in neurotransmitters like
serotonin (5-HT), norepinephrine (NE), dopamine (DA), glutamate, and brain derived neurotrophic factor
(BDNF) [7]. The multifactorial reasons contributing to depression can cause modifications in
neuroendocrine and behavioral reactions, which can cause functional and anatomical alterations such as
enhanced hyperintensities in subcortical areas and decreased anterior brain metabolism on the left side,
respectively [6].
The following is a list of the DSM-5's nine symptoms (Table 1) [7]. To make a clinical diagnosis, five
symptoms out of the nine must be present (one of which should be a sad mood or anhedonia):
1 2 3 4
5 6 7 8
Open Access Review
Article DOI: 10.7759/cureus.24363
How to cite this article
Saji Parel N, Krishna P, Gupta A, et al. (April 21, 2022) Depression and Vitamin D: A Peculiar Relationship. Cureus 14(4): e24363. DOI
10.7759/cureus.24363

Sl. no. DSM-5 Criteria
1. Feeling sad/low
2. Anhedonia
3. Thoughts of unworthiness/guilt
4. Changes in energy/fatigue
5. Psychomotor retardation or agitation
6. Difficulty concentrating
7. Changes in appetite/weight
8. Thoughts of suicide/death
9. Difficulty sleeping
TABLE 1: Clinical features of depression
DSM-5 - Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
Depression can be managed by different treatment approaches, which include lifestyle modification,
pharmacological (such as selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake
inhibitors (SNRIs), atypical antidepressants, serotonin-dopamine activity modulators (SDAMs), tricyclic
antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs)) [8-13], interventional and
psychotherapeutic approaches (such as cognitive behavioral therapy) [6], and combining pharmacological
and psychotherapeutic approaches have been proven to be more effective in treatment [14-16]. For severe
major depression, electroconvulsive therapy has been more effective than any other therapeutic option [17].
The various treatment approaches to depression are summarized in Table 2.
Types of
treatment Mechanisms
Lifestyle
Modifications Improving quality of sleep, exercise, healthy eating, meditation, stress management, avoiding alcohol/drug use
Classes of
Medications
SSRI-inhibit reuptake of 5HT by binding to SERT; SNRI-inhibit reuptake of both serotonin and NE by binding to SERT and NET and
weakly inhibits dopamine reuptake; TCA-inhibit reuptake of both 5HT and NE by binding to SERT and NET, antihistamine &
anticholinergic; MAOI inhibits the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and
increasing their availability; SDAMs- partial agonist at 5-HT1A and D2 receptors and an inhibitor at 5-HT2A and NE alpha type 1B and
type 2C receptors, with similar potencies; Atypicals - dopamine reuptake inhibitor, 5HT receptor modulator, inhibits alpha two
receptors
Psychotherapy:
CBT,
Interpersonal
and
psychodynamic
It aids in the recognition and modification of negative thoughts and behaviours.
ECT A seizure is triggered by electrical stim ulation when used a few times a week for a short time and eliminates depression symptoms for
a prolonged time.
TABLE 2: Summary of various approaches to management of depression
SSRI- selective serotonin re-uptake inhibitor, 5HT- serotonin, SERT- serotonin transporter, NE- norepinephrine, SNRI- serotonin norepinephrine reuptake
inhibitor, NET- norepinephrine transporter, TCA- tricyclic antidepressants. MAOI- m onoamine oxidase inhibitor, SDAM- serotonin dopamine activity
modulator, 5HT1A- serotonin type 1A receptor, D2- dopamine type 2 receptor, 5HT2A-serotonin type 2A receptor, CBT- cognitive behavioral therapy, ECT-
electroconvulsive therapy
Hypovitaminosis can lead to various conditions, some of which affect mental health [18]. An increasing
number of studies link depression with vitamin D deficiency [19]. Since it is theorized that vitamin D plays a
2022 Saji Parel et al. Cureus 14(4): e24363. DOI 10.7759/cureus.24363 2 of 10

role in gene expression, it regulates the level of 5-HT, DA, and NE receptors in the brain, and low vitamin D
levels result in a decrease of these neurotransmitters, which leads to depression [20-23]. This article aims to
discuss the role and association of vitamin D in the pathophysiology and management of depression,
highlight the impact of vitamin D deficiency and depression in different population groups, and look into
the possibility of using vitamin D as an adjunct to antidepressants for a better prognosis.
Review
Vitamin D, a fat-soluble vitamin, can be obtained from various sources, including sun exposure, regular
dietary intake, and dietary pills [24]. Ultraviolet (UV) B radiation from sunlight enters the skin and
transforms 7-dehydrocholesterol to previtamin D3, quickly transforming to vitamin D3 [25]. UV light
irradiation produces vitamin D2 from yeast, while vitamin D3 is made by UV irradiation of 7-
dehydrocholesterol from lanolin [24]. Vitamin D that is absorbed from the skin and dietary intake is
converted in the liver to 25-hydroxyvitamin D (25(OH)D), which can be used to assess a patient's vitamin D
level [25-28]. The kidneys then convert 25(OH)D by the enzyme 25(OH)D-1α-hydroxylase (CYP27B1) to its
active form, 1,25-dihydroxy vitamin D [25-28]. It subsequently binds to vitamin D receptors in target organs
to control gene transcription and cell membrane structures to conduct different non-genomic responses
[29]. Vitamin D receptors are seen in almost every tissue and cell in the body [30,31]. In the brain, it can be
found primarily on the hippocampus, prefrontal cortex, hypothalamus, cingulate gyrus, substantia nigra,
and thalamus [30,31]. This is important because many of those brain areas have been linked to depression's
physiology [32]. According to increasing research, vitamin D is a neuroactive steroid that plays a critical role
in the expression of neurotransmitters with its regulation and neuroimmunomodulation, antioxidant
production, and various neurotrophic factors, making it biochemically plausible that vitamin D is associated
with depressive symptoms [33]. Although the mechanism by which vitamin D works in the body is unknown,
a few hypotheses show us an association between these two [33].
According to the neurotrophic hypothesis, immunohistochemical research has discovered vitamin D
receptors (VDRs) in the central nervous system (CNS), providing a solid indication that vitamin D plays a
significant role in brain functions [33]. VDRs are found all over the brain, including the hippocampus, which
plays a role in controlling memory and emotional function [33]. Because the hippocampus is vital in the
causes of depression, discovering VDR within it has encouraged many researchers to investigate the effects
of vitamin D on hippocampal shape and function in animals [34]. Numerous investigations using in vitro
culturing of hippocampus cells and in vivo experiments on the brains of adult mice have revealed that
vitamin D deficiency can alter the shape or function of the hippocampal development [33]. Croll et al.
conducted a cross-sectional analysis on 2716 people in the Netherlands (from 2006 to 2009), which showed
that those with vitamin D deficiency (serum concentration 30 nmol/L) had decreased brain tissue and
hippocampal volume, as seen in their brain magnetic resonance imaging (MRI) [35].
Numerous studies have demonstrated that vitamin D is a potent regulator of the production of neurotrophic
substances, such as BDNF, a neurotrophin (NT)-3, and nerve growth factor (NGF) [33]. Neurotrophic factors
are necessary for neuron survival, development, and migration, in which they drive their physiological
function by combining with their corresponding tropomyosin-related kinase (Trk) receptors, including
BDNF/TrkB, NT-3/TrkC, NGF/TrkA, as well as the common p75 neurotrophin receptor (p75NTR) [36]. Various
research has shown that 1,25(OH)2D can enhance the production of BDNF, NGF, and NT-3 and
downregulate NT-4 in the astrocytes of the brain, indicating that vitamin D plays a role in neuronal survival
and differentiation during the development [37,38]. In the adult hippocampus, BDNF is critical for the long-
term viability, specialization, and performance of new neurons [33]. NT-3 and NT-4 are necessary for the
survival of growing neurons and for the differentiation and proliferation of precursor cells, thereby directly
or indirectly affecting the cause of depression [33]. As a result, vitamin D can influence neurotrophic agents,
whose aberrant performance has been linked to various psychiatric disorders [33]. According to the classic
monoamine neurotransmission hypothesis, the deficiency of monoamines such as 5-HT, DA, and NE can
cause depression [33].
On the other hand, vitamin D deficiency may interfere with the synthesis of 5-HT, resulting in the aberrant
development of serotonergic and brain neurons [33]. 5-HT also functions on the hippocampus, where the
production of new neurons and synaptic plasticity have been linked to the onset and treatment of
depression [33]. The VDR is found in dopaminergic neurons in the substantia nigra, prefrontal cortex, and
hippocampus of humans and rats, all of which are linked to depression [39]. Vitamin D deficiency can cause
a delay in DA cell differentiation because of its effects on VDR expression in the substantia nigra, which can
lead to DA-mediated behavioral deficits [40]. It also suggests that vitamin D deficiency can affect
dopaminergic neuron development and have severe effects on the evolution of depression [33]. Hence,
vitamin D directly or indirectly influences the levels of monoamines in the body and is involved in the
pathogenesis of depression [33].
Literature review of the association between vitamin D and depression
In Adults and Elderly
It is crucial to note that vitamin D deficiency has been seen in a range of populations, including children,
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adolescents, adults, and the elderly, irrespective of race, ethnicity, or nation [41-43]. Depression is related to
cardiovascular (CV) events, and it has been indicated that vitamin D deficiency may be linked to depression
and a significant contributor to a higher risk of CV events [44]. May et al. conducted a nine-year cohort study
in Utah, USA, which found that lower vitamin D levels were significantly associated with depression among
7358 patients aged 50 years or older with cardiovascular disease [44]. In the elderly, vitamin D deficiency is a
risk factor for developing depression [45]. Milaneschi et al. conducted a population-based cohort study in
Tuscany, Italy, to explore the connection between 25(OH)D levels and depression symptoms in 423 men and
531 women aged 65 years and older over six years [45]. Men (hazard ratio = 1.6; 95 % confidence interval (CI)
= 0.9-2.8; P = 0.1) and women (hazard ratio = 2.0; 95 % confidence interval (CI) = 1.2-3.2; P = 0.005) with a
serum 25(OH)D of less than 50 nmol/L had a higher risk of depression, with the magnitude of the potential
association being greater in women than in men [45]. The study mentioned above is similar to a cohort study
by Chan et al. in Hong Kong, China, which included 939 males aged 65 and up [46]. The results demonstrated
that there is an inverse relationship between serum 25(OH)D and depression (odds ratio = 0.46, 95 percent
CI: 0.22-0.98, P=0.004) in 629 males after a four-year follow-up period [46]. A non-interventional
prospective cohort study done by Lee et al. in Europe also concluded an inverse relationship between
depression and 25(OH)D levels [47]. The study had included 3369 men, aged between 49 to 71 years, that
were taking part in the European Male Ageing Study, depression was evaluated using the Beck Depression
Inventory-II (BDI-II), and radioimmunoassay was used to assess serum 25(OH)D and parathyroid hormone
(PTH) levels [47]. Its results showed decreased levels of 25(OH)D were associated with increased BDI-II score
(p = 0.004) [47]. Late-life depression can also be linked to vitamin D deficiency [48]. According to Stewart and
Hirani's data analyzed among 2070 people in England 65 years or older showed that depressive symptoms
were related to vitamin D deficiency when the 25(OH)D levels were lower than 10ng/mL [48].
In Women and During Pregnancy
Vitamin D deficiency has traditionally been known to harm the bones, such as having osteopenia and
osteoporosis due to having low bone mineral density (BMD) [49]. Premenopausal women with depression
and older African-American adults with Vitamin D deficiency are more likely to have low BMD [49,50].
Depression is the most common mood illness in pregnancy and postpartum due to significant hormonal,
physical, and social changes [51]. In developing countries, the occurrence of depression in pregnancy has
been estimated to be as high as 20%, while it was between 10% and 15% in developed countries [52].
Moreover, 20-40 percent of women globally suffer from postpartum depression (PPD), which is defined as a
nonpsychotic depressive disorder that occurs within a year following childbirth [53,54]. Lower levels of
Vitamin D in pregnant women have resulted in increased depressive symptoms [55]. A study by Cassidy-
Bushrow et al. in Detroit that assessed vitamin D levels and depression screening in 178 pregnant African
American women showed that there was a strong inverse correlation between log (25-OHD) and Center for
Epidemiologic Studies-Depression scale (CES-D) score of ≥16 [54]. The chances of CES-D ≥16 decreased by
46% for every 1-unit rise in log (25-OHD) (equivalent to 2.72 ng/mL increase in 25-(OH)D) (OR=0.54, 95% CI.
0.29-0.99, p=0.046) [55]. The above study results are comparable to a cohort study done in Amsterdam by
Brandenbarg et al. among 4101 pregnant women whose vitamin D levels were assessed at 13 weeks gestation
[56]. Screening for depression was done using the CES-D scale (score ≥ 16) at 16 weeks gestation, and the
study concluded that early-pregnancy vitamin D deficiency was linked to increased depression symptoms
during pregnancy [56]. Gur et al. conducted a cohort study in Turkey that included 179 pregnant women
between 24 and 28 weeks of pregnancy [57]. Depression was screened for using The Edinburgh Postnatal
Depression Scale (EPDS), and vitamin D levels were assessed [57]. The above study is similar to a cohort
study done by Fu et al. in Beijing, China, where serum vitamin D levels were assessed 24-48 hours
postpartum, and EPDS was used to screen for depression (score ≥12) three months postpartum [58]. The
study also concluded that lower 25(OH)D levels were linked to PPD [58]. The above-mentioned studies [44-
48, 54, 56-58] are summarized in Table 3 below:
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References Type of
study
Sample
size Population Location Diagnostic criteria Conclusion
May et al. (2010)
[44] COHORT 7358
Adults aged 50
years or older with
CVD
UTAH, USA
Depression- ICD-9 Vit D-
>50, 31-50,16-30 and or =
15
Vit D levels were significantly
associated with depression .
Milaneschi et al
(2010) [45] COHORT 954 Age ≥65 years TUSCANY,
ITALY
Depression- CES-D Vit D- <
50nmol/L
VDD is a risk factor for the development
of depression.
Chan et al.
(2011) [46] COHORT 939 Men aged ≥65
years
HONG
KONG,
CHINA
NA Inverse relationship exists between
serum 25(OH)D and depression
Lee et al. (2011)
[47] COHORT 3369 Men aged 49-71
years EUROPE
Depression- BDI-II Vit D and
PTH levels by
radioimmunoassay
Inverse relationship between
depression and 25(OH)D levels
Stewart et al.
(2010) [48] NA 2070 Adults ≥ 65 years ENGLAND Depression- GDS Vit D
levels Late-life depression is linked to VDD
Cassidy-
Bushrow et al.
[54] (2012)
NA 178 African- American
Pregnant women
DETROIT,
USA
Depression- CES-D Vit D
levels
Increased depressive symptoms were
seen in pregnant women with lower Vit
D levels
Brandenbarg et
al. [56] (2012) COHORT 4101 Pregnant women AMSTERDAM Depression- CES-D Vit D
levels
Increased depressive symptoms were
seen in pregnant women with lower Vit
D levels
Gur et al. [57]
(2014) COHORT 179 Pregnant women TURKEY Depression- EPDS Vit D
levels
VDD during pregnancy may have a role
in the onset of PPD
Fu et al. [58]
(2014) COHORT 213 Pregnant women BEIJING,
CHINA
Depression- EPDS Vit D
levels PPD associated with low vit D levels
TABLE 3: Summary of included studies linking depression and vitamin D deficiency
BDI-II - Beck Depression Inventory-II, Vit D-Vitamin D, PTH- Parathyroid hormone, 25(OH)D-25 - Hydroxyvitamin D, ICD-9 - International Classification of
Diseases, Ninth Revision, GDS- Geriatric Depression Scale, VDD- Vitamin D Deficiency, CES-D - Center for Epidemiological Studies-Depression Scale,
EPDS- Edinburgh Postnatal Depression Scale, PPD- Postpartum depression, NA- not available
Treatment and management
Even though studies evaluating the relationship between vitamin D and mental well-being use a variety of
study groups, outcomes, and behavioral assessments, the findings are consistent, suggesting that vitamin D
blood levels or supplementation may positively influence mental health [59]. Based on these observations, it
is possible to conclude that vitamin D is essential for mental health, regardless of the examined group or
effect linked with mental health [59].
In Adolescents
Högberg et al. concluded a positive association between vitamin D supplementation and improvement of
depressive symptoms in depressed adolescents with low serum 25(OH)D in Sweden [60]. Their mean serum
25(OH)D was 41 nmol/L at baseline and 91 nmol/L (p < 0.001) after supplementation, with a significant
amelioration of depression according to the Mood and Feelings Questionnaire (MFQ-S) (p < 0.05) [60]. This
study is similar to the interventional study done in Iran by Bahrami et al., where for nine weeks, 940
adolescent girls were given vitamin D3 at a level of 50,000 IU/week, and a substantial reduction in
depression scores (8 (4-16) vs 7 (2-14); p =.001) after nine weeks of vitamin D treatment along with a
dramatic increase in median serum 25(OH)D levels (6.7 ng/mL at baseline vs 35.5 ng/mL after the
intervention; p >.001) was noticed [61]. Their results indicate that vitamin D supplementation benefits
adolescents with depressive symptoms and low levels of vitamin D at baseline [60,61].
In Adults
Sepehrmanes et al. randomly assigned adults diagnosed with MDD to receive 50,000 IU of Vitamin D (n = 20)
or placebo (n = 20) for eight weeks (Table 4) [62]. Improvements in serum 25(OH)D concentrations were
considerably greater in the vitamin D group (+20.4 μg/L) than compared to the placebo group (-0.9 μg/L, P <
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0.001) after eight weeks of intervention. Also, there was a trend toward a higher decline in the BDI scores in
the vitamin D group than in the placebo group [62]. This study can be compared to a cross-sectional and
interventional analysis done by Stokes et al. [63], in which 77 depressed patients with chronic liver disease
were given 20,000 IUs of Vitamin D for six months (Table 4). In the study's conclusion, it was seen that the
severity of depression was inversely related to vitamin D serum levels (β = -0.483, P = 0.004). BDI-II scores
also improved significantly from baseline after three and six months (P = 0.003 and P = 0.004, respectively),
and vitamin D's antidepressant impact was found to be more prevalent in women in subgroup studies [63].
In Pregnancy
According to Vaziri et al., vitamin D supplementation during pregnancy can help decrease perinatal
depression (Table 4) [64]. One hundred sixty-nine pregnant women received 2000 IU of vitamin D3 or a
placebo every day from 26 to 28 weeks of pregnancy until delivery. Although both groups had comparable
baseline 25(OH)D concentrations, the vitamin D group had a considerably greater 25(OH)D concentration
than the control group at childbirth (p 0.001). There was no link between 25(OH)D concentration and
depression score at the start (r = 0.13, p = 0.09). While the vitamin D group had a bigger reduction in
depression scores than the control group at 38-40 weeks of pregnancy (p = 0.01), the vitamin D group also
showed a greater reduction in depression scores at four and eight weeks after birth (p 0.001) [64].
In Conjunction With Other Antidepressants
Vitamin D combined with other antidepressants could be beneficial in managing depression. Khoraminya et
al. randomized adults with depression into two groups to receive a combination of 1500 IU Vit D3 and
fluoxetine or fluoxetine alone (Table 4) [65]. At the end of eight weeks, the study showed that vitamin D and
fluoxetine combination was more effective than fluoxetine alone in managing depression. Mozaffari-
Khosrav et al. studied randomized patients (diagnosed with depression and had vitamin D deficiency) to
verify if correcting vitamin D deficiency alleviates depressive symptoms (Table 4) [66]. One hundred twenty
patients received an intramuscular injection of 150,000 IU vitamin D (n = 40) or 300,000 IU vitamin D (n=40)
or nothing (n=40). After three months, it was found that there was a significant difference in mean BDI II
test score (P = 0.003) between the group that received 300,000 IU vitamin D injection and the group that
received nothing. The study's findings demonstrated that correcting vitamin D deficiency alleviates
depressive symptoms and that a single injectable dose of 300,000 IU of vitamin D was both safe and
beneficial compared to a 150,000-IU dose [66]. Therefore, management of depression with vitamin D
supplementation can significantly impact, as vitamin D is both an effective antidepressant and a cost-
efficient option [33]. While those with severely low levels of serum vitamin D would benefit from
supplements, people with adequate amounts of serum vitamin D levels will not benefit from it and would
not notice a reduction in depression [33].
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References Type of
study
Sample
size Population Location Duration Intervention Diagnostic
criteria Conclusion
Sepehrmanesh
et al. [62] 2015 RCT 40
Aged
between
18-65
years
Diagnosed
with MDD
NA 8 weeks
50,000 IU vit D
per week (n =
20) or placebo
(n = 20)
BDI Vit D
level
Glucose,
CRP Lipid
profile
improvement of BDI score after
Vit D supplementation
Stokes et al.
[63] 2016
Cross
sectional &
Interventional
188
Chronic
liver
disease
patients
with
depression
GERMANY 6 months 20,000 IU per
week
BDI-II Vit D
leveL
BDI-II scores improved
significantly from baseline after
three and six months & Vit D's
antidepressant impact was found
to be more prevalent in women
in subgroup studies
Vaziri et al. [64]
2016 RCT 169
Pregnant
women ≥18
years, GA
26-28 week
SHIRAZ,
IRAN
From 26-
28 week
gestation
to 8 week
postpartum
2000 IU Vit D3
daily from 26 to
28 weeks of
gestation until
delivery.or
placebo
EPDS Vit d
level
Use of 2000 IU vitamin D3 per
day throughout late pregnancy
was found to be beneficial in
decreasing perinatal depression.
Khoraminya et
al. [65] 2013 RCT 42
Aged
between
18-65
years
Diagnosed
with MDD
TEHRAN 8 weeks
1500 IU VitD3
+ 20 mg
fluoxetine or
fluoxetine
alone
HDRS BDI
Vit D level
Vit D and fluoxetine combo is
more effective than fluoxetine
alone.
Mozaffari-
Khosrav et al.
[66] 2013
RCT 120
Depressed
patients
with VDD
YAZD,
IRAN 3 months
1 single
injection of
150,000 IU or
1 single
injection of
300,000 IU of
vit D or none
BDI-II Vit D
level Ca, P,
PTH
Correcting vitamin D deficiency
alleviates depressive symptoms,
and a single injectable dose of
300,000 IU of vit D was both
safe and beneficial when
compared to a 150,000-IU dose
TABLE 4: Summary of included studies showing the association between vitamin D
supplementation and depression
RCT- randomised controlled trial, GA- gestational age, MDD - major depressive disorder, VDD- vitamin D deficiency, IU- International units, Vit D- Vitamin
D, BDI- Beck depression inventory, EPDS- Edinburgh Postnatal Depression Scale, CRP- C-reactive protein, Ca- Calcium, P- phosphate, PTH-
Parathyroid hormone, HDRS- Hamilton D epression Rating Scale, NA- not available
Limitations
The causes of depression are multifactorial and include multiple genetic, environmental, and social factors,
and this article has solely focused on the causes and effects of vitamin D deficiency. Also, this study does not
address the effect of vitamin D deficiency in the paediatric population.
Conclusions
In this article, we discussed depression and determined vitamin D's relationship with depression in its
pathogenesis and management across various population groups. We notably discussed how vitamin D
deficiency could impact brain structure, function, and effects among adults. The inverse correlation between
depression and serum vitamin D levels and the therapeutic benefits of supplementing vitamin D levels
highlights the clinical implication of this article. Depressed patients require a tailored approach to
treatment, and vitamin D levels should be evaluated as part of their routine assessment. Furthermore, we
feel that additional studies need to be conducted in exploring vitamin D's relationship with depression
management and universally defining low vitamin D status, thereby formally correlating the two to form an
integrated approach to managing depression.
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Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
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