Iron and vitamin D reduce depression risk, while selenium and magnesium raise it

Researchers unveil how specific micronutrients impact depression, revealing iron and vitamin D as protective, while cautioning against high levels of selenium and magnesium for mental well-being.

Study: Micronutrients and Major Depression: A Mendelian Randomisation Study. Image Credit: Lightspring / Shutterstock.com

Micronutrients like vitamins and minerals are essential to physical health; however, their role in depression remains unclear. A recent study published in the journal Nutrients explores the causality of observed associations between micronutrient intake, major depressive disorder (MDD), and recurrent depression (rMDD) using Mendelian randomization (MR).

Micronutrients and depression

Traditional foods provide most micronutrients at adequate levels. However, as populations worldwide consume more processed foods, rising levels of subclinical micronutrient deficiency are expected to increase, which has important public health implications.

For example, several micronutrients have been implicated in the development of MDD and its rising prevalence. These nutrients are crucial in numerous neurological and endocrine pathways, which suggests some mechanisms that may be involved in how nutrients impact the risk of depression. However, this hypothesis lacks validity due to the presence of confounding factors, the possibility of reverse causality, and publication bias.

How MR helps assess causality

Randomized controlled trials (RCTs) on micronutrient supplementation are expensive and must be large enough to identify possibly small effects. This may explain conflicting results from two large previous RCTs, which compared the effects of vitamin D or a mixed supplement comprising selenium, folic acid, vitamin D, and omega-3 fatty acids among people with excess body weight, respectively.

As compared to RCTs, MR utilizes single nucleotide polymorphisms (SNPs) as the variables substituting for potentially modifiable risk factors. The two alleles in every chromosome pair are randomly derived from different sources, reducing the risk of confounding and reverse causation often present in traditional epidemiological studies.

As compared to the well-documented relationship between carbohydrate and fat intake on depression risk, previous studies have failed to establish associations between micronutrient deficiency or any form of depression. The lack of an observed association in these studies may be due to different ancestries in exposure and outcome samples or inadequately powered samples.

About the study

The aim of the current study was to detect causal associations between fourteen micronutrients, MDD, or rMDD, the latter of which is the most severe and chronic form of MDD.

Data were obtained from the genome-wide association studies (GWASs) of MDD performed by the Psychiatric Genomics Consortium (PGC). The study cohort comprised 116,209 cases and 314,566 controls for MDD, 17,451 cases, and 62,482 controls for rMDD.

With conventional MR techniques, no associations between micronutrient exposures and either MDD or rMDD were observed. When genetically correlated variants were incorporated into the analysis, thus increasing its power, causal effects were identified for five micronutrient-depression associations.

Three micronutrients were found to be protective against rMDD, of which included serum iron, erythrocyte copper, and vitamin D. More specifically, a 10% reduction in the risk of rMDD for every unit increase in standard deviation (SD) for serum iron levels was observed, as compared to a 3% and 20% decrease in risk per unit increase in SD for erythrocyte copper and vitamin D, respectively. 

The metabolic functions of the genetic variants used strengthened the causal association of iron and vitamin D with depression. Conversely, higher serum selenium levels increased the risk of MDD by 3% for every unit SD increase.

The risk of rMDD increased by 8% and 21% for every unit SD increase in selenium and serum magnesium levels, respectively. However, these effects were both inconsistent, and variants were used without established functional status.

Ruling out reverse causality

In the reverse MR analysis, the exposure was MDD, and the outcome was micronutrient exposure. Herein, a weak association was observed between the development of MDD, reduced vitamin D levels, and increased selenium levels.

These findings emphasize the need for additional research to identify causality in the association between micronutrients and MDD due to weak evidence for a reduced depressive tendency with increased vitamin D and serum iron levels. The highest effect sizes were observed with rMDD, thus suggesting the potential of a dose-response relationship.

The current analysis avoided pleiotropy, where different exposures affect the same outcome, by utilizing certain well-validated SNPs and established functional variants rather than many possibly irrelevant SNPs.

The negative association between magnesium levels and MDD risk contradicts the generally favorable reports on magnesium in mood disorders. This finding may be due to pleiotropy, as suggested after adjusting for the effects of vitamin D and calcium, which are closely related to magnesium metabolism.

Conclusions

The observed inverse associations between iron, copper, and vitamin D with the risk of MDD and rMDD suggest that these minerals may protect against depression, whereas increased selenium and magnesium levels may increase the risk of depressive outcomes.

There remains a lack of genetic tools capable of detecting significant but slight causal effects of micronutrients on depression with adequate power. Future trials should ensure that statistical power is present to capture small causal effects.  

The potential adverse effects associated with excessive levels of certain micronutrients should guide supplementation protocols to prevent their administration in supraphysiological amounts.