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Intakes of folate, vitamin B6 and B12 and risk of depression in community-dwelling older adults: the Quebec Longitudinal Study on Nutrition and Aging

Abstract

Background/Objectives:

Depression can decrease quality of life and affect health outcomes in older population. We investigated whether different intake levels of folate, vitamin B6 and B12 were associated with a 3-year depression incidence among generally healthy, community-dwelling older men and women.

Subjects/Methods:

Participants in the Québec Longitudinal Study on Nutrition and Aging (NuAge), free of depression (that is, 30-item Geriatric Depression Scale (GDS) <11) at baseline (N=1368; 74±4 years old; 50.5% women), were screened annually for incident depression (GDS 11) or antidepressant medication. Tertiles of intakes (food only and food+supplements) were obtained from the mean of three non-consecutive 24-h recalls at baseline. Sex-stratified multiple logistic regression models were adjusted for age, physical activity, physical functioning, stressful life events and total energy intake.

Results:

Over 3 years, 170 participants were identified as depressed. Women in the highest tertile of B6 intake from food were 43% less likely to become depressed when adjusting for demographic and health factors (multivariate odds ratio (OR) 0.57, 95% confidence interval (CI) 0.39–0.96), but adjustment for energy intake attenuated the effect. Men in the highest tertile of dietary B12 intake had decreased risk of depression (energy-adjusted multivariate OR 0.42, 95% CI 0.20–0.90). No other association was observed.

Conclusions:

This study provides some evidence of decreased depression risk among women with higher intakes of vitamin B6 from food, which was dependent on total energy intake, and among men with higher intakes of B12 from food, independently of energy intake.

Introduction

In patients with psychiatric disorders, including depression, higher prevalence rates of B-vitamin deficiency, particularly folate, B6 and B12, have been reported when compared with their healthy peers.1, 2 Although the mechanism is still elusive, it is suggested to lie mainly in the role of these vitamins in neurotransmitter synthesis (norepinephrine, serotonin and dopamine) and their participation in one-carbon metabolism as methyl donors for methyl transferases involved in monoamine metabolism and re-methylation of homocysteine.3, 4 It is unknown, however, whether the role of these vitamins on mental health goes beyond frank vitamin deficiency, that is, whether higher intakes would decrease risk of developing depression.2, 5 Some evidence from longitudinal observational studies shows potential inverse associations between the levels of intakes of B vitamins and the risk of depression among young adults,6, 7, 8, 9, 10 but studies exploring such an association in the older population are scarce. Observational studies that reported significant associations between B vitamins and depression in older adults have been limited to cross-sectional designs and focused mainly on blood levels11, 12, 13, 14, 15 not intakes. Whether diet predicts depression or depression affects dietary intake in these studies remains unclear.16

Moreover, because of the lack of observational studies, whether the source (food vs supplements) could have a role in decreasing the risk of depression incidence among community-living older adults is largely unknown. To our knowledge, the only longitudinal evidence on depression and B-vitamin intakes among community-dwelling older adults comes from the Chicago Health and Aging Project (CHAP) in approximately 3500 US older men and women (73.5±6.1 years, 59% African American) followed for 7 years.17 It showed a significantly lower incidence of depression with higher total intakes (food+supplements, measured by food frequency questionnaires) of B12 and B6 but not from food alone. In contrast, four Australian and one American randomized, double-blind, placebo-controlled trials in men and women older than 60 and living in the community found no evident benefits from B-vitamin supplementation on measures of depression incidence.18, 19, 20, 21, 22 Their duration ranged from 35 days18 to 2 years19, 20, 21 or 7 years.22

In this study, we examined whether higher intakes of B6, B12 and folate either from food alone (that is, dietary intake) or from food+supplements (that is, total intake) may be protective of incident depression among generally healthy community-dwelling Canadian older adults.

Subjects and methods

Study design and population

The Québec Longitudinal Study on Nutrition and Aging (NuAge) is a 4-year observational study of 1793 men and women in good general health at recruitment, described in detail elsewhere.23 In summary, the sample was drawn from a random sample obtained from the Québec Medicare database for the regions of Montreal, Laval and Sherbrooke (QC, Canada) and stratified by age and sex. Community-dwelling men and women were included if they spoke French or English, were free of disabilities in activities of daily living, were without cognitive impairment (scores in the Modified Mini-Mental State (3MS) Examination >79 out of 100), able to walk one block or to climb one flight of stairs without rest and willing to commit to a 5-year study period. Those who had heart failure class II, chronic obstructive pulmonary disease requiring oxygen therapy or oral steroids, inflammatory digestive diseases or cancer treated either by radiation therapy, chemotherapy or surgery in the past 5 years were excluded. The number of participants recruited into each age stratum were as follows: 68–72 years: 337 F, 329 M; 73–77 years: 305 F, 289 M; 78 years: 298 F, 235 M. Data were collected by trained research dietitians and nurses using computer-assisted personal interview methodology (MD William, Multispectra, 1997–2004 data capture software) following rigorous standardized procedures. Baseline data collection for this study took place between December 2003 and March 2005. Participants were then examined annually using a series of nutritional, biological, medical, functional and social measurements.23

All participants signed an informed consent approved by the ethics committees of both of the Geriatric University Institutes of Montréal (Institut Universitaire de Gériatrie de Montréal) and Sherbrooke (Institut Universitaire de Gériatrie de Sherbrooke). This study was approved by McGill’s Faculty of Agricultural and Environmental Sciences Research Ethics Board.

For this study, we limited the analysis to participants deemed free of depression at baseline. Those with scores 11 on the 30-item Geriatric Depression Scale (GDS) (n=183) or reporting the use of antidepressant medication (n=78) were excluded, as well as those with invalid or missing GDS scores at baseline (n=14), with no GDS scores for follow-up years (n=141) and with invalid or missing dietary information at baseline (n=9). The final sample size for this study was 1368 individuals aged 67–84 years: 691 women (74.5±4.3 years) and 677 men (74.1±4.3 years).

Dietary assessment at baseline

Mean nutrient intakes at baseline were obtained from three non-consecutive 24-h dietary recalls, including one weekend day. According to studies on the reliability of diet records, the three 24-h recalls can reliably estimate group’s mean intakes and allowed for adequate ranking.24

The dietary intake data were recorded by research dietitians, coded for entry by trained professionals and analyzed using the CANDAT software (Godin London Inc., London, ON, Canada) with then-current 2007b Canadian Nutrient File.25 The dietary data were carefully checked with the initial paper record of the intake when variation between days exceeded 1000 kcal. Outliers in nutrient intake were verified following a thorough data cleaning protocol.

Supplement use was recorded and analyzed using the Natural Product Number or Homeopathic Medicine Number, which denotes the nutrient levels. 'Total intakes' represent the 3-day average intakes of B vitamins from both food and supplements (food+supplement).

Main outcome measure: incidence of depression

Incidence of depression was identified on the basis of the 30-item GDS score 11 or new use of antidepressant medication at any annual follow-up. The GDS tool is an inventory with a yes/no format in which each response signaling depressive mood contributes one point to a total of 30 points.26 It is considered a reliable and a valid self-rating screening tool that indicates the likelihood of clinically diagnosed major depression in an older adult population, with 84% sensitivity and 95% specificity at a cutoff score of 11.26, 27 Therefore, the term 'depression' used in this study reflects the probability of clinically diagnosed major depression. Subjects with scores <11 are considered likely not-depressed.26 Only three subjects presented scores 21 on follow-up years—the suggested cutoff for possible severe depression.

Medications with the therapeutic classification name, according to the American Hospital Formulary System, as 'antidepressants', 'miscellaneous antidepressants', 'selective-serotonin reuptake inhibitors' and 'serotonin modulators' were also used to define cases of depression—benzodiazepine was not included because they are often mis- and/or overprescribed by physicians, particularly in geriatric populations.28

Baseline confounders

Preliminary analyses tested several health, social and lifestyle confounders including age, years of schooling, marital status, smoking status, self-reported hypertension, body mass index and measures of social activities. However, because of the relatively low incidence of depression, we were parsimonious in the number of confounders and restricted covariates to the following baseline characteristics shown to differ between participants deemed depressed and not-depressed at follow-up: age, physical activity, functional autonomy, stressful life events and total energy intake. Although smoking was a potential confounder among women, it was not retained because of low prevalence (n=9 or 8% in the depressed group; n=22 or 4% in the non-depressed group) and the borderline significance (P=0.042). Potential confounding from intakes of other micronutrients was also not controlled for because of increased risk of multicollinearity in the regression analysis.

Overall, 94.7% of all seniors in this study felt that their income was sufficient for their needs, indicating little variation in the ability to purchase foods or pay for housing, for example. No detailed information on actual income from work, pensions and savings was collected.

Physical activity was measured by the Physical Activity Scale for the Elderly (PASE),29 a 10-item instrument specifically designed and validated to assess physical activity levels in large samples of older adults over a 1-week period. Total PASE score is calculated by multiplying the average number of hours per day spent in different activities and a weight assigned for each item and summing these products.29 Higher PASE scores indicate higher activity levels.

Functional autonomy was assessed by the Functional Autonomy Measuring System (SMAF, Système de Mesure de l’Autonomie Fonctionnelle), a 29-item rating scale to record functional disabilities and the available material and social resources that could compensate for the disabilities.30 It assesses present and actual performance—rather than potential—in activities of daily living (7 items), mobility (6 items), communication (3 items), mental function (5 items) and instrumental activities of daily living (8 items). For each item, disability is rated on a scale ranging from independent to dependent on assistance. Scores range from 0 to 87, with higher scores indicating greater dependence.

Finally, stressful life events were measured through the question, ‘Have you recently suffered a stressful life event (e.g., personal illness/death of a loved one)?’ from the Elderly Nutrition Screening tool (ENS).31

Statistical analyses

Continuous variables are presented as means±s.d. Demographic differences according to the incidence of depression were assessed using Fisher’s exact test for categorical variables and independent t-tests for continuous variables.

Baseline dietary and total intakes of the B vitamins from multiple 24-h recalls were categorized into sex-specific tertiles based on their distribution, allowing a robust estimation of risk of depression across levels of intakes without a strong influence of extreme values, normality violations or potential collinearity with energy intake. Tertiles were then used in all logistic regression analyses, with first tertile as the reference group (odds ratio (OR) 1.00).

Scores in PASE and SMAF were not normally distributed. Preliminary analyses on transformed (logarithmic base 10) and untransformed scores produced comparable results, and, therefore, untransformed scores were used in all analyses.

The lowest tertile of intake was taken as the reference in multiple logistic regression models, yielding an estimated OR and 95% confidence interval (CI). We tested three models. The unadjusted model includes only the tertiles of absolute ('crude' or non-energy adjusted) intake. Adjusted model 1 includes the tertiles of intakes and controls for age, physical activity, physical functioning and stressful life event. Adjusted model 2 includes the same variables as in model 1 plus total energy intake in kilocalories and, hence, tests for tertiles of B-vitamin intake relative to energy consumption. Two-sided P-values <0.05 were considered as statistically significant. All statistical analyses were conducted using the SPSS software package for Windows version 19.0 (IBM SPSS Inc., Chicago, IL, USA).

Results

Compared with those included in the study at baseline, the 425 participants excluded from this analysis were more likely women (58.6 vs 50.5%, x2(1)=8.481, P=0.004), had greater proportions of reporting a stressful life event (48.8% vs 34.9%, x2(1)=26.065, P<0.001), had lower physical activity scores (PASE 88.8±48.2 vs 104.1±52.2, t(1779)=−5.307, P <0.001), lower functional autonomy (SMAF scores 4.7±4.2 vs 3.8±3.3, t(585.974)=3.883, P<0.001) and lower energy intake (1765±495 vs 1865±510 kcal, t(1776)=−3.498, P <0.001).

Incidence of depression

There were 170 (12.5%) new cases of depression (GDS 11 and/or started antidepressant use) during the 3 years of follow-up (63% women). Among these 170 people deemed depressed, 36 (20 women, 16 men) were identified on the basis of antidepressant medication use alone.

Baseline characteristics

Table 1 shows the baseline characteristics for depressed and non-depressed men and women at follow-up visits. Men who developed depression were older, less physically active, had lower physical functioning and lower energy intake compared with those who did not develop depression. Women who became depressed had lower physical functioning and lower energy intake. Depressed men and women were more likely to have reported a stressful life event at baseline.

Table 1 Baseline characteristics of men and women according to the incidence of depression over a 3-year follow-upa

We cannot assess intake adequacy as within-person variability was not accounted for, but median B-vitamin intake from food, except folate in depressed women, was above the estimated average requirements32 for the sex and age group (Figure 1).

Figure 1
figure1

Box plot with the distribution of B6 (a), B12 (b) and folate (c) intakes from diet according to sex and depression incidence (as per GDS scores 11 and/or antidepressant use). The horizontal line indicates the estimated average requirements (EARs) for men and women aged 51 years (refer to the text in the discussion section for the specific EARs) and is for informative purposes only, as intakes are mean from three non-consecutive 24-h recalls and does not account for within-person variability. Legend: circles indicate outliers farther than 1.5 interquartile and closer than 3 interquartile ranges; triangles indicate outliers farther than 3 interquartile ranges.

Associations between B vitamins and depression incidence

Table 2 shows the results of the multivariate logistic regression models for the association between tertiles of dietary vitamin B6, B12 and folate intakes and depression incidence in men and women. Models with tertiles of total intakes (that is, from food+supplement) for each of the B vitamins yielded no significant associations (data available as Supplementary Information).

Table 2 Associations between B6, B12 and folate intakes from food at baseline and incidence of depression over 3 years of follow-upa

When controlling for age, physical activity, physical functioning and stressful life events, women in the highest tertile of intake of dietary B6 (1.71 mg/day) were 43 percent less likely to develop depression in the 3 years of follow-up (multivariate OR 0.57, 95% CI 0.39–0.96) compared with women in the lowest tertile (1.33 mg/day). This protective association was no longer significant after controlling for total energy intake (multivariate OR 0.70, 95% CI 0.37–1.30). In men, there was no association of B6 intake and depression (Table 2).

Men in the highest tertile of dietary B12 intake (4.79 μg/day) were 58% less likely to become depressed in comparison with men in the lowest tertile (3.16 μg/day) after controlling for all confounding factors, including energy intake (multivariate OR 0.42, 95% CI 0.20–0.90). B12 intakes were not associated with incidence of depression in women.

In unadjusted models, depression risk was lower among women in the highest tertile of dietary folate (390 μg/day as dietary folate equivalent) (unadjusted OR 0.60, 95% CI 0.36–0.99), but the effect was no longer significant once controlled for confounders. No association was observed between folate and depression in men.

Discussion

This study on the association of B6, B12 and folate intakes and the 3-year depression incidence in a large cohort of healthy older Canadians indicates a lower incidence of depression among older women with higher intakes of B6 from food and among men with higher energy-adjusted intakes of B12 from food, when compared with peers at lower rankings of intakes. Total intakes (food+supplement) had no detectable benefits, possibly due to the very low proportion of supplement use, increasing the variability in overall intakes.

To date, most studies with community-dwelling seniors have used a cross-sectional design and blood levels to investigate these vitamins.8, 11, 13, 14, 33,34,35,36 Randomized, placebo-controlled trials among older adults found no significant effect of B-vitamin supplements on participants' affective health.18, 19, 20, 21, 22 Our longitudinal observation of the relationship between B-vitamin supplements and depression corroborates these findings. In contrast, findings from the longitudinal CHAP17 showed a significant decrease in depressive symptoms with higher energy-adjusted intakes of total B12 and B6 (food+supplements) but not from food alone.

Researchers hypothesized that stronger associations between depression risk and nutrients are seen when there is lower adequacy or status, in this case B6, B12 or folate.6, 7, 10, 34, 37, 38, 39 A threshold, as proposed by Sanchez-Villegas et al.,10 is plausible, 'Once a minimal level is attained, further increases in intake do not lead to further reduction in depression risk.' It is noteworthy that most of the studies that found depression to be associated with low folate levels (blood or intakes) were conducted in countries where folate fortification was not mandatory, at least at the time of the study, for example, Finland,6, 39 France,7 Greece,11 Japan,37, 40 Norway,33 Singapore,41 Spain10, 42 and Australia before 2009.9, 43 Mandatory fortification of flour with folic acid in Canada may have attenuated the effect of folate, which corroborates the aforementioned hypothesis that lower vitamin status may be more strongly associated with depression compared with higher vitamin status because of mandatory fortification. In unadjusted models, we observed a protective effect of folate from food among women but not with supplementation.

Despite B vitamins having a role in the one-carbon metabolism, each vitamin appears to have different underlying mechanisms15 and a distinct effect on outcomes. In our study, the effect of B6 in women is dependent on total energy intake. We postulate that B6 intake can be a marker of other health or lifestyle behaviors associated with better mental and affective health. Dietary sources of B6 include fortified, ready-to-eat cereals, fish, meat, poultry, yeast, certain seeds, bran, white potato and other starchy vegetables and non-citrus fruits,32 which make up a varied diet. In another study from our group, a 'varied diet' pattern (determined by the principal component analysis on participants’ diet), which was characterized by the consumption of many of these B6 sources, was not found to be a protective factor against depression when controlling for health and social confounders, but higher total energy intake was clearly associated with less depression.44

The protective effect of higher intakes of B12 from food in men was independent of energy intake and other confounding factors. As the main sources of that vitamin are foods of animal origin,32 we postulate that B12 may have a direct effect on the risk of depression or it may be a proxy for social eating behaviors. Biologically, decreased or deficient B12 status have been reported among depressed seniors (for example, Ng et al.13 and Robinson et al.4); hence, better B12 status may result in those with greater intakes compared with peers with lower intakes, directly affecting the function of the nervous system.2 Socially, an increased consumption of food items source of vitamin B12 (items of animal origin) could reflect better socioeconomic status, social networks and available food systems,45 which, in turn, are associated with decreased risk of depression.46 In the 10-year National Health and Nutrition Examination Follow-Up Study, Wolfe et al.47 assessed dietary protein and protein-rich food in relation to severely depressed mood among 1947 men and 2909 women aged 25–74 years. The weighted prevalence of severely depressed mood significantly declined with increased protein and protein-rich food consumption among men, whereas prevalence increased among women.47 Although measures of social activity were not associated with depression in the NuAge cohort in the preliminary analysis, the reduced OR for higher intakes of B12 in men in a fully adjusted model coupled with the lack of association among women deserves further attention to determine whether a true diet effect exists or whether it reflects social engagement.

It is interesting to note that the participants in our study may have generally good intakes of B vitamins. The estimated average requirements for those aged >51 years are 1.3 mg/day of B6 for females and 1.4 mg/day for males, 2.0 mcg/day of B12 for both sexes and 320 mcg/day of dietary folate equivalent for both sexes,32 and these values fell within the lowest tertiles of dietary intake. This raises the concern of lack of power, particularly in studies where the protective effect is fairly small.8 The detectable alternatives for women with power of 0.8 are 0.07 mg/1000kcal for dietary B6, 1.15 mcg/1000 kcal for dietary B12 and 17.11 dietary folate equivalent mcg/1000 kcal for dietary folate. These values were similar for men as well. A difference smaller than these values are unlikely to be clinically relevant.

Strengths to this study include its longitudinal design with rigorous dietary assessment not commonly seen in such large studies in the older population, particularly the use of multiple 24-h recalls. Confounding factors were also controlled for, allowing for a complex exploration of the research question. Some intrinsic limitations related to the design of the study include residual confounding, particularly related to measurement tools used, and the inability to draw causality because of its observational nature. As a result of the use of a screening tool to assess depression, the incidence rate does not reflect clinically diagnosed depression in this population. No dietary biomarker was used; therefore, participants’ nutritional status could not be ascertained. Finally, these findings may not be applicable to the general older population, as seniors included in the study are generally healthy and tended to differ in several important demographic and health characteristics compared with those not included.

Conclusion

This 4-year longitudinal study on B-vitamin intake and depression risk among generally healthy community-dwelling older adults provides some evidence of decreased depression risk among women with higher intake of vitamin B6 from food, which was dependent on total energy intake, and among men with higher intake of B12, independent of energy intake. Although maintaining an adequate consumption in quantity and quality of food sources of these vitamins may have a role in protecting generally healthy older adults from becoming depressed, these associations warrant further investigation in older people whose diets are more compromised.

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Acknowledgements

We thank the men and women of the NuAge cohort for their generous participation in the study and the research personnel for their highly professional and devoted work. The NuAge study was supported by the Canadian Institute of Health Research (CIHR), grant no. MOP-62842, the Fonds de la Recherche en Santé du Québec (FRSQ) and the Québec Network for Research on Aging.

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Correspondence to L Gougeon.

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This work was presented in part, as a poster, at the 42nd Canadian Association on Gerontology’s Annual Meeting, 17–19 October 2013, Halifax, NS, Canada.

Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website

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Gougeon, L., Payette, H., Morais, J. et al. Intakes of folate, vitamin B6 and B12 and risk of depression in community-dwelling older adults: the Quebec Longitudinal Study on Nutrition and Aging. Eur J Clin Nutr 70, 380–385 (2016). https://doi.org/10.1038/ejcn.2015.202

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