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Depression is the fourth leading cause of disability, impacting more than 264 million people globally [1]. The COVID-19 pandemic also increased rates worldwide, with reports of a rise in depressive symptoms in American adults [2,3]. Economically, the U.S. spends approximately $1 trillion on mental health and treatments [1]. When left untreated, depression can lead to suicidal ideation and attempts [4,5].

Many occupational groups, including law enforcement, healthcare and social worker professionals, artists, academia and administration, food service industries, and the government, are impacted by depression [6]. The highly trained and agile warfighter community is a group that embodies strength and resiliency; however, this community is not immune to the wider societal issues of depression and other mental health disorders, and it has suffered rising rates of depression and suicide [7]. The Armed Forces are consistently faced with the challenges of high-stress work environments and multiple deployments, which have led to high incidences of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), substance abuse, obesity and being overweight, and other comorbid illnesses [8]. According to the Health of the Force report, 18% of warfighters were obese, and 15% of this vulnerable population had at least one behavioral health diagnosis [9]. Depression is prevalent in the warfighter population due to the intense performance demands and requirement to stay operationally fit and ready [10,11]. In a recent Armed Forces surveillance report, 853,060 active component service members were diagnosed with at least one mental health disorder, including depression [12].

The Monoamine Hypothesis of Depression proposes that altered psychological health is an imbalance of neurotransmitters. Neurotransmitters are instrumental in regulating mood, learning, memory, appetite, sleep, and other executive functions [26]. Decreasing levels of monoamine neurotransmitters can lead to impaired psychological health, such as depression [27]. To mitigate these harmful psychological impacts, standard pharmacological therapies, such as MAOIs, SSRIs, and SNRIs, are typically prescribed by healthcare providers to treat the neurotransmitter imbalances [26]. These pharmacological therapies are often effective; however, dietary substances may interact and interfere with their efficacy or cause adverse effects. An example of this is the “cheese effect” that occurs when tyramine, an ingredient found in cheese, interacts with MAOIs, leading to the acute onset of hypertension that may lead to serotonin accumulation and neurotoxicity [28]. Moreover, these treatments do not address the root cause that led to the imbalance in the first place.

Depression is also associated with cardiovascular disease [1,29]. A “vascular depression hypothesis” was proposed to underscore the link between depression and vascular diseases, including coronary artery disease, hypertension, and peripheral vascular disease. Alterations in vascular structure and the expression of endothelial cell molecules, such as nitric oxide, have been reported in individuals with depression [30]. This suggests that there may be a common mechanism linking the altered function of these two distinct physiological systems. Oxidative stress that occurs when there is an overproduction of reactive oxygen species (ROS) or an imbalance of antioxidants and ROS [31] emerged as a potential common threat. Inflammation and oxidative stress have independently been linked to both impaired psychological health, such as negative mood [32,33], and cardiovascular disease [1,29].

Lifestyle and environmental or occupational factors can contribute to the development of oxidative stress and lead to impaired neuronal and cardiovascular function. Studies suggest that impaired brain health may be related to the increased production of ROS and induced nitric oxide synthase, elevated cytokines, and increased inflammatory processes [34,35]. Over the last decade, flavonoids have garnered significant interest for their role in bolstering neuroplasticity and dendritic branching, which are necessary processes for neuronal function and connectivity [36]. These bioactive compounds also seem to be neuroprotective, inhibiting apoptosis and downregulating oxidative stress [24,37,38]. Notably, berries such as elderberry, black chokeberry, and blackcurrant are rich in flavonoids called anthocyanins that provide fruits, vegetables, and flowers their color pigments of red, blue, and purple hues [39,40]. Cyanidin 3-glucoside (C3G), a common bioactive ingredient found in berries, is the most frequently detected phenolic compound (out of a total of 203 compounds) in human urine and plasma after the consumption of berries [41]. C3G was detected in 69% of human plasma samples and 58% in urine samples after berry consumption [41]. C3G was also detected in the vascular endothelium and the brain [41]. This suggests that C3G is absorbed and taken up into the body’s tissues, and that it can cross the highly selective blood–brain barrier. Flavonoids can counter the negative cellular effects of oxidative stress and inflammation by modulating cellular signaling pathways [24,38,42]. Although it can vary based on the origin, seasonal conditions, preparations, and primary ingredients, anthocyanins contained in berries generally have a higher antioxidant capacity than other flavonoids [43]

Several studies have investigated the effects of flavonoids on mood as well as cognition [44,45,46]. Depression was found to be increased in older adults who had low intakes of fruits and vegetables [21]. Several studies also demonstrated the benefits of flavonoid-rich diets or beverages in reducing depressive symptoms [47,48,49]. In a double-blind, placebo-controlled crossover study investigating the effect of wild blueberry (WBB) drinks in young adults and children, drinking the WBB drink resulted in significantly higher positive affect scores than sipping the placebo beverage compared to baseline in young adults [50]. A similar improvement in positive affect was observed in children [50]. Similarly, following a diet rich in flavonoids from fruits as well as berries, vegetables, and chocolate for eight weeks was found to decrease depressive symptoms and improve general mental health statuses in mildly hypertensive patients [51]. Moreover, Watson et al. found blackcurrant increases alertness and lowers fatigue in healthy adults [52]. The results of these studies show that flavonoids may improve memory, attention, and cognitive reaction time in both human and animal models [53,54,55]. In a recent article, Kontaogianni et al. randomized participants with hypertension to consume either a low polyphenol diet (LPD), which consisted of two or fewer portions of fruits and vegetables per day with no dark chocolate, or a high polyphenol diet (HPD), which consisted of six portions of fruits and vegetables per day plus dark chocolate, over the course of eight weeks with a washout period [51]. The findings show that the participants within the HPD had reduced depressive symptoms and overall improved well-being in comparison to the control group [51]. Taken together, these studies suggest that berry flavonoids have a promising role in psychological health.

Studies also suggest that the amelioration of depressive-like behaviors correlates with the antioxidant activities of whole berry extracts or constituent flavonoids [51,56,57,58,59]. For example, a recent study showed that Grewia asiatica extracts improved depressive symptoms while increasing antioxidant activity in a rat model [60]. Similarly, blueberry extract improved the antioxidant profile and depression symptoms in a mouse model of depression [57]. In a more recent study, Lycium barbarum berry (Lyc), commonly referred to as Goji berry, was orally administered for four weeks to eight-week-old male rats in an ionizing radiation-induced depression and spatial memory impairment rodent model. Results showed improved cognition, spatial memory, and depression symptoms [61].

There are other possible mechanisms of the beneficial actions of berry flavonoids. Studies analyzing the relationship between flavonoids and mood suggest that berry flavonoids may modulate monoamine neurotransmitter activity in the CNS [20,32,53]. Acute supplementation with flavonoid-rich blackcurrant was shown to inhibit MAO-A and MAO-B enzymes that suppress dopamine and serotonin levels [64]. Consistent with the positive effect of berry-derived flavonoids on psychological health, blackcurrant extract drinks decreased mental fatigue and improved cognition and mood in healthy adults after a 3-day intervention [64]. This was associated with changes in blood biomarkers, including reduced platelet MAO-B activity. In another study of the effects of blackcurrant juice on mood and physiological biomarkers following treadmill exercise in healthy, sedentary adults, results showed that consuming blackcurrant juice one hour before a walking exercise resulted in a 90% decrease in platelet MAO-B activity (p < 0.001) and remained at 25% of baseline by the end [65].

Alternatively, Hritcu et al. highlighted the relationship of antidepressant-like flavonoids and neuropsychiatric disorders through the suggested modulation of a neurotrophin called brain-derived neurotrophic factor (BDNF) [58]. BDNF plays a critical role in brain health, as it ensures proper neurotransmission, neuronal growth, plasticity, and survival [58,66]. Evidence showed various flavonoids enhanced BDNF expression in the hippocampus of mice models, attenuated oxidative stress and inflammatory properties, mimicked anti-depressant actions, and inhibited monoamine oxidase activities and L-arginine-NO pathways [58]. Earlier reports triangulated a link between decreased BDNF expression, high cortisol levels, and atrophy of the hippocampus with depression [58,66]. Diets possessing appropriate sources of naturally occurring bioactive compounds found in strawberries, grapes, other berry polyphenols, nuts, and spices were shown to play a critical role in hippocampus neurogenesis [67]; conversely, diets that are high in fats and refined sugar lead to decreased hippocampus neurogenesis and decreased BDNF, which is an essential factor in neuroplasticity [67]. Another pathway that has gained greater attention is nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is a nuclear transcription factor, and it plays a significant role in protecting against oxidative stress by regulating antioxidant defense and detoxifying gene expression [68], which contributes to cytoprotection [68]. In a recent review highlighting the role of Nrf2 and natural flavonoid activators by Zuo et al., flavonoids such as curcumin, quercetin, and resveratrol reportedly reduced oxidative stress and inflammation, upregulated glutathione levels in vitro, diminished depressive-like behaviors within a mouse model, and decreased malondialdehyde (MDA) levels, which are a by-product of lipid peroxidation through Nrf2 activation [68].

Studies also point to other possible anti-inflammatory and neuroprotective mechanisms. Ebenezer et al. showed that rodents with induced post-traumatic stress disorder (PTSD) demonstrated a significant decrease in proinflammatory cytokines, TLR4, and HMGB1 post-2% blueberry enriched diet through a suggested role of antioxidant defense compared to the control group [69]. Similarly, kaempferol-3-glucoside and narirutin may potentially modulate depressive-like effects in the offspring of a rodent model, whereas a high-sugar diet increased expression of an inflammatory protein marker, TBK1, in the hippocampus [59]. In a study of anxiety-like behavior post-myocardial infarction (MI) in rodents, epigallocatechin-3-gallate (EGCG), which is commonly found in green tea, reduced anxiety-like behavior, decreased inflammatory and apoptosis markers of IL-6 (specifically, caspase 3, 8, and 9 mRNA), and downregulated the STAT3 protein [70].

It was also suggested that cardiovascular dysfunction, particularly in older individuals, can lead to the development of depression. The “vascular depression hypothesis” suggests that white matter damage resulting from ischemia may contribute to the onset of depression and cognitive dysfunction [71]. Moreover, rates of depression are elevated following myocardial infarction [72]. Cardiovascular disease continues to be a leading cause of death of Americans [73], and the U.S. active-duty military force is not exempt from its occurrence [9]. One recent study demonstrated that several different classes of anti-hypertensive drugs were associated with a reduced incidence of depression [72]. Several studies have also shown that flavonoids and berry-derived flavonoids improve cardiovascular health [42,62,74,75,76]. Understanding the potential role of flavonoids in cardiovascular health may also help to shed further light on their relationship to psychological health. In a randomized, double-blind, placebo-controlled classic study conducted by Engler et al., young healthy participants during a two-week period were randomized into either a high-flavonoid dark chocolate group or a low-flavonoid dark chocolate group for daily consumption [77].

Finally, there is an apparent bidirectional association between obesity (defined as a body mass index (BMI) of 30 kg/m² or higher) and depression [80,81,82,83]. Schvey et al. found in their study consisting of 119 active-duty service members of both male and female participants that obesity and being overweight are associated with depressive symptoms, weight stigma, and maladaptive behaviors and eating patterns [84]. Berry flavonoids as a targeted nutritional approach against obesity may provide anti-inflammatory and antioxidant health benefits. For example, in a prospective cohort study consisting of approximately 124,000 men and women that healthcare professionals conducted over 24 years, the results showed that participants who consumed a high flavonoid diet self-reported less weight gain [85]. Although the soluble fiber present in flavonoids has been linked to contributions to weight loss, there may be other underlying mechanisms at play. In reviews by Sandova et al. and Tsuda et al., the potential mechanisms influencing the role of flavonoids in anti-obesity effects include downregulation of lipid accumulation and inhibition of lipogenesis in the liver. Moreover, there was increased browning of white adipose tissue (WAT) and stimulation of brown adipose tissue (BAT), which is important for storing of energy, fat metabolism, and burning calories in the body through induced thermogenesis [86,87]. It is also increasingly recognized that the function of the gut microbiome contributes to overall human health, including brain health [88]. It is postulated that anthocyanins may have inhibitory effects on epithelial cell inflammation, thereby supporting intestinal health through modulation of the gastrointestinal microbiota [89]. Bioactive compounds commonly found in berry flavonoids and teas, such as anthocyanins, quercetin, resveratrol, and EGCG, have shown, individually and collectively, promising actions on increased lipolysis, adiponectin signaling, modulating of the gut microbiota, and influences on body weight reduction [86,87].