Polyphenols: A top-down approach to nutrition and depression

Abstract

Depression is a common psychiatric condition with a considerable influence on global health. Although current pharmacotherapeutic choices are of indisputable relevance, there is sustained interest in natural medicines for treating depressive symptoms. Polyphenols, a class of plant-derived natural compounds, have received attention due to their possible neuroprotective and anti-depressive properties. In this review, we aimed to present the intricate mechanisms through which polyphenols modulate inflammation, neurogenesis, oxidative stress, and the gut microbiota. Consumption of polyphenol-rich diets is emerging as a non-invasive, natural, and cost-effective approach to supporting brain health, with potential influence on depressive symptoms. While there have been promising results, more research is needed to draw solid conclusions regarding the medicinal potential of polyphenols.

Key Words: Polyphenols; Depression; Nutrition; Animal models; Inflammation; Gut microbiota; Oxidative stress; Neurogenesis

Core Tip: Dietary polyphenols are promising nutraceuticals for treating brain disorders. They have been elucidated as a non-invasive, natural, and cost-effective approach to alleviating depressive symptoms. Polyphenols may target a variety of pathophysiological pathways to exert neuroprotective effects. These effects may be accomplished by modulating inflammatory pathways and the immune system, trophic factors, neurotransmitters, gut microbiota, and oxidative stress. Understanding these mechanisms may lead to more tailored therapeutic strategies and novel antidepressant therapies. Clinical studies regarding polyphenols are crucial to support the beneficial effects of these compounds as demonstrated in preclinical research.

INTRODUCTION

Depression is the most common mental illness globally and represents the leading cause of disability worldwide[1]. According to the World Health Organization’s assessment study on global disease burden, depression was the second highest burden and disability-causing disease in 2020, and it is expected to become the world’s most significant disease burden by 2030[2]. Targeting molecular interactions and metabolites that are crucial for depression and cognitive changes is challenging and limits efficient therapeutic protocols[3-5]. Although pharmacotherapy and psychotherapy are essential and unavoidable components of overall treatment, a recent meta-analysis by Leichsenring et al[6] demonstrated the limited benefits of psychotherapy and pharmacotherapy, indicating that mental disorders are not sufficiently addressed by available treatments. Although antidepressant medications are efficient for some individuals, they are associated with multiple concerns, including delayed onset of therapeutic effects, incomplete or non-response in a considerable number of patients, high relapse rates, and a range of undesirable side effects, including weight gain, sexual dysfunction, gastrointestinal disturbances, insomnia, and increased risk of withdrawal symptoms upon discontinuation. These issues can compromise treatment adherence and overall quality of life. While these data should not be considered unfavorably, there is a clear necessity to investigate additional therapy alternatives and strategies that might improve the symptoms of this mental illness.

Investigations of nutritional status and its impact on mental health have opened up a new field of research into how the quality and type of food we consume can significantly affect our mental status. There has been sustained interest in natural substances within this context. Among the many investigated chemicals and formulations, polyphenols have attracted notable scientific interest in recent studies[7]. Natural chemicals created only by plants, polyphenols are defined by one or more phenyl rings and at least one or more hydroxyl groups. They represent a large class of molecules consisting of heterogeneous compounds. They are divided into two main classes: Flavonoids (e.g., anthocyanins, flavanols, flavanones, flavonols, flavonones, and isoflavones) and non-flavonoids (e.g., phenolic acids, stilbens, lignans, and tannins) polyphenols[8]. Polyphenols are found in fruits such as pears, cherries, oranges, and apples, and in vegetables such as cereals, pulses, dried legumes, spinach, tomatoes, and beans. They are also present in beverages like tea, coffee, wine, and fruit juices, but also in nuts, peppermint, cinnamon, and ginger[9]. Their protective effect has been explored in various disorders, including diabetes, obesity, osteoporosis, cardiovascular diseases, neurodegenerative diseases, and cancer[10,11]. These chemicals demonstrate neuroprotective, anti-inflammatory, and antioxidant properties that may affect mood regulation and neurotransmitter activity[12]. Polyphenols have gained recognition for their possible influence on mental health, especially in mitigating the risk of depression[13]. Their antidepressant and neuroprotective effects have been extensively studied[14,15]. Unlike conventional pharmacotherapy, polyphenol-rich diets may offer a holistic approach. Their multi-target mechanisms of action, favorable safety profile, along with their adjunctive potential with conventional antidepressant use[16], strengthen the rationale for investigating polyphenols not only as an alternative but also as adjunctive interventions in depression therapy.

In this mini-review, we discuss the current knowledge regarding the role of polyphenols in depression. The classification of polyphenols, their sources in various types of food, as well as dietary patterns based on polyphenol content, and their beneficial role in depression will be presented. We aim to summarize the role of polyphenols in modulating inflammatory mediators, neurogenesis, oxidative stress (OS), and gut microbiota from preclinical models. We also present the results of recent clinical studies on the influence of dietary polyphenols on depression symptoms. Future perspectives are also outlined.

POLYPHENOLS-MAIN REPRESENTATIVES AND FOOD SOURCES

Polyphenols can be classified into five groups: Flavonoids, phenolic acids, lignans, stilbenes, and tannins. Flavonoids, the most common polyphenols in the human diet, are categorized as flavanols, isoflavones, flavanones, anthocyanins, flavones, and flavonols based on their molecular structure[17]. Rich in catechins (from the flavanol subgroup), chocolate and green tea decrease stress-related cortisol by hypothalamic-pituitary-adrenal axis modulation. Studies on humans and animals show their anxiety-reducing and antidepressant effects[18]. Isoflavones, with the main representatives being daidzein and genistein, are found in soy and legumes; they act as phytoestrogens and modify estrogen receptors, both of which influence brain activity[19]. In postmenopausal women, they have a strong connection to higher serotonin activity and reduced depressive symptoms[20]. Flavanone subgroup members hesperidin and naringenin are widely present in citrus fruits, grapefruits, and tomatoes. They exert strong antioxidant and free radical scavenging activities[21]. Anthocyanins, such as malvidin, cyaniding, and delphinidin, which give berries and red wine their pigmentation[22], activate serotonin and dopamine (DA) systems, thus enhancing mood and minimizing depression[23]. Flavones, such as baicalein, apigenin, chrysin, and luteolin are present in celery, parsley, peppers, chamomile, mint, ginkgo biloba, and red wine, and have been shown to have antioxidant, anti-inflammatory, antiallergic, neuroprotective, and cardioprotective effects[24]. Flavonols, such as quercetin and kaempferol, present in onions, apples, and tea, protect neurons from oxidative damage. Additionally, they may promote synaptic plasticity, which is essential for regulating emotions and cognitive processes[25]. Phenolic acids, such as hydroxybenzoic acids (gallic and protocatheutic acid) present in berries and whole grains, improve mitochondrial function and reduce neuroinflammation, hence providing antidepressant effects[26]. Also, phenolic acids, hydroxycinnamic acids (ferulic and caffeic acid), present in coffee and tomatoes, can control inflammatory cytokines and OS markers, therefore helping maintain neuronal integrity and neurotransmitter balance[27]. Lignans such as sesamin, medioresinol, syringaresinol are primarily found in flaxseeds, sesame seeds, whole grains, and vegetables. Their estrogenic and antioxidant effects have linked them to lower risks of cardiovascular disorders and hormone-related malignancies[28]. Stilbenes, such as resveratrol and its derivative viniferin, are found in grapes and red wine. Resveratrol activates sirtuins, proteins that regulate neuroprotection and cellular stress resilience. It can regulate inflammatory pathways and increase brain-derived neurotrophic factor (BDNF) levels to help achieve antidepressant-like effects[29]. Tannins (ellagic acid, punicalagin, procyanidin B2) can be found in fruits, cereals, cacao, peas, some leafy and green vegetables, coffee, tea, herbs, and spices. They possess antioxidant, anticancer, anti-allergic, and antimicrobial properties (Figure 1)[30].

Figure 1 Dietary polyphenol classification and main representatives.

PROTECTIVE ROLE OF POLYPHENOLS IN DEPRESSION: MECHANISTIC INSIGHTS FROM PRE-CLINICAL STUDIES

Numerous pre-clinical studies have investigated the molecular mechanism of various compounds, diets[31], and polyphenols related to their antidepressant effects. These studies showed that polyphenols may alleviate depressive symptoms through various mechanisms.

Polyphenols’ influence on the immune system and inflammation in depression

The immune system and inflammation are significant factors in the etiology of depression[32]. By modulating neurotransmission and neurocircuitry, inflammatory cytokines significantly impact central nervous system (CNS) homeostasis, neurogenesis, and mood regulation, influencing behavior[33]. Dysregulation of immune functions can lead to depression. The anti-inflammatory properties of various polyphenols have been investigated in different preclinical depression models. Baicalin is a flavone glycoside with various properties, including antibacterial, antiviral, anticancer, antioxidant, and neuroprotective effects[34]. Studies using the Chronic unpredictable mild stress (CUMS) model demonstrated its antidepressant effects through suppression of pro-inflammatory cytokines[35] and pathways like the glycogen synthase kinase/nuclear factor kappa B (NF-κB)/nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3)[36] and high mobility group box 1 protein (HMGB1)/toll-like receptor 4 (TLR4)/NF-κB[37] and by inhibiting TLR4 expression[38]. Furthermore, baicalin decreased depression-related inflammation in the olfactory bulbectomy model (OBX) by modulating sirtuin-1 and NF-κB p65 acetylation[39]. Resveratrol, a polyphenolic compound found in grapes, peanuts, and berries, exerts strong anti-inflammatory properties[40]. Resveratrol reduced neuroinflammation by suppressing NF-κB and NLRP3 pathways[41,42] and by decreasing the levels of pro-inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)[41,43,44] and microglial activation[42,45]. Resveratrol modulated anti-depressive effects through protective mechanisms like sirtuin-1 activation[42,45] and BDNF upregulation[46]. Hesperidin is a flavanone glycoside present in citrus fruit with a variety of positive effects[47]. In the CUMS model, hesperidin decreased IL-1β, IL-6, TNF-α, NLRP3, and caspase-1 Levels in the prefrontal cortex and microglia[48]. In the same model, hesperidin reduced inflammatory cytokine levels by attenuating the HMGB1/receptor for advanced glycation end products (RAGE)/NF-κB signaling pathway and BDNF/tropomyosin-related kinase receptor type B (TrkB) pathway both in vivo and in vitro[49]. Hesperidin alleviated lipopolysaccharide (LPS)-induced neuroinflammation in mice by promoting the microRNA-132 pathway[50] and alleviated chronic restraint stress and LPS-induced damage in the hippocampus and frontal cortex by decreasing pro-inflammatory cytokine levels[51]. It also decreased depression-related symptoms in mice with mild traumatic brain injury[52]. Another extensively explored flavonoid polyphenol is curcumin, which originates from the rhizomes of the Curcuma longa plant. It possesses a variety of biological effects, including anti-inflammatory effects[53]. Curcumin application reversed CUMS-induced behavioral and neuroimmune abnormalities by decreasing the levels of IL-1β, IL-6, and TNF-α[54,55], and by suppressing the NLRP3 inflammasome and tryptophan-kynurenine (TRP-KYN) pathway[54] and microglial activation[55]. Quercetin, a flavonol found primarily in berries, apples, and onions, possesses beneficial effects on mental health[56]. Studies have shown that quercetin can reduce depressive-like behavior in models of chronic stress-induced depression by reducing levels of OS markers and inflammatory cytokines, including TNF-α, IL-6, and IL-1β (Figure 2)[57-60].

Figure 2 Main mechanisms implicated in the antidepressant-like effects of dietary polyphenols in pre-clinical animal studies. The potential of phenolic compounds in reducing depressive behaviors can be exerted by regulating factors related to neuroinflammation, oxidative stress, monoaminergic neurotransmission, neurogenesis, and by modulation of the intestinal microbiota. TNF-α: Tumor necrosis factor-alpha; IL-6: Interleukin-6; IL-1β: Interleukin-1beta; NLRP3: Nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing protein 3; HMGB1: High mobility group box 1 protein; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor kappa B; SCFA: Short-chain fatty acids; BDNF: Brain-derived neurotrophic factor; NGF: Nerve growth factor; MDA: Malondialdehyde; TBARS: Thiobarbituric acid reactive substances; NO: Nitric oxide; GSH: Glutathione; CAT: Catalase; SOD: Superoxide dismutase; GSH-Px: Gluthatione peroxidase; 5-HT: 5-hydroxytryptamine; DA: Dopamine; NE: Norepinephrine; IDO: Indoleamine 2,3-dioxygenase; KYN: Kynurenine; TRP: Tryptophan; 5-HIAA: 5-hydroxyindoleacetic acid.

Chronic neuroinflammation affects many molecular and cellular processes in the CNS, thereby facilitating depression onset and development. Dietary polyphenols can reduce depression symptoms by blocking transcription factors, proinflammatory cytokines, and protein complexes that stimulate neuroinflammatory processes. Polyphenols are considered a potential alternative for the treatment of depression associated with inflammation due to their potent anti-neuroinflammatory effects.

Polyphenols and depression: the role of gut microbiota

The gut-brain axis is an essential factor influencing mental health. Interactions of brain and gut microbiota can be exerted through the neurological, endocrine, immunological, and metabolic pathways, which can result in disturbances in mood, sleep, and cognitive functions[61-63]. This bidirectional link can significantly influence psychiatric disorders including depression and anxiety[64]. The existence of a mutual and bidirectional interplay between polyphenols and the gut microbiota is well established[65]. Polyphenols modulate gut microbiota by preserving intestinal stability and regulating intestinal flora[66]. Polyphenol absorption and bioavailability are generally low but vary based on an individual’s gut microbiome[67]. Around 95% of polyphenols are not absorbed by the small intestine and reach the colon, where they interact with gut microbiota[68]. Dietary polyphenols act as prebiotics, enhancing the growth of specific beneficial bacterial species[69]. On the other hand, the gut microbiota can increase the production of bioactive phenolic acids derived from dietary polyphenols, increasing their beneficial biological activity[70-72]. Polyphenols can impact gut microbiome composition through the stimulation of probiotic bacteria populations, such as Lactobacillus and Bifidobacterium, and the suppression of pathogenic strains, including Clostridium perfringens and Clostridium histolyticum[73,74]. Microorganisms classified as psychobiotics (probiotics and prebiotics that provide mental health advantages via interactions with commensal gut bacteria) synthesize neurotransmitters and short-chain fatty acids (SCFAs), which directly influence the nervous system[75]. Tea polyphenols suppress the proliferation of Bacteroides-Prevotella and Clostridium histolyticum while promoting the growth of Bifidobacterium, Lactobacillus, and Enterococcus bacteria and enhanced SCFA synthesis[76,77]. Flavonoids, present in citrus fruits, onions, and green tea, improve gut microbiota diversity and produce metabolites that cross the blood-brain barrier, modulating neurotransmitters like serotonin and DA[78]. In an adrenocorticotropic hormone (ACTH)-induced rat model of depression, chlorogenic acid improved depression-like behavior, normalized serum levels of 5-hydroxytryptamine (5-HT), DA, IL-6, TNF-α, and modulated bacterial strains, including Desulfovibrio, Klebsiella, Burkholderiales, and Bifidobacterium[79]. Bifidobacteria-fermented red ginseng alleviated anxiety/depression in stress-induced gut dysbiosis and inflammation by ameliorating gut and hippocampal inflammation[80]. In a CUMS model of depression, soy isoflavones attenuated depressive behavior by increasing monoamine neurotransmitters and modulating gut microbiota composition[81]. In the same model, the phenolic acid compound coniferyl ferulat restructured gut microbiota and microbial metabolism to decrease depressive-like behavior[82]. Polyphenols can modulate intestinal barrier function and signaling pathways[83], while tea polyphenols affect the microbiome by preserving optimal redox status[84].

Taken together, polyphenols can interact with the gut flora by modulating its composition, promoting the proliferation of good strains and reducing that of pathogenic ones. Furthermore, the gut microbiota directly affects the immune system, which then affects nervous system function. This interaction implies a gut-brain-immune axis, which polyphenols might significantly control.

Polyphenols’ influence on neurotrophic factors in depression

The process of generating new neurons from neural stem or progenitor cells primarily occurs during fetal development and is denoted as neurogenesis. It continues in adults, particularly in the hippocampus, and plays a key role in synaptic plasticity, cognition, and stress resilience[85]. Brain neurotrophic factors have an important role in the pathophysiology of depression. BDNF promotes neuronal growth, differentiation, and survival by activating the TrkB receptor[86]. It is a key regulator of neurogenesis and synaptic plasticity, fundamental to learning, memory, and behavior[87]. Inflammatory cytokines, including IL-1β, IL-6, and TNF-α, suppress the BDNF and TrkB expression while also inhibiting TrkB phosphorylation[88]. Plant-derived flavonoid baicalein showed antidepressant effects and increased the hippocampal level of BDNF[89]. Furthermore, the antidepressant effect was partially modulated through the extracellular signal-regulated kinase signaling pathway, which is associated with neurotropic action, cell survival, and proliferation[89]. The same flavonoid exerted antidepressant effects by regulating the Wnt/β-catenin signaling pathway and improved nerve cell survival in the hippocampal dentate gyrus[90]. Baicalin improved depressive-like behavior by promoting neuronal maturation, preventing apoptosis, and enhancing BDNF levels[36]. The up-regulation of 5-HT1A receptors and BDNF in chronically stressed mice verified the beneficial effects of curcumin[91]. Hesperidin, a flavonoid polyphenol from the flavanone glycoside subgroup highly present in citrus fruit[92], promotes neurogenesis by enhancing BDNF and nerve growth factor. Its antidepressant effects are mediated through the inhibition of neuroinflammation, modulation of OS, and regulation of important signaling pathways, including NF-κB, HMGB1/RAGE, and TLR4, which contribute to neuronal plasticity and survival[49,51,93,94]. Quercetin mitigated depressive-like behaviors by modulating the BDNF/TrkB/β-catenin axis in the prefrontal cortex[95]. Grape-derived polyphenols[96], chrysin from bee propolis, honey, and various plants[97], resveratrol[41,46], and salvianolic acid[98], also improved depressive-like behavior in animal models through modulation of BDNF, along with other mechanisms (Figure 2).

Dietary polyphenols show promising neuroprotective effects by increasing BDNF expression, suggesting they may play a role in preventing and treating depression symptoms. Future research should focus on identifying the specific molecular pathways through which polyphenols modulate BDNF signaling. This could lead to new nutraceutical interventions for depression treatment.

Polyphenols’ influence on OS in depression

OS is considered to be in the background of depression[99]. Dietary intake of polyphenols has significant effects against many diseases that involve OS[100]. A diet rich in polyphenolic compounds, consisting of a variety of vegetables, especially yellow, orange, red, and green leafy vegetables, can help reduce depression symptoms[101]. Numerous studies have demonstrated an increase in antioxidant parameters and a decrease in OS parameters after the application of various polyphenol compounds[102]. Phenolic compounds exert antioxidant properties by scavenging reactive oxygen species (ROS), reducing ROS production through oxidative enzyme inhibition and trace element chelation, enhancing endogenous antioxidant activity and donating electrons or hydrogen atoms to neutralize singlet oxygen[103]. The application of quercetin mitigated OS by restoring antioxidant enzyme levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and total thiol, and by reducing lipid peroxidation[57-60]. Curcumin ameliorated behavioral deficits and restored biochemical and molecular alterations by increasing GSH, SOD, and CAT activity[104]. Curcumin also effectively reduced OS in the CUMS model by decreasing lipid peroxidation and enhancing antioxidant enzyme activities[105]. Administration of baicalin decreased apoptosis and protected cells from OS by reducing malondialdehyde (MDA) levels and increasing SOD levels[36]. Enhanced oxido-nitrosative stress and lower antioxidants GSH, SOD, and CAT were restored by hesperidine application, alleviating anxiety and depressive-like behavior[51]. Ferulic acid and salvianolic acid B were also effective in counteracting OS by reducing lipid peroxidation and restoring the key antioxidant enzymes GSH, SOD, CAT, and GSH peroxidase (Figure 2)[106-108].

Polyphenols’ influence on neurotransmitters in depression

Based on the monoamine hypothesis of depression, modulation and restoration of the monoamine neurotransmitter system are crucial in treating depression. Numerous studies showed that increased 2,3-dioxygenase (IDO) activity correlates with depressive severity. This important enzyme is involved in the TRP/KYN metabolic pathway, as it decreases TRP and inhibits serotonin (5-HT) synthesis. The role of polyphenols within this concept has been widely investigated. Curcumin supplementation attenuated IDO activation and an increased KYN/TRP ratio[54], modulated DA and norepinephrine (NE) levels, downregulated monoamine oxidase B, and upregulated DA receptor mRNA in the limbic region[109]. These changes were followed by improvement in behavioral deficits. Curcumin dose-dependently ameliorated behavioral deficits by decreasing biogenic amine levels (DA, NE, 5-HT) in the cortex and hippocampus of reserpine-treated rats[104]. Similar effects were observed after chrysin administration[97,110]. Ferulic acid improves depression-like behaviors by regulating the monoaminergic system[106]. Deoilled sunflower seeds have been found to alleviate depressive-like behaviors in a CUMS model by increasing DA, 5-HT, and NE levels[111]. Similarly, Epigallocatechin Gallate (EGCG), catechin from apples, pears, tea, and cocoa, has been shown to improve depression-like behaviors[112], along with navel orange essential oil[113]. Nobiletin, a flavone from citrus peels, exhibits antidepressant effects by targeting 5-HT1A, 5-HT2, α1-adrenoceptors, and D1/D2 DA receptors, highlighting its therapeutic potential in depression[114]. Naringenin, a flavanone from grapefruit, improves serotonergic neurotransmission and 5-HT synthesis, contributing to its antidiabetic, antioxidant, and memory-improving effects[115]. The flavone apigenin mitigated stress-induced alterations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), DA levels, and the 5-HIAA/5-HT ratio in various brain regions of the CUMS rat model, confirming its role in mood regulation (Figure 2)[116].

Polyphenols exhibit neuroprotective properties by regulating neurotransmitter metabolism and modulating neurotransmitter receptor function, which poses them as potential adjunctive therapeutics.

IMPACT OF POLYPHENOLS ON BEHAVIOR IN ANIMAL MODELS OF DEPRESSION

Various animal models of depression have demonstrated that diverse phenolic compounds can alleviate depressive-like behavior.

Baicalin reduced depressive-like behaviors in CUMS rodent models of depression. Behavioral improvements were reflected through reduced anhedonia, decreased behavioral despair, and increased locomotor activity[35-38,117]. Baicalin enhanced neuronal survival and maturation and reduced apoptosis in the hippocampus[36]. In an LPS-induced depression model, baicalin reduced depressive-like behaviors by suppressing neuroinflammation via the peroxisome proliferator-activated receptor-γ coactivator-1α/NF-κB pathway[118], while in the OBX model of depression, it reversed depressive behaviors by normalizing corticosterone levels and reducing inflammatory cytokines in the hippocampus and hypothalamus[39]. In the CUMS and chronic unpredictable stress model, quercetin improved behavioral symptoms, including reduced depressive symptoms (anhedonia, despair-like behavior) and improved cognitive functions[57,58]. In the OBX model[60] and 1,2-dimethylhydrazine-induced depression model[95], quercetin improved anxiety, depressive-like behaviors, and cognitive dysfunction by decreasing oxidative-nitrosative stress and inflammation-related apoptosis in the brain[60], and by enhancing neuroprotective factors[95]. Curcumin is another widely investigated polyphenol. Its application for 4[54] or 5 weeks[119] in rats exposed to CUMS improved mood-related behavior, as measured by increased percent of sucrose consumption and increased mobility[119]. Similar results were obtained with curcumin in the chronic mild stress model[120]. Curcumin improved mood and cognitive function by restoring neurotransmitter balance and reducing OS and inflammation in ovariectomized-induced depression in female rats[109] and reversed pain-related depressive behaviors by modulating neuroinflammation-related pathways[104]. Treatment with curcumin reversed LPS-induced alterations in the forced swim test, tail suspension test, and sucrose preference test[121]. Resveratrol reversed depressive behaviors in CUMS[41,43,44], LPS-induced inflammation[45,46], ovariectomized[42], and social stress-induced depression models[122]. These effects were manifested as decreased anhedonia, decreased behavioral despair, and decreased anxiety. Using a model of agitated depression, Filho et al[97] found that the natural flavonoid chrysin alleviates depression-like behaviors in animal models by regulating the TRP-KYN pathway, reducing indoleamine IDO activity and restoring 5-HT levels. It also decreases ACTH and corticotropin-releasing hormone levels, suggesting stress modulation[97]. Antidepressive effects were also demonstrated in animal models after the application of epicatechin[123] and apigenin[124,125], and various polyphenolic acids like chlorogenic acid[126], dehydrozingerone[126], ellagic acid[127], ferulic acid[128,129], gallic acid[130], rosmarinic acid[131,132], and syringic acid[133,134].

Based on the presented data, polyphenols’ behavioral effects are strongly linked to their anti-inflammatory and neuroprotective properties, suggesting their potential as therapeutic agents for depression.

POLYPHENOLS AND DEPRESSION IN HUMANS: EVIDENCE FROM CLINICAL STUDIES

Despite the existence of many preclinical studies, research on the influence of individual phenols on depressive symptoms in humans is scarce. Observational studies have investigated the correlation between habitual polyphenol consumption and the prevalence of depressive symptoms. A study involving more than 1500 adults in southern Italy[135] suggested that higher total polyphenol intake was inversely related to depressive symptoms. Similarly, research focusing on older adults found that certain polyphenol-rich foods may contribute to a lower depression risk[101]. One meta-analysis of randomized controlled trials investigating the effectiveness of polyphenol supplementation in improving depression, anxiety, and quality of life revealed their beneficial effect on depressive symptoms[136]. Reduced depression scores in comparison to milk chocolate confirmed the positive effects of cocoa, which is high in polyphenols and has significant antioxidant properties[137]. A meta-analysis of dark chocolate/cocoa intake showed significant reductions in OS markers, including plasma MDA and higher nitric oxide levels, suggesting overall antioxidant advantages[138]. Consumption of grape seed proanthocyanidin extract (GCPE) decreased anxiety but with no significant impact on depression. GSPE’s anxiolytic effects are mostly based on its antioxidant activity and a potential interaction with Gamma-aminobutyric acid-A receptor[139].

A randomized, open-label intervention trial found that eating foods high in antioxidants (vitamin E, C, carotenoids, polyphenols), minerals (selenium, zinc), fiber, and polyunsaturated fatty acids improved quality of life and reduced anxiety and depression symptoms. A limitation of the study is the absence of a control group missing nutritional intervention for comparative analysis[140]. Walnuts are abundant in neuroprotective compounds, including vitamin E, folic acid, melatonin, antioxidant polyphenols, and omega-3 fatty acids. A clinical trial investigating the impact of > 8 weeks of walnut consumption on the mood of healthy individuals showed no effects on women, while men’s overall mood disorder scores significantly improved[141]. One placebo-controlled study examined the benefits of curcumin on people with major depressive disorder and demonstrated its significant antidepressant effects at 12 and 16 weeks after treatment initiation. The administration of curcumin showed safety and tolerability, even when used alongside antidepressants. The advantages of curcumin were more pronounced in males compared to females[142].

A study by Almudhi and Gabr[143] found that six cups of decaffeinated green tea daily over 6 weeks significantly reduced depression scores in the adolescent population. A trial from the United States exploring the effects of 8 weeks of 1500 mg chamomile daily also reported improvements in participants with comorbid depression[144]. Positive results were also reported for dietary flavonoids in postpartum women[145], flavonoid-rich orange juice[146], curcumin[147], wild blueberry supplementation in adolescents[148], and green tea extract in human immunodeficiency virus patients[149]. In another trial, Kontogianni et al[150] observed significantly lower Beck depression inventory (BDI)-II scores in a group consuming high amounts of fruits, vegetables, and dark chocolate compared to a low-consumption control group, with no effect on the depression, anxiety, and stress scale-21 depression subscale. A significant reduction in BDI scores among participants with multiple sclerosis was observed after the application of EGCG and coconut oil[151] or ellagic acid[152]. Parilli-Moser et al[153] found that peanut products reduced depression scores in healthy young adults. Meta-analyses have also confirmed antidepressant effects for curcumin[154], cocoa[155], and resveratrol[156].

Overall, the results reported from recent trials and meta-analyses suggest that certain dietary polyphenol interventions may reduce depressive symptoms across clinical and non-clinical populations. Yet, the limitations of these studies make it challenging to properly interpret the results. Polyphenol types, dosages, forms, and intervention durations significantly vary among these studies. Furthermore, various depression assessment tools make it difficult to compare the results. Future studies should focus on long-term, well-designed randomized controlled trials with diverse populations to better understand the potential role of polyphenols in managing depression.

POLYPHENOL-RICH DIETS AND NUTRITIONAL STRATEGIES IN DEPRESSION

The recognition of the role of diet in depression has led to the development of dietary interventions as adjunctive treatments for mental health disorders[157]. Among these, the Mediterranean diet (MD) and plant-based diets have gained attention for their potential protective effects against depression[135,158-160].

MD and depression

The MD is a nutritional pattern that has traditionally been followed by Mediterranean populations and has been associated with better health[161,162]. It emphasizes a diet rich in vegetables, fruits, legumes, whole grains, nuts, and olive oil, with modest amounts of fish, meat, and dairy. This eating pattern has been extensively studied for its role in preventing chronic diseases like cardiovascular disorders[163], metabolic syndrome[163], and neurodegenerative disorders[164]. Furthermore, accumulating evidence suggests its protective role in mental health, particularly in reducing the risk of depression[165-167]. The dietary components of the MD, including omega-3 fatty acids found in fish and olive oil, contribute to neuronal membrane function and neurotransmitter regulation. Polyphenols that are abundant in the MD, present in olive oil, nuts, and red wine, possess anti-inflammatory and neuroprotective properties[168,169], while whole grains and legumes provide B vitamins essential for neurotransmitter synthesis[170]. Additionally, minerals such as magnesium and zinc, found in nuts, seeds, and leafy greens, contribute to synaptic plasticity and neurogenesis[171].

The MD includes lots of fruits and vegetables including tomatoes, leafy greens, peppers, citrus fruits, and berries. These foods are high in fiber, vitamins, and polyphenols. It also contains whole grains, including bulgur, brown rice, oats, and whole wheat, which offer necessary vitamins, fiber, and complex carbs. Nuts and legumes include chickpeas, lentils, almonds, and walnuts, which provide plant-based protein, fiber, and good fats. Olive oil, which is high in monounsaturated fats and polyphenols with anti-inflammatory and cardiovascular benefits, is the main source of fat. Sardines, salmon, and mackerel, fish and shellfish have omega-3 fatty acids that help heart and brain function. While moderate consumption of red wine offers polyphenolic compounds like resveratrol, which have neuroprotective and anti-inflammatory properties, moderate consumption of dairy products, including yogurt and low-fat cheese, as well as eggs, provides protein and probiotics that support gut health important for modulating the gut-brain axis. While chicken and turkey are eaten in modest amounts, red meats such as beef and pork are eaten only occasionally. To reduce saturated fat intake, lean, unprocessed cuts are recommended[13,172].

Numerous studies have examined the impact of the MD on mental health. An inverse relationship between adherence to the MD and depression risk was outlined by a meta-analysis of cohort studies[173]. A systematic review by Bayes et al[159] linked higher polyphenol intake to a 32% lower depression risk but emphasized variability in study designs and the need for randomized trials. A meta-analysis of 14 observational studies (56043 participants) found no significant effect in cohort studies, while cross-sectional studies suggested a protective role between MD adherence and depression risk. Limitations of this meta-analysis were variations in dietary assessment and depression measurements[174]. Parletta et al[175] found a 45% reduction in depression scores with a combination of MD and fish oil, though these results are limited, constrained by a small sample size and a 3-month duration. Although these studies have their limitations, MD has confirmed its beneficial effect on mental health.

Plant-based diets and depression

Plant-based diets, abundant in polyphenols and low in animal products, are associated with lower inflammation, improved gut microbiota, and better mental health[176,177]. However, strict vegan diets may lead to deficiencies in vitamin B12, iron, and omega-3 fatty acids, thus increasing depression risk[178]. Recent research has explored the potential impact of plant-based diets rich in polyphenols on depression risk[179,180]. These studies suggest an inverse relationship with depression. A study of 219 adults found that specific polyphenols, especially from citrus fruits and wine, were associated with reduced depressive symptoms, though total polyphenol intake showed no effect[181]. Another study showed that plant-based diets, particularly the MD, positively influenced mood in adults, while the Plant-based Diet Index was linked to positive mood in children[182]. Further research is needed to explore age-related effects.

Synergistic effects of polyphenols with other nutrients

Polyphenols function in concert with other nutrients to improve their absorption and efficacy[183,184]. A study by Li et al[185] found that ferulic acid combined with piperine significantly increased serotonin and noradrenaline levels in the frontal brain and hippocampus, thereby decreasing depressive symptoms. In addition to the interactions between polyphenols, their synergistic effects with other nutrients are essential to improving health effects[186]. Polyphenols enhance the absorption of critical minerals, including iron and zinc, by modifying the intestinal flora and preventing the formation of insoluble complexes[187]. Vitamin C increases the bioavailability of catechins and enhances their antioxidant activity[188]. Omega-3 fatty acids from fish or flaxseeds work with polyphenols to reduce neuroinflammation and OS, mechanisms linked to depressive disorders[189]. Additionally, dietary proteins such as casein and whey influence polyphenol stability and efficacy, forming complexes that enhance their bioactivity in the CNS[190].

Implementation methods and evaluation of dietary interventions

Dietary interventions can be implemented through concentrated polyphenol-rich supplements (e.g., capsules containing curcumin, resveratrol, etc.) or through whole-food dietary patterns, such as the MD, which is naturally abundant in polyphenols. While supplements provide an exact dose and are convenient for use in clinical trials, whole-food diets contain many different nutrients and bioactive compounds, which can act synergistically and produce a stronger and more balanced effect. Whole-food diets can be integrated more easily into daily life and for longer time periods and have benefits beyond mental health (e.g., for heart disease, and diabetes). Methods for implementing diet commonly include structured meal plans, and dietitian-led counseling, while the evaluation of outcomes is based on standardized psychological scales, such as the Hamilton depression rating scale, BDI, etc. Studies have shown that personalized coaching, regular follow-ups, the use of dietary tracking tools (e.g., apps or food diaries), and integration with behavioral interventions (e.g., cognitive behavioral therapy) can significantly enhance adherence and outcomes of interventions applied[191].

Polyphenols and human health: Safety, toxicity, interactions, and delivery challenges

While polyphenols are generally considered safe when consumed as part of a balanced diet rich in fruits, vegetables, herbs, and tea, their excessive intake, especially from supplements, may pose risks, particularly for individuals on polypharmacy or with chronic conditions. Overdosing on purified polyphenols (like aglycones) can potentially lead to prooxidant, mutagenic, or genotoxic effects[192]. These supplements can contain extremely high concentrations of pure polyphenols that are impossible to reach through natural foods. This discrepancy raises safety concerns, especially since such supplements are easily available, not expensive, and often taken without medical supervision.

It is important to note that substantial inter-individual differences may exist in response to polyphenol intake. These differences may arise from a combination of genetic, microbial, metabolic, dietary factors, age, and sex-related factors, but also from the presence of metabolic disorders such as diabetes, obesity, and liver or kidney impairment[192].

Polyphenol-drug interactions are based on their effects on drug-metabolizing enzymes and transporters and should be considered, especially in cases of polypharmacy. These interactions can lead to changes in drug efficacy or increase their toxicity, particularly for drugs with a narrow therapeutic index. Notably, polyphenols can interact with anticoagulants such as warfarin[193,194] and rivaroxaban[195], cardiac drugs such as digoxin[196], nadolol[197], and lisinopril[198], statins[199-201], and metformin[202].

It is difficult to distinguish the definitive interactions between polyphenols and other bioactive components. The expected dominant interaction of polyphenols is hydrogen bonding, along with other dipole-dipole, dipole-induced dipole, and hydrophobic interactions. Suggested sites for hydrogen bonding polyphenol to proteins include hydroxyl and amino groups of amino acid residues[203]. The range of possible synergistic or antagonistic effects of these interactions influences polyphenol bioavailability, stability, and activity.

The use of polyphenols as nutriceuticals is limited by their poor oral bioavailability, poor water solubility, and rapid metabolism. This can be overcome by optimized delivery systems such as nanoencapsulation, liposomes, or coadministration with enhancers.

FUTURE PERSPECTIVES

The high rate of treatment resistance, significant suicide risk, and heavy financial burden emphasize the need for investigating new therapeutic approaches in treating depression. Yet, the path from discovering the mechanisms underlying depression and their translation into therapy is long and challenging. There is a need for larger and long-term human studies to determine the potential for using polyphenol-rich foods or supplements as adjunct therapies for depression. Furthermore, it is important to explore personalized nutrition approaches and consider individual variability in response to polyphenols, along with their potential for interactions with other medications.

The safety and tolerability of high doses of polyphenols should also be explored. Novel immune-based therapeutics could potentially address unmet clinical needs of patients resistant to conventional antidepressant medications. It is critical to investigate the potentially complex interactions between dietary polyphenols and numerous bioactive components, which may lead to beneficial complementary, additive, synergistic, as well as negative or neutralizing interactions. The diversity and richness of gut microbiota play a crucial role in determining dietary polyphenol bioavailability. Combining dietary polyphenols with an optimized probiotic formulation as a synbiotic could enhance the production of specific metabolites, whose neuroprotective mechanisms could be further elucidated and optimized for depression treatment.

The computational and semi-empirical methods can be effectively applied to investigate the molecular interactions between polyphenols and other bioactive molecules, such as neurotransmitters, receptor proteins, and cofactors involved in depression-related pathways. These computational methods can guide the design of novel polyphenol formulations with enhanced bioavailability and synergistic interactions, potentially leading to tailored treatments for different depression subtypes. Subsequently, in vitro and in vivo studies are necessary to distinguish whether targeted structures and supplements can support depression treatment. As methods for experimental testing evolve, this fundamental approach combining theory with experiment will be validated and yield novel polyphenol-based therapeutics.

CONCLUSION

Dietary polyphenols are promising nutraceuticals for treating brain diseases. Evidence from diverse animal and human studies discussed here supports that dietary sourced polyphenols play a potential protective role in modulating depressive symptoms. Although extensive results originate from preclinical studies, clinical evidence remains scarce. Furthermore, additional research is required to determine the pharmacokinetic properties, bioavailability, and safety of polyphenols to facilitate their clinical application in managing depressive symptoms. However, translating preclinical findings into clinical practice requires more rigorous human studies to unlock the full potential of these natural compounds.