Vitamin D3 in depression - the lost link?

If you were a regular reader of this blog in 2020-2021, you would remember that vitamin D & depression was my first blog post back in late 2020. So you may be thinking, “this topic again?”


Well, there are several reasons. When I wrote it the first time…. Well, let’s say my research interpretation skills were -insert poop emoji, so a year and a half later, I wanted to give this another shot since I feel a little more able to do that now. Some readers may find the writing style dull and boring or be short on time. In such a case, you may either wait for a YouTube video or head to the article summary at the end.


Why are we talking about vitamin D?

In the post-covid world, many people have started appreciating the importance of vitamin D in the immune system and protection from infection and complication risks. The sales of this supplement must have exponentially been increasing since the mid-2020s when the pandemic hit.


But a little less known is that vitamin D deficiency has also been associated with psychological distress, depressive symptoms and psychotic episodes, at least in epidemiology – in a human language, this means some extensive population studies found that people deficient in vitamin D had higher odds of being depressed and experience more mental distress.


It has also been found that humans have receptors (docking stations) for vitamin D in different regions of our brain, and so it was thought that if vitamin D is low, the brain must surely suffer consequences such as depression, stress and decline in cognitive performance. But epidemiological studies, despite being interesting, are not that reliable in formulating clinical guidelines. If we want to know if humans who suffer from depression get better after getting their vitamin D levels sorted, we need randomised clinical trials that are tightly controlled and should be more reliable in telling us what to do.


Included studies

There is a decent amount of research on this topic and so to simplify it and also to prevent diluting the overall effects for the type of population I am interested in, I have chosen the following criteria for my analysis:

  • All studies were on humans and were randomised clinical trials

  • The participants were otherwise healthy (besides suffering depression) and had no other health conditions.

  • I focus on a mainly mixed audience and exclude a 100% female audience where I can as the focus of my clinic is the primary male population. Unfortunately, there are no male-only studies on this topic.

  • Where possible, I try to focus on non-geriatric (younger) populations

NOTE: In the hierarchy of clinical evidence (pic below), a structure that tells us which types of studies are most reliable in helping us form clinical guidelines, you will notice that Randomized Controlled Trials are NOT at the top. Yes, indeed, there is a better way to do this. There are two types of studies called Systematic Reviews and Meta-Analysis (often put together), which aim to pool all available evidence to form clinical guidelines for doctors, dietitians and healthcare professionals.


And in the early phase of my deep-dive, I did collect these and spent hours & days interpreting them. The conclusion I came to was that these studies are unusable for my research question. They include different populations, different dosages, different timelines, different health conditions and generally are muddying up the water (for what I wanted to do), so I chose to go back to the original randomised trials and collect them one by one, focusing on those that meet the criteria above.

Picture Source: https://pressbooks.library.upei.ca/montelpare/chapter/the-hierarchy-of-evidence/


Re-telling the story

An important thing to do when interpreting research into a particular topic is to put our preconceptions and biases aside (e.g. I have a preference for product A to do XYZ, so I will ignore all studies that show otherwise – this is called cherry-picking and is a widespread practice in the nutrition world on Instagram and Youtube) and tell the “story” of the evidence as it is, not as I want it to be so I can sell you pills or expensive tests. So here is my best attempt at doing this.


I have included 6 studies and 6 randomised clinical trials for this review.

  1. Kjærgaard,2012

  2. Frandesen, 2014

  3. Hansen, 2019

  4. Okereke, 2020

  5. Kaviani, 2020 (abstract only)

  6. Vellekkatt, 2020 (abstract only)

I could not find a full paper (only an abstract) for two of these, so the first limitation goes right there. I contacted the authors of those studies but have not heard back. If I do, I will update the article if I hear back and have a chance to review it.


Study 1 (Kjærgaard,2012)

  • This study was formed based on a large ongoing prospective cohort study in Norway, called Tromsø, which has been going on since 1974 and has been investigating the incidence of cardiovascular disease and cancer in a population of over 45,000 Norwegians.

  • This small study recruited 357 participants (nested case-control study) from the sixth Tromsø study (originally including 12,984 participants) based on their vitamin D levels. They only invited two groups. Those with less than 55nmol/L and those with Vit D over 70nmol/L.

  • Of these 357 participants, 114 were later removed because their vit D levels were above 70nmol/L, so the remaining 243 were randomly assigned to placebo (n=121) and vitamin D group (n=122).

  • The study lasted six months, during which the Intervention group took 20,000 International Units (500mcg) of vitamin D twice a week, and the Control group took a placebo capsule twice a week (nobody knew what they were taking, and the capsules were identical in smell, taste and appearance)

  • Results: After six months, the groups had no difference in mood and depression scores. Even after the data were stratified for age, smoking, vitamin D levels and BMI, there was no difference in mood scores. (stratification is a process during which participants with similar secondary characteristics, such as smokers or those being obese, are grouped in additional sub-groups to see if other factors, originally not thought of, could have impacted study results).

  • Limitations of this study: We have to remember that this started as a nested case-control study where they pulled data from a much larger prospective cohort study. The original prospective cohort (Tromsø) did not have depression as their main outcome, so it is possible that the type of population recruited did not reflect this. Tromsø was mainly focused on heart disease, not depression. This may or may not be a factor here, but it is something to remember when telling this story. Let’s now move on to study 2.


Study 2 (Frandesen, 2014)

  • Another Scandinavian study. This time from a health centre in Esbjerg, Denmark. Forty-three health professionals with a previous occurrence of Seasonal Affective Disorder (SAD) were recruited. (SAD is a winter type of depression characterised by low mood, fatigue and motivation difficulties during winter and early spring when the days are dark and cold).

  • The participants were randomly assigned to receive either placebo or 2800 IU (70mcg) Vitamin D3 for 12 weeks

  • They measured overall quality of life, individual depression rating score and the rate of Seasonal Affective Disorder.

  • Results: At the end of the 12 weeks, no statistically significant difference in any scores was found. Both groups improved, so it was hard to tell whether vitamin D3 did anything.

  • Limitations: There were a few potential limiting factors here.

  • First of all, in both groups, most people were NOT vitamin D deficient, and only about 30% of each group had sub-optimal levels (25-50nmol/L). Actual deficiencies start at about below 20nmol/L, and not a single person had those levels – maybe if they did, the results would have been different – hence the first limitation

  • Secondly, these people were healthcare workers recruited from the same centre. Health care workers may be more aware of the risks of vit D deficiency than the regular population, so they could have been taking precautions, having a healthier diet and more broad sunshine exposure. And although the researchers excluded participants who were supplementing when the study began, they did not look into things like dietary exposure, sunshine exposure and past supplementation (as you probably know, it takes years to develop a severe deficiency)

  • Lastly, Seasonal Affective Disorder is not precisely the same as depression (begs the question of whether this study should have even been included in my analysis in the first place). However, the symptoms are quite similar.


Study 3 (Hansen, 2019)

62 participants, all diagnosed with mild-to-moderate depression, were randomly assigned into two groups

  • Intervention group – received 2800 IU (70mcg) vitamin D3 daily for six months.

  • Control Group – received 1 placebo capsule daily for 12 weeks

  • Over half of the study population was already taking some antidepressants (some more than one)

The primary outcome was to assess if the vitamin D supplementation improved their depression score on a Hamilton Rating Scale for Depression. Secondary outcomes included a few more assessment methods, including overall subjective wellbeing.


Results: Both groups significantly reduced depression,and there was nearly no difference between the placebo and vitamin D groups. We might assume that the effect was primarily down to the pharmaceuticals. Subjective wellbeing has also improved in both groups, but there was no difference between the two. This study did not convincingly demonstrate any benefits of vitamin D supplementation.


Study 4 (Okereke, 2020)

  • This study called VITAL-DEP (Vitamin D and Omega 3 Trial-Depression Endpoint Prevention) was based on a much larger parent trial called VITAL Trial, which aimed to test the effectiveness of combined vitamin D & fish oil in reducing cancer and cardiovascular disease incidence. Both of these trials ran at the same time.

  • The aim of VITAL-DEP as to assess the effects of vitamin D3 supplementation over the period of 5-years on depression among 18,353 adults. An important aspect here was that the participants had NO depression in the beginning and what was assessed was the development of depression over the five years in the vitamin D group vs the placebo group.

  • Results: Within 5 years, 1234 people developed depression, nearly half: half in each group. Vitamin D supplementation appeared no more protective from depression than placebo. Taking factors such as age, race, gender or baseline vitamin D into account did not seem to make any difference.

  • Limitations: Vitamin D levels in the study were mostly adequate, as is the issue in these studies, so we can’t tell if deficient subjects would fare better. Secondly, this study did not recruit already depressed subjects but rather reported occurrence as the trial progressed, which is a different methodology from what other trials did. This is not a limitation but rather interesting observation.


Study 5 (Kaviani, 2020) – abstract only.

  • So far, I have not been able to obtain the full text of this study, so this interpretation is only based on the study abstract.

  • Fifty-six clinically depressed participants were randomly assigned to either placebo or vitamin D supplementation (50,000 IU twice a week for eight weeks.

  • At the end of week 8, the depression scores of the vitamin D group improved significantly compared to only mild improvement in the placebo group.

  • They also measured oxytocin levels, but those improved in both groups; hence statistical significance was not achieved.

I will add more info here, if I can get my hands on the full paper.


Study 6 (Vellekkatt, 2020) – abstract only

  • 46 patients who were already receiving depression treatment (SSRIs) were randomly divided into two groups

  • Intervention Group received a single parental (through IV) dose of 300,000 International units of vitamin D3 alongside receiving standard medical treatment

  • Control group – only received standard treatment without vitamin D3

  • Results: At the checkup (3 months later), both groups improved; however, the vitamin D intravenous group improved more, and their quality of life score was much better than the control (no vit D) group.

I will also add more info here once/if I can get my hands on the full study


So what can we learn from all this?

To this day, I would say that the topic remains unaddressed. It appears that more studies point towards no effects of vitamin D supplementation in depression and 2 studies show promising effects, one of which is parental (intravenous) supplementation.


You may notice that only six studies were included in this analysis. This is because my research criteria are well set up mostly for younger and otherwise healthy people as these are most of my readers (and clients). There are many other studies which I did not include done on diabetics, kidney disease patients and much older populations that show more improvements but I chose to omit these as most of my readers are not in those groups.


Based on the trials, reviewed above, we could say that there appears to be no persuasive evidence that vitamin D supplementation compared to placebo improves the outcomes of depression in people who suffer from depression but are otherwise healthy.


That being said, we need to address a few points

  • Most of these studies are done in people who are not deficient in vitamin D. Maybe with more data on deficient populations, results would be different.

  • A single large dose of intravenous megadose administered by Vellekatt (2020) actually showed some promising results and this may be a path worth pursuing for those whose doctors would be open to administering parental supplementation

  • Some of these studies are created of larger trials such as larger prospective cohorts or larger randomized studies. And while this is an excellent method of saving costs and utilizing existing data, it also presents a challenge. The challenge is that those large parent studies might have a different focus completely For example if the aim of the parent study is to assess heart disease in men over 50, then the nested trial aims to assess the incidence of depression (utilizing the population of the parent study) may not be looking at the most reliable and most representative population.


SUMMARY & KEY POINTS

  • Vitamin D3 supplementation does not appear to make difference in people who suffer from depression, who are otherwise healthy (and below 65)

  • A single study showed a benefit of parental (IV) megadose of 300,000 IUs for patients suffering depression and receiving a standard medical treatment however this is a method that needs to be supervised by a medical doctor or a nurse

  • There are many limitations affecting most of these studies that could be impacting the final results which are discussed above such as lack of standardised dosing, missing baseline vit D data and lack of sub-group analyses.

  • Supplementation might potentially be useful where vitamin D levels are critically low however studies on such populations are mostly missing.

With time, hopefully, more research will accumulate and this research question will become clearer. For now, I can’t recommend Vitamin D3 supplementation specifically targeting depression although it is worth checking one’s levels at least once a year due to other effects of vitamin D on bone health, immune system, brain health and disease prevention. According to epidemiological research, it is a good idea to be somewhere between 70-99 nmol/L for maximum heart disease and cancer protection. < add photos?


Stay in touch

If you enjoyed this article and would like to stay up to date with my work into mental health nutrition & lifestyle advice, feel free to sub on YouTube or join our small Facebook group or Insta.


References

Frandsen TB, Pareek M, Hansen JP, Nielsen CT. Vitamin D supplementation for treatment of seasonal affective symptoms in healthcare professionals: a double-blind randomised placebo-controlled trial. BMC Res Notes. 2014 Aug 14;7:528. doi: 10.1186/1756-0500-7-528. PMID: 25125215; PMCID: PMC4141118.


Hansen JP, Pareek M, Hvolby A, Schmedes A, Toft T, Dahl E, Nielsen CT. Vitamin D3 supplementation and treatment outcomes in patients with depression (D3-vit-dep). BMC Res Notes. 2019 Apr 3;12(1):203. doi: 10.1186/s13104-019-4218-z. PMID: 30944021; PMCID: PMC6446320.


Kaviani M, Nikooyeh B, Zand H, Yaghmaei P, Neyestani TR. Effects of vitamin D supplementation on depression and some involved neurotransmitters. J Affect Disord. 2020 May 15;269:28-35. doi: 10.1016/j.jad.2020.03.029. Epub 2020 Mar 13. PMID: 32217340.


Kjærgaard M, Waterloo K, Wang CE, Almås B, Figenschau Y, Hutchinson MS, Svartberg J, Jorde R. Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial. Br J Psychiatry. 2012 Nov;201(5):360-8. doi: 10.1192/bjp.bp.111.104349. Epub 2012 Jul 12. PMID: 22790678.


Michaëlsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundström J, Berglund L, Arnlöv J, Hellman P, Blomhoff R, Wolk A, Garmo H, Holmberg L, Melhus H. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr. 2010 Oct;92(4):841-8. doi: 10.3945/ajcn.2010.29749. Epub 2010 Aug 18. PMID: 20720256.


Okereke OI, Reynolds CF 3rd, Mischoulon D, Chang G, Vyas CM, Cook NR, Weinberg A, Bubes V, Copeland T, Friedenberg G, Lee IM, Buring JE, Manson JE. Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2020 Aug 4;324(5):471-480. doi: 10.1001/jama.2020.10224. PMID: 32749491; PMCID: PMC7403921.


Vellekkatt F, Menon V, Rajappa M, Sahoo J. Effect of adjunctive single dose parenteral Vitamin D supplementation in major depressive disorder with concurrent vitamin D deficiency: A double-blind randomized placebo-controlled trial. J Psychiatr Res. 2020 Oct;129:250-256. doi: 10.1016/j.jpsychires.2020.07.037. Epub 2020 Aug 4. PMID: 32823218.

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