A study published in the journal Translational Psychiatry reveals that targeted vitamin D supplementation in individuals with vitamin D deficiency may reduce the risk of probable lifetime major depression.

Study: Vitamin D, chronic pain, and depression: linear and non-linear Mendelian randomization analyses. Image Credit: Aria Armoko / Shutterstock

Background

Vitamin D deficiency, defined as low blood levels of 25-hydroxyvitamin D, is known to trigger a state of chronic pain through its action on bone biology, immune responses, and inflammation. Several observational study findings have highlighted an association of vitamin D deficiency with chronic pain, fibromyalgia, and depression.

Randomized controlled clinical trials of vitamin D supplementation in patients with chronic pain have mostly produced mixed results. In contrast, systematic reviews of randomized trials have highlighted the positive impact of vitamin D supplementation on depression, depressive symptoms, and negative emotions.

Observational epidemiological studies can be associated with possible bias from confounding factors and reverse causality. Mendelian randomization can overcome these challenges. This method uses genetic variants as instrumental variables to determine the causal effect of an exposure on an outcome, providing a more accurate overview of any causal associations between vitamin D levels and chronic pain.

In Mendelian randomization analysis, genetic variants that are specifically associated with circulating vitamin D levels can be used as proxies for the body’s vitamin D status to determine the causal association between vitamin D level and chronic pain.

Since genetic variants are randomly distributed at conception, they are unlikely to be related to possible confounding factors. Moreover, chronic pain conditions cannot affect the genotype, nullifying the possibility of reverse causality.

In this study, scientists have investigated the causal effect of circulating vitamin D levels on chronic pain and depression outcomes using linear and non-linear Mendelian randomization analyses.

Study design

The scientists performed linear and non-linear Mendelian randomization analyses of individual-level data collected from the UK Biobank, which includes approximately 500,000 participants aged 40–69 years at recruitment.

The scientists restricted their analyses to 333,025 unrelated participants of European ancestry with a valid vitamin D measurement. They determined the causal impact of vitamin D level on four outcomes, including fibromyalgia, clinical fatigue, chronic widespread pain, and probable lifetime major depression.  

They used genetic variants from four gene regions with known connections to vitamin D biology as instrumental variables, which are used to control for confounding factors and measurement errors.

They conducted linear analyses to investigate a causal effect in the population and non-linear analyses to determine a causal effect in subgroups of the population. The subgrouping was based on the circulating levels of vitamin D.   

Important observations

The linear Mendelian randomization analyses revealed that genetically predicted levels of vitamin D are not associated with fibromyalgia, clinical fatigue, chronic widespread pain, and probable lifetime major depression.

The non-linear Mendelian randomization analyses revealed that genetically predicted levels of vitamin D are associated with depression in participants with the lowest circulating vitamin D levels. However, no such associations were observed for other tested outcomes.

Study significance

The study finds that genetically-predicted vitamin D levels are associated with probable lifetime major depression in individuals with the lowest levels of circulating vitamin D. This finding suggests that vitamin D supplementation can reduce the risk of depression in individuals with vitamin D deficiency.

However, the study could not find any significant associations between genetically predicted vitamin D levels and fibromyalgia, clinical fatigue, chronic widespread pain, or probable lifetime major depression. This finding suggests that vitamin D supplementation is unlikely to reduce the risks of these outcomes in the population as a whole.

Overall, the study indicates that the beneficial effects of vitamin D supplementation are limited to people with vitamin D deficiency and that supplementation beyond a threshold level is unlikely to provide any additional benefits.

Considering these observations, scientists advise that future clinical trials of vitamin D supplementation should focus on recruiting a larger group of individuals with vitamin D deficiency to more realistically determine the beneficial effects of this vitamin.

Several mechanistic studies have proposed that vitamin D might play a role in reducing the risk of depression through its anti-inflammatory effect. Recent animal studies have shown that a lack of circulating vitamin D might influence the gut microbiota diversity related to mood disorders. It has also been observed that vitamin D influences the hypothalamic-pituitary-adrenal axis through its interaction with glucocorticoids, which has a known role in the development of depression.  

This study was conducted on individuals of European ancestry, which may restrict the generalizability of the findings to other populations. Moreover, the study has only identified about 4% of UK Biobank participants with depression, whereas the lifetime prevalence of major depression is around 10-20%, according to general population studies. This highlights the possibility of missing out on some cases.