Treatment Options

To date, the antidepressant properties of vitamin D are yet to be conclusively demonstrated (1,2). However, various studies have shown a benefit in the management of depression via improving vitamin D levels.

• Vitamin D supplementation (minimum of 800 IU daily) may be beneficial in the management of depression. However, when vitamin D levels are not raised as a result of the supplementation, the beneficial effect on depression may be absent (3)
• A 12-week program of behavioural intervention emphasising safe sun exposure can remediate vitamin D deficiency status and produce positive results in depressive symptoms in individuals with severe vitamin D deficiency and clinically significant depression (4)
• High dose vitamin D₃ supplementation (50,000 IU/week for 9 weeks) can reduce depression scores where there is a moderate vitamin D deficiency (5)
• Vitamin D supplementation (4000 IU per day) during the winter months can improve depression scores. Improvements may be seen after two winters of treatment (6)
• In individuals with major depressive disorder who are vitamin D deficient, 1500 IU vitamin D₃ combined with 20 mg fluoxetine over 8 weeks can significantly improve depression, compared to fluoxetine alone. Improvements can be seen after 4 weeks of treatment (7)
• In individuals with low serum vitamin D levels and depression associated with chronic liver disease, 20,000 IU vitamin D per week for six months may improve depression scores (8)
• In women with polycystic ovary syndrome (PCOS), vitamin D supplementation (50,000 IU every 2 weeks) in conjunction with omega-3 (2000 mg/day) for 12 weeks may improve depression scores (9)
• In individuals with bipolar disorder and low serum vitamin D levels, 2000 IU D₃ daily for 8 weeks may improve depression scores (10). However, 5000 IU D₃ per day for 12 weeks does not reduce depression symptoms in individuals with bipolar disorder, or remediate vitamin D deficiency (11). It is possible that the unresolved vitamin D deficiency in these individuals results in the nil effect on symptoms, as per a previous finding indicating that when vitamin D levels are not raised as a result of the supplementation, the beneficial effect on depression may be absent (3)
• In major depressive disorders, 50,000 IU per week vitamind D supplementation for eight weeks can significantly improve depression scores (12)
• Daily vitamin D₃ (2000 IU) during late pregnancy (from 26 to 28 weeks of gestation until childbirth) can decrease perinatal depression levels (13)
• In individuals with mild to moderate ulcerative colitis, treatment with vitamin D (a 300,000 IU D₃ injection) lowers depression scores 3 months later, but only in those individuals who do not have a baseline vitamin D deficiency (>75 nmol/L) (14)

Absorption/Bioavailability

Vitamin D is initially obtained as vitamin D₂ (ergocalciferol) or D₃ (cholecalciferol) from diet or supplements, or as D₃ from synthesis in the skin after sunlight exposure. It is synthesized into an active hormone that binds to vitamin D receptors (VDRs) found in more than 30 cell types (15).

After synthesis in the skin, D₃ is converted in the liver to 25-hydroxyvitamin D₃ (25(OH)D₃), or calcidiol, the major circulating vitamin D₃ which is not particularly active. It is this component which is routinely checked in clinical practice to assess vitamin D status. The D₂ form is synthesized by plants and is obtained solely from dietary sources. D₂ also undergoes 25-hydroxylation in the liver producing 25(OH)D₂. Both 25(OH)D₃ and 25(OH)D₂ become hormonally active after a second hydroxylation step in the kidney resulting in 1,25-dihydroxyvitamin D (calcitriol) formation (See Figure 1) (16,17).

Figure 1. The metabolism of vitamin D to its active form (18)

Vitamin D deficiency

Vitamin D deficiency can have many causes, even in sunny climates, including (19,20):

• Season, time of day and latitude affects the amount of solar radiation reaching the skin
• Current lifestyle factors play a role, as the majority of people spend their working hours unexposed to sunshine
• The elderly may be at particular risk for low levels if housebound or living in nursing homes
• Ageing, darker skin tones and sunscreen use affect vitamin D absorption
• Liver failure and chronic renal disease result in decreased vitamin D levels
• Decreased bioavailability due to factors such as malabsorption and obesity
• Increased catabolism due to certain medications, such as anticonvulsants and glucocorticoids

Mechanism of Action

Vitamin D plays a dual role as hormone and fat-soluble vitamin, regulating the expression of more than 900 genes via binding to the vitamin D receptor (VDR), a steroid hormone receptor (21,22,23). VDRs and vitamin D metabolizing enzymes are expressed in the brain. Due to its pleiotropic function, vitamin D is also involved in signalling cascades and neurobiological pathways which may affect mental health (24,25).

Vitamin D deficiency may set the stage for both the onset and the progression of depression by acting synergistically with other factors (26).

The exact mechanisms behind the association between vitamin D and depression are still to be elucidated, although several theories have been suggested:

• Vitamin D is a neurosteroid, capable of crossing the blood-brain barrier, with physiological effects on neuroprotection, neuroplasticity, brain development and regulation of neurotrophic factors (27)
• The VDRs in areas of the brain that are implicated in depression could be the link between vitamin D and depression. VDRs are found in the promoter regions of serotonin genes which are related to depression. The active metabolite, calcitriol, is thought to modulate the differentiation and maturation of dopaminergic neurons (26) and to affect brain serotonin concentrations (24,28,29)
• VDRs are present in neurons and glial cells of the limbic system, hippocampus, hypothalamus and other cortical and sub-cortical regions with possible consequences on mood, behaviour and cognition (30)
• Abnormalities in the cortisol response to stress might be involved in depression and there is a link between VDRs and glucocorticoid receptors in the hippocampus. Vitamin D also has an antagonist effect on some of the glucocorticoid-mediated functions (31)
• Depression is associated with chronic low-grade inflammation, which vitamin D might be able to moderate through its modulatory effects on immunity (31)
• Experimental studies suggest that vitamin D has antioxidant and anti-inflammatory properties (32) and improves myelination (33)
• Depression very often leads to social withdrawal and inactivity which probably contributes to reduced sun exposure and therefore lower levels of vitamin D. Similarly, vitamin D deficiency may promote depressive symptoms. These two issues, depressive symptoms and vitamin D deficiency, may actually exacerbate each other (4)

Figure 2. Possible effects of vitamin D on depression risk

Foods Containing

The main source of vitamin D for humans is D₃, synthesized in the skin from provitamin D₃ (7-dehydrocholesterol) upon ultraviolet B (UVB) exposure. Dietary sources of provitamin D₃ are animal-derived foods with oily fish as the most important, non-fortified food source (34).

Vitamin D₂ is naturally found in very low concentrations in plant sources (35) for example, sun-exposed mushrooms (36). However, dietary intake is often insufficient to cope with seasonal deficits of sunlight exposures during winter (37).

Table 1. Dietary, supplemental and pharmaceutical sources of vitamins D₂ and D₃ and approximate vitamin D content (15,38)

Common Markers

Serum concentrations of total 25(OH)D₃ are routinely used in clinical practice to assess vitamin D status. 25(OH)D₃ is the major circulating form of vitamin D, however, it is not the most active metabolite of vitamin D. Vitamin D assays do not distinguish between the three forms of vitamin D – DBP-bound vitamin D, albumin-bound vitamin D and free, biologically active vitamin D (17).

Cautions/Contraindications

Due to the limitations of measuring inactive vitamin D concentrations in serum, it is possible that a deficiency might be identified when no true deficiency exists. In this case, vitamin D supplementation could lead to vitamin D toxicity. Most of the symptoms of vitamin D toxicity are due to hypercalcemia, and early symptoms include gastrointestinal disorders such as anorexia, diarrhoea, constipation, nausea, and vomiting (39). High dose vitamin D supplementation needs to be administered with caution.

Takeaway on Vitamin D and Depression

• Whether vitamin D inadequacy is a causative factor in depression, or simply a marker associated with depression remains undetermined
• There is promising evidence supporting the beneficial effect of maintaining adequate vitamin D levels in the management and prevention of depression
• Vitamin D supplementation may be beneficial in treating depression, specifically when there is an accompanying vitamin D deficiency which is corrected as part of the treatment
• Unresolved issues regarding the accurate assessment of vitamin D status and the lack of reference values for vitamin D in mental health makes it difficult to compare and consolidate the evidence
• High dose vitamin D should be administered with caution