1. Introduction
Depression is one of the major causes of disability worldwide and an important contributor to the global burden of disease [
1]. It has been estimated that direct medical costs of managing depression in Europe account for approximately 38 billion Euros [
2]. Moreover, leading causes of global age-specific years lived with disability in 2015 showed that, beside para-physiological conditions such as back and neck pain and sense organ diseases, depression had the highest rate of change (making it the third-leading cause of disability worldwide) from 1990 among adults older than 25 years [
1]. Therefore, identification of modifiable risk factors and development of preventive strategies are needed in order to decrease the overall burden of the disease.
From a patho-physiological point of view, depressive disorders have been associated with a subclinical inflammatory status characterized by an increase in pro-inflammatory cytokines and neuronal damage (i.e., loss of plasticity) [
3]. An intriguing hypothesis proposed over the last years suggests that dietary factors might influence the risk of depression due to various mechanisms, including: (i) antioxidant intake, (ii) increase in homocysteine concentrations and reduced availability of
S-adenosylmethionine through folate intake, (iii) long-chain omega-3 polyunsaturated fatty acids intake, (iv) influence on monoamine concentrations [
4]. There is evidence that diet quality might influence occurrence of depression [
5]: dietary patterns characterized by high content of fruit, vegetables, whole grain, fish, olive oil, low-fat dairy and antioxidants and low content of animal foods have been associated with a decreased risk of depression [
6]. The recent epidemiological evidence indicates that dietary intake of some plant-based foods and beverages, such as coffee, tea, fruit and vegetable, may be associated with lower likelihood of having depression [
7,
8]. The common characteristic of the aforementioned food groups is their natural richness in polyphenols, a wide range of compounds with antioxidant and anti-inflammatory properties. Dietary polyphenols have been associated with a number of health outcomes, including decreased risk of mortality, cardiovascular diseases, and several types of cancer [
9,
10,
11,
12]. Furthermore, the dietary intake of various classes of polyphenols has been associated with higher adherence to healthy dietary patterns [
13], including the Mediterranean diet [
14]. Interestingly, several studies conducted in a Mediterranean area showed the association between higher adherence to the Mediterranean pattern with an overall better metabolic health (including dyslipidemia [
15], obesity [
16,
17,
18,
19,
20] and hypertension [
21,
22,
23]), mental-wellness [
24], and importantly, psychological resilience [
25] and depressive symptoms [
26].
The evidence from in vitro and in vivo studies suggests that different dietary polyphenols, such as flavonoids, phenolic acids, lignans, and others, may play a role in brain health, with special regard to depression-linked aspects [
27]. Dietary polyphenols have been shown to exert numerous mechanisms that may be involved in depression pathophysiology, including exerting anti-neuroinflammatory properties, suppressing neuronal apoptosis and stimulating adult neurogenesis [
28].
Nevertheless, despite promising, the evidence from epidemiological studies is limited. Up to date, solely one investigation on dietary flavonoid intake and risk of depressive symptoms has been conducted [
29], while no evidence on other polyphenol classes or individual compounds have been reported. Therefore, the aim of this study was to assess the association between estimated habitual dietary intakes of total polyphenols, their classes, subclasses and individual compounds and depressive symptoms among the participants of the Mediterranean healthy Eating, Lifestyle and Aging (MEAL) study.
2. Results
The sample comprised 1572 individuals of mean age of 46.6 years (range 18–92 years). A sensitivity analysis comparing total polyphenol intake between individuals included in the analyses due to availability of the CES-D-10 score and excluded ones revealed no significant differences (629.0 mg/d vs. 671.7 mg/d respectively,
p = 0.227). Baseline characteristics of the sample are presented in
Table 1.
Participants with higher total polyphenol intakes had moderate levels of physical activity, and were moderate or regular alcohol drinkers (
Table 1). The individuals in the highest quartile of total polyphenol intake had lower prevalence of hypertension, as well as higher total calorie intake compared to those in the lowest category (
Table 1). A higher prevalence of diabetic was found among individuals in the intermediary quartiles of polyphenol intake compared to the extreme ones (
Table 1). No other relations with background and lifestyle characteristics were found. Additionally, baseline characteristics of study participants by presence of depressive symptoms are presented in
Table S1.
Among the main classes of polyphenols, phenolic acids were the most consumed, despite the widest range of intake (
Table S2). Flavanols (including catechins) and isoflavones contributed the most and the least to total flavonoid intake, respectively. Among individual compounds, hesperetin was the most consumed. Regarding major food sources of polyphenols, not all food groups followed a linear trend over total polyphenol intake: indeed, the highest intake of coffee and olive oil occurred in the third quartile of total polyphenol intake, while mean intake of the other food groups followed a linear trend over total polyphenol intake quartiles (
Table S2).
A total of 509 (32.4%) cases of depressive symptoms were found in the cohort. No association was found between total polyphenol intake and depressive symptoms (
Table 2).
After adjusting for potential confounding factors, none of the polyphenol classes showed linear association with depressive symptoms, despite individuals in the fourth quartile of phenolic acid (OR = 0.64, 95% CI: 0.44, 0.93), and individuals in the third quartile of flavonoid intake (OR = 0.49, 95% CI: 0.32, 0.75), were less likely to have depressive symptoms than those in the lowest category of exposure (
Table 2). Among subclasses of flavonoids, a significant contribution to the association of the overall class was provided by anthocyanins (Q4 vs. Q1, OR = 0.61, 95% CI: 0.42, 0.89;
p for trend = 0.001), flavanones (Q4 vs. Q1, OR = 0.54, 95% CI: 0.32, 0.91;
p for trend <0.001) and, in a non-linear manner, flavonols intake (Q3 vs. Q1, OR = 0.51, 95% CI: 0.34, 0.77;
p for trend = 0.034) (
Table 3). Among phenolic acids, hydroxycinnamic acids intake was associated with lower odds of having depressive symptoms, despite not in a linear manner (Q3 vs. Q1, OR = 0.65, 95% CI: 0.44, 0.97;
p for trend = 0.007) (
Table 3).
When taking into consideration individual compounds, inverse association was observed for quercetin (OR = 0.53, 95% CI: 0.32, 0.86) and naringenin (OR = 0.51, 95% CI: 0.30, 0.85), for the highest versus lowest quartile of intake. Naringenin was associated with depressive symptoms in a dose-response fashion (
Table 4). In contrast, certain compounds, such as hesperetin (OR = 0.67, 95% CI: 0.45, 0.99), kaempferol (OR = 0.63, 95% CI: 0.41, 0.97), matairesinol (OR = 0.32, 95% CI: 0.21, 0.49) and lariciresinol (OR = 0.51, 95% CI: 0.34, 0.76) showed a significant association with depressive symptoms in the third quartile of exposure.
Regarding major food sources of polyphenols, none of the food groups examined showed a significant association with depression, with exception of red wine and citrus fruits; individuals in the highest quantile of intake had lower likelihood of depression than those in the lowest category of exposure (
Table 5).
3. Discussion
The present study investigated the association between estimated habitual dietary polyphenol intakes and depressive symptoms in a cohort of adults living in the Mediterranean area. Based on multivariate logistic regression analyses, total polyphenol intake was not associated with depressive symptoms. However, several significant associations have been observed for certain polyphenol classes, specifically for high total flavonoid and phenolic acids intake. Among flavonoid class, flavanones and anthocyanin were inversely associated with depressive symptoms, in a dose-response manner. When taking into consideration individual compounds, an inverse association was observed for naringenin and quercetin, for the highest versus lowest quartile of intake. To the best of our knowledge, this is the first study investigating such a broad range of polyphenol classes, subclasses and individual compounds, together with major food sources of polyphenols in order to identify key dietary components possibly implicated in prevention of depressive disorders.
In this study, we found a relatively high prevalence of depressive symptoms (about one third of the sample). It is noteworthy that the tool used to investigate depressive status is able to capture symptoms of depression but should not be considered as equal as diagnosis of depression (which should be performed in the clinical setting). In fact, compared with other studies using this tool, we reported similar prevalence rates [
30]. The only epidemiological study on dietary polyphenols and depressive symptoms was focused on flavonoid consumption. The study, conducted on the Nurses’ Health Study and Nurses’ Health Study II cohorts, showed a significant decreased risk of depressive symptoms among women in the highest quintile of flavonol, flavone, and flavanone intake. These findings are partially in line with those related to flavonoid intake found in the present study, including, but not limited to, the association between flavonol consumption and lower likelihood of having depressive symptoms. Evidence from intervention studies showed, in general, significant results in improving mood or ameliorating symptoms of depression. Results from the present study are in line with intervention trials showing potential effects of cocoa- [
31], berry- [
32], citrus- [
33], legume- and wine- [
34], and tea-polyphenols [
35] against depressive symptoms. The results from the meta-analysis on the association between dietary components and depression suggest that polyphenol-rich foods may play an important role in preventing depression [
7,
8]. In this study, we did not find association of individual food groups rich in polyphenols (such as fruit and vegetable) and depressive symptoms, suggesting that the potential beneficial effects are not driven by an individual dietary component but rather its content in specific phenolic compounds. Nonetheless, citrus fruits and red wine consumption was significantly associated with depressive symptoms. Interestingly, the report from NHS and NHSII demonstrated that compared with citrus intake of less than one serving/week, intakes of more than two servings/d were associated with an 18% reduction in depression risk. Moreover, results from other cohorts of adults living in the Mediterranean area showed that moderate alcohol consumption, mainly represented by wine, was associated with lower risk of depression [
36,
37]. Despite these results must be considered with caution due to the potential detrimental effects of excessive alcohol consumption, further investigations involving wine-polyphenols (i.e., stilbenes and anthocyanins) can be considered in relation to symptoms of depression. Nonetheless, the present study did not found any other association between food groups and depressive symptoms, suggesting that either minimum intake of polyphenols to observe a significant effect is hardly reachable from one unique food source in a normal diet or that a certain degree of synergy between various polyphenol classes and compounds might be needed. Previous reports from this cohort showed that higher intake of flavonoids [
23], phenolic acids [
38] and phytoestrogens [
39] may exert beneficial effects toward health. In contrast, certain compounds (such as lignans, flavonols, and hydroxycinnamic acids) showed null association with depressive symptoms at high intake, while a significant association was found in the third group of exposures. It has been previously suggested that a potentially non-linear association between flavonoid intake and health outcomes may exist [
10], despite it is still not clear whether the lack of positive effect depends on flavonoid itself (i.e., high intake of flavonoid may be detrimental through stimulation of pro-oxidant processes) or due to other factors associated with their intake (i.e., high intake of flavonoid may be associated with excess calorie intake or alcohol consumption). This matter is still object of observation and further studies are needed to clarify such issue.
From a mechanistic point of view, growing evidence supports a potential beneficial effect of polyphenols on mood and brain health [
40]. It has been suggested that dietary polyphenols may be involved in depression pathophysiology through direct and indirect mechanisms. Direct mechanisms may include suppression of neuronal apoptosis, modulation of signalling pathways implicated in neuron survival, and stimulation of adult neurogenesis [
28]. On the other hand, indirect mechanisms may comprise anti-neuroinflammatory properties and reduction of oxidative stress through improved blood flow [
28]. Despite the increasing amount of evidence for the bioavailability of polyphenols in the systemic circulation [
41], limited information is available regarding their ability to reach the central nervous system (CNS). Studies using in vitro models, demonstrated that polyphenols permeation through the blood-brain barrier (BBB) depends on the degree of lipophilicity of the compound, with less polar polyphenols or metabolites capable of greater brain uptake than the more polar ones [
42]. For example, naringenin was found in brain tissue after intravenous administration [
43], while anthocyanins after oral administration [
44,
45]. Finally, the data suggest that the concentration of polyphenols in brain tissue may reach approximately 1 nmol/g tissue [
46], in different brain regions, and generally in non-specific manner [
44,
45]. Another intriguing indirect mechanism has been suggested to be the influence of polyphenols on gut microbiota. Indeed, there is evidence that the gut microbiota may affect brain and behaviors of relevance to anxiety and that its manipulation may influence depression-like behaviors [
47]. The mechanisms rely on the modification of bacterial ratios through difference polyphenol classes intake determining pro and anti-inflammatory balance in the gut, which in turn may have an impact at systemic level. The literature from this field is just emerging and there is a need for a critical mass of high-quality research to investigate the potential association between polyphenol intake, gut microbiota and mental health.
With a special regard to the individual subclasses of polyphenols demonstrated to be associated with depressive symptoms in the present study, current scientific evidence from animal models suggest the potential involvement of anthocyanins in inhibiting monoamine oxidases (MAOs), mitochondrial enzymes that catalyse the oxidation of monoamines, which elevated activity has been associated with depression [
48]. Hydroxycinnamic acids were shown to modulate the parameters of neuro-inflammation [
49]. Moreover flavanones (i.e., hesperetin) were shown to exert antidepressant-like activity dependent on interaction with the serotoninergic and kappa opioidergic receptors [
50]. Nevertheless, there are some questionable issues to be addressed. For instance, polyphenol absorption, metabolism, and disposition in tissues and cells highly depends on the chemical structure of the compounds, with a wide range of variability between and within classes [
41]. Moreover, in order to exert the aforementioned effects in human brain, polyphenols must cross the BBB at pharmacologically effective concentrations [
51].
The present study has the strength to investigate the association between a wide range of polyphenol classes, subclasses and individual compounds, polyphenol-rich foods and depressive symptoms for the first time. However, some limitations should be pointed out before considering the results. First, the cross-sectional nature of the study does not allow defining causal relation; despite we may hypothesize that dietary habits are relatively stable among the individuals recruited for the study, we cannot rule out the possibility of reverse causation. Second, a common limitation of studies in nutritional epidemiology assessing food intake rather than biomarkers is the possibility of collinearity, as many phytochemicals are contained in the same food sources. Thus, it is not possible to disentangle the real association of an individual compound from the others. Third, the use of FFQs may be subject to recall bias and potential inaccuracy in estimating micronutrients or other compounds. Finally, considering the stability of the results after adjustment for a wide range of lifestyle and dietary confounding factors, including vitamins and adherence to the Mediterranean diet, a residual confounding is unlikely.