Abstract
We evaluated the association between vegetable and fruit consumption – particularly flavonoid-rich fruits – in mid-life and major depressive disorder (MDD) in later life. We also evaluated the association of nutrients in fruits and vegetables with MDD. Vegetable and fruit consumption and nutrient intake for 1204 individuals were averaged from data obtained in 1995 and 2000. MDD was diagnosed by certified psychiatrists in 2014–2015. Logistic regression was used to examine the odds of MDD according to quintile of vegetable and fruit consumption and quartile of nutrient intake. We fitted two regression models, using hierarchical adjustment for age, sex, employment status, alcohol consumption, current smoking, and physical activity. Bias-corrected and accelerated bootstrap confidence intervals were used to obtain accurate information. In fully adjusted models, the highest quintile of total fruit consumption excluding juice and flavonoid-rich fruit consumption showed decreased odds of MDD compared with the lowest quintile (OR = 0.34, 95% CI = 0.15–0.77; OR = 0.44, 95% CI = 0.20–0.97, respectively). No significant association was found for total vegetables and fruits, total vegetables, or total fruits. No significant association was found for any nutrient. This study provides novel information on the association between MDD and flavonoid-rich fruits.
Similar content being viewed by others
Introduction
Mental illness is a significant cause of disability and a major component of the global burden of disease [1, 2]. Mental illness has the longest years lived with disability (YLDs) and the same level of disability-adjusted life-years (DALYs) as cardiovascular and circulatory diseases [3]. Among mental illnesses, depression accounts for the largest portion of the burden in YLDs and DALYs [3]. The prevalence of major depressive disorder (MDD) reportedly ranges from 6.0% in low-income countries to 7.1% in high-income countries [4]. The estimated cost of depression and anxiety to the global economy is US$ 1 trillion per year in lost productivity [5]. Thus, the prevention of depression is crucial to reducing the overall burden of disease [6].
Prospective cohort studies have suggested that vegetables and fruits have a preventive effect on depression [7,8,9,10]. A meta-analysis showed an inverse association between vegetable and fruit consumption and the risk of depression [11]. This finding was subsequently validated in a newer meta-analysis [12]. The mechanisms underlying this antidepressive effect might be explained by Vitamin C, Vitamin E, or carotenoids that reduce oxidative stress [13,14,15,16,17]. Of note, however, little effort has been made to examine such effects in cohort studies, particularly using data from Asian participants.
Flavonoids are polyphenolic compounds present in fruits that may have a preventive effect against depression. Suggested mechanisms of this effect include an increase in brain-derived neurotrophic factor levels [18, 19], suppression of oxidative stress [13, 20], and neuroinflammation [21,22,23]. A recent meta-analysis demonstrated antidepressive effects of flavonoids [24]. Moreover, food-based analyses reported that the consumption of apples, pears, and citruses, which are rich in flavonoids, was associated with lower depression risk [25]. To date, however, little information has appeared on the antidepressive effects of overall flavonoid-rich fruits using population-based data from men and women.
Here, to evaluate the association between flavonoid-rich fruits and MDD, we analyzed data from 1204 participants of the Japan Public Health Center-based Prospective Study. We hypothesized that flavonoid-rich fruit consumption would be inversely associated with a diagnosis of MDD. Further, we also studied vegetables, other fruits, and nutrients contained in fruits and vegetables to determine mechanisms potentially involved in this preventive effect.
Methods
Study population
We used data for participants from one region of the Japan Public Health Center-based prospective study (JPHC study) [26]. Among 12219 individuals aged 40–59 years as of 1990 in the Saku Public Health Center catchment area, 8827 were invited to a mental health screening in 2014–2015 after the exclusion of 3392 who moved out, died, or did not respond to questionnaires. Of the 1299 individuals who completed the screening, 1204 (704 women and 500 men) had data from food frequency questionnaires conducted in 1995 and 2000 and were included in the final sample (Fig. 1). All participants provided written informed consent. The present study was approved by the Institutional Review Board of the National Cancer Center and the National Center of Neurology and Psychiatry.
Diagnosis of major depressive disorder (outcome)
In 2014–2015, certified psychiatrists interviewed the participants and diagnosed MDD using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition [27], with reference to the Japanese version of the Patient Health Questionnaire-9 [28] and the Center for Epidemiological Scale-Depression [29]. Participants with both depressive and dementia symptoms were not diagnosed with MDD if the temporal order of events was not ascertainable.
Vegetable and fruit consumption (exposure)
In 1995 and 2000, vegetable and fruit consumption was evaluated using a validated food frequency questionnaire [30, 31]. We used these data to calculate average vegetable and fruit consumption [32]. Participants reported the frequency and relative portion size of vegetables and fruits consumed in the preceding 12 months. The questionnaire included 29 vegetables (cabbage, Chinese radishes, komatsuna, broccoli, Chinese cabbage, leaf mustard, [Swiss] chard, spinach, Chinese chives, garland chrysanthemums, chingensai, mugwort, green pepper, carrots, tomatoes, pumpkins, tomato juice, onions, cucumbers, bean sprouts, snap beans, lettuce, bitter gourds, and loofah; and the following pickled vegetables: Chinese radishes, green leaf [Nozawana or leaf mustard], Chinese cabbage, cucumbers, and eggplant) and 17 fruits (papaya, apples, persimmons, strawberries, grapes, melons, watermelon, peaches, pears, kiwi fruit, pineapple, bananas, oranges, other citruses, pickled plums, 100% apple juice, and 100% orange juice). Flavonoid-rich fruits were defined as fruits containing a total flavonoid content of 50 mg/100 g [33]. We categorized each item into the following food groups: total vegetables and fruits, total vegetables, total fruits (including juice), total fruits excluding juice, and flavonoid-rich fruits (apples, pears, oranges, other citruses, grapes, and strawberries). Vegetable and fruit consumption was calculated by multiplying the frequency by the relative portion size. The food frequency questionnaire was previously shown to have acceptable validity and reproducibility [30, 31]. Spearman’s rank correlations between the food frequency questionnaire and independently evaluated dietary records were 0.22 in men and 0.32 in women for vegetable consumption and 0.41 in men and 0.23 in women for fruit consumption [31].
Nutrient intakes (exposure)
Nutrient intakes obtained from vegetables and fruits were evaluated using the Fifth Revised and Enlarged Edition of the Standard Tables of Food Composition in Japan [34], again with averaging of data from 1995 and 2000. We included α-carotene, β-carotene, Vitamin C, Vitamin E, and folate. These measurements of nutrient intake were shown to have acceptable validity [35].
Sociodemographic factors
We evaluated sociodemographic factors in 1995 that may be potential confounders. We included the following variables: age (continuous), sex (male or female), employment status (employed or unemployed), alcohol consumption (none, sometimes but not daily, or daily), current smoking (yes or no), and physical activity (none, sometimes but not weekly, or weekly).
Statistical analysis
Statistical analyses were conducted using Stata 15 (Stata Corp LP; College Station, Texas). Multivariable logistic regression was used to examine the odds of MDD (outcome) according to quintiles of consumption of each food group (exposure) [36] and quartiles of nutrient intake (exposure) [37]. For flavonoid-rich fruits, we also studied individual fruit consumption. Grape and strawberry consumption was relatively low and was thus categorized into quartiles [36]. All vegetable and fruit consumption values were energy-adjusted to avoid confounding by total energy intake [38]. We fitted two regression models, an age- and sex-adjusted model and a fully adjusted model. We performed hierarchical adjustments for age, sex, employment status, alcohol consumption, current smoking, and physical activity. We evaluated linear trends by treating quantiles of vegetable and fruit consumption and nutrient intakes as a continuous variable. Further, we also evaluated odds ratios (ORs) of MDD per 10-g increase in the consumption of each group and flavonoid-rich fruit. We used bias-corrected and accelerated bootstrap confidence intervals (CIs) to obtain accurate information [39,40,41]. The size of the bootstrap sample was set at 1000 with 95% CIs [42].
Results
Table 1 summarizes the demographics of participants in 1995 according to the lowest and highest quintiles of total vegetable and fruit, total fruit, and flavonoid-rich fruit consumption. Overall, the highest quintile groups were older, more likely to be female, less likely to be employed, and had fewer alcohol drinkers and smokers compared with the lowest quintile groups. Physical activity did not appear to be substantially different.
Table 2 summarizes the odds of MDD by quintiles of vegetable and fruit consumption. In fully adjusted models, the highest quintile of total fruit consumption excluding juice and flavonoid-rich fruit consumption showed significantly decreased odds of MDD compared with the lowest quintile (OR = 0.34, 95% CI = 0.15–0.77; OR = 0.44, 95% CI = 0.20–0.97, respectively). Among flavonoid-rich fruits, strawberries showed significantly decreased odds of MDD in the highest quartile (OR = 0.37, 95% CI = 0.18–0.79, see Supplementary Table 1). No significant association was found for total vegetables and fruits, total vegetables, or total fruits. Odds of MDD per 10-g increase in consumption were significantly decreased for strawberries (OR = 0.76, 95% CI = 0.59–0.99) but not in any group, including the flavonoid-rich fruits group (Supplementary Table 2).
Table 3 summarizes the odds of MDD according to quartiles of nutrient intake. No significant association was found for any nutrient.
Discussion
As hypothesized, we found that consumption of flavonoid-rich fruits was inversely associated with a diagnosis of MDD. Similar findings were seen for the association of total fruit consumption excluding juice and MDD. These associations remained significant after adjusting for sociodemographic factors, including physical activity. These findings are consistent with past reports that fruit consumption had preventive effects on depression [7,8,9,10,11,12]. While a previous study showed that depression was inversely associated with the consumption of apples, pears, and citruses that contain flavonoids using data from older women, the present study is to our knowledge the first to demonstrate the antidepressive effect of overall flavonoid-rich fruits in a cohort that included both men and women.
We did not find antidepressive effects of vegetables, which is not consistent with previous studies [7,8,9,10,11,12]. The reason for this lack of association is unclear, but might reasonably be attributed to our study’s focus on MDD in later life, and longer follow-up period than previous studies [7,8,9,10]. Further, the data did not allow us to adjust for some potential confounders, e.g., psychosocial factors, that may confound the relationship between total vegetable consumption and MDD. Adjustments for other potential confounders are warranted.
While this study verified our hypothesis of an association between MDD and flavonoid-rich fruit consumption, an antidepressive effect was also found for total fruit consumption excluding juice. Considered together, the antidepressive effect might be attributed not to flavonoid-specific mechanisms [19] but rather to mechanisms involving fruit as a whole, e.g., reducing oxidative stress [13,14,15,16,17]. In contrast, total fruit consumption including juice produced non-significant results. Fruit juice is reported to have a lower antioxidant density than raw fruits [43], and may also have a higher glycemic index than raw fruits [44], which is suggested to be a risk factor for depression [8]. These mechanisms may partly explain the null findings when we included juice in the analyses. Indeed, a previous study showed that processed juice consumption was associated with an increased risk of depression [45]. Regarding nutrients, we did not find either protective or detrimental effects on MDD. However, this might have been caused by a lack of power to detect significant associations, considering that the highest quartile of the intakes of all nutrients showed decreased odds, albeit without significance. This lack of significance in nutrients in the present study warrants further exploration using a larger sample.
Limitations
Some characteristics of the present study warrant cautious consideration. First, as mentioned above, we may not have adjusted for some potential confounders. Individuals with higher fruit consumption may have a healthier lifestyle. In the present study, such individuals may have positive factors other than dietary habits, e.g., psychosocial factors, which confounded the association between MDD and fruit consumption. Second, we did not have information on a diagnosis of MDD at baseline. On the other hand, we had information on a history of depression evaluated at mental health screening. To reduce the effect of reverse causation, we re-conducted the analysis with the exclusion of participants with a history of depression at mental health screening and found that the results were not changed (data not shown). Also, we used data for energy-adjusted fruit consumption to minimize the influence of appetite loss due to MDD at baseline. Nevertheless, the findings might have been affected by MDD at baseline. Third, although this is a population-based study, the sample comprised individuals aged 40–59 years at baseline, and the results might not be generalizable to populations with different characteristics. In the present study, we accounted for depression caused by dementia. Nevertheless, a sample comprising younger individuals may show a different association. Fourth, the sample size may not have provided sufficient power to detect the antidepressive effect of nutrients, e.g., Vitamin C. Similarly, the number of cases was limited, which restricted us to include only a limited number of covariates in the logistic models [46]. Finally, while our purpose was to evaluate the long-term effect of vegetable and fruit consumption on depression, some factors during the long-term follow-up might have affected the results. The long-term follow-up may have led to nonresponse of participants, causing selection bias. Further, although we used five-year average data, vegetable and fruit consumption might have been time-varying during the follow-up period, and our traditional models might have yielded biased estimates.
Conclusions
The present study provides novel information on the association between MDD and flavonoid-rich fruit consumption, adjusted for sociodemographic confounders. Considered in the context of prior studies, these data further support the benefit of the consumption of fruit, including flavonoid-rich fruits. Future studies should employ a larger sample and adjustment for other potential confounders.
References
Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet Lond Engl 2012;380:2197–223.
Rehm J, Shield KD. Global burden of disease and the impact of mental and addictive disorders. Curr Psychiatry Rep. 2019;21:10.
Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry. 2016;3:171–8.
Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW, Patel V, et al. The global prevalence of common mental disorders: a systematic review and meta-analysis 1980-2013. Int J Epidemiol. 2014;43:476–93.
The Lancet Global Health null. Mental health matters. Lancet Glob Health 2020;8:e1352.
Reynolds CF, Cuijpers P, Patel V, Cohen A, Dias A, Chowdhary N, et al. Early intervention to reduce the global health and economic burden of major depression in older adults. Annu Rev Public Health. 2012;33:123–35.
Akbaraly TN, Sabia S, Shipley MJ, Batty GD, Kivimaki M. Adherence to healthy dietary guidelines and future depressive symptoms: evidence for sex differentials in the Whitehall II study. Am J Clin Nutr. 2013;97:419–27.
Gangwisch JE, Hale L, Garcia L, Malaspina D, Opler MG, Payne ME, et al. High glycemic index diet as a risk factor for depression: analyses from the Women’s Health Initiative. Am J Clin Nutr. 2015;102:454–63.
Mihrshahi S, Dobson AJ, Mishra GD. Fruit and vegetable consumption and prevalence and incidence of depressive symptoms in mid-age women: results from the Australian longitudinal study on women’s health. Eur J Clin Nutr. 2015;69:585–91.
Sánchez-Villegas A, Delgado-Rodríguez M, Alonso A, Schlatter J, Lahortiga F, Serra Majem L, et al. Fruit and vegetable consumption and the risk of depression: a meta-analysis. Arch Gen Psychiatry. 2009;66:1090–8.
Liu X, Yan Y, Li F, Zhang D. Fruit and vegetable consumption and the risk of depression: a meta-analysis. Nutrition. 2016;32:296–302.
Saghafian F, Malmir H, Saneei P, Milajerdi A, Larijani B, Esmaillzadeh A. Fruit and vegetable consumption and risk of depression: accumulative evidence from an updated systematic review and meta-analysis of epidemiological studies. Br J Nutr. 2018;119:1087–101.
Van Duyn MA, Pivonka E. Overview of the health benefits of fruit and vegetable consumption for the dietetics professional: selected literature. J Am Diet Assoc. 2000;100:1511–21.
Akbaraly TN, Brunner EJ, Ferrie JE, Marmot MG, Kivimaki M, Singh-Manoux A. Dietary pattern and depressive symptoms in middle age. Br J Psychiatry. 2009;195:408–13.
Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R. Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors. Redox Rep. 2003;8:365–70.
Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S. Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Hum Psychopharmacol. 2007;22:67–73.
Tapiero H, Townsend DM, Tew KD. The role of carotenoids in the prevention of human pathologies. Biomed Pharmacother Biomed Pharmacother 2004;58:100–10.
Yang T, Nie Z, Shu H, Kuang Y, Chen X, Cheng J, et al. The role of BDNF on neural plasticity in depression. Front Cell Neurosci. 2020;14:82.
Rendeiro C, Rhodes JS, Spencer JPE. The mechanisms of action of flavonoids in the brain: Direct versus indirect effects. Neurochem Int. 2015;89:126–39.
Hritcu L, Ionita R, Postu PA, Gupta GK, Turkez H, Lima TC, et al. Antidepressant flavonoids and their relationship with oxidative stress. Oxid Med Cell Longev. 2017;2017:5762172.
Lee C-H, Giuliani F. The role of inflammation in depression and fatigue. Front Immunol. 2019;10:1696.
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22–34.
Vafeiadou K, Vauzour D, Lee HY, Rodriguez-Mateos A, Williams RJ, Spencer JPE. The citrus flavanone naringenin inhibits inflammatory signalling in glial cells and protects against neuroinflammatory injury. Arch Biochem Biophys. 2009;484:100–9.
Jia S, Hou Y, Wang D, Zhao X. Flavonoids for depression and anxiety: a systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2022;1–11.
Chang S-C, Cassidy A, Willett WC, Rimm EB, O’Reilly EJ, Okereke OI. Dietary flavonoid intake and risk of incident depression in midlife and older women. Am J Clin Nutr. 2016;104:704–14.
Tsugane S, Sawada N. The JPHC study: design and some findings on the typical Japanese diet. Jpn J Clin Oncol. 2014;44:777–82.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edn. (1994).
Muramatsu K, Miyaoka H, Kamijima K, Muramatsu Y, Tanaka Y, Hosaka M, et al. Performance of the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) for depression in primary care. Gen Hosp Psychiatry. 2018;52:64–9.
Wada K, Tanaka K, Theriault G, Satoh T, Mimura M, Miyaoka H, et al. Validity of the Center for Epidemiologic Studies Depression Scale as a screening instrument of major depressive disorder among Japanese workers. Am J Ind Med. 2007;50:8–12.
Ishihara J, Sobue T, Yamamoto S, Yoshimi I, Sasaki S, Kobayashi M, et al. Validity and reproducibility of a self-administered food frequency questionnaire in the JPHC Study Cohort II: study design, participant profile and results in comparison with Cohort I. J Epidemiol. 2003;13:S134–47.
Sasaki S, Kobayashi M, Tsugane S, JPHC. Validity of a self-administered food frequency questionnaire used in the 5-year follow-up survey of the JPHC Study Cohort I: comparison with dietary records for food groups. J Epidemiol. 2003;13:S57–63.
Nozaki S, Sawada N, Matsuoka YJ, Shikimoto R, Mimura M, Tsugane S. Association between dietary fish and PUFA intake in midlife and dementia in later life: the JPHC Saku Mental Health Study. J Alzheimers Dis 2021;79:1091–104.
McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr. 2012;95:454–64.
The Council for Science and Technology. Standard Tables Of Food Composition in Japan, 5th Revised And Enlarged Edn. (National Printing Bureau, 2005).
Ishihara J, Inoue M, Kobayashi M, Tanaka S, Yamamoto S, Iso H, et al. Impact of the revision of a nutrient database on the validity of a self-administered food frequency questionnaire (FFQ). J Epidemiol. 2006;16:107–16.
Yang Y, Dong J-Y, Cui R, Muraki I, Yamagishi K, Sawada N, et al. Consumption of flavonoid-rich fruits and risk of CHD: a prospective cohort study. Br J Nutr. 2020;124:952–9.
Makiuchi T, Sobue T, Kitamura T, Ishihara J, Sawada N, Iwasaki M, et al. The relationship between vegetable/fruit consumption and gallbladder/bile duct cancer: a population-based cohort study in Japan. Int J Cancer. 2017;140:1009–19.
Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 1997;65:1220S–8S.
Cumming G. The new statistics: why and how. Psychol Sci. 2014;25:7–29.
Felsenstein J. Confidence limits on phylogenies: an approach using the bootstrap. Evol Int J Org Evol. 1985;39:783–91.
Lumley T, Diehr P, Emerson S, Chen L. The importance of the normality assumption in large public health data sets. Annu Rev Public Health. 2002;23:151–69.
Carpenter J, Bithell J. Bootstrap confidence intervals: when, which, what? A practical guide for medical statisticians. Stat Med. 2000;19:1141–64.
Crowe KM, Murray E. Deconstructing a fruit serving: comparing the antioxidant density of select whole fruit and 100% fruit juices. J Acad Nutr Diet. 2013;113:1354–8.
Atkinson FS, Foster-Powell K, Brand-Miller JC. International tables of glycemic index and glycemic load values: 2008. Diabetes Care. 2008;31:2281–3.
Meller F, de O, Manosso LM, Schäfer AA. The influence of diet quality on depression among adults and elderly: a population-based study. J Affect Disord. 2021;282:1076–81.
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996;49:1373–9.
Acknowledgements
This study was conducted under the framework of the Collaborative Cohort Research Network Project to the Six National Centers for Advanced and Specialized Medical Care.
Funding
This study was supported by a Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (22K14858), MAFF Comissioned project study (JPJ009842), the National Cancer Center Research and Development Fund (since 2011), and a Grant-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010).
Author information
Authors and Affiliations
Contributions
Initial research questions were devised by ZN. Analyses were conducted by ZN. The manuscript was written by ZN and finalized by NS with substantial text contributions from all authors.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Ethics approval
The present study was approved by the Institutional Review Board of the National Cancer Center and the National Center of Neurology and Psychiatry.
Informed consent
All participants provided written informed consent.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Narita, Z., Nozaki, S., Shikimoto, R. et al. Association between vegetable, fruit, and flavonoid-rich fruit consumption in midlife and major depressive disorder in later life: the JPHC Saku Mental Health Study. Transl Psychiatry 12, 412 (2022). https://doi.org/10.1038/s41398-022-02166-8
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41398-022-02166-8