Does Vitamin D Prevent Depression?

Why You Can’t Believe Everything You Read

depressionThe days are getting shorter and Seasonal Depression, often called the “winter blues”, will soon be upon us. Most of the research on Seasonal Depression has centered on the effect of sunlight on our hormones.

However, sunlight is also responsible for the synthesis of vitamin D in our skin cells. So, some experts have hypothesized that low levels of 25-hydroxyvitamin D, the active form of vitamin D, in our blood also play a role in the winter blues.

If so, that could have important implications for managing depression, especially in older adults. Depression is estimated to affect around 6.5 million of the 49 million adults over the age of 65 in our country. Treatment costs for older adults in this country are estimated at $9 billion/year.

If something as simple and inexpensive as a vitamin D supplement could reduce the risk of depression, it would be a huge boon to our health care system.

Association studies suggest that may be a possibility. For example, one recent meta-analysis of 6 clinical studies (H Li et al, The American Journal of Geriatric Psychiatry, 27: P1192-1202, 2019) reported that every 10 ng/mL increase in 25-hydroxyvitamin D was associated with a 12% decrease in the risk of depression in older adults.

However, association studies do not prove cause and effect.

Unfortunately, randomized, placebo controlled clinical trials have given mixed results. A few studies suggested that vitamin D might reduce depression risk, but most of the studies found no effect of vitamin D on depression risk. However, most of the published studies have been poorly designed They were too small, too short, or did not use validated methods for measuring depression.

This was the genesis of the current study (OI Okerke et al., JAMA, 324: 471-480, 2020). It was designed to be a definitive study that would avoid the defects of previous studies.

The study concluded that vitamin D supplementation does not decrease the risk of depression in older adults, and those were the headlines you have probably seen. But is that conclusion true? Let’s take a peek behind the curtain and analyze the study.

How Was The Study Done?

Clinical StudyThis study was an offshoot of the VITAL (VITamin D and OmegaA-3 TriaL) clinical study, so let me start by describing the characteristics of that study.

The VITAL study (JE Manson et al, New England Journal of Medicine, DOI: 10.1056/NEJMoa1811403) enrolled 25,871 healthy adults (average age = 67) in the United States. The study participants were 50% female, 50% male, and 20% African American. None of the participants had preexisting cancer or heart disease.

Study participants were given questionnaires on enrollment to assess clinical and lifestyle factors including dietary intake. Blood samples were taken from about 65% of the participants to determine 25-hydroxyvitamin D levels (a measure of vitamin D status) at baseline and at the end of the first year to assess the effectiveness of vitamin D supplementation. The participants were given either 2,000 IU of vitamin D/day or a placebo and followed for an average of 5.3 years.

This study consisted of 18,353 participants from the VITAL study. Ninety percent of the participants had no previous history of depression. Ten percent had previously been diagnosed or treated for depression but had been depression-free for over 2 years.

The participants filled out annual questionnaires to quantify the onset of depression by three criteria:

  • A diagnosis of depression by a physician.
  • Treatment for depression (medications, counseling, or both).
  • A questionnaire designed to evaluate symptoms of depression. The authors of the study referred to this as an assessment of their mood.

During the 5.3 year follow up period 3.6% of the participants reported the onset of diagnosed depression or a mood consistent with depression. This is consistent with previous studies showing that 1-5% of healthy, non-institutionalized older adults suffer from depression.

Does Vitamin D Prevent Depression?

thumbs down symbolThe results of the study were clear.

Treatment with 2,000 IU of vitamin D3 compared to placebo for 5.3 years did not have a statistically significant effect on:

  • The incidence or recurrence of depression diagnosis, or…
  • Treatment for depression, or…
  • Clinically relevant depressive symptoms.

The authors concluded, “These findings do not support the use of vitamin D3 in adults to prevent depression.”

Why You Can’t Believe Everything You Read

It would be tempting to say, “Case closed. We now know for certain that vitamin D has no effect on depression.”

After all, this was an excellent study. It was large (18,353 participants), lasted a long time (5.3 years), and used well established measures of depression. What’s not to like?

Peek Behind The CurtainUnfortunately, even well-designed studies can give misleading results. Let’s take a peek behind the curtain and see where this study went astray.

There were two glaring deficiencies in this study.

#1: Most of the participants had adequate vitamin D status at the beginning of the study. The average 25-hydroxyvitamin D level of participants at the beginning of the study was 31 ng/mL (78 nmol/L). The NIH considers 20-50 ng/mL (50-125 nmol/L) to be an adequate level of 25-hydroxyvitamin D for most physiological functions. This means that study participants started in the middle of the adequate range with respect to vitamin D status.

This was not a failure of study design. In fact, the authors of the study are to be commended for measuring the vitamin D status of participants at the beginning of the study. Many previous studies have neglected to do that.

The problem is that vitamin D has become extremely popular. Many Americans are already taking multivitamins or vitamin D supplements. To recruit enough people for the study the authors were forced to allow participants to enter the study even if they were taking vitamin D supplements, as long as the amount did not exceed 800 IU/day.

In short, most of the participants in this study were already supplementing with up to 800 IU/day of vitamin D. If so, they were allowed to continue taking their vitamin D supplements. The 2,000 IU of vitamin D was added to what they were already taking.

The question then becomes, if people are already taking RDA levels of supplemental vitamin D and their blood levels of 25-hydroxyvitamin D are already in the adequate range, do we really expect additional supplemental vitamin D to have a beneficial effect?

The author’s answer to that question was, “The mean baseline 25-hydroxyvitamin D level was 30.8 ng/mL; this value is already at a threshold for extraskeletal health benefits [health benefits other than bone health], and so the ability to observe effects of vitamin D3 supplementation may have been attenuated. [To determine whether vitamin D supplementation reduces the risk of depression] large-scale studies would be required to address the effects of high-dose, long-term vitamin D3 supplementation among those with nutrient deficiency.”

My more direct answer would be, “This study provides no useful information on whether vitamin D3 supplementation reduces the risk of depression. What is needed are studies that start with a population that is deficient in vitamin D.”

An accurate conclusion from this study would have been, “If you are already taking vitamin D supplements and/or have an adequate vitamin D status, supplementation with an extra 2,000 IU of vitamin D3 provides no additional benefit with respect to the risk of developing depression.” But that is not what the headlines said.

#2: The study did not record the reason for the onset of depression. That is important because the top 3 causes of depression in adults 65 and older are:

  • Loss of a spouse or partner.
  • Chronic health issues.
  • Restricted blood flow to the brain.

It is unlikely that vitamin D supplementation would have much of an effect on these issues.

In contrast, seasonal depression, which is more likely to be affected by vitamin D supplementation, was not measured in this study.

The Bottom Line

You may have seen recent headlines saying that vitamin D supplementation has no effect on the risk of developing depression.

The study behind these headlines was a very well-designed study. It was large (18,353 participants), lasted a long time (5.3 years), and used well established measures of depression.

It would be tempting to say, “Case closed. We now know for certain that vitamin D supplementation has no effect on depression.”

Unfortunately, even well-designed studies can give misleading results. This one had a major flaw that made the data almost useless.

The problem is that most Americans are already taking multivitamins or vitamin D supplements. To recruit enough people for the study the authors were forced to allow participants to enter the study even if they were taking vitamin D supplements, as long as the amount did not exceed 800 IU/day.

That meant that most participants already had adequate blood levels of 25-hydroxyvitamin D at the beginning of the study.

The question then becomes, if people are already taking RDA levels of supplemental vitamin D and their blood levels of 25-hydroxyvitamin D are already in the adequate range, do we really expect additional supplemental vitamin D to have a beneficial effect? The answer is, “Probably not”.

Rather than saying that this study definitively shows that vitamin D supplementation has no effect on the risk of developing depression, I feel it would be more accurate to say, “This study provides no useful information on whether vitamin D3 supplementation reduces the risk of depression. What is needed are studies that start with a population that is deficient in vitamin D.”

An accurate conclusion from this study would have been, “If you are already taking vitamin D supplements and/or have an adequate vitamin D status, supplementation with an extra 2,000 IU of vitamin D3 provides no additional benefit with respect to the risk of developing depression.” But that is not what the headlines said.

For more details, read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.

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