Folate intake and depressive symptoms in Japanese workers considering SES and job stress factors: J-HOPE study
© Miyaki et al.; licensee BioMed Central Ltd. 2012
Received: 11 October 2011
Accepted: 29 March 2012
Published: 20 April 2012
Recently socioeconomic status (SES) and job stress index received more attention to affect mental health. Folate intake has been implicated to have negative association with depression. However, few studies were published for the evidence association together with the consideration of SES and job stress factors. The current study is a part of the Japanese study of Health, Occupation and Psychosocial factors related Equity (J-HOPE study) that focused on the association of social stratification and health and our objective was to clarify the association between folate intake and depressive symptoms in Japanese general workers.
Subjects were 2266 workers in a Japanese nationwide company. SES and job stress factors were assessed by self-administered questionnaire. Folate intake was estimated by a validated, brief, self-administered diet history questionnaire. Depressive symptoms were measured by Kessler’s K6 questionnaire. “Individuals with depressive symptoms” was defined as K6≧9 (in K6 score of 0–24 scoring system). Multiple logistic regression and linear regression model were used to evaluate the association between folate and depressive symptoms.
Several SES factors (proportion of management positions, years of continuous employment, and annual household income) and folate intake were found to be significantly lower in the subjects with depressive symptom (SES factors: p < 0.001; folate intake: P = 0.001). There was an inverse, independent linear association between K6 score and folate intake after adjusting for age, sex, job stress scores (job strains, worksite supports), and SES factors (p = 0.010). The impact of folate intake on the prevalence of depressive symptom by a multiple logistic model was (ORs[95% CI]: 0.813 [0.664-0.994]; P =0.044).
Our cross-sectional study suggested an inverse, independent relation of energy-adjusted folate intake with depression score and prevalence of depressive symptoms in Japanese workers, together with the consideration of SES and job stress factors.
Depression is the most common psychiatric condition and regarded as a major cause of disability worldwide. In Japan, the life time prevalence of major depression has been estimated at 3-7% . The presence of depressive symptoms considerably increases the risk of major depression. Among many putative risk factors, folate deficiency has been recognized since the 1960s as an important contributor to the depression [2, 3]. A lot of studies examining the risk of depression in the presence of low folate were performed [4–8], including in Japanese subjects. In 2006, Gilbody reported that there is accumulating evidence that low folate status is associated with depression by meta-analysis . Contrast to that in these observational studies, the effects of folate supplementation on depressive symptomatology obtained from several intervention studies were inconsistent, Taylor et al. performed a systematic review and meta-analysis then suggested that folate may have a potential role as a supplement to other treatment for depression , although another study failed to provide evidence for the potentiation of antidepressant medication by folate + vitamin B12 supplementation .
Another risk factor of depression is low socioeconomic status (SES) [12, 13]. Low-SES groups are often exposed to an accumulation of life event stressors and chronic problems related to their low-SES state, such as poor education, poor labor circumstances and unemployment, financial strain, inadequate housing, or neighbor violence. In 2003, V. Lorant reported socioeconomic inequality in depression by meta-analysis . In their report, 51 studies reported an odds ratio greater than 1, of which 35 were statistically significant.
Workplace mental health has also garnered increasing attention over the past decade because depressive disorders are highly prevalent in the workplace and have an enormously negative impact on performance, productivity, absenteeism and disability costs. Several studies have found significant associations between sources of perceived stress and major depression onset [15–17], suggesting that work stress is an independent risk factor for the development of depression. The Job Demand-Control -Support (JDCS) model has dominant research on occupational stress in which three major components are used to describe workplace qualities: demands, control, and support . Sanne et al. showed that high demands, low control and low support individually, but particularly combined, are risk factors for anxiety and depression .
Folate has been implicated to have negative association with depression, but to our knowledge, the contribution of the SES or job stress factors is still unclear. Recently, the Japanese study of Health, Occupation and Psychosocial factors related Equity (J-HOPE study) was performed to develop and expand research to elucidate mechanisms underlying the social disparity in health and establishment of measures to control over it. The current study is a part of the J-HOPE, and our objective of this study was to clarify the association between folate intake and depressive symptoms in Japanese general workers by using large-scale samples, together with the consideration of SES and job stress factors.
The present cross-sectional study was based on a baseline survey of our occupational cohort study on social class and health, supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Employee of a Japanese major manufacturing company (Headquarter is in Kyoto and the other major 11 offices were spread all over the Japan) were recruited. All workers were invited to participate, and 2266 agreed (aged from 21–65 years; response rate 90.1%). 241 of them are women and account for 10.6%. The protocol and explanation documents of our study were approved by the ethics committee of University of Tokyo School of Medicine, and written informed consent was obtained from each subject.
Height, weight, systolic and diastolic blood pressures, fasting blood glucose level, serum lipid levels (total cholesterol, triglyceride, high density lipoprotein [HDL] cholesterol), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gamma-GTP), blood urea nitrogen (BUN), serum creatinine (Cr), and serum uric acid (UA) levels were measured in health checkups in all subjects.
Depressive symptom was assessed by using the Kessler 6 (K6) scale . K6 scale is a 6-question scale to quantify the non-specific psychological distress and now is used in clinical populations to identify those people who have a serious mental illness. It comes in a self-administered version and an interviewer-administered version  and is ideal for monitoring prevalence of depressive disorders on a large scale. In the current study, the self-administered version was used. The Japanese version of K6 scale was developed by using the standard back-translation method and included in the World Mental Health Survey Japan (WMH-J) . The WMH-J used the WMH Survey Initiative version of the Composite International Diagnostic Interview (CIDI) to assess the 30-day Diagnostic and Statistical Manual of Mental Disorders--Fourth Edition (DSM-IV). This version demonstrated screening performances equivalent to that of the original English version. There are two scoring systems for K6 based on responses of “1-5” or “0-4”, resulting in score ranges of 0–24 or 6–30, respectively. In the current study we used the 24-scoring system. A cut-offs of ≥9 for the K6 for identifying subjects at high risk of depressive symptom was suggested according to a validation report, in which the sensitivity and specificity were estimated at 77.8 and 86.4 in Japanese population .
Job strain score is defined as a ratio of job demands to job control followed by multiplied by 2 in order to adjust for the difference in scoring ranges between the job demand scale (12–48) and the job control scale (24–96) . Worksite support score is calculated by adding the scores of supervisor support and colleague support. Job demands and control, supervisor support and colleague support were obtained from a self-administered questionnaire. Years of education, annual household income, and the number of household were assessed by the same self-administered questionnaire as above.
Dietary habits during the preceding month were assessed with a validated, brief, self-administered diet history questionnaire (BDHQ) .
Responses to the BDHQ were checked for completeness and, where necessary, clarified by direct questioning of the subject. The BDHQ is a 4-page structured questionnaire that enquires about the consumption frequency of a total of 56 food and beverage items, with specified serving sizes described in terms of the natural portion or the standard weight and volume measurement of servings commonly consumed in general Japanese populations. The BDHQ was developed based on a comprehensive (16-page) version of a validated self-administered diet history questionnaire [26–28]. The BDHQ includes the main food sources for the Japanese with regard to folate (vegetables [nine items: lettuces; tomatoes; dark-green leafy vegetables; cabbages; carrots and pumpkins; radishes and turnips; onions, burdocks, and lotus roots; mushrooms; and seaweeds] and green tea [one item]). The validation of the BDHQ was performed by using 16-d weighed dietary records as the gold standard , and Pearson correlation coefficients for folate intake in 92 Japanese men and 92 Japanese women aged from 31 to 76 years were 0.50 and 0.62, respectively. Adjusted folate intake was calculated as daily folate intake divided by daily total calories (per 1000Kcal).
Student’s T test or Mann-Whitney’s U test was applied to compare variables between groups after Levine’s test for equality of variance. Difference in more than 2 groups was assessed using Turkey’s post hoc test of analysis of variance (ANOVA). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression analysis. All statistical analyses were performed using SPSS for Windows version 19.0 J (IBM Corporation, New York, USA). Statistical significance was accepted for a two-tailed p-value of < 0.05.
Comparison for clinical characteristics, job stress, socioeconomic status between subjects with or without depressive mood
Total subjects (n = 2266)
Subjects without depressive mood (n = 1771)
Subjects with depressive mood (n = 495)
43.5 ± 9.8
44.0 ± 9.8
41.7 ± 9.3
Proportion of women (%)
Body mass index (kg/m2)
23.1 ± 3.3
23.0 ± 3.2
23.3 ± 3.5
Systolic blood pressure (mmHg)
123.4 ± 16.1
123.7 ± 16.1
122.2 ± 16.0
Diastolic blood pressure (mmHg)
77.1 ± 12.0
77.1 ± 12.0
77.0 ± 11.9
Total cholesterol (mg/dL)
200.0 ± 35.1
200.2 ± 35.2
199.1 ± 34.5
125.8 ± 180.0
125.4 ± 195.3
127.4 ± 104.5
HDL cholesterol (mg/dL)
61.8 ± 16.5
62.0 ± 16.3
61.2 ± 17.4
Fasting plasma glucose (mg/dL)
95.0 ± 23.2
95.1 ± 21.7
94.9 ± 28.0
23.7 ± 18.3
23.6 ± 19.7
24.0 ± 11.8
25.8 ± 18.1
25.5 ± 18.1
26.7 ± 18.0
47.4 ± 56.8
47.1 ± 55.9
48.5 ± 60.2
Years of education (year)
14.5 ± 2.5
14.6 ± 2.5
14.4 ± 2.5
Proportion of management position (%)
Years of continuous employment (year)
20.6 ± 11.6
21.1 ± 11.7
19.2 ± 11.1
Working hours (hour/week)
46.6 ± 7.2
46.5 ± 7.1
47.0 ± 7.6
Annual household income (ten thousands yen/year)
704.4 ± 297.5
717.9 ± 303.3
656.3 ± 270.7
Adjusted annual household income (ten thousands yen/year)
443.0 ± 188.5
446.1 ± 188.7
431.8 ± 187.7
Number of families (n)
2.9 ± 1.4
2.9 ± 1.4
2.8 ± 1.5
Job stress scores
4.7 ± 2.5
4.5 ± 2.4
5.5 ± 2.6
3.0 ± 1.4
3.0 ± 1.4
2.7 ± 1.4
4.0 ± 3.4
3.7 ± 3.1
5.2 ± 4.0
11.8 ± 1.8
11.9 ± 1.6
11.3 ± 2.0
5.1 ± 4.6
3.2 ± 2.6
12.2 ± 3.3
Daily folate intake (μg/day)
295.6 ± 127.3
297.6 ± 125.9
288.5 ± 131.9
Energy-adjusted folate intake (μg/1000 kcal·day)
163.0 ± 56.9
165.0 ± 57.4
155.8 ± 54.7
As to SES factors, proportion of management positions, years of continuous employment, and unadjusted annual household income were found to be significantly lower in the subjects with depressive symptom. Also the daily folate intake levels adjusted by total energy intake were significantly different between two groups (155.8 ± 54.7 vs 165.0 ± 57.4 μg/1000 kcal·day, P = 0.001), although the unadjusted folate intake were not different (P = 0.162).
For job stressor scores, notable differences were found between subjects with or without depressive symptom in job demands, control, strain and worksite supports. All of the P values were less than 0.001.
Association of energy-adjusted folate intake with K6 score by linear regression models
Energy-adjusted folate intake
We also considered the gender difference on this association. By the separate linear regression analysis performed in two genders, the association between energy-adjusted folate intake and K6 score remained in male subjects (β = −0.050, P = 0.021), but disappeared in females (β = −0.054, P = 0.412).
The multiple logistic regression analysis of energy-adjusted folate intake as to with or without depressive mood
Odds Ratio [95% CI]
Sex (male = 1, female = 2)
Job stress scores
Years of education (year)
Management position (others = 0, manager = 1)
Annual household income (million yen/year)
Energy-adjusted folate intake (100 μg/1000 kcal·day)
In the current study, we confirmed an inverse, independent linear relation of K6 score with the energy-adjusted folate intake level in Japanese workers. These results are in agreement with previous study of Japanese [5, 29]. It is worthy of note that comparing with the small sample size of their studies (517 in Ref. 5 and 530 in Ref. 29), our study was a large-scale investigation with more than 2,200 participants, providing more convincing evidence for this association. Furthermore, we took various job stress scores into account as potential relative factors at the first time. When the job stress scores were not added and the analysis was adjusted for age, sex and SES factors only, the folate intake was also associated with K6 score by linear regression (standard β was −0.059; P value for trend was 0.006) and prevalence of depressive symptom by logistic regression (ORs [95% CI]: 0.813 [0.671-0.985]; P value was 0.035). After further adjusted for the job stress scores, the relations of folate intake to K6 score and prevalence of depressive symptom remained (P values are 0.010 and 0.044, respectively), and the stress factors also showed association with depressive symptom, providing inspiration to understand thoroughly the relationships among depression and relative factors.
The results that the association between folate intake and depressive mood was found in men only, were consistent with that of Murakami et al.  and Nanri et al. , who found that higher folate intake was associated with lower prevalence of depressive symptoms in Japanese men but not in women, although in another study the association was found only in USA women . The possible explanation for the gender difference is the relatively sufficient folate intake in women. In the present study, mean (±SD) values of adjusted intake of men and women were 159.4 ± 54.1 and 192.9 ± 69.9 μg/1000 kcal·day, respectively, therefore the higher intakes of female subjects maybe mask the effect of folate intake on depression. However, because of the relative small size of female subjects in our study and the importance of folate intake in pregnant women, whether the dietary folate intake affect mental health should be further investigated in larger scale and well-designed studies.
The mechanism of folate intake relate to depressive symptom was thought to be that a decreased folate intake results in an accumulation of homocysteine and then elevated homocysteine levels, which cause vascular disease of the brain, and/or transmitter alterations, could cause depression . Higher total plasma homocysteine concentrations were associated with older age, male gender  and dietary deficiency of folate, vitamins B12 and B6 . It was described that the lesions of atherosclerosis could be induced by administering homocysteic acid by animal experiment . Early studies suggested a relationship between depression and cerebrovascular and cardiovascular disease , and deficiency of folate and elevated homocysteine levels was considered to increase the risk for vascular disease of the brain [35–37]. However, more recent evidences strongly supported a different role of folate. Folate plays a role in the 1-carbon cycle, and eventually produces S-adenosyl-L-methionine (SAMe), which is an important methyl donor and thought to be involved in the synthesis of three key neurotransmitters in the brain-dopamine, serotonin and norepinephrine . Homocysteine is a critical branch point metabolite that can influence cellular levels of SAMe and S-adenosylhomocysteine (SAH), which regulate the activity of methyltransferases important in posttranslational modification of proteins and synthesis of nucleic acids, phospholipids, and neurotransmitters . Thus, low folate intakes, which result in elevated homocysteine levels, lead to a deficiency of these neurotransmitters and then cause depression. The homocysteine hypothesis of depression reviewed by Folstein et al.  centering around hyperhomocysteinemia leading to an increased risk of stroke, heart disease, neurotransmitter imbalances and thereby depression was further extended by a brief comment in the American Journal of Psychiatry in 2007 . The authors herein stated that homocysteine is metabolized to SAMe, then influence DNA methylation. Secondly, homocysteine itself was shown to affect global and gene promoter DNA methylation, and the administration of acute homocysteine usually leads to demethylation of promoter DNA with a subsequent increase in gene expression . A further study supported the hyperhomocysteine hypothesis of depression, reporting significantly higher homocysteine levels in patients with moderate depressive symptoms and eating disorder diagnoses . Our observations epidemiologically confirmed with this hypothesis.
Some limitations of the present study are worth mentioning. Firstly, the cross-sectional nature of the study does not permit the assessment of causality owing to the uncertain temporality of the association. Depressed persons may eat less or more and the intakes of nutrition are influenced by the total amount of intake. In order to remove this effect, we used the total energy adjusted folate intake level (μg/1000 kcal per day). Our data showed energy adjusted low folate intake was significantly related to depressive symptoms, and the probability of the reverse causation seems slim. Secondly, our subjects were workers in one large company and not a random sample of Japanese workers, and thus the results may not apply to the general Japanese population. However, the workers were recruited from 12 offices all over the Japan (From Hokkaido to Kyushu). So the geographical deviation was reasonably diluted, but it is noteworthy fact that our result is the result of a large company, not a small company. Finally, dietary data were obtained from a self-administered semi-quantitative dietary assessment questionnaire . Because the actual dietary habits were not observed, the results should be interpreted with caution, although the validity of this questionnaire appears reasonable [26–28].
In conclusion, low folate intake was independently related to higher depression scores and increased prevalence of depressive symptoms in Japanese workers, adjusting for job strains, supports and various SES factors. Further prospective or intervention studies are warranted to determine this association as well as the roles of SES and stress effect on mental health outcomes.
Job Demand-Control –Support
High density lipoprotein
Blood urea nitrogen
Serum uric acid
- K6 scale:
Kessler 6 scale
Brief-type self-administered diet history questionnaire
Analysis of variance
Body mass index
Standard error of the mean
The present study was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (Research in a Proposed Research Area) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Chief: Norito Kawakami). We appreciate professional advices as to clinical aspects of depression by Dr. Setsuko Taneichi (Tokyo University and National Center for Global Health and Medicine).
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