Hard to say, but there’s some evidence that hormones could play a role. One line of evidence suggesting this is that young women are at the greatest risk^[20] for major depression and mental disorders starting at puberty, when prevalence of depression^[21] is doubled in women compared to men for ages 14-25. However, other social factors around this age could equally play a role. What’s more confusing is that a reduction in estrogen also looks to be linked to depression. In the time right before menopause, when estrogen levels begin to decrease in an irregular fashion, the risk of depression^[22] appears to increase, and studies^[23] suggest that hormone replacement therapy (particularly estrogen) may prevent or alleviate depression experienced during the transition. In fact, women using oral contraceptives^[24], especially the monophasic (same amount of hormones in each pill) type, reported reduced rates of depression and anxiety in comparison to non-users. Unfortunately, since researchers suspect hormonal fluctuations can influence depression, most studies tend to avoid women participants for this reason, so not much human data is available.

Dietary trends appear to emerge across dietary intervention trials investigating changes in depressive symptoms, and several align with the Mediterranean diet. Increases in fruit and vegetables, nuts and seeds, and fish intake appear to be the way to go^[17], and that’s not just for^[18] depressive symptoms. In addition, decreases in processed meats, refined carbohydrates, and other inflammatory foods^[19] have previously been found to be associated with a greater mental well-being. Even though the state of the evidence isn’t ideal, there is some evidence that certain food groups may impact depression.

Major depressive disorder (MDD) appears to have a genetic component to it, but it’s unknown how much of the disease is preventable. Along with other predictive markers of depression^[16] (e.g. income) we can predict to some extent which individuals may be at higher risk of developing MDD. While numerous methods are used as preventive approaches, the brain-energetics side remains largely unexplored.

Overall, the current evidence is insufficient to recommend supplementation for MDD prevention. Nevertheless, because creatine supplementation is quite safe (with minimal to no side effects), it may prove to be a candidate for those at risk of depression, and the dose would also be relatively easy to titrate (always making sure you discuss your supplementation with your physician or health professional).

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”,^[29] 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.^[30][31]

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”.^[32] 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.^[33] 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.^[34] Additionally, a 2016 randomized controlled trial of vitamin D supplementation in people with major depressive disorder purportedly saw an antidepressant effect,^[35] but this study was retracted in 2021 due to concerns over the validity of the participant data.^[36]

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.^[37] 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.^[38] However, randomized controlled trials don’t consistently find beneficial effects of vitamin D supplementation on depression.^[39][40] 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.^[41][42]

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,^[43][44] and since low testosterone can impair the mood of both men^{[45][46][47][48]} and women.^[49]

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,^[50] 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),^[51] but so is a decrease in illumination,^[52] since one meta-analysis^[53] and a more recent RCT^[54] 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,^[55] but another study found no effect of supplemental vitamin D on SAD.^[56] 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.

A large-scale observational study of nearly 18,000 individuals compared self-reported moderate to vigorous-intensity aerobic physical activity, muscle-strengthening exercise, and a combination of the two.^[14] The researchers observed that individuals who met Centers for Disease Control and Prevention (CDC) guidelines for both aerobic and muscle-strengthening exercise^[15] had the lowest prevalence ratios for depressive symptom severity. The results can be seen below, which are sorted by depression severity.

Impact of meeting CDC activity guidelines on depression

Reference: Bennie et al. Prev Med. 2019.^[14]

Despite the considerable number of individual studies on this topic, further work is needed to refine potential recommendations to account for the following.

• Aerobic versus non-aerobic physical activity versus a combination of the two
• The type(s) of physical activity that may confer the greatest benefit
• Differences between males and females
• Differences across age groups
• The severity of the depression
• Comorbidities

Furthermore, it would be helpful to know the minimum duration and intensity of physical activity that still exerts a meaningful level of protection from depression.

Exercise seems to compare at least comparably with the current medical standard of care for depression.^[25][26] In one clinical trial, researchers randomly assigned 156 moderately depressed males and females to an exercise intervention, medication, or a combined exercise and medication group.^[27]

• The exercise group walked or jogged on a treadmill for thirty minutes, three times per week for sixteen weeks.
• The medication group received the common selective serotonin reuptake inhibitor (SSRI) sertraline (Zoloft)
• The combination group received the medication and performed the exercise program concurrently.

Results showed that the medication worked more quickly to reduce symptoms of depression, but exercise was equally effective at the end of the sixteen-week program and created more lasting alleviation of depression at a ten-month follow-up.^[28]