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Keywords:

  • vitamin D;
  • depression;
  • seasonal affective disorder;
  • nutrition

Abstract

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References

Parker G, Brotchie H. ‘D’ for depression: any role for vitamin D?.

Objective:  While there has long been interest in any nutritional contribution to the onset and treatment of mood disorders, there has been increasing scientific evaluation of several candidate nutritional and dietary factors in recent years. In this paper, we overview research into any vitamin D insufficiency and deficiency contribution to depression.

Method:  The relevant literature was reviewed.

Results:  Cross-sectional studies have identified associations between depression and low vitamin D levels, but studies have failed to clarify whether vitamin D deficiency is an antecedent cause, correlate or consequence of depression. While vitamin D deficiency and insufficiency have been linked with seasonal affective disorder, suggested associations have not been rigorously tested. There has been insufficient research to establish whether and when vitamin D supplementation should be considered as an augmentation strategy with antidepressant drugs.

Conclusion:  There is currently insufficient evidence to argue strongly for vitamin D supplementation in patients with depression, but such a strategy is worthy of consideration in depressed patients whose lifestyle and geographical residence may indicate a risk of vitamin D insufficiency – or where low vitamin D levels have been quantified.


Clinical recommendations

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References
  •  Vitamin D deficiency and insufficiency are common and may contribute to the onset and persistence of depression.
  •  Causal studies currently fail to clarify whether vitamin D may be a true antecedent risk factor as against a consequence of lifestyle factors in depressed patients.
  •  Any persuasive argument for vitamin D supplementation in depressed patients (and those with seasonal affective disorder) cannot be mounted from the current evidence.

Additional comments

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References
  •  Despite vitamin D deficiency being common and associated with depression status and severity in a number of studies, study designs disallow clarification of its current status as a risk factor.
  •  This review was based only on studies published in scientific journals.
  •  Most investigatory studies of depressed subjects have considered vitamin D alone rather than as a component of general dietary limitations.

Introduction

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References

While there has long been consumer interest and folk lore beliefs about the roles of multiple dietary factors as causes and treatments of depression, their scientific evaluation has been limited. In the last decade, that literature has increased in relation to a number of candidates. They include omega-3 fatty acids, which we considered in some depth in a 2006 review (1), vitamin D, the vitamin B group including folate, phospholipids, minerals (including zinc, iron and magnesium), antioxidants (including vitamin C) and soy (as an isoflavone). The recent discovery that the brain possesses vitamin D receptors encouraged interest in the possibility that mood and depressive disorders may be related to vitamin D deficiency or insufficiency. While vitamin D deficiency has been implicated as having a role in other psychiatric conditions (e.g. infantile autism and schizophrenia) and several neurological conditions (e.g. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis), these domains are outside the parameters of this review focussing on any contribution to depression.

Aims of the study

To review the role, physiology and metabolism of vitamin D. To then consider vitamin D deficiency and insufficiency as potential causes of depression, and whether there is sufficient evidence to support a prophylactic role for vitamin D or as a supplementary treatment in managing patients with depression, whether showing formal evidence of vitamin D deficiency or not.

Material and methods

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References

We undertook a literature search of relevant databases and synthesised information from primary studies and overview papers that addressed review objectives.

Results

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References

As reviewed by Holick (2), our vitamin D sources include exposure to sunlight, diet and dietary supplements. Most vitamin D is produced in the body by exposure and penetration of the skin to ultraviolet B (UVB) radiation from sunlight and with a wave length of 290–320 nm. Variations in age, skin colour, latitude, time of day of exposure and time of the year affect the actual amount of exposure. In a fair-skinned person, adequate amounts of vitamin D should be generated after twice weekly exposure of the arms and legs to direct sunlight (albeit dependent on the time of the day, season, latitude and skin pigmentation) for 5–30 min. Following penetration of the skin, solar UVB radiation (wave length 290–315 nm) converts 7-dehydrocholesterol to pre-vitamin D3, which is rapidly converted to vitamin D3. In terms of dietary intake, Maxwell (3) observed that ‘the diet is thought to contribute very little to vitamin D stores’. Dietary sources provide either ergocalciferol (D2) from plant sources or cholecalciferol (D3) from animal sources. Such dietary sources are few, but include fish such as salmon, sardines, mackerel, tuna, cod-liver oil, shiitake mushrooms (especially sun dried) and egg yolk. Unless an individual eats oily fish frequently, it is very difficult to obtain sufficient vitamin D on a daily basis. Thus, sensible exposure to sunlight (i.e. avoiding the risk of skin cancer) and/or the use of vitamin D supplements in the form of vitamin D2 (ergocalciferol) or D3 (cholecalciferol – and which is three times stronger than vitamin D2) are needed to fulfil the body’s vitamin D requirements. In Holick’s review (2), recommendations from the Institute of Medicine of the National Academies for an adequate daily intake of vitamin D in the form of vitamin D3 were 200 IU for children and adults up to 50 years of age, 400 IU for adults 51–70 years of age and 600 IU for adults 71 years of age or older. A more recent 2010 report from that institute (4) recommends 600 IU for children and adults <70 years, and 800 IU/day for adults over the age of 70 years. However, without adequate sun exposure, children and adults require 800–1000 IU per day. To correct a vitamin D deficiency and to then maintain adequate levels of 25-hydroxyvitamin D, 1000 IU/day is required (2). In terms of enzymatic metabolism, vitamin D from the skin and diet is metabolised in the liver to 25-hydroxyvitamin D or 25 (OH) D – and it is this component that is used to quantify an individual’s vitamin D status. The reference range for 25 (OH) D varies internationally and there is no precise agreement, although Holick (2) suggests that most experts consider the preferred range being 30–60 ng/ml and with deficiency defined as <20 ng/ml – and relative insufficiency being defined as occurring across a 21–29 ng/ml band (2). In other laboratories, differing units (especially nm) are reported, and, for that unit, a level of <50 nm is judged as defining vitamin D deficiency status. Subsequently, 25 (OH) D is metabolised in the kidneys to its active form 1, 25-dihyroxyvitamin D, and is tightly regulated by plasma parathyroid hormone levels as well as by serum calcium and phosphorus levels. This metabolite binds to nuclear vitamin D receptors in target tissues to regulate gene transcription and binds to caveolin type structures within cell membranes to mediate a number of non-genomic responses. Most tissues and cells in the body have vitamin D receptors, including the brain. For example, vitamin D receptors exist in both neuronal and glial cells, with Eyles et al. (5) detailing the presence of vitamin D receptors in the prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus and substantia nigra – of theoretical relevance here as many of these regions have been implicated in the pathophysiology of depression (6).

Holick (2) estimated that one billion people worldwide have vitamin D deficiency or insufficiency. Even in sunny climates such as Australia, where most vitamin D is produced through solar exposure of the skin, insufficiency can occur in certain areas (southern latitudes in winter) and in certain groups, including the elderly who are housebound or in nursing homes, those with naturally dark skins who need more sun to make vitamin D, certain ethnic groups who cover their skin for religious or cultural reasons, those who avoid exposure to sunlight because of the risk of skin cancer, and in relation to the reality that many people spend their working (sunlight) hours indoors (7).

There are a number of causes of vitamin D deficiency. Reduced skin synthesis can occur as a consequence of ageing, when there is a reduction of 7-dehyrocholesterol in the skin. Darker skin pigmentation- because melanin absorbs more UVB radiation. Sunscreen use absorbs UVB radiation. The season, latitude and time of the day impact on the amount of solar radiation reaching the skin, as the number of solar UVB photons reaching the earth depends on the zenith angle of the sun. Decreased synthesis of 25 (OH) D can occur as a consequence of liver failure and chronic renal disease, while a nephritic syndrome can lead to increased urinary loss of 25 (OH) D (2).

Decreased bioavailability can occur as a consequence of malabsorption, obesity and other factors, while increased catabolism can occur as a consequence of certain medications (e.g. anticonvulsants and glucocorticoids). As there is low vitamin D content in human milk, breast feeding does not preclude the risk of vitamin D deficiency. In utero, and during childhood, vitamin D deficiency can cause growth retardation and skeletal deformities and may increase the risk of hip fracture in later life. The maintenance of bone health requires adequate levels of vitamin D and inadequate levels lead to serum calcium deficiency which, in turn, can cause osteoclastogenesis, dissolving the skeletal matrix and causing reduced bone density. In adults, lack of bioavailability can precipitate or exacerbate osteopenia and osteoporosis, cause osteomalacia and muscle weakness, and increase the risk of fractures. Besides actions on the bony skeleton, the metabolism of 25 (OH) D to 1, 25-dihyroxyvitamin D has implications as an immunomodulator in promoting immunity and in inducing the destruction of infectious agents. In addition, vitamin D is judged as having the potential to prevent breast, colon and prostate cancer through its regulation of genes controlling cellular proliferation, it can down-regulate renin production in the kidney affecting blood pressure regulation as well as having other effects on the circulation, and it impacts on blood sugar control through its effects on insulin production (2). Our focus is, however, on mood disorders and we therefore overview studies that have examined the role of vitamin D in depressive disorders.

Epidemiologic studies of vitamin D levels and depression

Cross-sectional studies.  There have been at least five cross-sectional epidemiological studies based on different international community groups over the last few years. In a recent representative study, Hoogendijk et al. (8) undertook a population-based cohort study in the Netherlands of those aged 65 years or older. Depression status and severity were quantified by use of the Centre for Epidemiologic Studies-Depression (CES-D) scale. Those researchers established that 25 (OH) D levels were 14% lower in 169 individuals diagnosed with minor depression and also 14% lower in those 26 diagnosed with major depression, while lower 25 (OH) D levels were linked with greater depression severity. The last association remained significant after controlling for age, gender, BMI level, smoking status and number of medical conditions. Pan et al. (9) reported a population-based cross-sectional study in middle-aged and elderly Chinese from the Nutrition and Health of Ageing population in China (NHAPC) project, evaluating the association between depression and blood 25 hydroxyvitamin D (25(OH) D) levels in the general population. Participants included 3262 community residents aged 50–70 years. The assessment of depressive symptoms used the 20-item Centre for Epidemiologic Studies-Depression (CES-D) Scale and validated for major depression in Chinese populations. Those authors concluded that their study failed to provide evidence linking depressive symptoms with 25(OH) D levels. Bertone-Johnson (10) reviewed those two latter studies of general community populations and seven other studies of community subsets – such as a study of older adults by Wilkins et al. (11) – who reported that vitamin D deficiency was associated with a distinctly increased chance of a mood disorder (odds ratio = 11.7) and concluded that, while several samples did show lower 25 (OH) D levels to be associated with depression caseness or severity, there were a number of non-significant studies. Bertone-Johnson (10) noted that any such positive studies did not separate out the antecedent vs. consequence explanations and suggested that (in considering the latter explanation) it remained possible that depressed patients may be at greater risk of lower vitamin D levels as a consequence of spending less time outdoors, being less physically active, changing their diet or increasing their smoking.

Many of the latter factors are also associated with the incidence of depression. Since Bertone-Johnson’s review (10), there have been three more published community studies. A large United Kingdom epidemiological study of 3369 European men with a mean age of 60 years by Lee et al. (12) reported an inverse association between 25 (OH) D levels and depression. While this study did factor in lifestyle variables, their analyses were largely independent of several lifestyle and health factors. The two other recently published community-based cross-sectional studies (13, 14) factored in seasonality changes and are considered in more detail in our review of seasonal affective disorder (SAD). Cross-sectional studies do not, of course, determine causality.

A causal explanation requires clarification by prospective studies that assess changes in mood over time in individuals with low vs. sufficient vitamin D levels, but is also supported by examining effects of supplementation.

Longitudinal studies.  A 6-year prospective study was undertaken by Milaneschi et al. (15), who studied 954 adults aged 65 years or older, and examined the association between low vitamin D levels at baseline and subsequent (incident) depression. Those with levels of 25(OH)D3 <50 nm (or <20 ng/ml) at baseline returned significantly higher depression measure scores at 3- and 6-year follow-up reviews compared to those with high levels at baseline. The strength of the prospective association was more distinctive in women than in men. This study added to the evidence of a causal link between low vitamin D and depression by adjusting for a range of potential confounding variables and examined the association between the variables of interest in a prospective fashion. However, understanding the causal pathway between vitamin D deficiency and depression requires more specific study designs.

Randomised controlled trials (RCTs).  Jorde et al. (16) enrolled a large sample of overweight or obese individuals, involving men and women aged 21–70 years, in an RCT with a 1-year follow-up. At baseline, depression scores as measured by the Beck Depression Inventory (BDI) were higher in those with insufficient levels of 25 (OH) D – although the latter did not correlate with depression severity levels. Those randomly allocated to receive vitamin D supplementation of either 40 000 or 20 000 IU/week showed an improvement in depression levels over the following 12 months, while there was no improvement with placebo. The authors acknowledged that, as their study involved a community sample, there were a few individuals with clinical depression. In addition, the level of supplementation was very high. Support for a causal relationship between vitamin D and mood is suggestive since supplementation preceded evaluation of change in BDI scores.

If the relationship is causal – in that vitamin D insufficiency or deficiency precedes and provides a risk to depression – possible mechanisms have been postulated, including compromised nerve growth factor synthesis and involvement of a variety of potential neurotransmitter targets. As overviewed by Humble (17), the vitamin D-endocrine system acts within the central nervous system as a neurosteroid with multiple actions. The active form of vitamin D, calcitriol, interacts with the synthesis, and degradation of some neurotransmitters has an important role in the regulation of several neurotrophic factors and supports the brain’s antioxidative defence. For example, calcitriol activates the gene expression of the enzyme tyrosine hydroxylase which is considered to be the rate-limiting step in the synthesis of the catecholamines, thus increasing the availability of dopamine, noradrenaline and adrenaline – neurotransmitters implicated in the pathophysiology of mood disorders. The availability of vitamin D has the potential to alter the brain endocrine function relevant to psychiatric and neuropsychiatric disorders, and particularly in those mental disorders with seasonal patterns and where marked variations in sun (UVB) exposure could result in vitamin D deficiency.

SAD and SAD symptoms.  A possible depressive subtype is SAD, where depression occurs and recurs at the darkest time of the year (i.e. winter months), a winter depression often characterised by hypersomnia, hyperphagia, anergia and worsening in the evening, abating in the spring and summer, and where light deficiency has been hypothesised as causal. The prevailing theory is that SAD is related to the shorter daily photoperiod of winter, with suboptimal light input to retinal photoreceptors disturbing the optimal functioning of the suprachiasmatic nucleus (SCN) and its interactions with the pineal gland and melatonin secretion. While results of studies into the effect of phototherapy on SAD have been inconsistent, it has been suggested that light and the circadian regulation of the SCN are closely related to the pathophysiology of SAD and perhaps other depressive disorders, and probably via serotoninergic dysfunction (17). The possibility that vitamin D insufficiency may play a role in SAD is suggested by the higher prevalence of that syndrome at increased latitude (and where there is reduced sun exposure to UVB radiation), and with Humble (17) suggesting that this may be more related to dopaminergic dysfunction via pathophysiological changes noted earlier.

Cross-sectional studies of mood disorder, seasonality and vitamin D.  A recently published community-based observational study from Japan involving 527 subjects aged between 21 and 67 years has also reported a lack of association between 25(OH) D3 and symptoms of depression (13), although they did find a trend for vitamin D to have a protective effect on depressive symptoms in late autumn (i.e. their sun-deprived season) compared to the summer season. Stewart and Hirani (14) also recently published a national community study of 2070 older people (65 years of age or older) living in England and concluded that vitamin D deficiency was associated with late life depression in northern latitudes, although increased depressive symptoms were only seen in those with the most severe deficiency state, and with no marked increases in association with milder relative deficiency. These findings correspond with the results from an Amsterdam study (8), although that study found lower 25 (OH) D levels associated with both major and minor depression. Stewart and Hirani (14) also factored in – and established – that the association between low 25 (OH) D and depression was not modified by season.

RCTs and open studies of SAD symptoms and vitamin D.  Bertone-Johnson (10) overviewed several small randomised trials involving seasonal mood and the effect of vitamin D supplementation. One, by Lansdowne and Provost (18), reported a trial of 44 healthy subjects randomised to receive varying doses of vitamin D3 for 5 days over winter with improved positive affect and decreased negative affect in those who received supplementation. Another trial, by Vieth et al. (19), randomised 82 adults with vitamin D deficiency to supplementation with vitamin D3 over two winters at doses of 600 and 4000 IU daily and found some improvement on well-being depression scores in the higher dosage group after 2 months. However, a randomised control trial by Dumville et al. (20) did not find any significant improvement in the mental health scores of elderly women over 6-month winter supplementation with 800 IU of vitamin D daily. However, this was a relatively low level of supplementation and probably did not reach necessary blood levels compared to other studies. Reporting on these and five other small intervention trials, Bertone-Johnson (10) concluded that there was ‘only modest support that vitamin D is effective in treating the symptoms of SAD symptoms’. Since then, in an open study, Shipowick et al. (21) have reported a small uncontrolled North American study of nine women who had vitamin D deficiency or insufficiency and who were given supplementation of 5000 IU vitamin D daily over winter. While there was distinct improvement in depression levels, this pilot study did not formally study those with a distinct SAD syndrome.

Clinical studies.  Berk et al. (22) also considered that there was increasing evidence ‘to suggest that vitamin D may be the link between seasonality of mood and seasonal change in photoperiod’. Their group collected serum 25(OH) D levels from a clinical cohort of 17 individuals with both unipolar and bipolar depression (and mostly in-patients) during the summer months when levels are higher than in other seasons. The mean serum level was 47.0 nm/l (males having a lower level than females), and only three individuals had values in the normal range for their laboratory (60–160 nm/l). The mean 25 (OH) D level was significantly lower than levels in an epidemiological cohort collected from the same geographical area and during the summer season. The authors acknowledge that this association does not differentiate cause and effect. Gloth et al. (23) undertook a small double-blind intervention study, randomising eight patients with SAD to receive 100 000 IU of vitamin D daily and seven to receive phototherapy, and reported that those who received the vitamin D supplementation improved on depression measures. The improvement in mood significantly correlated with the increase of 25(OH) D levels.

Discussion

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References

We conclude that there is some evidence to suggest that vitamin D deficiency or insufficiency may make a contributory role to depression. At this stage, there is the suggestion that supplementation may be of some benefit but, as few studies have been undertaken, no firm recommendation can be advanced by the data base.

As Young (24) suggests, the main dietary source of vitamin D is fish and while the ‘cross-national inverse correlation between fish consumption and depression has usually been interpreted as an association between omega-3 unsaturated fats and depression’, the role of vitamin D in such dietary studies requires clarification. Nevertheless, for most people, exposure of skin to ultraviolet light resulting in the conversion of cutaneous 7-dehydrocholesterol to vitamin D3 is their most important source of vitamin D, and this review has therefore focussed on this principal source in considering reasons for vitamin D insufficiency or deficiency.

While seasonal variations in exposure to UV light affecting vitamin D intake through the skin make it a plausible candidate for contributing to SAD, any such causal role has not been established, while there are no definitive studies examining for any impact of vitamin D supplementation on those with formalised SAD syndromes. Supplementation studies will require more precise delineation of study groups with depression (i.e. formalised clinical depression as against measuring state depression levels) and examining the impact of such supplementation on those with both established low levels and normal levels of vitamin D. According to Joshi et al. (7), toxicity is unlikely with vitamin D when it is administered as cholecalciferol, as it has a wide safety window and no evidence of toxicity has been associated with doses up to 4000 IU daily. However, replacement needs to be tailored to the degree of deficiency and the adequacy of replacement should be monitored, by measuring serum 25-hydroxyvitamin D concentrations in those found to be deficient.

Most articles overviewing vitamin D recommend that it can be used as a safe dietary supplement. Young (24) presented a cautious position statement suggesting that treatment of depression with vitamin D is an idea worth testing in carefully selected populations – those with low 25-hydroxyvitamin D levels, and especially the elderly and patients with SAD who do not respond to light therapy. Then, if there are patients for whom vitamin D is an effective antidepressant, it would both be cost-effective and relatively safe. It already has established clear benefits to bone health and is used as a supplement for those with osteopenia and osteoporosis causing osteomalacia as well as bone and muscle pain and weakness.

This review suggests, however, that there is currently insufficient evidence to support vitamin D as a general augmentation strategy in depressed patients. This is consistent with the conclusion from the Institute of Medicine of the National Academies in their report of 30 November 2010 (25) which stated that ‘Whether there is a functional relationship between measures of serum vitamin D or intake and mood or depression has not been determined’. However, in the light of the data indicating that insufficiency is surprisingly common in the general population, and particularly in certain groups (e.g. the elderly, those whose diet is poor, those with limited sunlight exposure), it is worthy of consideration as a supplement in depressed patients who are at any such insufficiency risk. This conclusion is consistent to some degree with the views expressed by McGrath (26) in considering vitamin D supplementation as a primary prevention of schizophrenia and stating that ‘there is a cogent argument to fast track any type of safe intervention’ that could (in that instance, have a primary preventive role for schizophrenia). More importantly, vitamin D levels should be checked in all depressed patients who are at risk of deficiency or insufficiency as a consequence of geographical or lifestyle issues.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References

This study was supported by an NHMRC Program Grant (510135) and an Infrastructure Grant from NSW Health. We thank Jacinta Marks for research assistance.

Declaration of interests

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References

Gordon Parker has received research support from Pfizer International and Servier Pharmaceuticals and serves on advisory boards for Astra Zeneca, Eli Lilly, Janssen Cilag, Lundbeck and Pfizer. H. Brochie has nothing to declare.

References

  1. Top of page
  2. Abstract
  3. Clinical recommendations
  4. Additional comments
  5. Introduction
  6. Material and methods
  7. Results
  8. Discussion
  9. Acknowledgements
  10. Declaration of interests
  11. References