Vitamin D deficiency and depression: Causal relationship or artifact?

To the Editor: Vitamin D is a secosteroid hormone with numerous proposed nonskeletal effects. In particular, it has been hypothesized that the lack of vitamin D may induce negative affect and depression [1]. The presence of vitamin D receptors in the limbic system [2] and the finding that vitamin D regulates gene expression of monoamine neurotransmitters such as serotonin [2,3] were consistent with this hypothesis. Since then, a number of observational studies have reported that serum concentration of 25-hydroxyvitamin D (25(OH)D) was lower among older people with depression when compared with controls [4–7]. Conversely, results from randomized therapeutic trials were divergent, some found a potential benefit of vitamin D on symptoms of depression [8–10], whereas others did not [11,12]. For instance, in a small double-blind study of 5 days of treatment with vitamin D, 44 healthy participants demonstrated increased positive affect and decreased negative affect during winter when compared with vitamin A [10]. In contrast, the administration of 800 IU vitamin D per day for 6 months during the winter failed to improve depressive symptoms among 1,621 older women [9]. It is of note that these previous findings were constrained by important methodological limitations including the lack of placebo-controlled group or the use of a single measure of depression. Thus, a direct causal relationship could not be inferred, and the key question remains whether the low 25(OH)D concentration is the cause of depression or simply a marker of some other processes that are responsible for the depression. Importantly and contrary to the few previous observational studies conducted mostly among older adults [4,6,7], a recent large well-conducted cross-sectional study among US adults of all ages failed to show a significant association between vitamin D deficiency and depression, after adjustment for a number of potential confounders including an indirect measure of sun exposure, the level of physical activity, age, and the body mass index (BMI) [13]. We therefore suggest that the relationship between vitamin D levels and mood may be not as direct as initially proposed because 1) it may have been overestimated in elderly populations as both outcome (depression) and exposure (vitamin D deficiency) are very prevalent in these populations [2,14]; and 2) it could be explained indirectly by innate (genetics) and acquired processes (degree of sun exposure, diet, age, physical exercise level, and BMI). Vitamin D is synthesized from a cholesterol derivative. It exists in two forms: vitamin D2 or ergocalciferol, which is provided mainly by fortification of food products and by commercially available vitamin D2 supplements; and vitamin D3 or cholecalciferol, which is provided by animal food products including fatty fish or dairy products, food fortification, and D3 supplements, or by endogenous production under the action of ultraviolet B light radiation on cutaneous cholesterol [14]. These different sources of vitamin D may account for differences in baseline vitamin D status and explain some of mixed results in previous trials. As studied populations were heterogeneous, discrepancies among published studies may be explained, in part, by differences in dietary habits (more or less rich in vitamin D), skin color (darker skin synthesizes less vitamin D on exposure to sunlight), and age (the risk of hypovitaminosis D is particularly high in older adults due to, among others, undernutrition and reduced capacity of the skin to produce vitamin D) [14,15]. Policies of vitamin D supplementation and food fortification differ across countries and continents. In some countries such as Canada, which mandates fortification of dairy products and margarines, or the United States, where supplementation and fortification of dairy products, orange juice, breakfast cereals, and margarines are common, people have a reasonably high vitamin D status [15]. Conversely, studies conducted in countries where fortification and supplementation are less common may include participants with significantly lower baseline vitamin D status. The latter participants are likely to allow detection of vitamin D effects because such effects may not be observed among participants whose higher baseline vitamin D status is already sufficient to meet the physiological needs associated with depression (if such needs exist). In parallel, as serum 25(OH)D is an integrative measure of both exposure to solar UVB radiation and diet [14–16], it could be suggested that the link between vitamin D and mood is explained with a more indirect relationship by exposure to sunlight or by everyday dietary habits in patients with depression. In particular, it is well known that exposure to light influences body circadian rhythms such as melatonin rhythms, and there is evidence that melatonin and serotonin circadian rhythms are involved in depression [17–20]. Moreover, the association found between vitamin D deficiency and depression may also be explained by decreased consumption of fish—the main natural dietary source of vitamin D [21]—or by low supplies of other nutrients found in vitamin D-rich foods, such as omega-3 unsaturated fats [22]. The apparent relationship between vitamin D deficiency and depression may also rely on the level of physical *Address for correspondence: C edric Annweiler, MD, PhD, Department of Neuroscience, Division of Geriatric Medicine, Angers University Hospital, 49933 Angers Cedex 9, France. Tel. : þ33-2-4135-5486; Fax: þ33-2-4135-4894; E-mail: ceannweiler@chu-angers.fr Received 27 September 2011; accepted 25 April 2012 DOI: 10.1002/biof.1028 Published online 2 June 2012 in Wiley Online Library (wileyonlinelibrary.com)