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Sharifan P, Ghazizadeh H, Darroudi S, Ghodsi A, Saffar Soflaei S, Tanbacoochi D, et al . Effect of Low-Fat Dairy Products Fortified with Encapsulated Vitamin D3 on Anxiety, Depression and Stress in People with Cardiovascular Risk Factors. JNFS 2024; 9 (1) :69-80
URL: http://jnfs.ssu.ac.ir/article-1-781-en.html
URL: http://jnfs.ssu.ac.ir/article-1-781-en.html
Payam Sharifan * 
, Hamideh Ghazizadeh , Susan Darroudi , Alireza Ghodsi , Sara Saffar Soflaei , Davoud Tanbacoochi , Mohammad Reza Fazl Mashhadi , Mohammad Amin Mohammadi , Ali Ebrahimi dabagh , Sara Moazedi , Maryam Mohammadi Bajgiran , Gordon Ferns , Habibollah Esmaily , Majid Ghayour-Mobarhan
, Hamideh Ghazizadeh , Susan Darroudi , Alireza Ghodsi , Sara Saffar Soflaei , Davoud Tanbacoochi , Mohammad Reza Fazl Mashhadi , Mohammad Amin Mohammadi , Ali Ebrahimi dabagh , Sara Moazedi , Maryam Mohammadi Bajgiran , Gordon Ferns , Habibollah Esmaily , Majid Ghayour-Mobarhan
Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Effect of Low-Fat Dairy Products Fortified with Encapsulated Vitamin D3 on Anxiety, Depression and Stress in People with Cardiovascular Risk Factors
Payam Sharifan; MD, PhD1,2, Hamideh Ghazizadeh; PhD2, 3, Susan Darroudi; PhD3, Alireza Ghodsi; BSc2, Sara Saffar Soflaei; MD, PhD3, Davoud Tanbacoochi; MSc4, Mohammad Reza Fazl Mashhadi; BSc5, Mohammad Amin Mohammadi; MSc5, Ali Ebrahimi dabagh; MSc5, Sara Moazedi; MSc5, Maryam Mohammadi Bajgiran; MSc3, Gordon Ferns; MD, PhD6, Habibollah Esmaily; PhD4,7 & Majid Ghayour-Mobarhan; MD, PhD*1,3
1 Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; 2 Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; 3 International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran; 4 Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; 5 Department of Nutritions, Varastegan Institute for Medical Sciences, Mashhad, Iran; 6 Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK; 7 Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran.
| ARTICLE INFO | ABSTRACT | |
| ORIGINAL ARTICLE | Background: Vitamin D deficiency is a worldwide condition, which has been linked to a variety of health-related issues. Vitamin D can be beneficial to cardiovascular patients and those suffering from depression and anxiety, based on Survey of Ultraviolet Intake by Nutritional Approach (SUVINA study), ,showing the potential effects of vitamin D-fortified dairy products on anxiety, depression, and stress in subjects with cardiovascular disease (CVD) risk factors. Methods: It was a quadruple-blind randomized controlled trial. Individuals were randomly allocated to one of four groups: fortified low-fat milk (FM), non-fortified low-fat milk (NFM), fortified low-fat yogurt (FY), and non-fortified low-fat yogurt (NFY). FM and FY groups were fortified with 1500 IU nano-encapsulated vitamin D3. Anthropometric parameters as well as depression, anxiety, and stress scores were measured at baseline and after a ten-week trial in Mashhad, Iran. Results: Totally, 289 participants (143 men, 146 women) with a mean age of 41.86±7.81years were enrolled in the study. There was no statistical difference between the scores of depression, anxiety, and stress in participants with and without CVD risk factors (P>0.05). No statistical difference was found in the subgroup analysis based on milk and yogurt consumption. Conclusions: Fortified low-fat milk containing 1,500 IU of vitamin D has no impact on improving depression, anxiety, and stress during ten weeks. However, further studies with higher vitamin D doses for a longer duration are recommended. Keywords: Vitamin D; Fortification; Anxiety; Depression |
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| Article history: Received: 8 Dec 2022 Revised: 18 Dec 2022 Accepted: 18 Dec 2022 |
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| *Corresponding author: ghayourm@mums.ac.ir Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Postal code: 99199-91766 Tel: +98 5138002288 |
Introduction
Vitamin D is a nutrient available in some foods from both animal and plant sources; however, it is mostly synthesized from 7-dehydrocholesterol in skin during sun exposure, especially 260–320 nm ultraviolet wavelength (Holick et al., 2011, Hossein-nezhad and Holick, 2013, Jäpelt and Jakobsen, 2013). Although the main role of vitamin D is in musculoskeletal development and bone health, the receptors for vitamin D are also widely found in the body, which include brain, heart, skin, gonads, prostate, breast, and gut (Amiri et al., 2021, Marino and Misra, 2019). Recent studies have shown a possible role of vitamin D in mental health(Ganji et al., 2010, Zhao et al., 2010). Furthermore, other studies have found an association between serum vitamin D status and mood disorders (Cuomo et al., 2019, Shah and Gurbani, 2019). Recent reports have revealed that high prevalence of anxiety, depression, and stress among patients with cardiovascular disease (CVD) can cause adverse outcomes and economic burdens for health care systems (Cohen et al., 2015).
Anxiety, depression and stress are three major mood disorders in Iran with a prevalence of 42%, 44%, and 40%, respectively (Casseb et al., 2019, Drozdenko et al., 2014, Khayyatzadeh et al., 2020, Milliken et al., 2012, Peirce and Alviña, 2019, Valizadeh et al., 2016). Regarding recent meta-analysis, the consumption of high-quality foods are associated with reduced depressive symptoms. Some studies have shown that functional microorganism within dairy products such as yogurt and milk may have beneficial effects on gut microbiome, and hypothesized that dairy products' consumption may change the mood indirectly. Previous studies have shown that vitamin D fortified dairy products can be good for heart and metabolic health. However, a recent review found that the results have been inconsistent (Valizadeh et al., 2016). In accordance with inconsistent results of studies and beneficial impacts of reduction in depression, anxiety, and stress among patients suffering from CVD risk factors, the authors evaluated the effect of low-fat dairy products fortified with 1500IU nano-encapsulated vitamin D3 on anxiety, depression, and stress in subjects with cardiovascular risk factors.
Materials and Methods
Study population: This is a report from the Survey of Ultraviolet Intake by Nutritional Approach (SUVINA), and the study protocol was published elsewhere (Sharifan et al., 2021a). The goal of SUVINA trial was production and intervention of dairy products fortified with nano-encapsulated vitamin D to determine its impact on physical and mental aspects of health. The authors designed the sample size based on anxiety (n=38) depression (n=174), and stress (n=174), then the maximum sample size was considered for depression and stress. The sample size was obtained on the basis of a 95% confidence interval, 80% power, and the standardized effect size of 0.3 as considered at least for 174 people in each group (Dean et al., 2011, Munro, 2005).
The case group consumed dairy products fortified with 1500 IU of nano-vitamin D once a day at breakfast for ten weeks, and the control groups received non-fortified dairy products concurrently. Before the beginning of the research, all the subjects provided written informed consent.
Anxiety, depression and stress are three major mood disorders in Iran with a prevalence of 42%, 44%, and 40%, respectively (Casseb et al., 2019, Drozdenko et al., 2014, Khayyatzadeh et al., 2020, Milliken et al., 2012, Peirce and Alviña, 2019, Valizadeh et al., 2016). Regarding recent meta-analysis, the consumption of high-quality foods are associated with reduced depressive symptoms. Some studies have shown that functional microorganism within dairy products such as yogurt and milk may have beneficial effects on gut microbiome, and hypothesized that dairy products' consumption may change the mood indirectly. Previous studies have shown that vitamin D fortified dairy products can be good for heart and metabolic health. However, a recent review found that the results have been inconsistent (Valizadeh et al., 2016). In accordance with inconsistent results of studies and beneficial impacts of reduction in depression, anxiety, and stress among patients suffering from CVD risk factors, the authors evaluated the effect of low-fat dairy products fortified with 1500IU nano-encapsulated vitamin D3 on anxiety, depression, and stress in subjects with cardiovascular risk factors.
Materials and Methods
Study population: This is a report from the Survey of Ultraviolet Intake by Nutritional Approach (SUVINA), and the study protocol was published elsewhere (Sharifan et al., 2021a). The goal of SUVINA trial was production and intervention of dairy products fortified with nano-encapsulated vitamin D to determine its impact on physical and mental aspects of health. The authors designed the sample size based on anxiety (n=38) depression (n=174), and stress (n=174), then the maximum sample size was considered for depression and stress. The sample size was obtained on the basis of a 95% confidence interval, 80% power, and the standardized effect size of 0.3 as considered at least for 174 people in each group (Dean et al., 2011, Munro, 2005).
The case group consumed dairy products fortified with 1500 IU of nano-vitamin D once a day at breakfast for ten weeks, and the control groups received non-fortified dairy products concurrently. Before the beginning of the research, all the subjects provided written informed consent.
Participants: 306 participants were recruited from among 30-50 staff and students with central obesity, according to the International Diabetes Federation (IDF) from Mashhad University of Medical Sciences (Alberti et al., 2006). The researchers used the following exclusion criteria: all the individuals with a history of weight changes (even 5 Kg) in the previous year, patients who used drugs interacting with vitamin D and calcium, alcohol consumption or positive smoking habit, patients diagnosed with a disease or started a special treatment, intolerance to dairy products, and pregnant and lactating women. Finally, 289 participants finished the trial. The results were analyzed according to completed questionnaires for depression, anxiety, and stress, and therefore, the number of remaining participants was different for variables of vitamin D, depression, anxiety, and stress.
Randomization and blinding: Qualifying participants underwent stratified permuted block randomization with the 1:1:1:1 allocation ratio according to gender and centers' condition. Then, the subjects were randomly allocated to one of the following groups, including: 1- “FY”: fortified low-fat yogurt including 1500 IU nano-encapsulated vitamin D3/per serve (150g/d), 2- “NFY”: non-fortified low-fat yogurt (150g/d), 3), “FM”: fortified low-fat milk containing 1500 IU nano-encapsulated vitamin D3/per serve (200 ml/d), and 4- “NFM”: non-fortified low-fat milk (200 ml/d); NFM and NFY were considered control groups. Sealed envelopes containing A or B labels were applied for allocation to any intervention group and its related control group, separately. Random allocation was accomplished by a staff member who was not involved in data collection, analysis, and reporting. All the participants, clinicians, statisticians, and the researchers responsible for randomizing subjects were blinded to the subjects of the groups (quadruple blind).
Dairy products manufacture: The production of vitamin D nano-particles has been discussed by Jafarifar et al. and Sharifan et al.(Jafarifar et al., 2022, Sharifan et al., 2021b) The fortification process of low-fat milk and yogurt was undertaken at Salamat pilot dairy product factory supervised by the Faculty of Food Sciences and Technology, Ferdowsi University of Mashhad, Iran. Nutritional constituents for 100 gr yogurt and milk were 56 kcal, 7 g protein, sugar-free, 3 g fat, and 0.04 g trans fatty acids. The authors performed delivery and consumption of products on manufacturing day or the day after. To ensure that products were consumed on production day or the next day, the empty labeled containers from participants were required.
Outcome measurements: Weight, body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) were obtained and blood samples were collected from all the participants after a 12-hour fasting before the beginning of the intervention. The case group received fortified yogurt with 1500 IU of nano-vitamin D once a day at breakfast for ten weeks. During the study, patient's history was required to assess the side effects of dairy products' intake. At least 1500 IU Vitamin D was applied for daily consumption due to possible toxicity for the subject based on endocrine society's clinical practice guideline (Holick et al., 2011). In addition, BMI, systolic and diastolic blood pressure, fasting blood glucose, and lipid profile were evaluated before and after the ten weeks of intervention.
Dietary intake and physical activity assessment: Participants were asked not to change their diet and not to use any extra vitamin D supplements or fortified food during the trial period. Besides, to ensure that there was no significant change in their diet, the food intake in participant was recorded at the beginning, middle, and end of the trial through a 3-day food record. The food registration was coded and analyzed by converting into gram and applying Nutritionist IV software. Finally, the average of food records was considered as dietary intake. The researchers used Beck physical activity questionnaire to assess the participants’ physical activity (Baecke et al., 1982). This 16-parts questionnaire is categorized into three indices; work index, sports index, and free time index. The summation of these three indices detected the severity of physical activity. The questionnaire's internal reliability and Cronbach's alpha 0.79 were calculated using the method previously described by Etemad and Ismaeilnasab (Etemad and Esmailnasab, 2012).
Anthropometric indices: A wall stadiometer with an accuracy of 0.1 cm was applied to evaluate height at baseline. A digital bio-impedance analyzer (TANITA BC 418) was used to analyze weight and fat mass with light clothes and shoes. BMI was measured by the following formula: weight (kg)/height2 (m2). WC was computed twice with a flexible tape by the single expert staff at the midpoint between the lower edge of the ribs and the iliac crest at the end of a normal exhalation (Mason and Katzmarzyk, 2009). In addition, hip circumference (HC) was assessed around the broadest part of the buttocks. The formula WC (cm)/ HC (cm) was used to measure WHR.
Laboratory measurements: Blood samples of all the participants were collected into two tubes; a tube including EDTA for complete blood count (CBC) test, and a gel tube for biochemical and hormonal tests after 12 hours of overnight fasting. To separate serum and aliquots of serum kept frozen at -80 °C for future analysis; samples were centrifuged at 5,000 g for 15 minutes at 4 °C. The researchers used enzymatic methods (Sperry et al., 2018) to determine serum triglyceride (TG) and total cholesterol (TC) using Pars Azmun kits (Tehran, Iran), and low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) using Pishtaz Teb kits on a BT-3000 auto-analyzer (Biotechnical, Rome, Italy). Serum insulin levels were measured on the samples transported on ice to the laboratory, which were rapidly separated using the ELISA method applying Demeditec kits (Kiel, Germany). The homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were determined based on the suggested definition (Gutch et al., 2015). Commercial ELISA kits (Pishgaman Sanjesh- Iran) were used to determine total serum 25(OH)D levels, and the result was read with a Microplate Reader Awareness/Stat Fax 2100 analyzer (SECA 217, Hamburg, Germany).
Metabolic syndrome diagnosis: Fasting blood glucose ≥100 mg/dl, systolic or diastolic blood pressure ≥130 or ≥85 mmHg; HDL-C <50 mg/dl for women or <40 mg/dl for men; TG≥150 mg/dl; and WC ≥80 cm for women or ≥94 cm for men, are the five features used for the diagnosis of metabolic syndrome based on the International Diabetes Federation (IDF) definition (Asadi et al., 2019).
Depression/anxiety/stress Test: the 42-item depression anxiety stress scales (DASS-42) was employed according to the overlaps of depression and anxiety beside their different concepts. Each scale includes 14 items. Depression subscale evaluates dysphoric mood types such as depreciation, low self-esteem, despair, and lack of motivation. Anxiety subscale calculates arousal state, like autonomic arousal, muscular rigidity, and anxious affect. Finally, nervous tension and irritability were checked out by the items related to stress subscale. The validation of this questionnaire was performed for the Iranian population previously (Bayani, 2010).
Blood pressure measurement: Blood pressure was measured by an experienced physician in the morning at baseline and follow-up assessments were done after individuals stopped fasting. Calculation was done twice over a period of 5 minutes using a mercury sphygmomanometer (Model Riester, Germany), and the average for each systolic and diastolic blood pressures was reported.
Dairy products manufacture: The production of vitamin D nano-particles has been discussed by Jafarifar et al. and Sharifan et al.(Jafarifar et al., 2022, Sharifan et al., 2021b) The fortification process of low-fat milk and yogurt was undertaken at Salamat pilot dairy product factory supervised by the Faculty of Food Sciences and Technology, Ferdowsi University of Mashhad, Iran. Nutritional constituents for 100 gr yogurt and milk were 56 kcal, 7 g protein, sugar-free, 3 g fat, and 0.04 g trans fatty acids. The authors performed delivery and consumption of products on manufacturing day or the day after. To ensure that products were consumed on production day or the next day, the empty labeled containers from participants were required.
Outcome measurements: Weight, body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) were obtained and blood samples were collected from all the participants after a 12-hour fasting before the beginning of the intervention. The case group received fortified yogurt with 1500 IU of nano-vitamin D once a day at breakfast for ten weeks. During the study, patient's history was required to assess the side effects of dairy products' intake. At least 1500 IU Vitamin D was applied for daily consumption due to possible toxicity for the subject based on endocrine society's clinical practice guideline (Holick et al., 2011). In addition, BMI, systolic and diastolic blood pressure, fasting blood glucose, and lipid profile were evaluated before and after the ten weeks of intervention.
Dietary intake and physical activity assessment: Participants were asked not to change their diet and not to use any extra vitamin D supplements or fortified food during the trial period. Besides, to ensure that there was no significant change in their diet, the food intake in participant was recorded at the beginning, middle, and end of the trial through a 3-day food record. The food registration was coded and analyzed by converting into gram and applying Nutritionist IV software. Finally, the average of food records was considered as dietary intake. The researchers used Beck physical activity questionnaire to assess the participants’ physical activity (Baecke et al., 1982). This 16-parts questionnaire is categorized into three indices; work index, sports index, and free time index. The summation of these three indices detected the severity of physical activity. The questionnaire's internal reliability and Cronbach's alpha 0.79 were calculated using the method previously described by Etemad and Ismaeilnasab (Etemad and Esmailnasab, 2012).
Anthropometric indices: A wall stadiometer with an accuracy of 0.1 cm was applied to evaluate height at baseline. A digital bio-impedance analyzer (TANITA BC 418) was used to analyze weight and fat mass with light clothes and shoes. BMI was measured by the following formula: weight (kg)/height2 (m2). WC was computed twice with a flexible tape by the single expert staff at the midpoint between the lower edge of the ribs and the iliac crest at the end of a normal exhalation (Mason and Katzmarzyk, 2009). In addition, hip circumference (HC) was assessed around the broadest part of the buttocks. The formula WC (cm)/ HC (cm) was used to measure WHR.
Laboratory measurements: Blood samples of all the participants were collected into two tubes; a tube including EDTA for complete blood count (CBC) test, and a gel tube for biochemical and hormonal tests after 12 hours of overnight fasting. To separate serum and aliquots of serum kept frozen at -80 °C for future analysis; samples were centrifuged at 5,000 g for 15 minutes at 4 °C. The researchers used enzymatic methods (Sperry et al., 2018) to determine serum triglyceride (TG) and total cholesterol (TC) using Pars Azmun kits (Tehran, Iran), and low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) using Pishtaz Teb kits on a BT-3000 auto-analyzer (Biotechnical, Rome, Italy). Serum insulin levels were measured on the samples transported on ice to the laboratory, which were rapidly separated using the ELISA method applying Demeditec kits (Kiel, Germany). The homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were determined based on the suggested definition (Gutch et al., 2015). Commercial ELISA kits (Pishgaman Sanjesh- Iran) were used to determine total serum 25(OH)D levels, and the result was read with a Microplate Reader Awareness/Stat Fax 2100 analyzer (SECA 217, Hamburg, Germany).
Metabolic syndrome diagnosis: Fasting blood glucose ≥100 mg/dl, systolic or diastolic blood pressure ≥130 or ≥85 mmHg; HDL-C <50 mg/dl for women or <40 mg/dl for men; TG≥150 mg/dl; and WC ≥80 cm for women or ≥94 cm for men, are the five features used for the diagnosis of metabolic syndrome based on the International Diabetes Federation (IDF) definition (Asadi et al., 2019).
Depression/anxiety/stress Test: the 42-item depression anxiety stress scales (DASS-42) was employed according to the overlaps of depression and anxiety beside their different concepts. Each scale includes 14 items. Depression subscale evaluates dysphoric mood types such as depreciation, low self-esteem, despair, and lack of motivation. Anxiety subscale calculates arousal state, like autonomic arousal, muscular rigidity, and anxious affect. Finally, nervous tension and irritability were checked out by the items related to stress subscale. The validation of this questionnaire was performed for the Iranian population previously (Bayani, 2010).
Blood pressure measurement: Blood pressure was measured by an experienced physician in the morning at baseline and follow-up assessments were done after individuals stopped fasting. Calculation was done twice over a period of 5 minutes using a mercury sphygmomanometer (Model Riester, Germany), and the average for each systolic and diastolic blood pressures was reported.
Safety considerations: Trained staff distributed dairy products daily to improve adherence of subject, and participants consumed the product in front of the staff as far as possible and returned the numerical coded container. Moreover, to make sure of daily consumption, the products were delivered on the weekend, and the participants were asked to consume and return empty coded package on the day after the weekend. A member of the research staff team visited the participants every day to evaluate possible side effects. The physician of the team excluded the participants from the research and referred them to a specialist for more evaluations if their symptoms were related to the intervention.
Ethical considerations: This study was approved by Ethics Committee of Mashhad University of Medical Sciences (Mums), Mashhad, Iran. Informed consent was obtained from all the participants using protocols approved by Ethics Committee of the National Institute for Medical Research Development (NIMAD) with protocol ID: IR.NIMAD.REC.1396.027). The trial was registered in http://www.irct.ir with ID: IRCT20101130005280N27)
Data analysis: SPSS version 18 was used for all the statistical analyses. The Kolmogorov-Smirnov test and Q-Q plot test were applied to check the normality of data for each variable. Descriptive statistics containing mean, median, frequency, standard deviation(SD), and inter quartile range were defined for all the variables and were stated as mean±SD for the variables with normal distribution or median ± IQR for the ones without a normal distribution variable. The researchers applied chi-square, or Fisher exact tests for categorical parameters. ANCOVA and Bonferroni correction were applied between group analyses, and changes were explained as mean differences and standard errors (mean ± SE). Intention-to-treat was done for all the participants who completed the trial, and the P-values of <0.05 were considered significant.
Results
Baseline characteristics of this study demonstrated that total of 289 participants (143 men, 146 women) with CVD risk factors were enrolled. The mean age of the participants was 41.86±7.81 years; and the mean for stress, anxiety, and depression scores were 14.21±6.68, 7.83±4.41, and 8.16±5.75, respectively. The prevalence of dyslipidemia, hypertension, metabolic syndrome, obesity, and diabetes among the patients were 81.7%, 33.1%, 40.3%, 24.4% and 7%, respectively. The mean of serum vitamin D in participants was 14.63±5.29 (ng/ml). Demographic characteristics of these research participants are presented in Table 1. According to Table 2, there were no significant associations between CVD risk factors (dyslipidemia, hypertension, syndrome metabolic, diabetes and obesity) and the scores of depression, anxiety and stress tests at base line. According to the results of Student t-test, the difference between pre- and post-intervention values was not statistically significant for depression, anxiety and stress scores based on (CVD) risk factors in both groups. The results of stress, anxiety, and depression score based on CVD risk factors before and after intervention in male and female are indicated in supplementary Tables of 1 and 2, respectively. The results of stress, anxiety and depression scores based on CVD risk factors before and after intervention of yogurt and milk are indicated in Tables 3 and 4 respectively.
Data analysis: SPSS version 18 was used for all the statistical analyses. The Kolmogorov-Smirnov test and Q-Q plot test were applied to check the normality of data for each variable. Descriptive statistics containing mean, median, frequency, standard deviation(SD), and inter quartile range were defined for all the variables and were stated as mean±SD for the variables with normal distribution or median ± IQR for the ones without a normal distribution variable. The researchers applied chi-square, or Fisher exact tests for categorical parameters. ANCOVA and Bonferroni correction were applied between group analyses, and changes were explained as mean differences and standard errors (mean ± SE). Intention-to-treat was done for all the participants who completed the trial, and the P-values of <0.05 were considered significant.
Results
Baseline characteristics of this study demonstrated that total of 289 participants (143 men, 146 women) with CVD risk factors were enrolled. The mean age of the participants was 41.86±7.81 years; and the mean for stress, anxiety, and depression scores were 14.21±6.68, 7.83±4.41, and 8.16±5.75, respectively. The prevalence of dyslipidemia, hypertension, metabolic syndrome, obesity, and diabetes among the patients were 81.7%, 33.1%, 40.3%, 24.4% and 7%, respectively. The mean of serum vitamin D in participants was 14.63±5.29 (ng/ml). Demographic characteristics of these research participants are presented in Table 1. According to Table 2, there were no significant associations between CVD risk factors (dyslipidemia, hypertension, syndrome metabolic, diabetes and obesity) and the scores of depression, anxiety and stress tests at base line. According to the results of Student t-test, the difference between pre- and post-intervention values was not statistically significant for depression, anxiety and stress scores based on (CVD) risk factors in both groups. The results of stress, anxiety, and depression score based on CVD risk factors before and after intervention in male and female are indicated in supplementary Tables of 1 and 2, respectively. The results of stress, anxiety and depression scores based on CVD risk factors before and after intervention of yogurt and milk are indicated in Tables 3 and 4 respectively.
| Table 1. Baseline characteristics of the study population | |
| Variables | N , Mean ± SD |
| Age (y) | 289, 41.86 ± 7.81 |
| Stress score | 184, 14.21 ± 6.68 |
| Anxiety score | 185, 7.83 ± 4.41 |
| Depression score | 185, 8.16 ± 5.75 |
| Vitamin D (ng/ml) | 242, 14.63 ± 5.29 |
| N (%) | |
| Gender Male |
143 (49.48) |
| Female | 146 (50.51) |
| Dyslipidemia | 236(81.7) |
| Hypertension | 96(33.1) |
| Syndrome Metabolic | 117(40.3) |
| Obesity (Body mass index≥30 kg/m2) | 71(24.4) |
| Diabetes (FBG≥126 mg/dl) | 20(7.0) |
| Table 2. Scores of depression, stress, and anxiety based on CVD risk factors at base line. | |||||||
| Diseases (N) | Depression | Anxiety | Stress | ||||
| Mean ± SD | P-valuea | Mean ± SD | P-valuea | Mean ± SD | P-valuea | ||
| Dyslipidemia (236) | Yes | 8.14 ± 5.72 | 0.742 | 8.02 ± 4.52 | 0.273 | 14.37 ± 6.86 | 0.484 |
| No | 7.79 ± 5.38 | 7.13 ± 3.23 | 13.49 ± 5.79 | ||||
| Hypertension (95) | Yes | 6.91 ± 4.97 | 0.098 | 7.19 ± 3.96 | 0.361 | 13.24 ± 6.08 | 0.356 |
| No | 8.41 ± 5.74 | 7.82 ± 4.35 | 14.21 ± 6.52 | ||||
| Metabolic syndrome (116) | Yes | 8.27 ± 6.06 | 0.751 | 8.02 ± 4.54 | 0.59 | 13.98 ± 6.83 | 0.746 |
| No | 8.00 ± 5.47 | 7.67 ± 4.27 | 14.31 ± 6.58 | ||||
| Diabetes (20) | Yes | 7.17 ± 6.35 | 0.537 | 8.17 ± 4.60 | 0.789 | 14.92 ± 6.51 | 0.706 |
| No | 8.23 ± 5.72 | 7.81 ± 4.41 | 14.16 ± 6.71 | ||||
| Obesity (69) | Yes | 7.49 ± 5.30 | 0.476 | 7.20 ± 4.42 | 0.307 | 12.41 ± 6.80 | 0.067 |
| No | 8.20 ± 5.70 | 7.98 ± 4.23 | 14.55 ± 6.38 | ||||
| a:Student t-test. | |||||||
| Table 3. Scores of stress, anxiety and depression based on CVD risk factors before and after intervention with yogurt. | ||||||||
| Variables | Before | After | P-valuea | Changes | P-valueb | |||
| Dyslipidemia | Yes | Depression score | Intervention | 7.25 ± 8.75 | 9.09 ± 9.09 | 0.41 | 1.84 ± 12.71 | 0.27 |
| Control | 7.90 ± 8.67 | 7.79 ± 8.16 | 0.46 | -0.104 ± 12.8 | ||||
| Anxiety score | Intervention | 8.03 ± 6.28 | 7.69 ± 6.45 | 0.38 | -0.34 ± 9.31 | 0.2 | ||
| Control | 8.27 ± 6.29 | 6.96 ± 6.90 | 0.34 | -1.31 ± 9.03 | ||||
| Stress score | Intervention | 14.63 ± 10.41 | 14.59 ± 9.81 | 0.79 | -0.031 ± 14.37 | 0.5 | ||
| Control | 14.83 ± 9.38 | 14.56 ± 9.22 | 0.45 | -0.27 ± 12.62 | ||||
| No | Depression score | Intervention | 12.50 ± 9.19 | 5.63 ± 6.36 | 0.03 | -6.87 ± 9.13 | 0.42 | |
| Control | 8.50 ± 12.16 | 3.17 ± 3,78 | 0.23 | -5.33 ± 13.41 | ||||
| Anxiety score | Intervention | 11.25 ± 6.34 | 4.63 ± 4.71 | 0.03 | -6.62 ± 7.58 | 0.97 | ||
| Control | 8.50 ± 4.09 | 4.68 ± 2.86 | 0.33 | -3.83 ± 4.24 | ||||
| Stress score | Intervention | 22.25 ± 10.14 | 10.0 ± 8.25 | 0.02 | -12.25 ± 14.48 | 0.99 | ||
| Control | 15.83 ± 11.63 | 6.17 ± 5.73 | 0.05 | -9.66 ± 15.32 | ||||
| Hypertension | Yes | Depression score | Intervention | 9.29 ± 9.70 | 8.24 ± 8.12 | 0.68 | 1.70 ± 12.93 | 0.57 |
| Control | 10.30 ± 6.70 | 7.20 ± 6.67 | 0.17 | -1.40 ± 11.09 | ||||
| Anxiety | Intervention | 8.62 ± 6.94 | 6.29 ± 6.68 | 0.26 | 0.20 ± 9.55 | 0.94 | ||
| Control | 9.52 ± 3.90 | 6.82 ± 4.97 | 0.07 | -0.10 ± 6.69 | ||||
| Stress score | Intervention | 17.24 ± 11.65 | 13.24 ± 11.4 | 0.20 | 1.30 ± 16.31 | 0.67 | ||
| Control | 17.36 ± 7.03 | 12.94 ± 7.00 | 0.06 | -1.40 ± 10.67 | ||||
| No | Depression score | Intervention | 9.19 ± 8.77 | 8.72 ± 8.59 | 0.81 | -0.47 ± 12.3 | 0.27 | |
| Control | 12.00 ± 10.13 | 8.14 ± 7.43 | 0.10 | -3.86 ± 13.73 | ||||
| Anxiety score | Intervention | 8.11 ± 6.34 | 7.92 ± 5.98 | 0.90 | 0.19 ± 9.48 | 0.48 | ||
| Control | 10.00 ± 6.41 | 8.22 ± 7.22 | 0.27 | 1.78 ± 9.58 | ||||
| Stress score | Intervention | 15.60 ± 10.13 | 14.06 ± 9.07 | 0.54 | 1.54 ± 15.06 | 0.51 | ||
| Control | 18.33 ± 9.70 | 14.53 ± 9.08 | 0.10 | 3.81 ± 13.60 | ||||
| Metabolic syndrome | Yes | Depression score | Intervention | 9.60 ± 10.06 | 10.76 ± 9.26 | 0.68 | 1.16 ± 14.03 | 0.25 |
| Control | 11.26 ± 8.81 | 7.63 ± 7.23 | 0.24 | -3.63 ± 13.1 | ||||
| Anxiety score | Intervention | 8.40 ± 6.56 | 10.40 ± 7.06 | 0.34 | -2.00 ± 10.36 | 0.35 | ||
| Control | 8.37 ± 6.64 | 7.58 ± 6.19 | 0.71 | 0.79 ± 9.26 | ||||
| Stress score | Intervention | 15.33 ± 10.68 | 15.75 ± 11.17 | 0.90 | -0.42 ± 16.51 | 0.88 | ||
| Control | 15.74 ± 9.08 | 15.53 ± 8.02 | 0.93 | 0.21 ± 10.33 | ||||
| No | Depression score | Intervention | 8.87 ± 7.91 | 7.39 ± 7.75 | 0.51 | -1.48 ± 10.7 | 0.9 | |
| Control | 11.10 ± 9.65 | 9.19 ± 8.3 | 0.43 | -1.90 ± 13.4 | ||||
| Anxiety score | Intervention | 8.09 ± 6.18 | 5.87 ± 4.32 | 0.17 | 2.21 ± 7.58 | 0.99 | ||
| Control | 10.65 ± 5.64 | 8.45 ± 7.05 | 0.16 | 2.19 ± 8.48 | ||||
| Stress score | Intervention | 17.22 ± 10.41 | 13.3 ± 7.95 | 0.16 | 3.91 ± 13.1 | 0.93 | ||
| Control | 18.55 ± 9.89 | 14.97 ± 9.64 | 0.17 | 3.58 ± 14.42 | ||||
| Diabetes | Yes | Depression score | Intervention | 7.00 ± 6.25 | 8.00 ± 5.20 | 0.86 | 1.00 ± 9.17 | 0.14 |
| Control | 6.33 ±1.50 | 4.00 ±1.10 | 0.28 | --2.66 ±11.72 | ||||
| Anxiety score | Intervention | 11.67 ± 4.51 | 7.33 ± 3.79 | 0.41 | -4.33 ± 5.69 | 0.11 | ||
| Control | 6.30 ±1.60 | 2.10 ±0.99 | 0.06 | -4.33 ± 7.08 | ||||
| Stress score | Intervention | 18.33 ± 14.22 | 13.33 ± 8.15 | 0.60 | -5.25 ± 19.7 | 0.73 | ||
| Control | 8.67 ±4.16 | 7.68 ±1.56 | 0.72 | -1.00 ±14.38 | ||||
| No | Depression score | Intervention | 9.40 ± 9.19 | 9.36 ± 8.82 | 0.98 | -0.04 ± 12.76 | 0.44 | |
| Control | 10.80 ± 8.97 | 8.71 ± 7.91 | 0.26 | -2.08 ± 12.87 | ||||
| Anxiety score | Intervention | 8.29 ± 6.45 | 8.49 ± 6.35 | 0.88 | -0.20 ± 9.48 | 0.44 | ||
| Control | 9.43 ± 5.60 | 8.18 ± 6.74 | 0.29 | 1.24 ± 8.29 | ||||
| Stress score | Intervention | 14.91 ± 10.39 | 16.25 ± 9.78 | 0.55 | 1.34 ± 14.79 | 0.82 | ||
| Control | 17.20 ± 9.50 | 15.18 ± 9.07 | 0.28 | 2.02 ± 12.99 | ||||
| Obesity | Yes | Depression score | Intervention | 8.03 ± 7.40 | 9.33 ± 8.74 | 0.54 | 1.30 ± 16.58 | 0.75 |
| Control | 7.35 ± 7.54 | 7.95 ± 9.21 | 0.59 | 0.59 ± 12.15 | ||||
| Anxiety score | Intervention | 8.13 ± 10.13 | 7.5 ± 6.27 | 0.17 | -0.63 ± 10.21 | 0.37 | ||
| Control | 8.22 ± 6.63 | 7.49 ± 5.21 | 0.36 | -0.73 ± 5.49 | ||||
| Stress score | Intervention | 16.13 ± 15.65 | 15.30 ± 6.62 | 0.73 | -0.83 ± 16.47 | 0.3 | ||
| Control | 14.59 ± 9.99 | 14.78 ± 11.01 | 0.93 | 0.18 ± 11.17 | ||||
| No | Depression score | Intervention | 8.03 ± 8.03 | 9.33 ± 8.52 | 0.83 | 1.30 ± 11.7 | 0.32 | |
| Control | 7.35 ± 9.73 | 7.95 ± 7.69 | 0.25 | 0.59 ± 13.63 | ||||
| Anxiety score | Intervention | 8.13 ± 5.47 | 7.50 ± 5.89 | 0.57 | -0.63 ± 8.87 | 0.27 | ||
| Control | 8.22 ± 6.11 | 7.49 ± 7.01 | 0.32 | -8.59 ± 9.30 | ||||
| Stress score | Intervention | 16.13 ± 9.30 | 15.3 ± 9.49 | 0.90 | 0.83 ± 14.57 | 0.59 | ||
| a: Paired t-test, b: Student t-test. | ||||||||
| Table 4. Scores of stress, anxiety and depression based on CVD risk factors before and after intervention with milk. | ||||||||
| Variables | Before | After | P-valuea | Changes | P-valueb | |||
| Dyslipidemia | Yes | Depression score | Intervention | 7.40 ± 5.98 | 7.80 ± 7.52 | 0.95 | 0.40 ± 10.34 | 0.70 |
| Control | 9.82 ± 8.39 | 8.96 ± 6.61 | 0.51 | -0.85 ± 9.61 | ||||
| Anxiety score | Intervention | 7.94 ± 6.48 | 8.14 ± 5.32 | 0.37 | 0.20 ± 9.58 | 0.77 | ||
| Control | 9.46 ± 6.96 | 8.57 ± 5.23 | 0.48 | -0.89 ± 7.57 | ||||
| Stress score | Intervention | 13.29 ± 8.81 | 13.56 ± 8.82 | 0.67 | 0.26 ± 12.64 | 0.70 | ||
| Control | 15.36 ± 9.87 | 13.86 ± 8.09 | 0.90 | -1.50 ± 12.88 | ||||
| No | Depression score | Intervention | 7.56 ± 6.01 | 5.67 ± 4.54 | 0.92 | -1.88 ± 7.91 | 0.93 | |
| Control | 10.08 ± 6.53 | 7.50 ± 5.55 | 0.97 | -2.58 ± 9.77 | ||||
| Anxiety score | Intervention | 7.00 ± 6.69 | 6.00 ± 3.51 | 0.65 | -1.00± 8.85 | 0.83 | ||
| Control | 8.75 ± 6.25 | 5.92 ± 4.29 | 0.33 | -2.83 ± 8.87 | ||||
| Stress score | Intervention | 14.56 ± 8.64 | 9.11 ± 6.53 | 0.14 | -5.44 ± 9.83 | 0.90 | ||
| Control | 16.17 ± 10.19 | 10.75 ± 5.94 | 0.18 | -5.41 ± 11.95 | ||||
| Hypertension | Yes | Depression score | Intervention | 4.60 ± 5.21 | 6.80 ± 7.35 | 0.54 | 2.2 ± 9.11 | 0.27 |
| Control | 6.56 ± 4.93 | 9.19 ± 6.69 | 0.14 | 2.62 ± 5.92 | ||||
| Anxiety score | Intervention | 6.80 ± 6.78 | 6.60 ± 5.37 | 0.94 | -0.20 ± 10.48 | 0.71 | ||
| Control | 8.06 ± 6.08 | 8.31 ± 5.58 | 0.90 | 0.25 ± 7.66 | ||||
| Stress score | Intervention | 13.00 ± 8.15 | 14.2 ± 9.55 | 0.83 | 1.2 ± 12.32 | 0.75 | ||
| Control | 13.75 ± 8.31 | 12.88 ± 8.3 | 0.71 | -0.87 ± 12.18 | ||||
| No | Depression score | Intervention | 7.25 ± 6.66 | 7.00 ± 7.17 | 0.77 | -0.25 ± 10.69 | 0.48 | |
| Control | 11.95 ± 10.09 | 7.32 ± 5.99 | 0.26 | -4.63 ± 12.14 | ||||
| Anxiety score | Intervention | 7.71 ± 6.67 | 5.52 ± 4.95 | 0.28 | -0.89 ± 9.22 | 0.44 | ||
| Control | 9.27 ± 7.01 | 7.00 ± 3.68 | 0.27 | -2.27 ± 7.13 | ||||
| Stress score | Intervention | 9.71 ± 9.20 | 12.52 ± 8.03 | 0.32 | 2.81 ± 12.77 | 0.52 | ||
| Control | 16.95 ± 12.23 | 12.55 ± 6.53 | 0.10 | -4.40 ± 13.46 | ||||
| Metabolic syndrome | Yes | Depression score | Intervention | 8.90 ± 5.58 | 9.65 ± 8.61 | 0.72 | 0.75 ± 11.09 | 0.89 |
| Control | 12.40 ± 8.42 | 7.73 ± 6.94 | 0.16 | -4.67 ± 8.59 | ||||
| Anxiety score | Intervention | 7.95 ± 6.31 | 9.45 ± 5.64 | 0.47 | 1.50± 9.58 | 0.75 | ||
| Control | 11.87 ± 7.56 | 8.27 ± 4.92 | 0.23 | -3.60 ± 7.70 | ||||
| Stress score | Intervention | 13.89 ± 7.03 | 14.95 ± 9.46 | 0.76 | 1.05 ± 12.30 | 0.96 | ||
| Control | 17.2 ± 9.50 | 13.47 ± 8.76 | 0.21 | -3.73 ± 12.71 | ||||
| No | Depression score | Intervention | 6.85 ± 6.14 | 6.52 ± 6.21 | 0.77 | -0.33 ± 9.26 | 0.61 | |
| Control | 8.40 ± 7.41 | 9.00 ± 5.75 | 0.66 | 0.6 ± 10.55 | ||||
| Anxiety score | Intervention | 7.52 ± 4.72 | 7.07 ± 6.61 | 0.33 | -0.44 ± 9.38 | 0.65 | ||
| Control | 7.68 ± 5.90 | 7.48 ± 5.04 | 0.66 | -0.20 ± 8.19 | ||||
| Stress score | Intervention | 13.52 ± 9.29 | 11.48 ± 8.03 | 0.16 | -2.37 ± 12.10 | 0.89 | ||
| Control | 14.64 ± 10.49 | 12.60 ± 6.40 | 0.14 | 2.04 ± 12.94 | ||||
| Diabetes | Yes | Depression score | Intervention | 11.75 ± 2.65 | 5.25 ± 5.51 | 0.47 | 3.33 ± 6.66 | 0.25 |
| Control | 12.33 ± 2.52 | 9.95 ± 0.58 | 0.20 | -2.67 ± 2.52 | ||||
| Anxiety score | Intervention | 10.50 ± 6.93 | 6.25 ± 7.81 | 0.75 | -3.00 ± 14.73 | 0.44 | ||
| Control | 6.33 ± 1.53 | 2.10 ± 1.00 | 0.06 | 4.23 ± 2.08 | ||||
| Stress score | Intervention | 24.25 ± 3.61 | 9.75 ± 9.82 | 0.09 | 7.67 ± 11.24 | 0.42 | ||
| Control | 8.67 ± 4.16 | 7.67 ± 0.58 | 0.72 | 1.00 ± 4.36 | ||||
| No | Depression score | Intervention | 7.44 ± 6.03 | 8.26 ± 7.19 | 0.87 | 0.74 ± 10.06 | 0.57 | |
| Control | 9.41 ± 8.04 | 8.67 ± 6.25 | 0.48 | -0.74 ± 9.84 | ||||
| Anxiety score | Intervention | 12.67 ± 6.47 | 13.21 ± 4.73 | 0.19 | 0.81 ± 8.88 | 0.67 | ||
| Control | 8.79 ± 6.93 | 7.85 ± 4.97 | 0.35 | -0.94 ± 8.13 | ||||
| Stress score | Intervention | 12.67 ± 8.78 | 13.21 ± 8.43 | 0.48 | 0.54 ± 12.3 | 0.26 | ||
| Control | 15.21 ± 10.21 | 12.87 ± 7.89 | 0.36 | -2.33 ± 13.35 | ||||
| Obesity | Yes | Depression score | Intervention | 6.00 ± 4.72 | 9.00 ± 9.79 | 0.62 | 3.00 ± 12.53 | 0.65 |
| Control | 5.38 ± 7.69 | 8.88 ± 5.43 | 0.84 | 3.57 ± 10.49 | ||||
| Anxiety score | Intervention | 7.29 ± 5.48 | 7.80 ± 6.51 | 0.97 | 0.57 ± 10.49 | 0.59 | ||
| Control | 6.63 ± 5.92 | 7.00 ± 4.19 | 0.15 | 0.37 ± 7.30 | ||||
| Stress score | Intervention | 11.14 ± 7.49 | 11.43 ± 8.61 | 0.96 | 0.28 ± 12.87 | 0.43 | ||
| Control | 11.75 ± 10.6 | 11.13 ± 5.10 | 0.85 | -0.62 ± 11.63 | ||||
| No | Depression score | Intervention | 7.60 ± 6.56 | 6.54 ± 5.74 | 0.52 | -1.05 ± 8.83 | 0.39 | |
| Control | 11.03 ± 8.02 | 8.44 ± 6.76 | 0.24 | -2.59 ± 9.13 | ||||
| Anxiety score | Intervention | 7.63 ± 7.01 | 7.34 ± 4.30 | 0.85 | -0.28 ± 9.11 | 0.64 | ||
| Control | 9.91 ± 7.20 | 7.97 ± 5.26 | 0.24 | -1.93 ± 8.33 | ||||
| Stress score | Intervention | 13.5 ± 9.38 | 12.35 ± 8.69 | 0.63 | -1.14 ± 12.35 | 0.53 | ||
| Control | 16.56 ± 9.76 | 13.38 ± 8.73 | 0.15 | -3.18 ± 13.60 | ||||
| a: Paired t-test, b: Student t-test. | ||||||||
Discussion
According to the results, dairy product consumption fortified with vitamin D showed no effect regarding the groups suffering from CVD risk factor. The same results were found in healthy subjects according to the scores of depression, anxiety, and stress.
It is reported that depression affects around 300 million people around the world and leads to suicide in 800 thousand depressed people. Suicide is the second leading cause of death in the age group of 15-29 years. This epidemiology should be addressed with respect to the fact that 76% to 85% of the people in low- and middle-income countries receive no treatment for their disorder (James et al., 2018). Anxiety also is estimated to affect 3.6% of the people around the world. Just like depression, anxiety has affected around 300 million people in different parts of the world. This condition affects the normal life of the patients (World Health Organization, 2017). Besides environmental and social factors, deficiency in many micronutrients play a role in developing these two disorders (Kimball et al., 2018, Rucklidge et al., 2016).
It is reported that vitamin D is a modulator of many inflammatory processes, and has positive effects on brain like increasing some neurotransmitters like dopamine, noradrenalin, and adrenalin; it also increases the expression of tyrosine hydroxylase gene. Furthermore, this vitamin affects cholinergic system by activating choline acetyltransferase (Ersoy and Ersoy). There is evidence that 25(OH)D may be converted into 1,25(OH)2D within the human brain parenchyma. In fact, vitamin D modulates cell proliferation, neurotransmitters production, biosynthesis of monoamine, calcium and redox homeostasis, mitochondrial function, and cell apoptosis in the brain. Besides, anti-inflammatory effects of vitamin D, antioxidant features have been reported that make this vitamin more beneficial for central nervous system and effective against developing depression and anxiety, as inflammation and oxidative stress have a role in developing these disorders (Casseb et al., 2019, Patki et al., 2013). However, the mechanism of the action of vitamin D on brain is not fully understood (Ersoy and Ersoy).
Although vitamin D deficiency is clearly reported to be associated with depression through systematic review studies (Amini et al., 2019, Anglin et al., 2013), the role of vitamin D supplementation is debated. A systematic review study in 2015 proposed that vitamin D supplementation has no role on improving depressive symptoms (Gowda et al., 2015). However, more recent meta-analysis in 2020 reported that vitamin D can enhance negative feelings (Cheng et al., 2020). Another recent systematic review and meta-analysis also reported that vitamin D favorably impacts major depressive cases, with a moderate effect size. However, controversies has remained, and more studies are needed (Vellekkatt and Menon, 2019). There is also another controversy in relation to the role of vitamin D supplementation in improving anxiety. Some believe that this micronutrient ameliorates symptoms of anxiety and increases circulation of serotonin level (Bicikova et al., 2015, Darroudi et al., 2019). However, some studies have reported no association between vitamin D and anxiety (Kjærgaard et al., 2012, Slow et al., 2014, Wepner et al., 2014). Furthermore, some of the studies were conducted on different populations like obese cases (Jorde et al., 2008), pregnant women (Bertone-Johnson et al., 2012), adolescents (Högberg et al., 2012), and old people (Alavi et al., 2019). This study was conducted to further help the completion of previous studies. No significant difference was found regarding depression, anxiety, and stress scores before and after vitamin D supplementation, both in those with cardiovascular risk factors and those without these risk factors. Differences regarding the results of various studies were due to using different doses, treatment duration, and fortification methods. Most of the studies with reports on the improvement of the symptoms regarding depression, used a dose of 4000 IU/day for a duration of at least 8 weeks (Gowda et al., 2015).
We used a dose of 1500 IU/day for a ten-week period, and this was not effective in reducing the symptom scores. In fact, depression, anxiety, and other mental changes are chronic mental changes and should be treated chronically. Therefore, this study was limited in case of duration and dose of vitamin D fortification. Moreover, the subgroup analysis in this study lacked enough statistical power for clinical judgment. However, this research was among the few studies which assessed the role of food staples fortified with vitamin D on CVD risk factors.
Conclusions
No impact of dairy products consumption fortified by nano-encapsulated vitamin D was found in improving depression, anxiety, and stress. However, only a daily dose of 1500 IU/day was used for ten weeks, and the result of vitamin D supplementation seems to be dose dependent. Further studies are needed to explain the role of vitamin D fortified dairy products in altering mood status, particularly individuals with CVD risk factors.
Acknowledgments
The authors would like to thank Mashhad University of Medical Sciences Research Council for their financial supports.
Funding
The study protocol was funded by Ethics Committee of the National Institute for Medical Research Development (957705), Tehran, Iran. This study was supported by a grant from the National Institute for Medical Research Development (NIMAD) and Research Council of the Mashhad University of Medical Sciences.
Availability of data and materials
The data which support the findings of this study are available from the corresponding author upon reasonable request.
Conflict of interests
The authors declared no conflict of interests.
Authors' contributions
Sharifan P, Ghazizadeh H, and Darroudi S did the literature research, designed the research, drafted the article, and revised the paper. Esmaily H, Ferns F, Tanbacoochi D, Ghodsi A, Saffar Soflaei S, Fazl Mashhadi MR, Mohammadi Bajgiran M, Ebrahimi dabagh A, Moazedi S and Mohamadi MA were involved in data analysis, conception and interpretation of results. Ghayour-Mobarhan M, Esmaily H conducted the final revision. All the authors read and approved the final manuscript.
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According to the results, dairy product consumption fortified with vitamin D showed no effect regarding the groups suffering from CVD risk factor. The same results were found in healthy subjects according to the scores of depression, anxiety, and stress.
It is reported that depression affects around 300 million people around the world and leads to suicide in 800 thousand depressed people. Suicide is the second leading cause of death in the age group of 15-29 years. This epidemiology should be addressed with respect to the fact that 76% to 85% of the people in low- and middle-income countries receive no treatment for their disorder (James et al., 2018). Anxiety also is estimated to affect 3.6% of the people around the world. Just like depression, anxiety has affected around 300 million people in different parts of the world. This condition affects the normal life of the patients (World Health Organization, 2017). Besides environmental and social factors, deficiency in many micronutrients play a role in developing these two disorders (Kimball et al., 2018, Rucklidge et al., 2016).
It is reported that vitamin D is a modulator of many inflammatory processes, and has positive effects on brain like increasing some neurotransmitters like dopamine, noradrenalin, and adrenalin; it also increases the expression of tyrosine hydroxylase gene. Furthermore, this vitamin affects cholinergic system by activating choline acetyltransferase (Ersoy and Ersoy). There is evidence that 25(OH)D may be converted into 1,25(OH)2D within the human brain parenchyma. In fact, vitamin D modulates cell proliferation, neurotransmitters production, biosynthesis of monoamine, calcium and redox homeostasis, mitochondrial function, and cell apoptosis in the brain. Besides, anti-inflammatory effects of vitamin D, antioxidant features have been reported that make this vitamin more beneficial for central nervous system and effective against developing depression and anxiety, as inflammation and oxidative stress have a role in developing these disorders (Casseb et al., 2019, Patki et al., 2013). However, the mechanism of the action of vitamin D on brain is not fully understood (Ersoy and Ersoy).
Although vitamin D deficiency is clearly reported to be associated with depression through systematic review studies (Amini et al., 2019, Anglin et al., 2013), the role of vitamin D supplementation is debated. A systematic review study in 2015 proposed that vitamin D supplementation has no role on improving depressive symptoms (Gowda et al., 2015). However, more recent meta-analysis in 2020 reported that vitamin D can enhance negative feelings (Cheng et al., 2020). Another recent systematic review and meta-analysis also reported that vitamin D favorably impacts major depressive cases, with a moderate effect size. However, controversies has remained, and more studies are needed (Vellekkatt and Menon, 2019). There is also another controversy in relation to the role of vitamin D supplementation in improving anxiety. Some believe that this micronutrient ameliorates symptoms of anxiety and increases circulation of serotonin level (Bicikova et al., 2015, Darroudi et al., 2019). However, some studies have reported no association between vitamin D and anxiety (Kjærgaard et al., 2012, Slow et al., 2014, Wepner et al., 2014). Furthermore, some of the studies were conducted on different populations like obese cases (Jorde et al., 2008), pregnant women (Bertone-Johnson et al., 2012), adolescents (Högberg et al., 2012), and old people (Alavi et al., 2019). This study was conducted to further help the completion of previous studies. No significant difference was found regarding depression, anxiety, and stress scores before and after vitamin D supplementation, both in those with cardiovascular risk factors and those without these risk factors. Differences regarding the results of various studies were due to using different doses, treatment duration, and fortification methods. Most of the studies with reports on the improvement of the symptoms regarding depression, used a dose of 4000 IU/day for a duration of at least 8 weeks (Gowda et al., 2015).
We used a dose of 1500 IU/day for a ten-week period, and this was not effective in reducing the symptom scores. In fact, depression, anxiety, and other mental changes are chronic mental changes and should be treated chronically. Therefore, this study was limited in case of duration and dose of vitamin D fortification. Moreover, the subgroup analysis in this study lacked enough statistical power for clinical judgment. However, this research was among the few studies which assessed the role of food staples fortified with vitamin D on CVD risk factors.
Conclusions
No impact of dairy products consumption fortified by nano-encapsulated vitamin D was found in improving depression, anxiety, and stress. However, only a daily dose of 1500 IU/day was used for ten weeks, and the result of vitamin D supplementation seems to be dose dependent. Further studies are needed to explain the role of vitamin D fortified dairy products in altering mood status, particularly individuals with CVD risk factors.
Acknowledgments
The authors would like to thank Mashhad University of Medical Sciences Research Council for their financial supports.
Funding
The study protocol was funded by Ethics Committee of the National Institute for Medical Research Development (957705), Tehran, Iran. This study was supported by a grant from the National Institute for Medical Research Development (NIMAD) and Research Council of the Mashhad University of Medical Sciences.
Availability of data and materials
The data which support the findings of this study are available from the corresponding author upon reasonable request.
Conflict of interests
The authors declared no conflict of interests.
Authors' contributions
Sharifan P, Ghazizadeh H, and Darroudi S did the literature research, designed the research, drafted the article, and revised the paper. Esmaily H, Ferns F, Tanbacoochi D, Ghodsi A, Saffar Soflaei S, Fazl Mashhadi MR, Mohammadi Bajgiran M, Ebrahimi dabagh A, Moazedi S and Mohamadi MA were involved in data analysis, conception and interpretation of results. Ghayour-Mobarhan M, Esmaily H conducted the final revision. All the authors read and approved the final manuscript.
References
Alavi NM, Khademalhoseini S, Vakili Z & Assarian F 2019. Effect of vitamin D supplementation on depression in elderly patients: A randomized clinical trial. Clinical nutrition. 38 (5): 2065-2070.
Alberti KGMM, Zimmet P & Shaw J 2006. Metabolic syndrome—a new world‐wide definition. A consensus statement from the international diabetes federation. Diabetic medicine. 23 (5): 469-480.
Amini S, Jafarirad S & Amani R 2019. Postpartum depression and vitamin D: A systematic review. Critical reviews in food science and nutrition. 59 (9): 1514-1520.
Amiri Z, et al. 2021. Factors determining the serum 25‐hydroxyvitamin D response to vitamin D supplementation: Data mining approach. BioFactors. 47 (5): 828-836.
Anglin RES, Samaan Z, Walter SD & McDonald SD 2013. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Journal of mental science. 202: 100-107.
Asadi Z, et al. 2019. Association Between dietary patterns and the risk of metabolic syndrome among Iranian population: A cross-sectional study. Diabetes & metabolic syndrome: Clinical research & reviews. 13 (1): 858-865.
Baecke JA, Burema J & Frijters JE 1982. A short questionnaire for the measurement of habitual physical activity in epidemiological studies. American journal of clinical nutrition. 36 (5): 936-942.
Bayani AA 2010. Reliability and preliminary evidence of validity of a Farsi version of the depression anxiety stress scales. Perceptual and motor skills. 111 (1): 107-114.
Bertone-Johnson ER, et al. 2012. Vitamin D supplementation and depression in the women’s health initiative calcium and vitamin D trial. American journal of epidemiology. 176 (1): 1-13.
Bicikova M, et al. 2015. Vitamin D in anxiety and affective disorders. Physiological research. 64: S101.
Casseb GA, Kaster MP & Rodrigues ALS 2019. Potential role of vitamin D for the management of depression and anxiety. CNS drugs. 33 (7): 619-637.
Cheng YC, Huang YC & Huang WL 2020. The effect of vitamin D supplement on negative emotions: A systematic review and meta‐analysis. Depression and anxiety. 37 (6): 549-564.
Cohen BE, Edmondson D & Kronish IM 2015. State of the art review: depression, stress, anxiety, and cardiovascular disease. American journal of hypertension. 28 (11): 1295-1302.
Cuomo A, et al. 2019. Prevalence and correlates of vitamin D deficiency in a sample of 290 inpatients with mental illness. Frontiers in psychiatry. 10: 167.
Darroudi S, et al. 2019. Oxidative stress and inflammation, two features associated with a high percentage body fat, and that may lead to diabetes mellitus and metabolic syndrome. Biofactors. 45 (1): 35-42.
Dean AJ, et al. 2011. Effects of vitamin D supplementation on cognitive and emotional functioning in young adults–a randomised controlled trial. PloS one. 6 (11): e25966.
Drozdenko G, Scheel T, Heine G, Baumgrass R & Worm M 2014. Impaired T cell activation and cytokine production by calcitriol‐primed human B cells. Clinical & experimental immunology. 178 (2): 364-372.
Ersoy N & Ersoy G Vitamin D deficiency and Depression: What Can We Do? Hacettepe Üniversitesi Sağlık Bilimleri Fakültesi Dergisi. 4 (3): 1-14.
Etemad Z & Esmailnasab N 2012. The relationship between the level of physical activity and some risk factors of coronary heart disease in the university students. Scientific Journal of Kurdistan University of Medical Sciences. 17 (1).
Ganji V, Milone C, Cody MM, McCarty F & Wang YT 2010. Serum vitamin D concentrations are related to depression in young adult US population: the Third National Health and Nutrition Examination Survey. International archives of medicine. 3 (1): 1-8.
Gowda U, Mutowo MP, Smith BJ, Wluka AE & Renzaho AM 2015. Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. 31 (3): 421-429.
Gutch M, Kumar S, Razi SM, Gupta KK & Gupta A 2015. Assessment of insulin sensitivity/resistance. Indian journal of endocrinology and metabolism. 19 (1): 160.
Högberg G, et al. 2012. Depressed adolescents in a case‐series were low in vitamin D and depression was ameliorated by vitamin D supplementation. Acta Paediatrica. 101 (7): 779-783.
Holick MF, et al. 2011. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal of clinical endocrinology & metabolism. 96 (7): 1911-1930.
Hossein-nezhad A & Holick MF 2013. Vitamin D for health: a global perspective. Mayo Clinic Proceedings. 88 (7): 720-755.
Jafarifar Z, et al. 2022. Preparation and characterization of nanostructured lipid carrier (NLC) and nanoemulsion containing vitamin D3. Applied biochemistry and biotechnology. 194 (2): 914-929.
James SL, et al. 2018. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 392 (10159): 1789-1858.
Jäpelt RB & Jakobsen J 2013. Vitamin D in plants: a review of occurrence, analysis, and biosynthesis. Frontiers in plant science. 4: 136.
Jorde R, Sneve M, Figenschau Y, Svartberg J & Waterloo K 2008. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. Journal of internal medicine. 264 (6): 599-609.
Khayyatzadeh SS, et al. 2020. Dietary antioxidants and fiber intake and depressive symptoms in Iranian adolescent girls. Public health nutrition. 1-18.
Kimball SM, Mirhosseini N & Rucklidge J 2018. Database analysis of depression and anxiety in a community sample—Response to a micronutrient intervention. Nutrients. 10 (2): 152.
Kjærgaard M, et al. 2012. 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. British journal of psychiatry. 201 (5): 360-368.
Marino R & Misra M 2019. Extra-skeletal effects of vitamin D. Nutrients. 11 (7): 1460.
Mason C & Katzmarzyk PT 2009. Variability in waist circumference measurements according to anatomic measurement site. Obesity. 17 (9): 1789-1795.
Milliken SV, et al. 2012. Effects of ultraviolet light on human serum 25-hydroxyvitamin D and systemic immune function. Journal of allergy and clinical immunology. 129 (6): 1554-1561.
Munro BH 2005. Statistical methods for health care research. lippincott williams & wilkins.
Patki G, Solanki N, Atrooz F, Allam F & Salim S 2013. Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain research. 1539: 73-86.
Peirce JM & Alviña K 2019. The role of inflammation and the gut microbiome in depression and anxiety. Journal of neuroscience research. 97 (10): 1223-1241.
Rucklidge J, Blampied N & Sole E 2016. Effects of Micronutrients on Anxiety and Stress in Children. In 8th World Congress of Behavioural and Cognitive Therapies, 22-25 Jun 2016.: Melbourne, Australia:.
Shah J & Gurbani S 2019. Association of vitamin D deficiency and mood disorders: A systematic review. In Vitamin D Deficiency (ed. F. Julia): london.
Sharifan P, et al. 2021a. The efficacy of dairy products fortified with nano-encapsulated vitamin D3 on physical and mental aspects of the health in obese subjects; the protocol of the SUVINA trial. Translational metabolic syndrome research. 4: 1-9.
Sharifan P, et al. 2021b. Effect of low-fat dairy products fortified with 1500IU nano encapsulated vitamin D3 on cardiometabolic indicators in adults with abdominal obesity: A total blinded randomized controlled trial. Current medical research and opinion. 37 (4): 579-588.
Slow S, et al. 2014. Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial. British medical journal. 349.
Sperry MF, et al. 2018. Probiotic Minas Frescal cheese added with L. casei 01: Physicochemical and bioactivity characterization and effects on hematological/biochemical parameters of hypertensive overweighted women–A randomized double-blind pilot trial. Journal of functional foods. 45: 435-443.
Valizadeh R, et al. 2016. A study of prevalence of anxiety in Iran: Systematic review and meta-analysis. Der Pharma Chemica. 8 (21): 48-57.
Vellekkatt F & Menon V 2019. Efficacy of vitamin D supplementation in major depression: A meta-analysis of randomized controlled trials. J Postgrad Med. 65 (2): 74-80.
Wepner F, et al. 2014. Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial. PAIN®. 155 (2): 261-268.
World Health Organization 2017. Depression and other common mental disorders: global health estimates. World Health Organization.
Zhao G, Ford ES, Li C & Balluz LS 2010. No associations between serum concentrations of 25-hydroxyvitamin D and parathyroid hormone and depression among US adults. British journal of nutrition. 104 (11): 1696-1702.
Type of article: orginal article |
Subject:
public specific
Received: 2022/12/8 | Published: 2024/02/21 | ePublished: 2024/02/21
Received: 2022/12/8 | Published: 2024/02/21 | ePublished: 2024/02/21
References
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2. Alberti KGMM, Zimmet P & Shaw J 2006. Metabolic syndrome—a new world‐wide definition. A consensus statement from the international diabetes federation. Diabetic medicine. 23 (5): 469-480.
3. Amini S, Jafarirad S & Amani R 2019. Postpartum depression and vitamin D: A systematic review. Critical reviews in food science and nutrition. 59 (9): 1514-1520.
4. Amiri Z, et al. 2021. Factors determining the serum 25‐hydroxyvitamin D response to vitamin D supplementation: Data mining approach. BioFactors. 47 (5): 828-836.
5. Anglin RES, Samaan Z, Walter SD & McDonald SD 2013. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Journal of mental science. 202: 100-107.
6. Asadi Z, et al. 2019. Association Between dietary patterns and the risk of metabolic syndrome among Iranian population: A cross-sectional study. Diabetes & metabolic syndrome: Clinical research & reviews. 13 (1): 858-865.
7. Baecke JA, Burema J & Frijters JE 1982. A short questionnaire for the measurement of habitual physical activity in epidemiological studies. American journal of clinical nutrition. 36 (5): 936-942.
8. Bayani AA 2010. Reliability and preliminary evidence of validity of a Farsi version of the depression anxiety stress scales. Perceptual and motor skills. 111 (1): 107-114.
9. Bertone-Johnson ER, et al. 2012. Vitamin D supplementation and depression in the women’s health initiative calcium and vitamin D trial. American journal of epidemiology. 176 (1): 1-13.
10. Bicikova M, et al. 2015. Vitamin D in anxiety and affective disorders. Physiological research. 64: S101.
11. Casseb GA, Kaster MP & Rodrigues ALS 2019. Potential role of vitamin D for the management of depression and anxiety. CNS drugs. 33 (7): 619-637.
12. Cheng YC, Huang YC & Huang WL 2020. The effect of vitamin D supplement on negative emotions: A systematic review and meta‐analysis. Depression and anxiety. 37 (6): 549-564.
13. Cohen BE, Edmondson D & Kronish IM 2015. State of the art review: depression, stress, anxiety, and cardiovascular disease. American journal of hypertension. 28 (11): 1295-1302.
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15. Darroudi S, et al. 2019. Oxidative stress and inflammation, two features associated with a high percentage body fat, and that may lead to diabetes mellitus and metabolic syndrome. Biofactors. 45 (1): 35-42.
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18. Ersoy N & Ersoy G Vitamin D deficiency and Depression: What Can We Do? Hacettepe Üniversitesi Sağlık Bilimleri Fakültesi Dergisi. 4 (3): 1-14.
19. Etemad Z & Esmailnasab N 2012. The relationship between the level of physical activity and some risk factors of coronary heart disease in the university students. Scientific Journal of Kurdistan University of Medical Sciences. 17 (1).
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21. Gowda U, Mutowo MP, Smith BJ, Wluka AE & Renzaho AM 2015. Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. 31 (3): 421-429.
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29. Jorde R, Sneve M, Figenschau Y, Svartberg J & Waterloo K 2008. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. Journal of internal medicine. 264 (6): 599-609.
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35. Mason C & Katzmarzyk PT 2009. Variability in waist circumference measurements according to anatomic measurement site. Obesity. 17 (9): 1789-1795.
36. Milliken SV, et al. 2012. Effects of ultraviolet light on human serum 25-hydroxyvitamin D and systemic immune function. Journal of allergy and clinical immunology. 129 (6): 1554-1561.
37. Munro BH 2005. Statistical methods for health care research. lippincott williams & wilkins.
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41. Shah J & Gurbani S 2019. Association of vitamin D deficiency and mood disorders: A systematic review. In Vitamin D Deficiency (ed. F. Julia): london.
42. Sharifan P, et al. 2021a. The efficacy of dairy products fortified with nano-encapsulated vitamin D3 on physical and mental aspects of the health in obese subjects; the protocol of the SUVINA trial. Translational metabolic syndrome research. 4: 1-9.
43. Sharifan P, et al. 2021b. Effect of low-fat dairy products fortified with 1500IU nano encapsulated vitamin D3 on cardiometabolic indicators in adults with abdominal obesity: A total blinded randomized controlled trial. Current medical research and opinion. 37 (4): 579-588.
44. Slow S, et al. 2014. Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial. British medical journal. 349.
45. Sperry MF, et al. 2018. Probiotic Minas Frescal cheese added with L. casei 01: Physicochemical and bioactivity characterization and effects on hematological/biochemical parameters of hypertensive overweighted women–A randomized double-blind pilot trial. Journal of functional foods. 45: 435-443.
46. Valizadeh R, et al. 2016. A study of prevalence of anxiety in Iran: Systematic review and meta-analysis. Der Pharma Chemica. 8 (21): 48-57.
47. Vellekkatt F & Menon V 2019. Efficacy of vitamin D supplementation in major depression: A meta-analysis of randomized controlled trials. J Postgrad Med. 65 (2): 74-80.
48. Wepner F, et al. 2014. Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial. PAIN®. 155 (2): 261-268.
49. World Health Organization 2017. Depression and other common mental disorders: global health estimates. World Health Organization.
50. Zhao G, Ford ES, Li C & Balluz LS 2010. No associations between serum concentrations of 25-hydroxyvitamin D and parathyroid hormone and depression among US adults. British journal of nutrition. 104 (11): 1696-1702.
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