Research Proposal

350 million people in the world suffer from depression. It is the leading cause of disability and number four on the leading causes of global disease burdens.[1] 44 percent of American college students report having symptoms of depression, while 75 percent of college students do not seek help for mental health problems. Depression is also the number one reason students drop out of school or commit suicide, and if diagnosed with depression, students are five times more likely than adults to attempt suicide [2]. It is commonly treated with antidepressants, which show little difference from placebo under scrutiny of meta-analyses. Electroconvulsive therapy lacks results and proof for specific cognitive interventions is weak[3]. Depression is often mentioned when talking about Vitamin D, and associations between depression and lack of sunlight is well established. It is formed in the body mainly through photosynthesis. Vitamin D deficiency is steadily increasing, likely caused by our ever-increasing indoor lifestyle. Other diseases linked to its deficiency are cancer, cardiovascular disease, diabetes, and premature mortality[4]. Almost all knowledge on Vitamin D has been published in the last 15 years[5], and we now know that it works via Vitamin D receptors in the endocrine, paracrine, and autocrine systems[6], meaning it affects the brain and most physiological systems. Enzymes responsible for conversion to its active form are found in the hypothalamus, substantia nigra, and the cerebellum [Husemoen, L.L., et al.]. Vitamin D has also been shown to regulate adrenaline and noradrenaline through the hypothalamic-pituitary-adrenal axis, and dopamine production through Vitamin D receptors[7], and to protect against depletion of serotonin and dopamine.[8] With this knowledge we can propose a link between depression and Vitamin D.

The relationship between Vitamin D and depression has been studied substantially, but few meet the strict standards of PRISMA. At the time of Spudding’s meta-analysis (2014) there were no other meta-analyses and only four systematic reviews published. However even in these reviews they lacked studies and they were inconclusive due to including inappropriate studies. My intentions are to design a study tailored after PRISMA guidelines and without biological flaws, only seven of which existed at the time of Spudding’s meta-analysis. In this study I will investigate if rectifying Vitamin D levels decrease feelings of depression in clinically depressed people. I strongly believe it will based on prior results, which show that six out of seven studies without flaws demonstrated improvements in depression with Vitamin D supplementation. If research in this domain progresses we are likely to see big changes to how we view and treat depression, among with new approaches for other mental illnesses. Supplementing with Vitamin D is remarkably economical to both personal health and finance, not to mention the diminished burden on healthcare, colleges, and taxpayers.

Definitions

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses. “PRISMA is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses. PRISMA focuses on the reporting of reviews evaluating randomized trials, but can also be used as a basis for reporting systematic reviews of other types of research, particularly evaluations of interventions.”

Beck Depression Inventory: “A 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression” (Beck, et al., 1961)

RCTs: randomized placebo-controlled trials

25-OHD: “A prehormone that is produced in the liver by hydroxylation of vitamin D3″ Used by physicians to measure Vitamin D intake. The conversion from Vitamin D to 25-OHD takes roughly 7 days.

Meta-analysis: “Meta-analysis is a quantitative, formal, epidemiological study design used to systematically assess previous research studies to derive conclusions about that body of research. Outcomes from a meta-analysis may include a more precise estimate of the effect of treatment or risk factor for disease, or other outcomes, than any individual study contributing to the pooled analysis.”

Confounding variables“variables that the researcher failed to control, or eliminate, damaging the internal validity of an experiment.” “an extraneous variable in a statistical model that correlates (directly or inversely) with both the dependent variable and the independent variable.”

Biological flaws: “limitations in the design of primary studies which preclude them from testing the research hypothesis.”[Spudding, S, et. al.]

IU: International Units

Lit Review

All sources originate from primary, peer-reviewed journal articles.

  • Husemoen, L.L., et al., Serum 25-hydroxyvitamin D and self-reported mental health status in adult Danes. Eur J Clin Nutr, 2016. 70(1): p. 78-84.
  1. “Low serum 25(OH)D is not associated with self-reported symptoms/diagnosis of depression and anxiety.”

This study is a prime example of the disagreements in the scientific community on this subject. The study was thorough, yet did not find an association between depression/anxiety and vitamin D.

  • Sparling, T.M., et al., The role of diet and nutritional supplementation in perinatal depression: a systematic review. Matern Child Nutr, 2016.

    This study looked at 35 prior studies that filled the inclusion criteria. One study pertained to vitamin D, where they, with post-partum women, compared a vitamin D and calcium supplement with a multivitamin. They found that the multivitamin group had a significantly lower EPDS score.

    This highlights the complexity of interactions that occur in the body, which could be one of the reasons data on this subject is split.

    Allan, G.M., et al., Vitamin D: A Narrative Review Examining the Evidence for Ten Beliefs. J Gen Intern Med, 2016.

     In this study we focus on part 4. Through review, they found that “vitamin D supplementation does not improve mental well-being scores in the general population without clear depression, even when 25-OHD levels are low.” Moreover, Vitamin D supplementation in patients with depression has conflicting, poor-quality evidence .” However, one case-control study found that patients with depression had lower vitamin D levels than the healthy control group.

More disqualifying and conflicting evidence. My main extract from this article is their insight to why we see conflicting results: “Many of the RCTs on mental health and vitamin D are at high risk of bias, with poor randomization, lack of blinding, no description of patient characteristics, no intention-to-treat analysis and large loss to follow-up.” I’ll see how I can propose to correct for these fallacies.

Okereke, O.I. and A. Singh, The role of vitamin D in the prevention of late-life depression. J Affect Disord, 2016. 198: p. 1-14.

  • Inverse associations of vitamin D blood level or vitamin D intake with depression were found in 13 observational studies
  • Results from all but one of the RCTs showed no statistically significant differences in depression outcomes between vitamin D and placebo groups
  • Vitamin D level-mood associations were observed in most, but not all, observational studies
  • “results indicated that vitamin D deficiency may be a risk factor for late-life depression. However, additional data from well-designed RCTs are required to determine the impact of vitamin D in late-life depression prevention.”
    • We can question whether vitamin D can help against depression. Many observational studies confirm vitamin D to help against depression and with general mood, I’ll have to check more clearly if this is preventative.

Sanders, K.M., et al., Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. Br J Psychiatry, 2011. 198(5): p. 357-64.

  • Even though the subjects had 41% higher 25-OHD levels than the control group, there was no correlation with depression scores.
    • I’ll look more into this one.

Spedding, S., Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients, 2014. 6(4): p. 1501-18.

  • With a strict eligibility criteria, 15 RCT studies were reviewed.
  • “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”
  • “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.”
  • “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 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. ; not measuring 25OHD levels throughout the study”
    • This is where things get interesting though and the reason we continue despite massive disqualifying evidence. My approach will be to examine the disqualifying studies listed above and look into their methods. I will look to use the best methods without biological flaws.

 

  • From  Husemoen, L.L., et al., Serum 25-hydroxyvitamin D and self-reported mental health status in adult Danes. Eur J Clin Nutr, 2016. 70(1): p. 78-84.
    • Vitamin D receptors and vitamin D-metabolising enzymes are present in the brain and in the central nervous system at sites responsible for the regulation of emotions and behaviour. This raises the hypothesis that low vitamin D is related to poor mental health. ; mental disorders, such as depression and anxiety, affect an increasing number of individuals worldwide.1,2 ; Poor mental health is related to a reduced quality of life, an increased sickness, absence from work”
    • “Vitamin D receptors and vitamin D-metabolising enzymes are also present in the brain and in the central nervous system at sites that are responsible for the regulation of emotions and behaviour.3 In addition, there is evidence suggesting that vitamin D affects the biosynthesis of numerous neurotransmitters and neurotropic factors relevant to mental health.4 and more hospital admissions.1”

Design Approach

I aim to have roughly 50 participants. Participants need to be diagnosed with clinical depression and have insufficient Vitamin D levels. Participants will hail from the hospitals in Boulder and Denver. I plan to do this by working with doctors through the hospital. If the patient shows insufficient levels of Vitamin D and is clinically depressed, the doctor will refer them to me. If there are not enough participants at any one point in time I will sustain the study over a longer period with less concurrent participants. Upon beginning the study, participants will complete the Beck Depression Inventory and have their 25-OHD levels tested. If 25-OHD levels are deficient, we will proceed. Participants will be given Vitamin D pills of 5,000 IU and instructed to take them daily. There will also be a control group intended to include 50 participants, all of which will be given a placebo.  After 8 weeks there will be a follow-up session where we check 25-OHD levels, BDI score, and compliance. I intend to oversee the study, collect, compile, and analyze the data. 25-OHD levels will be tested without supervision at a doctors or physician, then emailed to myself. 25-OHD levels are tested because it is the most reliable way to test for Vitamin D levels. Upon completion I will compile and analyze the data and finally present and publish it.

Ethics

There are minimal ethical concerns in this study, but they exist. The ethical issue at hand will be participants releasing personal information regarding their mental health to myself. There are two ways around this: A certified doctor or physician could be hired to manage personal details, or the participants could sign to release their information to myself and if needed I would sign a confidentiality agreement.

 

Reliability and Validity of Methods and Results

My method is carefully thought out, adheres to PRIMA, and is without biological flaw. Outcome variables are changes in 25-OHD levels and the BDI as functions of Vitamin D intake.

Timeline

September, 2016

– Begin working with hospitals to recruit participants

December, 2016

– Study begins

February, 2017

– Follow-up session

March, 2017

– Findings presented and published

Resources/Materials

  • A room to meet with participants and for them to take the BDI
  • 5,000 IU Vitamin D supplements
  • Placebo pills

Budget

25-OHD tests are expensive at roughly $60 per test.

at $60 * 100 people * 2 tests we have a cost of $12,000.

A 60 pill Vitamin D supplement costs $5, costing a total of $250

2600 placebo pills are needed, at a total cost of $18

A total of $12,268 will be needed to conduct this study.

 References

  1. Hyman, S.; Chisholm, D.; Kessler, R.; Patel, V.; Whiteford, H. Mental disorders. In Disease Control Priorities in Developing Countries, 2nd ed.; Jamison, D.T., Breman, J.G., Measham, A.R., Alleyne, G., Claeson, M., Evans, D.B., Jha, P., Mills, A., Musgrove, P., Eds.; Oxford University Press: New York, NY, USA, 2006; pp. 605–626.
  2. http://www.healthline.com/health/depression/college-students
  3. Bracken, P.; Thomas, P.; Timimi, S. Psychiatry beyond the current paradigm. Br. J. Psychiat. 2012, 201, 430–434.
  4. Holick, M.F. The Vitamin D deficiency pandemic: A forgotten hormone important for health. Public Health Rev. 2010, 32, 267–283.
  5. Heaney, R.P. Does inconclusive evidence for Vitamin D supplementation to reduce risk for cardiovascular disease warrant pessimism? [Letter to the editor]. Ann. Intern. Med. 2010, 153, 208–209.
  6. Hendrix, I.; Anderson, P.; May, B.; Morris, H. Regulation of gene expression by the CYP27B1 promoter—study of a transgenic model. J. Steroid Biochem. Mol. Biol. 2004, 89–90, 139–142.
  7. Puchacz, E.; Stumpf, W.; Stachowiak, E.K.; Stachowiak, M.K. Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. Mol. Brain Res. 1996, 36, 193–196.
  8. Cass, W.A.; Smith, M.P.; Peters, L.E. Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine. Ann. N. Y. Acad. Sci. 2006, 1074, 261–271.
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