Vitamin D supplementation does not protect against depression in middle-age or older adulthood according results from one of the largest ever studies of its kind.

This is a longstanding question that has likely encouraged some people to take the vitamin.

In this study, however, “There was no significant benefit from the supplement for this purpose.

It did not prevent depression or improve mood,” says Olivia I. Okereke, MD, MS, of Massachusetts General Hospital (MGH’s Psychiatry Department.

Okereke is the lead author of the report and principal investigator of this study, which will be published in JAMA on Aug. 4. It included more than 18,000 men and women aged 50 years or older.

Half the participants received vitamin D3 (cholecalciferol) supplementation for an average of five years, and the other half received a matching placebo for the same duration.

Vitamin D is sometimes called the “sunshine vitamin” because the skin can naturally create it when exposed to sunlight.

Numerous prior studies showed that low blood levels of vitamin D (25-hydroxy vitamin D) were associated with higher risk for depression in later life, but there have been few large-scale randomized trials necessary to determine causation.

Now Okereke and her colleagues have delivered what may be the definitive answer to this question.

“One scientific issue is that you actually need a very large number of study participants to tell whether or not a treatment is helping to prevent development of depression,” Okereke explains. “With nearly 20,000 people, our study was statistically powered to address this issue.”

This study, called VITAL-DEP (Depression Endpoint Prevention in the Vitamin D and Omega-3 Trial), was an ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among nearly 26,000 people in the US.

From that group, Okereke and her colleagues studied the 18,353 men and women who did not already have any indication of clinical depression to start with, and then tested whether vitamin D3 prevented them from becoming depressed.”

The results were clear. Among the 18,353 randomized participants, the researchers found the risk of depression or clinically relevant depressive symptoms was not significantly different between those receiving active vitamin D3 supplements and those on placebo, and there were no significant differences were seen between treatment groups in mood scores over time.

“It’s not time to throw out your vitamin D yet though, at least not without your doctor’s advice,” says Okereke. Some people take it for reasons other than to elevate mood.

“Vitamin D is known to be essential for bone and metabolic health, but randomized trials have cast doubt on many of the other presumed benefits,” said the paper’s senior author, JoAnn Manson, MD, DrPH, at Brigham and Women’s Hospital.

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Depression affects 350 million people worldwide, is the leading cause of disability and the fourth-leading cause of the global disease burden [1].

However, the effectiveness of conventional treatments for depression is questioned: meta-analyses of drug treatments demonstrate minimal difference from placebo, comparisons of real and sham electroconvulsive therapy show little difference after a month, and the evidence for the use of specific cognitive interventions is weak [2].

Therefore we examined the evidence for other approaches to the management of depression.

The association between depressive disorders and Vitamin D deficiency from a lack of sun exposure is well established and was first noted two thousand years ago [3], therefore we considered the evidence for the effectiveness of Vitamin D supplementation.

Vitamin D is a unique secosteroid hormone formed mainly by photosynthesis, so an indoor lifestyle and sun-avoidance leads to deficiency (25OHD <50 nmol/L) [4].

Vitamin D deficiency is now a global public health problem affecting a billion people worldwide [5]. Even in sunny Australia, deficiency affects one third of the population [6], with much higher rates observed in migrant populations [7,8].

There has been an increase in the prevalence of Vitamin D deficiency [9] and a ten-fold increase in spending on supplements in the US over the last decade [10].

Knowledge of Vitamin D has grown  exponentially  [11]  and  95%  of  our  current  knowledge  was published in the last 15 years [12].  This  demonstrates  new  mechanisms  and  diseases  associated with deficiency including cancer, cardiovascular disease,  diabetes,  and  premature mortality [4].

Whilst Vitamin D was believed to follow Funk’s model of vitamins, having a single mechanism and function limited to calcium and bone metabolism [13], the mechanisms of action of Vitamin D are now recognized to be endocrine, paracrine and autocrine via Vitamin D receptors (VDRs) [14] affecting most physiological systems, including the brain [15].

The enzymes necessary for the hydroxylation of 25hydroxyvitamin D (25OHD) to the active form 1,25dihydroxyvitamin D are present in the hypothalamus, cerebellum, and substantia nigra [16].

Vitamin D modulates the hypothalamic-pituitary-adrenal axis, regulating adrenalin, noradrenaline and dopamine production through VDRs in the adrenal cortex [17]; and protects against the depletion of dopamine  and  serotonin centrally [18].

Therefore, biological plausibility for the action of Vitamin D in depression  has been established.

Epidemiological evidence shows that Vitamin D deficiency is associated with an  8%–14%  increase in depression [19–22] and a 50% increase in suicide [23]; however, causality and efficacy of supplementation remain controversial [10,24] awaiting confirmation by systematic review and meta- analysis.

Four systematic reviews of Vitamin D efficacy in depression, but no meta-analysis, have been published [25–28]. These reviews provide conflicting results due to the limited number of studies found and the inclusion of inappropriate studies.

Based on six RCTs deemed relevant, the Institute of Medicine (IOM) [25] concluded there was “inconclusive evidence of an effect” although four of these RCTs showed a beneficial effect of Vitamin D supplementation in depression.

The inclusion of the other two studies [29,30] described by the IOM as “RCTs of Vitamin D” was inappropriate as; one used calcium and not Vitamin D as the intervention, and the other was not an RCT in the opinion of the study authors as the intervention decreased 25OHD levels. Similarly, consistent conclusions could not be drawn from the other systematic reviews [26–28], as these found so few of the primary studies.

These reviews mirror the inconsistent results found across Vitamin D research as demonstrated by the twenty four conflicting meta-analyses for falls, fractures, and all-cause mortality [31].

The reason Vitamin D meta-analyses fail to produce useful results is thought to be biological flaws in primary studies. These flaws lead to null results [32] as the intervention does not change the Vitamin D status however these flaws may be overlooked when evaluating the research for Vitamin D and other nutrients [33,34].

The concept of “biological flaws” arises from the work of Heaney and others [33,34], and refers to limitations in the design of primary studies which preclude them from testing the research hypothesis.

The hypothesis being addressed in this review is that rectifying Vitamin D deficiency decreases depressive symptoms. However some trials have limitations in their study design that prevent this evaluation.

This hypothesis can only be tested if participants are Vitamin D deficient at baseline and then receive a large enough dose of Vitamin D supplements to achieve Vitamin D sufficiency during the trial.

Vitamin D deficiency cannot be demonstrated if the level of 25OHD is sufficient or higher or not tested at baseline. An ineffective dose of Vitamin D is one that would not be expected to increase the level of 25OHD from deficient to sufficient.

Trials with these biological flaws may demonstrate the limitations of the study design rather than the effectiveness of Vitamin D supplements for changing health outcomes. The parallel in pharmaceutical research to these nutrient studies with biological flaws would be trialling a drug known to be ineffective or on patients already taking a full dose of the drug.

Thus biological flaws are a critical element that differentiates nutrient research from pharmaceutical research.

This review was designed to estimate the effect of Vitamin D supplementation in depression and examine the influence of biological flaws in primary studies on the meta-analyses.

Discussion

This is the most comprehensive systematic review of randomized controlled trials investigating the effectiveness of Vitamin D in the management of depression. Fifteen RCTs were found, whilst previous reviews captured few of the available RCTs. Although the methodological quality was good, biological flaws were common and more prevalent in recent studies.

For the meta-analysis of studies without biological flaws, the size of the effect was statistically significant being +0.78 (CI 0.24, 1.27). As the measure of effect size was the standardized mean difference (SMD), this was 0.78, using Cohen’s Rule-of-Thumb, a SMD of 0.8 is considered to indicate a large effect.

As less than half the study population were deficient the effect of the intervention was diluted such that if all subjects had been deficient the size of the effect would have been higher, perhaps double,

1.5 points on the BDI scale. This is similar to the size of effect seen in a large RCT of antidepressant medication, which was 0.8 point on the BDI scale for the blinded parts of the study and 1.7 points overall [53]. A review of antidepressant efficacy published in the NEJM [54] shows that the effect size of antidepressant medication was increased by selective publication of trials and altering the effect size. However the overall mean weighted effect size value for antidepressants was only 0.15 (CI 0.08, 0.22) for unpublished studies and 0.37 (CI 0.33, 0.41) for published studies. Thus, the effect size of Vitamin D demonstrated in our meta-analysis may be comparable with that of anti-depressant medication. For the meta-analysis of studies with biological flaws, the size of the effect was statistically significant and negative being −1.1 (CI −0.7, −1.5), indicating that Vitamin D supplementation in flawed studies may lead to deterioration in depression.

The main finding is that all studies without flaws and the meta-analysis of studies without  biological flaws support the efficacy of Vitamin D supplementation for depression, as compared with the negative results of meta-analysis for studies with biological  flaws.  The  Womens  Health  Initiative [38] (WHI), with more participants that all the other studies combined, had the highest methodological quality and the most biological flaws leading to non-significant outcomes for both bone strength and mood. Due to its sheer size, the WHI has dominated previous meta-analysis leading to null results.

The main limitation of this review was the diversity of study methodology precluding more extensive meta-analyses, and leaving only two studies in each meta-analysis. The variability in outcome measures and reporting suggest agreement should be sought within the research community to underpin standard conduct and reporting of future studies to support meta-analysis.

Conclusion

Traditional evidence, biological plausibility and epidemiological studies indicate Vitamin D has therapeutic effects in depression. There are no previous meta-analyses of Vitamin D and depression as

the evidence was deemed to be insubstantial [25]. This may be due to previous systematic reviews identifying few of the available studies and including RCTs with inappropriate methodology and biological flaws.

Meta-analysis of studies without biological flaws demonstrates that improving Vitamin D levels improves depression, whereas the meta-analysis of flawed studies had a negative result. Heaney [34] identified the most common flaw “baseline status” and the most pernicious flaw “(in)effective dosing”.

However we found other flaws: not measuring 25OHD levels throughout the study limits the ability to know if the 25OHD level actually changed. In this case, there would be no reason to believe that the intervention caused a biological difference in Vitamin D levels between intervention and control groups.

We also found more fundamental biological flaws where the intervention was not Vitamin D but calcium, and caused a decreased in the 25OHD level. These two studies were included in previous systematic reviews but rejected by this review.

The finding that meta-analyses for studies with biological flaws had the statistically significant effect of increasing depression, may lead to a conclusion that some of these trials led to levels for Vitamin D above the therapeutic range. This would be supported by a recent paper indicating that the therapeutic range for 25OHD in depression is 50 and 85 nmol/L [55].

It may be argued that meta-analysis including flawed RCTs reflect the trial methodology more   than the efficacy of the intervention, leaving reviewers unable to make valid conclusions about efficacy [34], resulting in uncertainty amongst researchers and clinicians.

This has led to calls for more RCTs and less “torturing of the data” by meta-analysis [56]. However, as this review demonstrates, it is excluding biological flaws that will lead to greater understanding of Vitamin D, not simply increasing the quantity of studies.

We note that biological flaws are more frequent in recent studies; this may be due to the belief that vitamins exert a function beyond deficiency.

Hence RCTs should test whether using supplementation to correct deficiency is beneficial, rather than testing whether additional supplementation on top of the recommended doses is beneficial in reducing disease [57].

Thus, it is unremarkable that Vitamin D supplementation would not benefit a population that are not deficient or where the dose was ineffective. To test the hypothesis that correcting Vitamin D deficiency leads to an improvement in depression, it is critical to exclude biological flaws from future studies.

The effect size for Vitamin D in depression demonstrated in this meta-analysis is comparable with the effect of anti-depressant medication, an accepted treatment for depression.

Should these results be verified by future research, these findings may have important clinical and public health implications.

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More information: JAMA (2020). DOI: 10.1001/jama.2020.10224