Gender Differences in Vitamin D and Depressive Symptoms: A Systematic Review

Abstract

Background: Both vitamin D insufficiency and depression are major public health concerns particularly in women. Recent animal and cross-sectional studies have suggested an association between low vitamin D levels and increased depressive symptoms with some evidence that vitamin D supplementation may be more beneficial in women.

Objective: (i) To examine the gender differences in the observational prospective association between vitamin D status (using serum levels) and depressive symptoms; (ii) to determine if vitamin D supplementation is more effective in women than in men.

Methods: MEDLINE, EMBASE, Web of Science & Knowledge, PsychInfo, the Cochrane Library and trial registers were searched with no language restrictions from inception to December 2015.

Results: 22 separate studies met the inclusion criteria, 5 observational prospective studies and 17 RCTs. The most robust cohort study found a significant association only in women. Only seven out of seventeen RCTs found a significant effect of vitamin D on depressive symptoms. Six of these were mixed-sex studies and one was a female only study that had the greatest effect size. The females included in these seven trials were mostly of childbearing age.

Conclusion: There is suggestive evidence of potential benefits of vitamin D supplementation in women of childbearing age with depressive symptoms. Further large randomized placebo-controlled secondary prevention trials in both men and women of childbearing age, with low vitamin D levels, are needed to investigate the relative efficacy of vitamin D supplementation in depression in men and women.

Keywords: Systematic review; Vitamin D; Depression; Gender differences; Randomized control studies; Observational studies; Prevention; Vitamin D; Gender differences; Female

Abbreviations

RCT: Randomized Control Trial; BDI: Beck Depression Inventory; CES-D: Centre for Epidemiologic Studies –Depression Scale; SCID: Structured Clinical Interview for DSM Disorders; CIDI: Composite International Diagnostic Interview; NOS: Newcastle-Ottawa Quality Assessment Scale; ADL: Activities of Daily Living; SPPB: Short Physical Performance Battery; PTH: Parathyroid Hormone; HDRS: Hamilton Depression Rating Scale; POMS: Profile of Mood States; ANCOVA: Analysis of Covariance; SF-12 MCS: Mental Component of the Short Form 12 Health Survey; HADS: Hospital Anxiety and Depression Scale; MADRS: Montgomery-Asberg Depression Rating Scale; GDS: Geriatric Depression Scale.

Introduction

Depression is the third most common cause of disease burden in the world for both men and women and is the leading cause of disease burden for women in the world [1]. Epidemiological data show that women are twice as likely as men, to develop depression during their childbearing years [2-4]. Furthermore, it is estimated that 1 billion people worldwide have either deficient or insufficient vitamin D levels [5], and some epidemiological data show that women may be more at risk of this than men [6-13] women. Vitamin D fortification of milk was mainstream in Europe in the early twentieth century; however this was banned in the 1950’s due to case reports of hypercalcaemia in children [5].

For both sexes, there is now epidemiological evidence of association of hypovitaminosis D with many non-skeletal health conditions [5,14] and more recently, cross-sectional and cohort studies have shown an association between low vitamin D levels and depression [15-17]. These epidemiological findings are corroborated by biological experimental evidence supporting a potential role of vitamin D in the pathogenesis of depression [18-20].

Given that women are at increased risk of depression and hypovitamonis D, there has already been some interest in the role of vitamin D in depression in women [21]. Some cross-sectional data show that the association between low vitamin D levels and depressive symptoms is stronger in women than in men [22,23]. It is not clear whether this is because women are, a priori, more at risk of hypovitaminosis D or whether there is a specific genderbased interaction between vitamin D and depression. Like the sex hormones, active vitamin D is a steroid hormone and there is evidence that oestrogen promotes the potency of vitamin D protective effects in animals and humans [24, 25].

One existing systematic review and meta-analysis [26] reported a modest significant effect of vitamin D supplementation on depressive symptoms in adults with depressive symptoms. Another metaanalysis [27] after eliminating studies with biological flaws also found benefit of vitamin D supplementation. In this systematic review, however we aim to investigate any sex-interaction in the association between vitamin D levels and depressive symptoms and in the effect of vitamin D supplementation on depressive symptoms, which has not been explored yet. From current evidence of micronutrient supplementation trials, where, supplementation is more effective in high-risk individuals [28], we hypothesise that the effect of vitamin D supplementation will be most clearly seen in (a) those with depressive symptoms at baseline of both sexes and (b) those who are vitamin D deficient. Furthermore, given the oestrogen promoted differences in local vitamin D metabolism, we hypothesize that both effects (a) and (b) will be greater in women than in men.

Materials and Methods

Search strategy and study selection

The following electronic databases were systematically searched with no language restrictions from their inception to December 2015; In MEDLINE; EMBASE; Web of Science; Web of knowledge; Web of Knowledge and Science (title); Psych Info; Cochrane Library and Meta RCT trial registers. Existing reviews and articles retrieved from the search terms were scanned for further studies and hand searching of various relevant journals was also performed. Due to the diverse nomenclature of vitamin D, extensive search strategies were created and tailored to individual databases. The search strategy for the various databases is shown in the appendix.

Studies met the inclusion criteria if they fulfilled the following criteria:

• Study design - observational prospective studies (cohort/ nested case control studies) or Randomized Control Trials (RCTs).
• Participants - Adults > 18 years free of depressive disorder at baseline for prospective observational studies and primary prevention trials and with a diagnosis of depressive disorder (either clinically or from validated depression/mood scales) for secondary prevention trials. Those with pregnancy, kidney, thyroid or parathyroid disease were excluded.
• Exposure/intervention – 25-hydroxyvitamin D3 serum levels or any vitamin D supplementation (including multivitamin compound containing vitamin D).
• Outcomes - change in depression/mood scores on a validated, standardized measure, diagnosis or no diagnosis of depressive disorder based on a clinical diagnosis, or a validated, standardized measure (e.g. BDI or CES-D etc.) or interview (e.g. SCID or CIDI).

After database searching, one author independently screened the titles and abstracts for potential relevance. Following this initial screening, full reports of short-listed studies were obtained and two of the study authors (CD & KR) independently assessed the studies for inclusion using the pre-specified inclusion criteria outlined above. If there was any disagreement over study inclusion a third author was consulted (SS).

Methodological quality

CD and KR independently assessed methodological quality by examining the method of randomization, allocation concealment, blinding and losses to follow-up for RCTs and by using the Newcastle- Ottawa Quality Assessment Scale to assess the quality of the cohort studies [29].

Analysis

Cohort studies

We planned to pool the adjusted effect estimate of developing depression for those with vitamin deficiency (<50nmol/L), vitamin D insufficiency (<75nmol/L) and sufficient vitamin D levels (>75nmol/L) in a meta-analysis 30.

Randomized control trials

We planned to pool the standardized mean changes in depression scores of participants who received vitamin D supplementation and of those who received placebo.

Results

Study selection

Searching electronic databases yielded 2097 references. (Figure 1) describes the flow of studies through the review. 1823 references were excluded after removal of duplicates and initial screening for relevance. Of the remaining 274 studies, 206 were excluded as they were reviews, animal studies, or cross-sectional studies or had irrelevant content, and 22 studies met the inclusion criteria. No ongoing trials were identified on the Meta RCT trial register. No further studies were identified by scanning the reference lists of relevant studies or by the performing citation searches of the 22 included studies.



Figure 1: Flow diagram of study selection.

Study characteristics

Details of the included studies are found in (Tables 1-5). Five cohort studies and seventeen RCTs met the inclusion criteria. Given the different populations, interventions, controls and outcomes it was inappropriate to pool the data statistically and so a narrative synthesis was performed.

Cohort Studies: Details of the cohort study characteristics are found in Supplementary (Table 1). All five cohort studies involved older adults without a history of depression; four were in both males and females [31-34] and one included only males [35]. For the exposure, the studies used serum 25-hydroxyvitamin D3 levels split into either quartiles [32,35], tertiles [33], ‘deficient’ (<20ng/ml (50nmol/ml) and ‘sufficient’ (>20ng/ml) levels [31] or levels<28nmol/L vs. >28nmol/L [34]. Three studies measured depression using well-validated depression scales, [31,33,35] one study measured depression by clinical diagnosis [32] and another by clinical diagnosis using a diagnostic algorithm [34]. Follow up periods ranged from 6 months [34], 1 year [32], 3 years [31], 4 years [35] and 6 years [33].



Table 1: Cohort Studies investigating association between vitamin D levels and subsequent depressive symptoms.

Randomized control trials: The study characteristics of the female-only RCTs and mixed sex RCTs are found in Supplementary (Tables 2,3) respectively. Seven out of fourteen RCTs recruited only female participants [36-42]. Five of these were in postmenopausal women, [36-40]. Mixed sex trials included fibromyalgia patients [43], obese & overweight subjects [44], acutely ill elderly hospitalized patients [45] and healthy students [46-49].



Table 2: Female only randomised control trial characteristics and summary of effect of vitamin D supplementation on depressive symptoms.



Table 3: Mixed sex randomized control trial characteristics and summary of effect of vitamin D supplementation on depressive symptoms.



Table 4: Newcastle-Ottawa Quality Assessment Scale (NOS) for cohort studies.



Table 5: Methodological quality of randomized control trials.

Two mixed sex trials included adults with a depressive disorder [50,51], one of which included only patients with low vitamin D levels [50]. One female-only study included those with mild-moderate depressive symptoms according to a well-validated depression scale at baseline, but who still did not have an existing clinical diagnosis of depression and who were not taking antidepressants [42]. Most other studies published baseline depressive symptom prevalences of 7% to 37% based on a cut-off on a well-validated scale.

Only two RCTs were specifically conducted among adults with low vitamin D levels [50,52]. Eight studies didn’t measure or report vitamin D levels [39,41,42,45,47-49,53]. Other baseline mean and median vitamin D levels ranged from 49nmol/L to 76.3nml/L [36- 38,44,46,50,51], which is regarded as adequate vitamin D status [54].

As with the participants, the intervention also differed widely between studies. The vitamin D3 dosage differed from low doses such as 200IU daily [41] to high doses of 5700IU daily [44]. The duration of intervention period varied from 2 years [36] to a one off injection [50]. Five RCTS used high dose vitamin D3 supplementation alone [38,43, 46,50,52] whereas three RCTs used low dose vitamin D as part of a multivitamin supplementation [41,42,45]. Six RCTs used vitamin D3 plus calcium as their intervention [36,39,44,47,48,53] and one RCT used vitamin D3 plus vitamin A [49] and one RCT used vitamin D3 plus fluoxetine [51].

Fifteen RCTs [36,37,39,41-48,50-53] measured changes in depression score before and after supplementation on validated scales. Two studies only measured depression scores after supplementation [38,49].

Methodological quality

Cohort studies: The methodological quality of the cohort studies was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS) [29] and see (Table 4) for their star ratings. Milaneschi et al. 2010 [33] had the lowest risk of bias. May et al. 2010 [32] had the high risk of bias with an unclear selection protocol, no adjustment for multiple confounders (other than parathyroid hormone) and unreported loss to follow up. This study and Yue et al. 2014 [34] involved patients with a cardiovascular and cerebrovascular disease, respectively, and so have poor generalizability. Only one study used standardized interviews plus diagnostic algorithm to diagnose depression [34] whereas the rest used less reliable self-report measures [31,33,35] or a clinical diagnosis [32] to diagnose depression. Chan et al. 2011 [35] did not include those with extreme vitamin D levels, had a high loss to follow up of 21% and an inadequate assessment of outcome as they measured prevalent depression at one time point 4 years after exposure rather than a more useful outcome such as incidence over 4 years.

Randomized control trials

The methodological quality of the seventeen included trials was assessed by means of the method of randomization and allocation concealment, blinding and losses to follow-up. Please see (Table 5). Most studies used a computer generated randomization and stated that they used a ‘double blind’ procedure however not all studies explicitly described how they did this.

Other possible biases: Five studies were secondary analyses of trials looking at bone health [36-39,53]. Jorde et al. 2008 [44] was a secondary analysis of a previous study whose primary outcome was weight loss [55]. Gariballa & Forster 2007 [45] was a secondary analysis of a study whose primary outcomes were disability, length of stay and morbidity and mortality [56]. The primary outcomes for Dean et al. 2011 [46] were working memory, response inhibition & cognitive flexibility whereas the depression outcome was one of many secondary outcomes. This was similar for Wepner et al. 2014 [43] whose primary outcomes were fibromyalgia scores.

Association between vitamin D levels and depression

Cohort studies: See Supplementary (Table 1) for the hazard and odds ratios of the five studies. Four out of the five cohort studies found that older adults with ‘deficient’ or ‘insufficient’ vitamin D levels and with no known history of depression have a higher likelihood of developing depression in the following few years than older adults with ‘sufficient’ or ‘optimal’ vitamin D levels [31-34]. The overall adjusted hazard ratios ranged from 1.54 (1.19-1.99) 31 to 2.7 (1.35-5.4) p = 0.00532 to 10.32 (4.97-28.63) p<0.00134 for both men and women. Milaneschi et al. 2010 [33] stratified their results by sex and found that 130 women (43.6%) and 70 men (20.5%) developed depressed mood. After adjustment for age, baseline CES-D, ADL disabilities, use of antidepressants, number of chronic diseases, SPPB, high PTH, and season of collection, both men and women with low vitamin D levels compared to those with sufficient levels showed an increased risk of developing depression over 6 years but this was only statistically significant in women (Women: (<50nmol/l) vs. (>50nmol/l) HR=1.97(1.22-3.17) p=0.005; Men: (<50nmol/l) vs. (>50nmol/l) HR=1.61 (0.92-2.82) p=0.1;). May et al. 2010 [32] also stratified their results by sex and found large but statistically insignificant hazard ratios in males compared to females (males (<<37.5nmol/l) vs. >125nmol/L) HR 6.68, p=0.07; females (<37.5nmol/l) vs. >125nmol/L) HR 2.13, p=0.05). Both Milaneschi et al. 2010 and May et al. 2010 [33,32] did not find any statistically significant vitamin D status-sex interactions. Chan et al. 2011 [35], whose cohort consisted only of older men, did not find any statistically significant association between low vitamin D levels and increased incidence of depression.

Effects of vitamin D supplementation

Randomized control trials: Seven out of the seventeen RCTs found a statistically significant overall effect of vitamin D compared to placebo on depressive symptoms; six mixed sex trials [44,45,47,48,50,51] and one female only trial [42]. The effect sizes were as follows; -5.55 (BDI), -4.7 (HDRS) [51]; -9.3 (BDI II) [50]; -1.5 (BDI) [44]; -5.35 (BDI) [47]; -3.05 (BDI) [48]; -0.58 [45]; female only trial -8.6 (CES-D) and -24.2 (POMS) [42]. The other ten RCTs did not find any statistically significant overall effect of vitamin D compared to placebo on depressive symptoms [36-39,41,43,46,49,52,53].

Effects of vitamin D supplementation in those with depressive symptoms at baseline: Khoraminya et al. 2013 [51] and Mozaffari- Khosravi et al. 2013 [50] found a significant effect of vitamin D supplementation compared to control in improving depressive symptoms in adults with a depressive disorder. (Khoraminya et al. 2013 [51]: BDI mean change at 8 weeks: vitamin D + fluoxetine group = -17.7, fluoxetine group: -13; repeated measure analysis of variance of time and group interaction; F8.54, p=0.006. HDRS mean change at 8 weeks; vitamin D + fluoxetine group = -19.25, fluoxetine group: -13.7; repeated measure analysis of variance of time and group interaction; F6.72, p=0.013. Mozaffari-Khosravi et al. 2013 [50]: BDI-II mean change (+- SD): control group: -2.1 (+-3.8); low dose group; -6.8 (+- 7.9); high dose group: -9.3 (+-8.7), analysis of variance p<0.001.) Brown et al. 2001 [42] found a very large statistically significant effect of vitamin D supplementation in women with mild to moderate depressive symptoms (CES-D mean change: intervention group = -8.6, control group = -5.5; ANCOVA p=0.004) POMS mean change: intervention group = -24.2, control group = -18.8; ANCOVA p=0.015). In a per protocol sub analysis Jorde et al. 2008 [44] found that the improvement in BDI 1-13 in the DD (high dose vitamin D (40,000IU per week) and DP (low dose vitamin D: 20,000IU per week) groups was most clearly seen in females (Female Delta scores: DD = -2.0 (p<0.01), DP = -1.8 (p<0.05), PP (placebo) = -0.5 (p>0.05) Male delta scores: DD=-1 (p>0.05), DP= 0 (p>0.05), PP = 0 (p>0.05) who were significantly more depressed at baseline than males (Females: BDI total score: 5 (0-28), Male BDI total score: 3.5 (0-24.5) Mann- Whitney test p<0.001). Sanders et al. 2011 [38], a female only study, found a trend for those taking anxiety/antidepressant medication to score higher (i.e. better) on the SF-12 MCS if they were randomized to receive vitamin D rather than placebo, although this did not reach a statistically significant interaction (p=0.11).

Arasteh 2 1994 [47], a mixed-sex trial, split participants into ‘depressed’ and ‘non-depressed’ before randomization (‘depressed’ = baseline BDI >9, ‘non-depressed; = baseline BDI < 9). The mean BDI score of the ‘depressed’ subjects in the intervention group decreased (improved) by 11.43 points, while that of the ‘depressed’ subjects in the placebo group decreased (improved) by 4 points. This interaction between group (intervention vs. control) and mood (‘depressed’ vs. ‘non-depressed’) produced a significant effect in BDI scores (F (1,47) = 4.76, p<0.05). Kjaergaard et al. 2012 [52], a large mixed-sex trial carried out post hoc analyses by stratifying groups according to baseline depression score. Participants with higher BDI scores at baseline (using the median value 4 as a cut-off) were found to have a significant positive effect (less depressed) of vitamin D compared with placebo on total HADS score (p=0.032). Participants with high HADS and MADRS scores at baseline (using 75 percentile as cut-off) had a significant positive effect of vitamin D compared with placebo on HADS score (p=0.01 and p=0.031) respectively. In a subgroup analysis, Yalamanchili et al. 2012 [37], a female only study, found that all women who were depressed at baseline showed a significant improvement, when compared to non-depressed people at baseline, in both placebo and intervention groups (One-way ANOVA, F=68.82, p<0.0001).

Effect of vitamin D supplementation in those with low vitamin D levels: Mozaffari-Khosravi et al. 2013 [50] found a significant of vitamin D supplementation in improving depressive symptoms in adults who not only were depressed, as stated above, but also vitamin D deficient. Although Khoraminya et al. 2013 [51] did not only include those with vitamin D deficiency, 95% of their patients had insufficient vitamin D levels at baseline (<75nmol/L) and as stated above, they also found a significant effect of vitamin D supplementation on depressive symptoms. Kjaergaard et al. 2012 [52] only included participants with low serum vitamin D levels (<55nmol/L) and they did not find any significant differences in delta scores (change in BDI, HADS-D & MADRS scores before and after supplementation) between intervention and control groups, even after stratifying by baseline vitamin D level and gender. Dean et al. 2011 [46] in their secondary analysis examined the effect of change in vitamin D concentrations in only participants with low vitamin D concentrations at baseline (<75.00 nmol/L) but did not find any significant treatment effects. Jorde et al. 2008 [44] carried out a sub analysis in those with baseline vitamin D levels <40nmol/l and >40nmol/l but did not find a distinct pattern. Although four other studies [36-38,43] measured vitamin D levels at baseline and after supplementation, the majority of participants were not deficient and they did not investigate response to treatment according to baseline vitamin D levels.

Adverse Events

Randomized control trials

Ten studies reported no adverse events [36,37,39,41,45,47-50,53]. Khoraminya et al. 2013 [51] excluded one patient from the fluoxetine + vitamin D group because of severe anxiety at week 2. Wepner et al. 2014 [43] reported one case of mild hypercalcaemia (2.71 nmol/L) and a serum calcifediol level of 63.6 ng/mL in the intervention group. Sanders et al. 2011 [38] reported an increased number of serious adverse events in the supplementation group that nearly reached statistical significance (244 vitamin D vs. 207 placebo (p=0.06) but these events were not considered related to study medication. Jorde et al. 2008 [44] reported sustained hypercalcaemia in one participant in low dose vitamin D group who was removed from the trial. Brown et al. [42] found that seven participants (14%) in the control group and sixteen (30%) in the intervention groups (30%) reported a single minor side effects from the vitamins, such as bright yellow urine, gastrointestinal symptoms, sleep disturbances and skin reactions.

Discussion

Our systematic review included seventeen randomized control trials and five cohort studies. Our findings from cohort studies corroborate the association between low vitamin D levels and increased risk of depressive symptoms in both sexes, and demonstrate that female gender may indirectly strengthen this association. Milaneschi et al. 2010 [33], the most methodologically robust cohort study, found that only women, and not men, with low vitamin D levels had a significantly higher hazard of developing depressed mood during 6 years of follow up compared to women with sufficient vitamin D levels. Given that 74.6% of women and 50.4% of men in this study had vitamin D levels less than 50nmol/L at baseline; these findings are possibly secondary to the increased prevalence of vitamin D deficiency in the female sample. May et al. 2010 [32] found a larger, (but non-statistically significant) hazard ratio in men compared to women with low vitamin D levels, however this study was deemed to have a high risk of bias. Both Milaneschi et al. 2010 [33] and May et al. 2010 [32] did not find a significant interaction by sex in the association between vitamin D and depressive symptoms. Furthermore, Yue et al. 2014 [34] who found the largest increased risk of depression in men and women with severe deficiency (<28nmol/L) unfortunately did not stratify by sex. Interestingly, the only cohort study involving men only did not find any association between vitamin D levels and development of depression [35].

Regarding randomized control trials, seven out of the seventeen RCTs found that vitamin D supplementation was significantly more effective than control, in improving depressive symptoms. Six of these were mixed-sex studies and one was female only. Interestingly, the females included in these trials were mostly of childbearing age [42,44, 47,48,50,51]. Furthermore, Brown et al. 2001 [42], which showed the largest effect size of all included trials (Effect size: -8.6Regarding randomized control trials, seven out of the seventeen RCTs found that vitamin D supplementation was significantly more effective than control, in improving depressive symptoms. Six of these were mixed-sex studies and one was female only. Interestingly, the females included in these trials were mostly of childbearing age [42,44, 47,48,50,51]. Furthermore, Brown et al. 2001 [42], which showed the largest effect size of all included trials (Effect size: -8.6Regarding randomized control trials, seven out of the seventeen RCTs found that vitamin D supplementation was significantly more effective than control, in improving depressive symptoms. Six of these were mixed-sex studies and one was female only. Interestingly, the females included in these trials were mostly of childbearing age [42,44, 47,48,50,51]. Furthermore, Brown et al. 2001 [42], which showed the largest effect size of all included trials (Effect size: -8.6Regarding randomized control trials, seven out of the seventeen RCTs found that vitamin D supplementation was significantly more effective than control, in improving depressive symptoms. Six of these were mixed-sex studies and one was female only. Interestingly, the females included in these trials were mostly of childbearing age [42,44, 47,48,50,51]. Furthermore, Brown et al. 2001 [42], which showed the largest effect size of all included trials (Effect size: -8.6Regarding randomized control trials, seven out of the seventeen RCTs found that vitamin D supplementation was significantly more effective than control, in improving depressive symptoms. Six of these were mixed-sex studies and one was female only. Interestingly, the females included in these trials were mostly of childbearing age [42,44, 47,48,50,51]. Furthermore, Brown et al. 2001 [42], which showed the largest effect size of all included trials (Effect size: -8.6 using CES-D and -24.2 using POMS) was carried out purely in females (>18 years) with mild to moderate depressive symptoms. Jorde et al. 2008 [44], a mixed sex study, found their improvement in BDI 1-13 scores was most clearly seen in females, although females had significantly more depressive symptoms at baseline than men. Sanders et al. 2011 [38], a female only study, found a non-significant trend in females taking anxiety/antidepressant medication to score higher (i.e. better) on the SF-12 MCS if they were randomized to receive vitamin D rather than placebo. The two largest RCTs [36,39] that were both in postmenopausal females, did not find a significant effect of vitamin D supplementation on depressive symptoms, but this is not surprising, as the majority of these females were not depressed at baseline. Furthermore both these studies were secondary analyses and had a high degree of confounding and bias.

The other five trials that found a significant effect of vitamin D supplementation on depressive symptoms in men and women unfortunately did not stratify according to gender [45,47,48,50,51]. However the two studies with large effect sizes included 85% [51] and 72% females [50]. These two trials [50,51] were the only two trials whose participants were both depressed and vitamin D deficient, which strengthens the hypothesis that the benefit of vitamin D supplementation will be most clearly seen in those who are depressed and/or vitamin D deficient.

With regard to the biological plausibility of a link between low vitamin D levels and depressive symptoms in both sexes, there is corroborative evidence from animal and laboratory studies. Eyles et al. 2005 [19] identified vitamin D receptors in the prefrontal cortex, hippocampus, cingulated gyrus, thalamus and hypothalamus, areas of the brain that have been associated with depression. Garcion et al. 2002 [57] found that 1,25 hydroxyvitamin D3 appears to increase expression of genes encoding for tyrosine hydroxylase, the precursor of noradrenaline in the adrenal glands, a neurotransmitter implicated in depression. It is also known that vitamin D protects against serotonin-depleting effects of neurotoxic doses of methamphetamine [58]. Furthermore Feron et al. 2005 [59] found that newborn rats deprived of Vitamin D3 in utero showed micro and macro-structural brain changes that persisted into adulthood such as increased cell proliferation, larger lateral ventricles, reduced cortical thickness, reduced expression of nerve growth factor and reduced expression of glial cell line-derived neurotrophic factor. These brain changes are not specific to depression per say and are also found in schizophrenia and neurodegenerative diseases such as Alzheimer’s disease. Also, human genetic studies have shown that Vitamin D receptor polymorphisms contribute to age-related changes in depressive symptoms [60].

Women have a higher lifetime prevalence of depression [3] than men and various biological, psychological and social theories have tried to explain this difference [61]. Evidence for an underlying biological process includes the increased risk of depression in women at times of sex steroid level changes; pre-menstrually, during and after pregnancy and peri-menopausally. The female to male ratio of depression at puberty rises from 1:1 to 2:1, pointing to oestrogen and progesterone as culprits [62]. Ovarian steroids have widespread effects throughout the brain; on serotonin pathways, catecholaminergic neurons [63,64]; on the hypothalamic-pituitary-adrenal axis [65] and in fact, animal studies suggest that the amygdala, a structure involved in emotion, has one of the highest densities of oestrogen receptors in the brain [66]. Furthermore, selective serotonin uptake inhibitors are effective in treating premenstrual dysphoric disorder, a disorder with overlapping symptoms to depression [67].

Whilst obesity, old age, latitude, dark skin, sunscreen use and cultural clothing practices are clear risk factors for vitamin D deficiency, female sex as a risk factor is under dispute. Many studies have found lower levels of vitamin D in women [6-13] although there is also some evidence to the contrary [68-70]. It is thought that external factors related to sunlight exposure as well as hormonal differences underline these sex differences in circulating vitamin D levels [12,54]. However, animal and human studies show that there may be oestrogen-promoted differences in vitamin D metabolism that do not effect circulating levels of vitamin D [24,25,71], hence why vitamin D levels may not necessarily be lower in women.

Strengths and Limitations

This is the first systematic review including randomized control trial data that has investigated the gender differences in the relationship between vitamin D deficiency and depressive symptoms and in the effect of vitamin D supplementation on depressive symptoms. In view of the existence of this data we did not feel it was necessary to include further cross-sectional data given the problem of reverse causality. This review has been subject to a rigorous methodology. Studies were initially found from a systematic search of multiple databases using comprehensive search terms (see supplementary data for search terms) and were then independently assessed using pre-written inclusion criteria forms by two people. Due to the heterogeneity of the studies included in the review in terms of participants, exposures/ interventions, and outcome data, meta-analyses were not appropriate and narrative syntheses were performed. We regard this as a strength, as previous systematic reviews in this area have fallen to the temptation of meta-analysis [26, 27], despite the heterogeneity and poor quality of included studies.

There are some limitations to this systematic review that require comment. Generally, we were mostly unable to set the context in which, we hypothesized, vitamin D would have its main effects: a) in those with depressive symptoms at baseline of both sexes, b) in those who are vitamin D deficient. Out of the seventeen randomized control trials included, there were only two studies in those with clinical depression [50,51] and one other study in those with depressive symptoms at baseline [42]. Not surprisingly these three studies displayed the largest significant effect sizes. In the other studies, baseline depression score ranges revealed that a few participants had depressive symptoms indicative of a diagnosis of depression, even though baseline mean scores were low. For example in Jorde et al. 2008 [44], whilst the mean BDI score of all subjects at baseline was 5, the range was 0-28 (score >9 = mild depression, score>18=moderate depression, score>29=severe depression). Therefore the effective sample size in most studies were very small and so the power to detect a difference, low.

Secondly, whilst eight RCTs measured vitamin D levels, only two studies included only those who were vitamin D deficient at baseline [50,52], the second context in which we hypothesized vitamin D supplementation would have a main effect.

It is therefore not possible for us to make conclusive statements on whether gender modifies the effect of vitamin d supplementation and depressive symptoms, as these two contexts, in which we would expect to see a main effect of vitamin D supplementation on depressive symptoms were mostly absent. It is worth noting however that, five of the seven female-only trials [36-39,53] included postmenopausal women. Given the biological hypothesis of oestrogen promoted differences in local vitamin D metabolism, we would not expect vitamin D to have a more dramatic effect in postmenopausal women.

Conclusion

In summary, there is suggestive evidence of potential benefits of vitamin D supplementation in women of childbearing age. However, there is a need for additional large randomized placebo-controlled trials in both men and women of childbearing age, with a diagnosis of depression and vitamin D deficiency or insufficiency with genderstratified analysis to further explore this. There is no indication that vitamin D supplementation causes hypomania.

Given, the growing body of evidence that vitamin D deficiency is associated with depression as well as multiple other highly prevalent diseases, the re-introduction of regulated and targeted vitamin D fortification in food stuffs should be re-evaluated.

Acknowledgement

I would like to thank Dr Saverio Stranges, Professor Scott Weich, Dr Karen Rees, Professor Aileen Clarke and Dr Mukesh Kripalani for their contributions to this review.

References

1. World Health Organization. World Health Organization: Global Burden of Disease Report. 2004.
2. Williams JB, Spitzer RL, Linzer M, Kroenke K, Hahn SR, DeGruy FV, et al. Gender differences in depression in primary care. Obstet Gynecol. 1995; 173: 654-659.
3. Noble RE. Depression in women. Metab Clin Exp. 2005; 54: 49-52.
4. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu H-G, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA. 1996; 276: 293-299.
5. Holick MF. Vitamin D Deficiency. N Engl J Med. 2007; 357: 266-281.
6. Hoogendijk WJG, Lips P, Dik MG, Deeg DJH, Beekman ATF, Penninx BWJH. Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Archives of General Psychiatry. 2008; 65: 508-512.
7. Mithal A, Wahl D, Bonjour J, Burckhardt P, Dawson-Hughes B, Eisman JA et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporosis Int. 2009; 20: 1807-1820.
8. Van der Wielen, Reggy PJ, De Groot L, Van Staveren W, Lowik MRH, Van den Berg H et al. Serum vitamin D concentrations among elderly people in Europe. The Lancet 1995; 346: 207-210.
9. Dawson-Hughes B, Harris SS, Dallal GE. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr. 1997; 65: 67-71.
10. Ganji V, Milone C, Cody MM, McCarty F, Wang YT. Serum vitamin D concentrations are related to depression in young adult US population: the Third National Health and Nutrition Examination Survey. Int Arch Med. 2010; 3: 29.
11. Carnevale V, Modoni S, Pileri M, Di Giorgio A, Chiodini I, Minisola S, et al. Longitudinal evaluation of vitamin D status in healthy subjects from southern Italy: seasonal and gender differences. Osteoporosis Int. 2001; 12: 1026-1030.
12. Bolland MJ, Grey AB, Ames RW, Mason BH, Horne AM, Gamble GD, et al. The effects of seasonal variation of 25-hydroxyvitamin D and fat mass on a diagnosis of vitamin D sufficiency. Am J Clin Nutr. 2007; 86: 959-964.
13. Hypponen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007; 85: 860-868.
14. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clinic Proceedings. 2006; 81: 353-373.
15. Bertone-Johnson ER. Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutrition Reviews. 2009; 67: 481-492.
16. Berk M, Sanders KM, Pasco JA, Jacka FN, Williams LJ, Hayles AL, et al. Vitamin D deficiency may play a role in depression. Medical Hypotheses. 2007; 69: 1316-1319.
17. Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013; 202: 100-107.
18. Fernandes de Abreu DA, Eyles D, Feron F. Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology. 2009; 34: 265-277.
19. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1a-hydroxylase in human brain. J Chem Neuroanat. 2005; 29: 21-30.
20. Wang T, Tavera-Mendoza LE, Laperriere D, Libby E, Burton Metal. Large-scale in silico and microarray-based identification of direct 1, 25-dihydroxyvitamin D3 target genes. Molecular endocrinology. 2005; 19: 2685-2695.
21. Murphy PK, Wagner CL. Vitamin D and Mood Disorders Among Women: An Integrative Review. Journal of Midwifery and Women's Health. 2008; 53: 440-446.
22. Toffanello ED, Sergi G, Veronese N, Perissinotto E, Zambon S, Coin A, et al. Serum 25-hydroxyvitamin d and the onset of late-life depressive mood in older men and women: the pro.v.a. study. J Gerontol A Biol Sci Med Sci, 2014; 69: 1554-1561.
23. Kjærgaard M, Joakimsen R, Jorde R. Low serum 25-hydroxyvitamin D levels are associated with depression in an adult Norwegian population. Psychiatry Res. 2011; 190: 221-225.
24. Correale J, Ysrraelit MC, Gaitan MI. Gender differences in 1,25 dihydroxyvitamin D3 immunomodulatory effects in multiple sclerosis patients and healthy subjects. J Immunol. 2010; 185: 4948-4958.
25. Spach KM, Hayes CE. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J Immunol. 2005; 175: 4119-4126.
26. Shaffer JA, Edmondson D, Wasson LT, Falzon L, Homma K, Ezeokoli N, et al. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom Med. 2014; 76: 190-196.
27. Spedding S. Vitamin D and Depression: A Systematic Review and Meta-Analysis Comparing Studies with and without Biological Flaws. Nutrients. 2014; 6: 1501-1518.
28. Guallar E, Stranges S, Mulrow C, Appel LJ, Miller ER. Enough is enough: stop wasting money on vitamin and mineral supplements. Ann Intern Med. 2013; 159: 850-851.
29. Wells G, Shea B, O connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non randomised studies in meta-analyses. 2000.
30. Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008; 88: 491-499.
31. Williams J, Houston D, Davis C, Cauley J, Rubin S, Tylavsky F, et al. Vitamin D Status and Depression in Community-Dwelling Older Adults. American Geriatric Society. 2011.
32. May HT, Bair TL, Lappe DL, Anderson JL, Horne BD, Carlquist FJ, et al. Association of vitamin D levels with incident depression among a general cardiovascular population. American Heart Journal. 2010; 159: 1037-1043.
33. Milaneschi Y, Shardell M, Corsi AM, Vazzana R, Bandinelli S, Guralnik JM, et al. Serum 25-hydroxyvitamin D and depressive symptoms in older women and men. Journal of Clinical Endocrinology & Metabolism. 2010; 95: 3225-3233.
34. Yue W, Xiang L, Zhang Y, Ji Y, Li X. Association of Serum 25-Hydroxyvitamin D with Symptoms of Depression after 6 Months in Stroke Patients. Neurochem Res. 2014; 39: 2218-2224.
35. Chan R, Chan D, Woo J, Ohisson C, Mellstrom D, Kwok T, et al. Association between serum 25-hydroxyvitamin D and psychological health in older Chinese men in a cohort study. J Affect Disord. 2011; 130: 251-259.
36. Bertone-Johnson ER, Powers SI, Spangler L, Larson J, Michael YL, Millen, AE et al. Vitamin D Supplementation and Depression in the Women,Aos Health Initiative Calcium and Vitamin D Trial. American Journal of Epidemiology. 2012; 176: 1-13.
37. 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: 697-703.
38. Sanders KM, Stuart AL, Williamson EJ, Jacka FN, Dodd S, Nicholson G, et al. Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. Br J Psychiatry. 2011; 198: 357-364.
39. Dumville JC, Miles JNV, Porthouse J, Cockayne S, Saxon L, King C. Can vitamin D supplementation prevent winter-time blues? A randomised trial among older women. Journal of Nutrition Health and Aging. 2006; 10: 151-153.
40. Harris PA, Scott KW, Lightner C, Hassan N, Pulley J, Edwards T, et al. Clinical and Translational Science. Conference. 2010.
41. Haskell CF, Robertson B, Jones E, Forster J, Jones R, Wilde A, et al. Effects of a multi-vitamin/mineral supplement on cognitive function and fatigue during extended multi-tasking. Human Psychopharmacology-Clinical and Experimental. 2010; 25: 448-461.
42. Brown MA, Goldstein-Shirley J, Robinson J and Casey S. The effects of a multi-modal intervention trial of light, exercise, and vitamins on women's mood. Women & Health. 2001; 34: 93-112.
43. 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: 261-268.
44. Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. Journal of Internal Medicine. 2008; 264: 599-609.
45. Gariballa S, Forster S. Effects of dietary supplements on depressive symptoms in older patients: A randomised double-blind placebo-controlled trial. Clinical Nutrition. 2007; 26: 545-551.
46. Dean AJ, Bellgrove MA, Hall T, Phan WMJ, Eyles DW, Kvaskoff, D et al. Effects of vitamin D supplementation on cognitive and emotional functioning in young adults–a randomised controlled trial. PLoS One. 2011; 6: 25966.
47. Arasteh K. A beneficial effect of calcium intake on mood - Experiment 1. Journal of Orthomolecular Medicine. 1994; 9: 199-204.
48. Lansdowne AT, Provost SC. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology. 1998; 135: 319-323.
49. 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 deficiency: a randomized clinical trial. J Clin Psychopharmacol. 2013; 33: 378-385.
50. 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: 271-275.
51. Kjaergaard M, Waterloo K, Wang CE, Almas B, Figenschau Y, Hutchinson MS, et al. Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial. Br J Psychiatry. 2012; 201: 360-368.
52. Harris S, Dawson-Hughes B. Seasonal mood changes in 250 normal women. Psychiatry Research. 1993; 49: 77-87.
53. Pearce S, Cheetham TD. Diagnosis and management of vitamin D deficiency. BMJ. 2010; 340: 142-147.
54. Sneve M, Figenschau Y, Jorde R. Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects. Eur J Endocrinol. 2008; 159: 675-684.
55. Gariballa S, Forster S, Walters S, Powers H. A randomized, double-blind, placebo-controlled trial of nutritional supplementation during acute illness. Am J Med 2006; 119: 693-699.
56. Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D. New clues about vitamin D functions in the nervous system. TRENDS in Endocrinology & Metabolism. 2002; 13: 100-105.
57. Cass WA, Smith MP, Peters LE. Calcitriol Protects against the Dopamine-and Serotonin-Depleting Effects of Neurotoxic Doses of Methamphetamine. Ann N Y Acad Sci. 2006; 1074: 261-271.
58. Feron F, Burne THJ, Brown J, Smith E, McGrath JJ, Mackay-Sim A, et al. Developmental Vitamin D< sub> 3 deficiency alters the adult rat brain. Brain Res Bull. 2005; 65:141-148.
59. Kuningas M, Mooijaart SP, Jolles J, Slagboom PE, Westendorp RGJ, Van Heemst D. VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiology of Aging. 2009; 30: 466-473.
60. Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, et al. Gender differences in chronic major and double depression. J Affect Disord. 2000; 60: 1-11.
61. Zender R, Olshansky E. Women's mental health: depression and anxiety. Nurs Clin North Am. 2009; 44: 355-364.
62. McEwen B. Estrogen actions throughout the brain. Recent Prog Horm Res. 2002; 57: 357-384.
63. Rubinow DR, Schmidt PJ, Roca CA. Estrogen–serotonin interactions: implications for affective regulation. Biol Psychiatry. 1998; 44: 839-850.
64. Young EA. Sex differences and the HPA axis: implications for psychiatric disease. J Gend Specif Med. 1998; 1: 21-27.
65. Amin Z, Canli T, Epperson CN. Effect of estrogen-serotonin interactions on mood and cognition. Behav Cogn Neurosci Rev. 2005; 4: 43-58.
66. Dimmock PW, Wyatt KM, Jones PW, O’Brien PM. Efficacy of selective serotonin-reuptake inhibitors in premenstrual lancet syndrome: a systematic review. 2000; 356: 1131-1136.
67. Hagenau T, Vest R, Gissel T, Poulsen CS, Erlandsen M, Mosekilde L, et al. Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis. Osteoporos Int. 2009; 20: 133-140.
68. Lagunova Z, Porojnicu AC, Lindberg F, Hexeberg S, Moan J. The dependency of vitamin D status on body mass index, gender, age and season. Anticancer Res. 2009; 29: 3713-3720.
69. Langlois K, Greene-Finestone L, Little J, Hidiroglou N, Whiting S. Vitamin D status of Canadians as measured in the 2007 to 2009 Canadian Health Measures Survey. 2010.
70. Nashold FE, Spach KM, Spanier JA, Hayes CE. Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. J Immunol. 2009; 183: 3672-3681.
71. Aarskog D, Aksnes L, Markestad T, Rodland O. Effect of Estrogen on Vitamin D Metabolism in Tall Girls. The Journal of Clinical Endocrinology & Metabolism. 1983; 57: 1155-1158.

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Citation: CMJ, Kripalani M, Rees K, Weich S, Clarke A and Stranges S. Gender Differences in Vitamin D and Depressive Symptoms: A Systematic Review. Austin J Psychiatry Behav Sci. 2016; 3(2): 1052. ISSN : 2381-9006

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