1. Introduction
The World Health Organization estimates that 350 million people worldwide are affected by depression and anxiety. The Global Burden of Disease Study in 2010 identified depressive disorders as a leading cause of burden and responsible for 3.8% of global Disability Adjusted Life Years (DALY) [
1]. As a contributor to DALY, depression is expected to be the second highest concern for all ages by 2020 [
2]. In Canada, it is estimated that over 6.7 million people live with a mental health problem (in comparison with 3.5 million with type 2 diabetes mellitus) [
3]. Economic costs of mental health problems are estimated to be at least
$50 billion per year [
3]. With current medications purported to only have a modest benefit [
4], few new psychiatric drugs on the horizon, and some studies suggesting medication can do more harm than good [
5,
6,
7,
8], there are calls to revisit the impact that nutrition can have on mental health [
4,
9].
Biologically, nutrition is interconnected with depression through hormonal, neurotransmitter and signalling pathways in the gut that modulate brain functions such as appetite, sleep, reward mechanisms, cognitive function and mood [
10]. All biochemical pathways require vitamins and minerals as co-factors for proper enzyme function and insufficient nutrient levels can negatively impact a wide range of metabolic processes. There are a number of different nutrients involved in pathways relevant to mental disorders and brain function [
11].
Many nutrients have been investigated individually, including: B vitamins, vitamin D, choline, iron, zinc, magnesium, S-adenosyl methionine, amino acids such as taurine and probiotics. For the most part, studies of single nutrient treatments for mood disorders such as vitamin D report only modest symptom improvement or null results [
12]. The evidence for B vitamins is stronger, such that a systematic review reported sufficient evidence to support the use of combination high dose B vitamins in the treatment of stress and anxiety in the general population [
13]. Overall, no single nutrient stands out as a treatment for mental health problems. However, a broad-spectrum multivitamin and multimineral approach may alleviate symptoms in a number of psychiatric ailments.
Nutrition and dietary patterns have been linked with depression onset, and the maintenance and severity of symptoms [
14,
15,
16,
17]. Furthermore, several trials have demonstrated improvements in not only depression, but anxiety and stress response through supplementation with multivitamin/multimineral formulas and B complex vitamins [
18,
19,
20,
21,
22,
23]. In fact, the International Society for Nutritional Psychiatry Research has issued a consensus statement that “nutrition and nutraceuticals should now be considered as mainstream elements of psychiatric practice, with research, education, policy and health promotion reflecting this new paradigm [
24]”. A full range of vitamins and minerals are obligatory cofactors involved in the production of neurotransmitters. For example, in the production of serotonin, the major neurotransmitter involved in depressive disorders, there are requirements for vitamin B6, vitamin D, iron, copper and molybdenum.
A multivitamin/mineral (MVM), in which many ingredients were given at levels higher than recommended dietary allowance (RDA) but generally lower than the upper level (UL), has been shown to improve depressive symptoms in bipolar individuals [
25,
26,
27,
28,
29]. A MVM was also found to significantly reduce stress and anxiety following a series of earthquakes and a flood [
22,
29,
30,
31]. Despite enrolling participants who were not clinically depressed, two clinical trials have found that micronutrient supplementation improved symptoms of depression [
32,
33]. Collectively, the evidence suggests that a spectrum of nutrients may be effective for reducing and preventing depression, stress and anxiety. We hypothesized that optimal nutrient status, as measured by serum 25-hydroxyvitamin D (25(OH)D) levels above 100 nmol/L [
34] and serum vitamin B12 above 450 pmol/L [
35], would have a protective effect against depression and anxiety and that supplementation to achieve “optimal” nutrient status would improve depression and anxiety.
In the present study, we characterize the prevalence and severity of symptoms of depression and anxiety in participants in a community-based prevention program, before and after one year of exposure to nutritional supplements (a combination of vitamin D3, MVM and other nutrients), to determine if there was a benefit of supplementation with a broad spectrum of nutrients in a comparison sample. We further investigated the impact of supplementation in a subgroup of participants who self-reported extreme or severe depression and anxiety at entry to the program.
2. Materials and Methods
2.1. Intervention
The Pure North S’Energy Foundation (Pure North) is a not-for-profit wellness program focused on the prevention of chronic diseases including mental illness, type 2 diabetes mellitus, cardiovascular disease and cancer. The Pure North program offers lifestyle advice, education and nutritional supplements to its participants. Dietary advice typically includes aspects of the DASH diet developed to lower blood pressure without medication when appropriate for physical health outcomes, proper food portion education, encouraging plenty of fruit and vegetables (5–10 servings/day) and foods rich in omega-3 fatty acids, restriction of added sugar to less than 25 g/day and sodium to less than 2300 mg/day. Other lifestyle advice consists of proper sleep hygiene, smoking cessation, at least 150 min of physical activity each week and moderate alcohol consumption.
Supplement recommendations are based on analysis of each participant’s biometric measurements (including BMI), blood results and clinical intake data. Health care professionals review and explain blood work results with the participant and, based on their clinical knowledge and nutrient expertise, make recommendations accordingly. Each participant is treated as an individual and a treatment plan developed to meet that individual’s nutrient requirements. All participants are encouraged to achieve a 25(OH)D level of at least 100 nmol/L and vitamin D dosages were adjusted accordingly for the individual.
The core supplements provided to everyone are in daily packets, Vitality Packs, and contain: the multivitamin and multimineral formula (Vital 2 Platinum;
Table S1), Omega-3 fatty acids (400 mg EPA and 200 mg DHA), Vitamin C (1000 mg), Vitamin B12 (5000 µg methylcobalamin), Probiotics (
Biffidobacterium and Lactobacillus strains, 10 billion CFU) and Vitamin D3 drops. Vitamin D3 supplementation is individualized to target an optimal serum 25-hydroxyvitmainD (25(OH)D) concentration, above 100 nmol/L [
36]. Doses of vitamin D3 are often in excess of the UL (4000 IU/d) and given under medical supervision [
37]. Further supplements in addition to the Vitality Packs may be recommended based on individual requirements.
2.2. Assessments
Participants in the Pure North program are assessed at each visit to the clinic. Visits typically occur every 6–12 months to monitor lifestyle modification or disease condition change, and to adjust supplement doses if required. Any participant with obvious clinical depression or anxiety who requires closer monitoring or psychiatric medications is referred to their family physician. Assessments include biometrics (including blood pressure, height, weight, BMI, etc.), clinical intake (including medical history (such as pernicious anemia and H. pylori infections that might affect vitamin B12 absorption), current medications (including acid blockers and proton pump inhibitors that might affect vitamin B12 absorption), complaints and health goals), blood work (a number of biomarkers are measured including serum 25(OH)D, vitamin B12, arachidonic acid (AA) and eicosapentaenoic acid (EPA)), and completion of a questionnaire (including demographic data and self-reported health assessments). All blood sample preparation and biochemical measurements were performed by Doctor’s Data Laboratory (St. Charles, IL, USA), a fully accredited laboratory. Serum 25(OH)D was measured using Liquid Chromatography and tandem Mass Spectrometry (LC/MS-MS) with the inter-assay CV of 2.4%. Serum vitamin B12 was measured on an automated analyser with a chemiluminescent immunoassay (Beckman Coulter) with a CV of 7.7%. AA and EPA were measured using gas chromatography.
For the present study, we utilized serum 25(OH)D and vitamin B12 concentrations, available measures of nutrient status. Low levels of vitamin D have previously been linked to mental health disorders, including mood disorders such as depression [
38,
39,
40]. Vitamin D is of particular interest due to its various roles in the brain and in neurotransmitter synthesis [
41] and the heightened prevalence of vitamin D deficiency (serum 25(OH)D <50 nmol/L) and mood disorders in Canada (more than 32% and nearly 13%, respectively) [
42,
43]. B vitamins are important for adrenal support, energy production and neurotransmitter synthesis [
44] and vitamin B12 deficiency (<148 pmol/L) is common worldwide [
45]. Serum vitamin B12 is a measurable indicator of B12 status. Unfortunately, we are not easily and reliably able to measure the status of all nutrients in the body.
2.3. Self-Reported Depression and Anxiety
The European Quality of Life Five Dimensions (EQ-5D) assessment is a standardised instrument used to measure health status in a wide range of health conditions and treatments. The EQ-5D is a widely used questionnaire for calculating quality-adjusted life years (QALYs) for assessing cost-effectiveness in healthcare. Participants complete the EQ-5D at each visit to the clinic. The EQ-5D reflects the impact of common mental health conditions, such as mild to moderate depression and anxiety, on daily function [
36] and has been found to be sensitive enough to pick up improvements associated with treatment in patients with depression [
46]. We utilized the EQ-5D to investigate self-reported depression and anxiety in a community sample.
In addition to the EQ-5D participants completed the Targeted Symptoms List (TSL)—a wellbeing assessment tool developed in-house. The TSL assesses 16 mental and physical health outcomes on a scale of 1–10 (1 = never through to 10 = always) with a focus on common health complaints including: anger, anxiety, confusion, coordination problems, depression, fatigue, headache, joint pain, loss of sense (smell/taste), memory loss, moodiness, muscle weakness, numbness in arms/legs, shakiness of hands, stomach problems (digestive), and unintentionally dropping things. In addition, the TSL mental health score (MHS) is a composite score of depression, anxiety, and moodiness. For the purposes of the present study, we have focused on 3 TSL scores: depression, anxiety and the calculated MHS.
Depression and anxiety were measured via self-report in the population at baseline, the time of their first interaction with the Pure North program with a closer look at participants who reported severe or extreme depression/anxiety on the EQ-5D. We further utilized blood markers of nutritional status, 25(OH)D and vitamin B12, to investigate whether the effects of the nutrition-based intervention on levels of reported depression, anxiety and MHS were associated with changes in these nutrients over time.
This study was an analysis conducted utilizing a database of participant information collected as part of a community program (secondary use of data). The protocol of current database analysis was approved by the Research Ethics Board at St. Mary’s University in Calgary, Alberta (File# 073FA2017). Informed consent was obtained from all individual participants included in the study to use their information to evaluate the program.
2.4. Statistical Analyses
Statistical analyses were completed using SPSS v23 (SPSS Inc., Chicago, IL, USA). Descriptive statistics are presented as mean ± standard deviation. Intent-to-treat analyses were performed; as such mean follow-up values were used for participants who had baseline measures but not follow-up measures (mean imputation method). Since the data were not normally distributed, non-parametric tests were applied. Wilcoxon Signed Rank Test (WSRT) was performed to evaluate changes in different parameters over one-year. Mann–Whitney U-test and Kruskal–Wallis tests were utilized to compare categorical groups of vitamin D and vitamin B12 status. Chi Square testing was performed to determine the association between levels of anxiety and depression and 25(OH)D (>100 nmol/L) and B12 status (>450 pmol/L). Binary Logistic Regression was performed to investigate the relationship between 25(OH)D and vitamin B12 with changes in mental health status over time. Body mass index (BMI), age, gender, tobacco use, alcohol use, physical activity, fruit and vegetable consumption, fish and tuna consumption, AA:EPA and inflammation (CRP ≥ 10 mg/L) were considered as cofactors in these analyses. Significance was defined as p < 0.05. For determining effect size (ES), Cohen’s test was conducted using STATA version 14. Cohen’s d was used to estimate effect sizes, with 0.2 indicating a small effect, 0.5 a medium effect and 0.8 a large effect.
4. Discussion
This study found that participants in an intervention program aimed at chronic disease prevention that provides nutritional supplements showed significant improvement in self-reported depression and anxiety over the course of one year. This was a large database with over 16,000 participants who had completed the questionnaires, EQ-5D and the TSL, at program entry. At baseline, over half of these participants reported some level of depression and anxiety, suggesting that a large number of people suffer from subclinical mood disturbances. Severe and extreme depression and anxiety was reported in 5.2% of the population which is consistent with a prevalence of depression of 5.4% in Canadians [
3,
51].
Overall, significant improvements were found for depression and anxiety after one year in the program. This is notable given that the majority of the population reported only mild levels of depression and anxiety at baseline (effect size 0.21 and 0.22, respectively). More notable, over 90% of those who reported severe or extreme depression or anxiety at program entry reported improvement at one year (effect size 1.85 and 1.94, respectively).
Vitamin D deficiency was highly prevalent among severely/extremely depressed/anxious participants and achieving physiological serum 25(OH)D concentrations (above 100 nmol/L) was found to have a significant influence on mental health improvements in the context of the rest of the program, particularly for depression.
All participants received multiple nutritional supplements including the Vital 2 Platinum multivitamin/mineral supplement, vitamin B12, omega 3 and vitamin D
3 supplementation. However, achieving serum 25(OH)D concentrations above 100 nmol/L and vitamin B12 levels above 450 pmol/L, safely [
37], positively influenced depression and anxiety outcomes. The results suggest that nutrient intervention impacts depression to a greater extent than anxiety, but both were positively influenced. Others have found that vitamin D
3 supplementation has led to improvements in depression [
40,
52,
53,
54,
55,
56,
57], yet others have not [
58,
59,
60]. A meta-analysis demonstrated the importance of dose, frequency and achieving measurable increases in 25(OH)D concentrations in being able to detect favourable depression outcomes [
61]. Our results support those of Kaplan et al. who demonstrated that vitamin B complex and multivitamin/mineral formulas have resulted in greater reductions in stress and anxiety compared with vitamin D
3 supplementation alone [
29]. A systematic review of the evidence demonstrates a significant number of trials that overall provide sufficient support for the use of B vitamins in the treatment of stress and anxiety in the general population, the benefit of which may be augmented with a broad array of minerals [
13]. It is hypothesized that assuring all of the necessary cofactors for all metabolic processes improves mental resilience to stress and thus improves one’s ability to cope. Given that the clinical intervention involves vitamin D
3 in combination with MVM and vitamin B12, among other nutrients, the authors posit that, where vitamin D
3 was found to be a significant predictor of improvements, the magnitude was dependent upon an optimal background of other nutrients. While optimal vitamin D levels are necessary for nearly every cell, it is but one component needed for proper functioning of all metabolic systems of the body. Moreover, the absorption of certain nutrients such as vitamin B12 may be affected by different disease conditions (pernicious anemia, and
H. pylori infection) or medications such as acid blockers or psychiatric medications that may inhibit vitamin D absorption. These may explain the discrepant results from other studies involving vitamin D
3 or vitamin B12 as a stand-alone treatment.
More strenuous physical activity was found to be associated with improved mental health status. There is growing evidence that physical activity has protective effects not only on physical health but also on mental health, particularly depression and anxiety. Engaging in regular physical activity led to fewer depression and anxiety symptoms than did being inactive, which may also be related to vitamin D synthesis via sun exposure [
62,
63,
64]. The anti-inflammatory effect of omega 3 have been successfully linked to preventing or treating depression [
65,
66], and B vitamins appears to treat anxiety, depression and stress [
13,
67], although we found the predominant effect for vitamin D.
The strengths of the present study include the large community-based population. The authors are unaware of any other study of a clinical intervention with as many participants as included here. Further, the population was not limited to clinically depressed individuals and found beneficial effects for the population in general.
The main limitations of this study are the lack of details of the other treatment options participants engaged in outside of the program (e.g., mediation or counselling). The data analysed here were collected as part of a clinical intervention, a real life program not specifically designed for research; hence, we were not able to ensure compliance and a high drop-out rate was expected. We used intent-to-treat analysis and found results compatible with the results of per protocol analysis. Following program entry, participants were provided with a standard package of multiple nutrients (multivitamin/mineral, vitamin D3, omega-3 fatty acids, vitamin B12, vitamin C and probiotics). In addition, nearly half of the participants were recommended additional supplements based upon individual requirements—for example, magnesium may have been recommended to an individual experiencing leg cramps or constipation. Vitamin D3 supplementation in the program was targeted at achieving a serum 25(OH)D concentration above 100 nmol/L rather than a specific dose of vitamin D3, but the rest of the supplements were provided at the standard dose. Because the data are from a voluntary health and wellness program, albeit a clinical intervention, there is likely to be a selection bias. Further, due to the nature of the study we were not able to measure compliance to the program, but the results do reflect real-life response. Small but significant differences were detected in a baseline comparison between those who persisted in the program and those who did not; there was a significantly higher proportion (6.0%) of severe/extreme depressed/anxious at baseline who dropped-out of the program in comparison with those who persisted to one year (2.7%). In addition, the measurement of depression and anxiety was through a standardized questionnaire rather than a clinical assessment. The results presented here represent a real-life scenario rather than a clinical study.
Currently, the front line form of treatment for depression is psychopharmaceutical, but there is growing interest in exploring the role of nutrients. Nutritional status plays an important role in mental health, and poor nutrition may contribute to the pathogenesis of mental illness. Nutritional deficiencies could have an influence on brain structure and function, including mood, anxiety and depression. We found depression and anxiety were commonly reported in the participants of this clinical intervention. This analysis showed that improvements in depression and anxiety were associated with achieving serum 25(OH)D concentrations of at least 100 nmol/L. A nutrient-based program aimed at achieving optimal nutrition may provide a safe, simple and economical means of supporting mental health.
