Klus W.Lnge*, Yukiko Nkmur Kthrin M.Lnge Hui Zho

a Department of Experimental Psychology, University of Regensburg, Regensburg 93040, Germany

b Tianjin Key Laboratory of Food and Biotechnology, University of Commerce, Tianjin 300134, China

Keywords:

Depression

Tea

L-theanine

Prevention

Treatment

A B S T R A C T

The available evidence, which derives from studies investigating mechanistic effects of tea, research on animal models as well as epidemiological studies and intervention trials in humans, suggests that compounds contained in tea may have the potential to aid in the prevention of depression or in its treatment as an addition to established therapies.A wide range of potentially antidepressive biological activities of tea components have been reported.However, the mechanisms of tea phytochemicals possibly capable of decreasing the risk of depressive symptoms are complex, multifaceted and not well understood.Potent pharmacological effects on circumscribed neurobiological systems may be produced not by individual tea components but rather by the synergistic action of various compounds on multiple pathophysiological mechanisms involved in depression.While epidemiological studies have generally demonstrated beneficial effects of tea consumption on mood and depressive symptoms, cross-sectional studies are unable to prove a cause-effect relationship.If positive effects on mood could be firmly established, tea drinking could support mental health.However, the moderate antidepressive effects observed in healthy people are not necessarily indicative of possible clinical effects in major depressive disorder.Randomized controlled intervention studies are needed to establish a causal relationship between bioactive compounds in tea and depression.

1.Introduction

Major depressive disorder is a highly debilitating mental disorder and has, with a prevalence of approximately 15% among adults in high-income countries [1], become an important public health issue.Depression is characterized by significantly depressed mood,anhedonia and altered cognitive functions [2], which severely diminish the quality of life and social functioning of people affected [3].Depressive disorders have been estimated to account for almost 10% of all years lived with disability [4].Furthermore, subclinical depressive symptoms are common in healthy individuals [5].A degree of non-response to drug therapy in up to 60% of patients with major depressive disorder poses a major challenge in the treatment of depression [3,6].Psychotherapy is relatively expensive [7]and is ineffective in severe depression [8].In light of the limited ability of pharmacotherapy and psychotherapy to mitigate disease burden [9],the search for alternative avenues in the prevention and therapy of depression has received growing attention.Lifestyle is increasingly recognized as a potentially modifiable factor influencing the incidence and outcomes of mental disorders including depression [10].The investigation of nutrition, dietary patterns and food bioactives may be of value in this respect, since diet quality has been found to be a modifiable risk factor for mental disorders [10,11].For example,the consumption of Mediterranean-type diets, with a high intake of vegetables, fruits, seeds, nuts, wholegrains and fish as well as low amounts of processed foods, appears to be negatively associated with risk of depression [12-14], whereas Western-style diets, with high amounts of sugar, fat and processed foods, have been shown to be positively correlated with depression [12].Several systematic reviews have reported this association between diet and depression, and reverse causality does not appear to provide an explanation for this relationship [12,14,15].Furthermore, potential therapeutic benefits of various food bioactives, including antioxidants, probiotics and polyunsaturated fatty acids, on mental disorders including depression have been studied [16-23].The effects of tea and its bioactive compounds on depression could warrant investigation, since tea is globally one of the most commonly consumed beverages.

Both the stimulating and calming effects of the tea plant (Camellia sinensis) have long been known and have aided in meditation or relaxation.However, scientific interest in the effects of tea on cognition and mood has only recently begun to develop, prompting various studies attempting to identify the major active compounds of tea that may help alleviate mental disorders including depression,anxiety and age-related cognitive decline [24,25].Epidemiological studies have linked tea consumption to reduced levels of psychological stress [26]and depression [27].Potential benefits of green tea consumption in the prevention of depression have been hypothesized to be due to, among other factors, stress relief and antiinflammatory effects [28].Several other mechanisms appear to be involved in the pathophysiology of depression and may be targets of tea compounds.This short narrative review describes the potential contribution of tea and its bioactive compounds to the prevention and treatment of depression.

2.Mechanistic actions of tea compounds in depression

The neurobiology of depression appears to be multifaceted, and the mechanisms underlying the pathophysiology of major depressive disorder are not completely understood.Different etiologies may be capable of causing depressive episodes, and various biological or psychosocial stressors may cause different pathogenetic trajectories and may therefore respond to different interventions.While extensive investigations in animal models have suggested several neurobiological explanations of depression, the translational relevance of these finding in humans remains unclear [29].The monoamine theory of major depressive disorder suggests a major role of monoamine neurotransmitters, i.e.serotonin, noradrenaline and dopamine, in the pathogenesis of depression and is supported by findings showing that enhancing monoamine neurotransmission through the administration of monoamine oxidase inhibitors and tricyclic antidepressants has some therapeutic efficacy [30].Structural neuroimaging studies have demonstrated significant reductions in hippocampal volume in individuals with depression [31].Alterations in the hypothalamic-pituitary-adrenal (HPA) axis and elevated plasma cortisol levels, which are the result of an excessive stressrelated release of cortisol and an impaired inhibition of glucocorticoid receptor-mediated feedback, have consistently been found in severe depression [32].Furthermore, a role of inflammation in the causation and exacerbation of depression has been suggested and is supported by findings including an increased prevalence of depression in individuals with severe infections, an association of inflammatory proteins with depressive symptoms and microglial activation and neuroinflammation observed in the brains of people with depression [33-35].Brain-derived neurotrophic factor may also play a role in the pathophysiology of depression [36], since it has been demonstrated to influence neurogenesis in the hippocampus [37]and to protect against stress-induced neuronal damage [38].Neurogenesis and neuroplasticity at a cellular level can be altered by inflammation and dysfunction of the HPA axis, both of which can be caused by environmental stress [39].The gut microbiota and intestinal microbial dysbiosis have also been implicated in depression [40,41].Moreover,a moderate genetic influence on major depressive disorder has been found [42], and epigenetic mechanisms may also be important [43].Some of these neurobiological explanations, such as the monoamine theory, are too reductionist to be able to provide a comprehensive theory of depression.A complex interaction of multiple dysfunctional systems may form the biological basis of depression [44,45], possibly with different pathogenetic mechanisms contributing in varying degrees to a seemingly uniform phenotype of clinical depression.

The association of the Mediterranean diet with a decrease in the risk of depression has led to speculation that the high polyphenol content of foods commonly present in this type of diet may play a role in the amelioration of depressive symptoms.A systematic review of 20 observational and 17 experimental studies on the relationship between polyphenol intake and depression scores in adults aged 18–80 years has recently been undertaken [46].Twenty-nine studies reported a statistically significant effect of dietary polyphenols on depression, with polyphenol consumption inversely associated with depression risk and with alleviation of depressive symptoms [46].The effects of tea on depression are worthy of exploration, since tea is a major source of dietary intake of polyphenols [47,48].Polyphenols contained in tea, particularly catechins, are capable of entering the brain [49]and may play a protective role against the development of depression [50].Several other mechanisms may explain the inverse association observed between tea consumption and depression risk.For example, the amino acid theanine(γ-glutamylethylamide) has been shown to exert antidepressant effects in humans [51].Furthermore, another compound of tea,folate, also seems to have protective effects against depression [52].However, a cause-and-effect relation between tea components and depression remains to be established.

In regard to depressive disorders, the major pathophysiological mechanisms currently investigated include changes within monoaminergic systems, stress and impaired HPA axis activity,inflammation and altered neurogenesis and neuroplasticity.A detailed review of the available studies on the effects of various tea compounds on these mechanisms has recently been published [53].A short summary of beneficial effects of tea compounds based on this review is presented in Table 1.However, it is important to note that the majority of the findings are from preclinical studies.Their translational relevance to clinical conditions in humans is as yet unknown, i.e., it is unclear whether or to what degree these changes in biological parameters might contribute to improvements in the clinical symptomatology of depression.

Table 1Beneficial effects of various tea compounds on the main pathophysiological mechanisms investigated in depression (based on review by Rothenberg and Zhang(2019) [53]).

3.Tea compounds in animal models of depression

Various animal studies have investigated the impact of tea compounds on psychological stress and anxiety [25,54]; stressreducing and anxiolytic effects may contribute to the relief of depressive symptoms.Specific animal models of depression are mainly selected according to their ability to reflect the effects of known antidepressant medications in humans.The commonly used models rely on behavioral paradigms such as learned helplessness,social defeat and chronic mild stress; behavioral screening of antidepressants in rodents is frequently performed using the forcedswim test and the tail-suspension test [55].For example, tea polyphenols [56]and theanine [57]have been shown to improve behavioral depression in mice models.In comparison with controls,the administration of theanine (1, 4 and 20 mg/kg) improved the performance of mice in the tail-suspension and forced-swim tests [58].The antagonistic effects of theanine on reserpine-induced ptosis and hypothermia suggests an effect mediated by monoamine neurotransmitters [58].An antidepressant effect as indicated by decreased immobility in the forced-swim test was also found in another study [59].This effect was at least partly mediated through induction of brain-derived neurotrophic factor in the hippocampus and, thus, through effects on neurogenesis and neuroplasticity.In a rat model of depression using chronic unpredictable mild stress, the oral administration ofL-theanine has been shown to improve depressivelike behaviors and to increase dopamine and serotonin concentrations in the prefrontal cortex, nucleus accumbens and hippocampus, when compared to controls [60].

Although the findings of available animal studies appear to support the efficacy of tea compounds in respect to depressive symptoms, it should be emphasized that the ability of rodents and other animal models to represent human mental states and disturbances is limited.

3.Tea compounds in human studies of depression

3.1 Observational studies

While the wide range of positive findings on depression-related pathophysiology in animal models is suggestive of a role of tea compounds in the prevention and treatment of depression, of greater interest is their efficacy in humans with depression.

The cross-sectional MEDIS study comprising 2 718 elderly people from Mediterranean islands examined the association of a wide range of dietary habits with depression [61].The dietary factors analyzed included the frequency and quantity offish, meat, vegetable,legume, coffee, tea and alcoholic beverage intake.The evaluation of the association of these factors with depression found that daily consumption of tea showed the lowest risk ratio (risk ratio: 0.51; 95%confidence interval: 0.40-0.65), suggesting a risk reduction resulting from daily tea intake [61].

An inverse relationship between depression and consumption of green tea has been found in several epidemiological studies,suggesting that green tea may be helpful in the prevention of depression.For example, a study from Korea, using data from a large nationally representative survey, investigated the association of green tea intake, as assessed using a validated food frequency questionnaire,with self-reported lifetime depression in 9 576 adults [62].Frequent consumption of green tea (≥ 3 cups/week) was associated with a 21% reduction in the prevalence of depression compared to nonconsumption following adjustment for potential confounders (odds ratio 0.79, 95% confidence interval 0.63-0.99) [62].In 537 Japanese adults aged 20–68 years, an association was observed between higher green tea consumption and a lower prevalence of depressive symptoms.In comparison with individuals consuming ≤ 1 cup/day,those with an intake of ≥ 4 cups green tea/day showed a prevalence reduction by 51% [63].While greater tea consumption was negatively correlated with depressive symptoms in Japanese and Korean populations [26,62,63], no association was found between severe depression and intake of tea in middle-aged Finnish males [64].However, this study was based on a diagnosis of severe depression at discharge from hospital and excluded non-hospitalized people with mild or moderate depression.

Several studies examining the association between tea drinking and depressive symptoms have focused on older people.In a study of 1 058 older individuals in Japan, more frequent consumption of green tea (≥ 4 cups daily) was associatedwith a decrease in the prevalence of severe depressive symptoms by 52% in comparison with infrequent intake (≤ 1 cup/day) [28].A community-based study of older Chinese people reported that daily tea consumption of 1 cup/day was associated with a reduction in therisk of depressive symptoms by 41% compared to no or irregular consumption of tea [65].Based on a nationally representative sample (Chinese Longitudinal Healthy Longevity Survey), consistent and frequent tea intake was found to be associated with significantly lower occurrence of depressive symptoms,as assessed using a 5-item depressive symptom scale, in people aged 65 years and older [66].Future studies are required to assess whether tea drinking could support mental health in older people.

A meta-analysis, including 13 observational studies (8 crosssectional and 5 cohort reports comprising a total of 22 817 participants with 4 743 cases of depression), evaluated the association between tea consumption and risk of depression [67].This analysis found that individuals with a higher tea consumption had a lower risk of depression than those with a lower intake of tea (pooled risk ratio: 0.69; 95% confidence interval: 0.63–0.75).Dose-response analysis based on 10 600 participants with 2 107 cases found a linear association between tea consumption and depression risk, with an increment of 3 cups of tea daily associated with a risk reduction by 37% (risk ratio: 0.63; 95% confidence interval: 0.55–0.71) [67].These findings suggest that tea consumption is associated with a reduced risk of depression.The aggregated risk ratio for studies assessing green tea (n= 3) was similar to those examining diverse tea types (i.e.oolong, black, white and puerh teas) [67].A more recent meta-analysis included 15 observational studies (9 cross-sectional and 6 prospective studies comprising a total of 347 691 participants with 20 572 cases of depression) of beverage consumption and depression and reported an inverse association between tea consumption and depression (pooled risk ratio of depression for high versus low categories of consumption: 0.71; 95% confidence interval:0.55–0.91) [68].

Taken together, the findings of meta-analyses of observational studies suggest that regular daily tea consumption may contribute to a decrease in the risk of depression in healthy people.However, the major limitation of observational studies is their inability to establish causal relationships.The highest level of evidence supporting a causal influence of tea and its components can be gained only by randomized controlled intervention studies.

3.2 Intervention studies

Clinical intervention studies in humans, particularly randomized placebo-controlled trials, assessing the effects of tea or its compounds on depression are rare.

In one such study, a 5-week, randomized, double-blind, placebocontrolled study comprising 74 healthy individuals examined the effects of oral administration of green tea versus placebo; the measures assessing depressive symptoms at the end of the study included scores on the 17-item Hamilton Rating Scale for Depression (HRSD-17)and the Montgomery-Asberg depression rating scale (MADRS) [69].Participants receiving green tea were shown to have reduced HRSD-17 and MADRS scores compared to placebo controls [69].This finding suggests that regular daily tea intake may contribute to a reduction in risk of depressive symptoms in healthy people.An open-label study investigated the effects of theanine on depressive symptoms in 20 individuals with major depressive disorders, who, at the beginning of the trial, had shown no remission under their antidepressant medication [70].The administration ofL-theanine (250 mg/day)for 8 weeks in addition to the current medication of the participants significantly reduced their Hamilton Depression Rating Scale(HAMD-21) score [70].A possible explanation of the antidepressive effects ofL-theanine could be related to stress reduction.Healthy volunteers who consumed a nutrient drink containing 200 mg ofL-theanine have been reported to have reduced cortisol levels and to feel more relaxed following the performance of stressinducing tasks, when compared to controls receiving placebo [71].Using magnetoencephalography, participants who were naturally more anxious were found to show an increase in alpha oscillatory activity, i.e.lower-frequency brainwaves indicating relaxed wakefulness [71].Several other studies have reported increased alpha brain wave activity in humans following theanine in different dosages [72,73].How this effect is mediated is unknown.

The paucity of available clinical studies does not allow any conclusions regarding the preventive and therapeutic efficacy of tea on depression.Placebo-controlled trials are needed to confirm the antidepressive effect of compounds contained in tea.

4.Future directions

While the available research findings of studies on potential pathophysiological mechanisms, observations and interventions in humans as well as animal models appear to point to the potential of tea and some of its chemical compounds in the prevention and treatment of depression, several cautionary notes need to be considered.

The impact of different types of tea on depressive symptoms requires further studies, since teas differ in their content of chemical compounds.For example, while the dry leaves of green tea contain around 30%–42% catechins, the amount in black tea leaves is reduced to 3%–10% due to oxidation during the manufacturing process [74].

The results of epidemiological studies suggesting beneficial effects of tea consumption on depression should be interpreted with caution, since other lifestyle factors, such as dietary habits, physical activity, smoking and alcohol intake, could also influence these findings.No conclusions regarding cause and effect can be drawn from cross-sectional studies.While consumption of green tea might decrease the occurrence of depressive symptoms, depression could also lead to a decline in the intake of tea.Therefore, prospective randomized controlled trials are needed to confirm the causal relation between tea consumption and depressive symptoms.

A variety of biological, social, environmental and cultural factors may be involved in the etiology of depression [3].Thus,depression is likely to be a pathogenetically, physiologically and clinically heterogeneous condition.The efficacy of tea compounds may therefore be confined to subgroups yet to be identified.There is unlikely to be a single bioactive tea compound that is efficaciousin the treatment of depressive disorders, and synergistic effects of various compounds may play a role.

Table 2Problems of available studies and factors for consideration in future research on the use of tea and its compounds in depression.

Various clinical aspects need to be taken into account when investigating tea and depression.For example, the comparison of the available studies in humans is problematic due to differences in diagnostic methods.While many studies relied on self-reporting of participants, others used more reliable semi-structured assessment tools or a clinical diagnosis made by specialists.Many studies on depression are confined to either community samples or clinical/medical samples, and their respective findings may not be generalizable to entire populations.The age groups included in such studies also need to be considered.

In regard to the potential therapeutic efficacy of tea components,their respective effects on depressive symptoms in individuals with mild, moderate and severe degrees of major depressive disorder should be considered.Furthermore, the choice of outcome measures is important.Most trials assessing medications in people with depression use rating scales, such as the Hamilton Depression Rating Scale [75].However, a statistically significant effect on the scores of such scales does not necessarily mean that the individual assessed has improved or feels better.Small though statistically significant improvements in scores may not be clinically noticeable by patients or physicians.A more helpful trial endpoint is the clinical relevance of the effect observed, i.e.whether an intervention really helps patients in their daily lives.The minimum difference in rating scale scores indicating a clinically relevant effect remains a matter of debate [76].

The role of reduced stress reactions associated with tea consumption requires further investigation.Various investigations in animals have suggested that theanine produces tranquilizing effects on the brain [77]; the stress response in humans has also been found to be decreased following oral intake of theanine [51].As well as the biological significance of tea compounds in the improvement of depression, the behavioral and social aspects of tea drinking, which is commonly accompanied by social activities, should be considered.A potential confounder in mental health-related tea research is the possible effect of the preparation and drinking of tea.A study addressing this issue examined whether the relaxing and stressrelieving effects of tea are linked to biological mechanisms or possibly to the social context of tea intake, since tea is often consumed during a period of rest or relaxation [78].This experimental study examined the effects in healthy males of drinking the equivalent of 4 cups of black tea for 6 weeks compared to a caffeinated placebo.Those consuming tea were demonstrated to recover more quickly from a stressful task, with a decrease in saliva cortisol concentrations to 53%of baseline levels within 50 min of the task in the groups drinking tea, compared to 73% in the placebo group [78].Tea drinkers also reported feeling more relaxed than those consuming the placebo drink.These findings of greater post-stress cortisol reduction and subjective relaxation suggest that the recovery from stress was mediated through biological mechanisms.However, the social and behavioral factors associated with consuming tea require further elucidation.

5.Conclusion

The available evidence, which derives from studies investigating mechanistic effects of tea, research on animal models as well as epidemiological studies and intervention trials in humans, suggests that compounds present in tea may have the potential to aid in the prevention of depression or in its treatment as an addition to established therapies.A wide range of possibly antidepressive biological activities of tea components have been reported.However,as long as the pathophysiological mechanisms of depression are poorly understood, an evaluation of the role of tea compounds in regard to neurobiological correlates of depression, such as dysfunction of the HPA axis, neuroinflammation, impaired neuroplasticity and altered monoaminergic neurotransmission, is difficult.While individual tea components may not exert potent pharmacological effects on circumscribed neurobiological systems, various compounds, such asL-theanine or polyphenols, may act simultaneously and synergistically on multiple pathophysiological mechanisms involved in depression,and the fine-tuning of these activities might ultimately lead to an overall risk reduction or therapeutic effect regarding depression.

The antidepressive effects of tea components in human studies appear to be moderate at best.In particular, mood improvement observed in healthy people should not lead to an overestimation of possible clinical effects in individuals with major depressive disorder.If positive effects on mood can be firmly established, tea drinking could become a cost-effective means in support of mental health, for example in older people.Randomized controlled intervention studies are needed to establish a causal relationship between depression and bioactive compounds present in tea.

Declaration of conflicting interest

The authors declare that there is no actual or potential conflict of interest.