Corresponding author : Woo Kyung Bae, MD, MPH Department of Family Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173Beon-gil, Bundang-gu, Seongnam 13620, Korea INTRODUCTION
Depression is a mood disorder, which is characterized by symptoms of eating disorders, memory disorders, and suicide attempts with emotions, such as sadness, disinterest, or loss of motivation. In recent years, depression has emerged as a major threat to health and quality of life worldwide, and the World Health Organization has reported that depression to be a major cause of disability [1]. As of 2018, the number of patients with depression in Korea was 750,000, which increased by 27.7% compared to 2014; considering the gender, the number of female patients was 1.8 times higher than that of men.
Vitamin D is a naturally produced vitamin, which is activated on skin exposure to ultraviolet rays; it is an essential substance for the human body that acts as a steroid hormone in the targeted organs to maintain calcium and phosphorus balance and skeletal health [2-4]. In addition, studies have shown that the level of vitamin D is associated with cancer, diabetes, high blood pressure, and cardiovascular disease. Recently, active vitamin D or vitamin D receptors have been reported to function specifically in the brain tissue or the nervous system, suggesting associations with mental illnesses, such as depression [5,6]. Several studies have suggested that metabolites of 25-hydroxyvitamin D (25[OH]D) in the blood can cross the blood-brain barrier and that 25(OH)D receptors are present in the central nervous system, showing the presence of vitamin D receptors (VDR) and related enzymes (CYP 24A1, cytochrome P450 family 24 subfamily A member 1; CYP 27B1, cytochrome P450 family 27 subfamily B member 1; also known as 25-hydroxyvitamin D 1-alpha-hydroxylase) in various areas of the brain; therefore, vitamin D, neuroactivity and neurotransmitters, can affect brain function [7,8].
The results of these studies to determine the relationship between vitamin D and depression experience are inconsistent, and only certain groups, such as the elderly population and teenagers have been studied in Korea. Furthermore, in a subgroup analysis of gender during the study of all Korean adults; in adult men, the associations have identified, but not in women [9,10]. The reasons for no association with female groups were analyzed, and previous studies have shown that menopause, caused by a decrease in estrogen, affects both blood vitamin D and depression in the process [11,12]. In a double-blind randomized controlled clinical trial in 152 healthy premenopausal women in New Zealand, oral vitamin D had no effect on mood disorders [13]. In addition, in a double-blind placebo-controlled prospective clinical trial conducted on 489 postmenopausal depressed women in the United States, hormone therapy and vitamin D co-supplementation were combined, but there was no improvement in depression [14]. However, no study has been found that compared vitamin D and depression status by dividing all women according to menopausal status.
Therefore, using the data from the 5th Korea National Health and Nutrition Examination Survey (KNHANES) (2010-2012), this study aimed to assess the association of serum vitamin D concentrations in Korea with the experience of depressive symptoms based on the menopausal status.
METHODS
1. Participants
This study integrated the 5th KNHANES data and used it for analysis. From the 33,592 participants, our study included adult women aged 19 years and older, without absence of major exposure-result factors, such as menopause, serum vitamin D levels, and depression (n=11,573). This study was approved by the Institutional Review Board (IRB no. X-2108-701-902) of Seoul National University Bundang Hospital.
2. Key variables
The general characteristics of the participants, including their age, occupation, household income level, education level, marital status, and residential area were analyzed. Smoking habits, drinking habits, physical activities, and underlying diseases among the health survey data were used. Data on menstruation, which is a major condition in women, were used; the dietary survey section analyzed whether dietary supplements were taken.
1) Serum vitamin D measurement
The levels of vitamin D in the participants were evaluated using serum 25(OH)D concentrations. This indicator is used to measure serum vitamin D in a number of vitamin D-related epidemiological studies, and the concentration measurements were analyzed using the radioimmunoassay method in specialized clinical institutions, and gamma counters (1470 WIZARD gamma-Counter, PerkinElmer®, Waltham, MA, USA). Serum 25(OH)D levels were categorized into quartiles.
2) Depressive symptoms experience
In the health survey section, the respondents who answered "Yes" to the question "Have you felt sad or hopeless enough to interfere with your daily life for more than 2 weeks in a row?" were designated as "Depressive conditions" and the participants who answered “No” were designated as “Not depressed”.
3. Statistical analysis
This study integrated the 3 years of the KNHANES data, and since there are differences in the number of participants by year, the survey analysis was conducted by generating integrated weights with different proportions. To analyze the general characteristics of the participants, chi-square tests were performed for categorical variables and independent sample t-test (independent two-sample t-test) for continuous variables, and multivariate logistic regression analysis were conducted to analyze the experience of depression according to serum vitamin D level in each group of women before and after menopause. The contents of each model are as follows. Model 1: uncorrected crude model, model 2: age, obesity, smoking status, frequency of drinking, exercise, comorbidity, and stress recognition rate, model 3: model 2 corrected additionally with marriage, household income, occupation, and education. All statistical processing in this study was conducted using STATA version 16.0 (STATA Corp., College Station, TX, USA). Statistical significance was tested at a significance level of P<0.05.
RESULTS
1. Characteristics of the participants
Of the 11,573 women, 5,442 were classified as premenopausal and 6,131 as postmenopausal women (Table 1). In women before and after menopause, the average serum vitamin D levels were 15.22±4.98 ng/mL and 17.87±6.24 ng/mL, respectively.
There were differences in age, body mass index, metabolic equivalents, comorbidities, and dietary supplements according to serum vitamin D levels in both premenopausal and postmenopausal women. Marriage showed differences only in premenopausal women and education in postmenopausal women.
2. Prevalence of depressive symptoms according to vitamin D quartiles
The prevalence of each group's depression experience on dividing into quartiles based on serum vitamin D concentration in all adult women is shown in Figure 1A. In the group with the lowest serum vitamin D level, the depression experience was 16.2%, 14.6%, 15.3%, and 17.5% in the second quartile (Q2), third quartile (Q3), and fourth quartile (Q4), respectively. In the premenopausal female group, the current prevalence of depression in each group is shown in Figure 1B, 16.3%, 13%, 11.9%, and 12.2% in the first quartile (Q1), Q2, Q3, and Q4, respectively indicating higher rates of depression in the lower serum vitamin D groups (P=0.002). In the postmenopausal female population (Figure 1C), the proportion of depression was 16.6%, 17.9%, 18.1%, and 20.1% in Q1, Q2, Q3, and Q4, respectively (P=0.083).
3. Multivariate analysis of depressive symptoms associated with vitamin D quartiles in pre- and post-menopausal women
Compared to Q1, the Q2 odds ratio (OR) was 0.85 for experiencing depressive symptoms in female adults. (95% confidence intervals [CI], 0.67-1.08), and in Q3 and Q4, the ORs of the depressive symptoms experience were not statistically significant (Q3: OR, 0.84; 95% CI, 0.65-1.09 and Q4: OR, 0.98; 95% CI, 0.78-1.22; P=0.371) (Table 2).
In premenopausal women, compared to Q1, the OR of depressive symptom experiences were in the order Q2: OR, 0.75 (95% CI, 0.53-1.07); Q3: OR, 0.70 (95% CI, 0.49-1.00); and Q4: OR, 0.62 (95% CI, 0.43-0.92) (P=0.016) (Table 3).
In postmenopausal women, compared to Q1, which had the lowest experience of depressive symptoms the ORs of the experience of depressive symptoms were in the order Q2: OR, 1.06 (95% CI, 0.78-1.44); Q3: OR, 1.18 (95% CI, 0.87-1.61); and Q4: OR, 1.27 (95% CI, 0.98-1.66) respectively (P=0.057) (Table 4).
DISCUSSION
This study examined whether there are differences in the relationship between vitamin D concentrations and depressive symptoms in Korean women based on their menopausal status. Analysis of all adult women showed that the proportion of depressive symptom experience was not related to serum vitamin D levels. Furthermore, this study assumes that the relationship between serum vitamin D concentration and experience of depressive symptoms would be affected by menopause, which was the main classification criterion for the entire adult female population, and further analysis was conducted. When dividing all adult women based on their menopausal status, premenopausal women tended to show decreased rates of depressive symptoms experience as serum vitamin D levels increased; however, it was not the same case in postmenopausal women. After confirming this trend, all female participants were divided into two groups; and the relationship between serum vitamin D concentration and experience of depressive symptoms was analyzed using multivariate logistic regression.
As a result, in premenopausal women, the increase in serum vitamin D was associated with the reduced prevalence of depressive symptoms. On the contrary, in postmenopausal women, the increase in serum vitamin D was associated with the increased prevalence of depressive symptoms.
In a study conducted using the data from the National Health and Nutrition Examination Survey in the United States, the likelihood of depression in groups lacking vitamin D increased significantly compared to those with sufficient serum vitamin D [15]. Other studies using the same data, however, showed no meaningful relationship between serum vitamin D concentration and depressive symptoms when classifying the depression groups according to depression levels and comparing their relationship with vitamin D [16]. A study in Korea examined the relationship between the concentration of vitamin D in the blood and depression in adults, but showed conflicting results [17,18]. Furthermore, an analysis of the entire adult population using the KHNAES data in 2014 showed that the lower the serum vitamin D level, the greater the experience of depression in adult men; however a similar association could not be demonstrated in adult women [19].
Postmenopausal women show a major characteristic of decreased estrogen, which causes 80% of women to undergo physical, hormonal and mental changes [20]. Several studies have shown that estrogen is strongly related to the pathogenesis of mental illness, including emotion and behavior control especially in older women, when they reach menopause [21-23]. Estrogen increases the effects of serotonin and norepinephrine, which are thought to be the neurotransmitters most related to the physiological cause of depression. Estrogen decreases monoamine oxidase (MAO) activity in the central nervous system, hindering the breakdown of serotonin and norepinephrine. In addition, estrogen increases serotonin synthesis, upregulates 5-hydroxytryptamine (5-HT)1 receptors, and downregulates 5-HT2 receptors. Estrogen also increases norepinephrine activity in the brain, perhaps by decreasing reuptake and degradation due to inhibition of MAO and catechol-O-methyltransferase [23].
Decrease in estrogen is also related to a decrease in serum vitamin D. During menopause, women experience thinner skin and lower ability to produce vitamin D, in addition to reduced intestinal absorption of vitamin D and decreased vitamin D hydroxylation in the liver and kidneys [24]. Vitamin D reportedly reduces depressive symptoms in postmenopausal women by controlling the concentration of the neurotransmitter, serotonin, which increases the production of sex hormones and reduces the frequency of depression-associated receptors, within the pituitary gland in the brain.[25]. VDR and 1-alphahydroxylase, which are responsible for active vitamin formation, are widely distributed in the human brain, including the prefrontal cortex, amygdala, hippocampus, hypothalamus, parenchymal nigra, and cerebellum [26,27]. Vitamin D deficiency has received more attention because of its potential effects on neuropsychological functions. In a systematic review and meta-analysis conducted to determine the relationship between vitamin D deficiency and depression, it was found that low vitamin D levels were associated with depression [28].
Postmenopausal women with low serum vitamin D may have experienced related symptoms, which could have increased the use of dietary supplements, including vitamin D, or treatments for depression [29]. This tendency may have disturbed the association between serum vitamin D concentration and depressive symptoms, and eventually showed a different trend in premenopausal women.
Postmenopausal women had a higher mean age; therefore, they had a high percentage of underlying chronic diseases, and were likely to belong to low-activity groups. Depressive symptoms are subjective problems affected by various physical and social factors, which can cause emotional instability combined with stress of chronic diseases, lack of confidence due to social and environmental changes, and reduced activity due to physical changes. These conditions in postmenopausal women were found to affect the rate of depression experience and have a greater impact than serum vitamin D concentration, resulting in different results from other groups in postmenopausal women. In this study, we tried to adjust for these factors by using social characteristics, underlying chronic disease and exercise and activity data.
This study had several limitations. First, this was a cross-sectional study; hence, it limits the explanation of the causal relationship between serum vitamin D concentration and the experience of depressive symptoms. If intervention such as vitamin D supplementation or antidepressants is carried out through a prospective future research method rather than a cross-sectional study, it would be possible to monitor the experience of depression following supplementation and reveal the direct causal relationship. Data from the KNHANES revealed only information about whether the participants were currently taking dietary supplements some of which could affect their serum vitamin D levels and depressive symptoms. In addition, depression was assessed using a questionnaire on subjective symptoms, and evaluated whether depression was present with a single question, "Have you felt sad or hopeless enough to interfere with your daily life for more than 2 consecutive weeks in the past year?" The errors could be reduced if information was obtained about depressive mood using structured questionnaires such as Patient Health Questionnaire-9, and about treatments for depression. However, as a screening test for depression, a single question is found to be useful [30], and simple depression rather than major depressive disorder is frequently observed in primary care. The analysis of postmenopausal women showed statistically insignificant results even though all the variables were calibrated. This could have been derived with the small number of participants, and this limitation could be overcome if further research is conducted on more participants. Finally, this study found that there was a difference in the correlation between serum vitamin D levels and depression in a group of women based on menopause. However, no exact basis for determining the cause of this difference has been provided. Therefore, subsequent research warrants follow-up studies that contain gritty information than those provided in this study to improve the rationale for the results in postmenopausal women.
This study used a representative sample, the KNHANES, and it is the first study to analyze the link between serum vitamin D concentration and experience of depressive symptoms by categorizing Korean adult women on the basis of menopause. The study showed that a stratification analysis based on menopause would show meaningful results and revealed the link between serum vitamin D concentration and depression in adult women. Furthermore, as the interest and the use of dietary supplements such as multivitamin are increasing in Korea, this study is expected to provide useful information in the future studies.
Based on previous studies and this study, it is known that low vitamin D concentrations in premenopausal women increase depressive symptoms; thus vitamin D supplementation could be considered. However, in postmenopausal women, it is need to consider supplementing estrogen along with vitamin D to create synergistic effects against depressive symptoms. In further studies, it will be necessary to study whether it is effective to supplement both vitamin D and estrogen for postmenopausal women, or supplement only estrogen, and or supplement vitamin D alone to depressive symptoms.
This study examined the association between serum vitamin D concentration and depressive symptoms in Korean adult women according to their menopausal status. In premenopausal women, the lower the serum vitamin D concentration, the more the depressive symptoms; however the opposite trend was observed in postmenopausal women.
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