Mental Health

Multiple lines of evidence have implicated increased brain inflammation (neuroinflammation) in mental health disorders. One example is autoimmunity, where inappropriate targeting of brain proteins by the immune system can increase neuroinflammation, negatively affecting brain function.^[5] Neuroinflammation isn’t always caused by autoimmunity, however, since increased systemic levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-β) and tumor necrosis factor-alpha (TNF-α), have been shown to cause social withdrawal, triggering “sickness behavior”^[6], a mechanism that may have evolved to encourage social isolation to decrease transmission of communicable diseases. While the mechanisms by which inflammation induces sickness behavior aren’t completely understood, experiments with lipopolysaccharide (LPS, an inflammation-inducing component from the cell wall of certain bacteria) have shown that increased levels of inflammation can have direct effects on the brain in humans. In one study where healthy participants were injected with low doses of LPS, reward signaling in the brain was suppressed, causing anhedonia (the inability to feel pleasure), a common symptom in people with depression.^[7]

In the 1930s, scientists discovered the presence of autoantibodies in a patient with schizophrenia,^[8] putting autoimmunity and autoimmune disorders on the radar as possible contributing factors to mental health disorders. Research in subsequent decades has found associations between autoimmunity and many mental health disorders,^[9] but the identification of specific autoantibody biomarkers has been elusive.^[10] Systemic autoimmune disorders such as lupus can lead to a number of neurological and psychiatric symptoms such as anxiety, mood disorders, and psychosis.^[5] While the mechanisms by which autoimmunity affects the brain are not completely understood, evidence is mounting that in addition to other parts of the body, the immune system may inappropriately target synaptic proteins in the brain, leading to psychiatric symptoms and mental health disorders.

Many people get depressed during the winter months, when we produce less vitamin D. So, can supplemental vitamin D cure seasonal depression, and maybe other types of depression? No, alas — but it may help.

Vitamin D is the “sunshine vitamin”,^[11] and sunshine is implicated in mood. So it makes sense that researchers have intently explored vitamin D supplementation for depression. But depression is complex, and the mechanisms at work are not well-understood. However, careful analysis of the trials testing the effects of vitamin D on depression and mood-related pathways will help provide some insight into whether, or if, vitamin D may be helpful for depression in different contexts or populations.

Two reviews of observational studies and intervention trials reached the same conclusions: When parsing the observational data, both reviews found a correlation between depression and low levels of vitamin D (≤20 ng/mL). When parsing the trial data, both reviews found benefits from supplementation, but also assessed some of the included studies as having low methodological quality and high risk of bias.^[12][13]

Those two reviews were published in 2017 and 2016, so shortly after a 2015 meta-analysis of randomized controlled trials (RCTs) reported finding no significant reduction in depression after vitamin D supplementation. Its authors, however, mentioned that “most of the studies focused on individuals with low levels of depression and sufficient serum vitamin D at baseline”.^[14] In other words, they didn’t rule out the possibility that in people with higher levels of depression or lower levels of vitamin D, supplementation might be more effective.

This hypothesis lines up with the conclusions of a 2014 meta-analysis, which found that, if one considered only the studies whose subjects had low levels of vitamin D at baseline (≤20 ng/mL) and were then given enough vitamin D to achieve sufficiency over the course of the trial, then supplemental vitamin D was about as effective as antidepressant medication.^[15] However, this meta-analysis did not account for publication bias.

A 2018 meta-analysis focused on major depression and found a moderate benefit from vitamin D. However, it stresses the low number of qualifying studies (four trials) and, like the 2017 and 2016 reviews, deplores the low methodological quality of some of the studies.^[16] Additionally, a 2016 randomized controlled trial of vitamin D supplementation in people with major depressive disorder purportedly saw an antidepressant effect,^[17] but this study was retracted in 2021 due to concerns over the validity of the participant data.^[18]

Finally, let’s mention a 2016 RCT that found that pregnant women who took a daily dose of 2,000 IU (50 μg) of vitamin D3 during late pregnancy had lower scores on a postpartum depression screening scale than those who did not supplement.^[19] However, this study only addressed postpartum depression in healthy women with a low-to-moderate pre-partum risk of depression; it may not have wider applicability, and further research is needed.

Vitamin D insufficiency (≤20 ng/mL) has been associated with depression. If your depression is severe, you are more likely to benefit from correcting an insufficiency. If your levels of vitamin D are sufficient, however, then whether your depression is severe or not, supplementation isn’t likely to help. (Due to the poor overall methodological quality of the studies, those conclusions are at best preliminary.)

In support of this, a number of observational studies have found that people with depression are more likely to have low vitamin D levels.^[20] However, randomized controlled trials don’t consistently find beneficial effects of vitamin D supplementation on depression.^[21][22] One reason for this could be that benefits only occur if a person has sufficiently severe depression symptoms. In support of this, two meta-analyses of randomized controlled trials found that vitamin D supplementation reduced the severity of depression symptoms in people with depression but had no effect on depression symptoms in people without depression.^[23][24]

Vitamin D receptors can be found pretty much everywhere in the human body, so the ways in which vitamin D might affect your mood are innumerable. One of those mechanisms could be hormonal, since vitamin D helps regulate testosterone levels,^[25][26] and since low testosterone can impair the mood of both men^{[27][28][29][30]} and women.^[31]

We should remember, however, that correlation is not causation. As stated above, the observational data suggests a correlation between depression and low levels of vitamin D, but that doesn’t mean that low levels of vitamin D cause the depression. It might be that depressed people go outside less, thus getting less sunlight, thus producing less vitamin D: the depression would then be the cause of the low vitamin D levels, rather than its consequence.

Even if depression is a consequence, not a cause, it doesn’t mean that low levels of vitamin D aren’t also a consequence. People who go outside less get less sunlight, but also probably less exercise — and we know that exercise benefits mood,^[32] both directly and by promoting better sleep.

And of course, a consequence can have more than one cause. For instance, a decrease in vitamin D production during the winter months is a possible factor in seasonal affective disorder (SAD),^[33] but so is a decrease in illumination,^[34] since one meta-analysis^[35] and a more recent RCT^[36] found that light therapy (using visible light, free of the UVB rays that allow your skin to produce vitamin D) can improve SAD symptoms, often as much as can pharmaceuticals. It should be noted, however, that a few trials with small sample sizes make for rather weak evidence, especially since the meta-analysis didn’t account for publication bias.

The findings on vitamin D are less consistent. One study found an association between depression and seasonal changes in vitamin D,^[37] but another study found no effect of supplemental vitamin D on SAD.^[38] And compounding the uncertainty, the researchers of both studies stressed that potential confounders were numerous.

To summarize:

• Low levels of vitamin D have been associated with depression, but it doesn’t follow that low levels of vitamin D are the cause of the depression. They’re probably one of the factors at play in seasonal depression, but so is the decrease in illumination.
• If your vitamin D levels are not low, supplementation isn’t likely to benefit your mood. If they are low, supplementation is more likely to help if you suffer from major depression.
• If you suspect your vitamin D levels are low, you can have them assessed through a 25-hydroxyvitamin D blood test. Assessing your vitamin D levels twice in a year — in midsummer and midwinter, when there is the most and least sunlight — is an efficient way of estimating what your levels are around the year.