Depression is the most common mental illness. Even among those who do not suffer from depression, many people experience depressed or melancholy moods on a daily basis. Being in a prolonged depressed state increases the risk of developing depression. Rather than starting treatment with antidepressants after depression has set in, attempts should be made to improve the depressed state in daily life as a form of preventive medicine, which could contribute to maintaining and improving mental health for many people. It has been suggested that regular daily tea consumption contributes to risk reduction in healthy individuals [1
]. It has also been suggested that L-theanine and polyphenols can function through multiple pathways simultaneously to collectively reduce the risk of depression. Furthermore, caffeine has also been reported to be involved in preventing depression [2
Key factors in depression include the excessive activation of the hypothalamus–pituitary–adrenal (HPA) axis, inflammation, a weakened monoaminergic system, reduced neurogenesis/neuroplasticity, and reduced diversity of the microbiome, affecting the gut–brain axis [1
]. In the stress response indicated by adrenal hypertrophy due to hyperexcitation of the HPA axis, we have reported that theanine (T) and arginine (A) reduce stress, whereas caffeine (C) and epigallocatechin gallate (EGCG, E) act to counteract their effects [3
], which can be assessed by the molar ratio of the sum of C and E to the sum of T and A, or CE/TA ratio. We have also shown that differences in the relative proportions of tea ingredients, according to the CE/TA ratio, affect stress responses in mice and humans [4
]. Therefore, we hypothesized that there is an optimal composition of tea components for improving depression-like moods.
The major components of green tea are EGCG, caffeine, theanine, and arginine, and the composition of these components varies depending on the type of tea (matcha, gyokuro, sencha, bancha, etc.), the quality (high, medium, or low grade), and the brewing conditions, including the temperature of the hot water and the brewing time [7
]. To address this complexity, in this study we evaluated the depression reduction effect of green tea in terms of the difference in composition balance of the major components. For example, high-grade matcha tea is considered to have a CE/TA ratio of 1 to 3 because of its high content of theanine and arginine [4
]. Mid-grade sencha, which is high in catechins and caffeine, is considered to have a CE/TA ratio of 4–6 [10
]. Low-grade bancha, which contains less theanine, is considered to have a CE/TA ratio of 7–10.
To investigate the effects of green tea on depression-like moods, we used an experimental animal model of depression with lipopolysaccharide (LPS) to observe the effects of green tea on the organism’s stress response and inflammation. EGCG, theanine, and caffeine have each been reported to suppress levels of inflammatory cytokines induced by LPS [11
], but their effects when taken together in green tea have not yet been elucidated. In this study, we conducted an evaluation using LPS-injected mice, which are widely used as a model of depression, and focused on the effects of green tea on HPA axis excitation and inflammation in the brain, to scientifically investigate what kind of green tea may actually prevent progression to depression. We then evaluated the effect of green tea intake on the improvement of depressed mood using a questionnaire in healthy subjects.
In this study, the effects of green tea on depressed mood were examined based on animal experiments using a depressed mouse model and a clinical study on healthy subjects, to determine whether green tea consumption improves anxiety and depression-like moods. We injected LPS intraperitoneally into mice after feeding them green tea components with different CE/TA ratios for 6 days, and we analyzed changes in depressive behavior by SPT, adrenal hypertrophy, and gene expression of inflammatory cytokines in the hippocampus.
Mice that ingested green tea components with a CE/TA ratio of 2 or less showed inhibited adrenal hypertrophy and brain inflammation on the first day after LPS injection. This result is consistent with previous findings showing that green tea with a CE/TA ratio of 2 or less had a stress-reducing effect in mice that underwent psychosocial stress in the form of confrontational housing conditions [4
]. On the other hand, mice that consumed green tea components with a CE/TA ratio of 4 or higher showed increased adrenal hypertrophy and accelerated inflammatory responses in the brain. This was thought to be due to the counteracting effects of caffeine and EGCG against theanine and arginine [3
]. Theanine content differs between CE/TA ratios of 1–2 and 4–12 (Table 2
), but this difference is negligible, as we confirmed that if the CE/TA ratio is the same, the degree of adrenal hypertrophy is the same, even if there are differences in the amounts of theanine and other components [3
On the second day of LPS injection, adrenal hypertrophy and brain inflammation were expected to decrease. Interestingly, however, they were suppressed in mice fed green tea components with CE/TA ratios of 4 and 8, unlike the day-1 data. The reason for the change in optimal CE/TA ratio is unknown, but it is possible that the optimal composition changed as the body’s response changed from excitation to inhibition over time after application of the stress load [24
]. Therefore, at present, green tea with a CE/TA ratio of 2 to 8 is considered to be effective in suppressing depression. In addition, Naps4
expression was significantly decreased on the second day after LPS injection, but in mice that ingested green tea components with a CE/TA ratio of 4, no changes in expression were observed even when the mice were injected with LPS. This suggests the potential importance of ingesting green tea components, especially those with a CE/TA ratio of 4. We previously found that theanine intake increases Npas4
expression, which is decreased during stress [25
], suggesting that arginine, caffeine, and EGCG also affect its expression. It has been reported that decreased expression of Npas4
in the hippocampus is associated with depression and anxiety [23
], and that rats with higher Npas4
expression are more stress tolerant [27
]. Thus, increased Npas4
expression after LPS injection may be important in subsequent recovery. From this perspective, it was assumed that green tea with a CE/TA ratio of about 4 may have a mitigating effect on depressive-like moods. Therefore, we investigated the effects of green tea intake in healthy subjects.
After 2 weeks of consuming green tea with a CE/TA of 3.9, the subjects had significantly reduced anxiety compared to before green tea consumption. There were also lower depression questionnaire scores in both green tea groups (CE/TA = 3.9 and 4.7) compared to pre-consumption. Although it is necessary to consider the effects of subjective bias in the case of questionnaires, these results alongside the depressed mouse model indicate that green tea intake can reduce the biological stress response and inflammation in the brain, suggesting that improving depression-like moods with green tea intake is promising.
Although caffeine, theanine, and EGCG have been suggested to suppress the levels of inflammatory cytokines induced by LPS via the Toll-like receptor 4–NF-kB signaling pathway [11
], the effects may differ depending on their coexistence. Theanine also normalizes HPA axis hyperactivity [8
], while caffeine and EGCG have been found to antagonize this effect [3
]. A CE/TA ratio of 2 or less in green tea is required for excitement immediately after stress [4
], but a higher CE/TA ratio is predicted to be required for subsequent depression. Although the accumulation of oxidative injury is also thought to be important in depression [28
], consumption of green tea components did not significantly suppress elevated lipid peroxide in the cerebral cortex of LPS-injected mice (data not shown).
Much research has been conducted on the functionality of green tea components [29
], and the importance of green tea as a form of preventive medicine has attracted attention. However, differences in the functionality of green tea can occur depending on the type and quality of the tea. Therefore, in this study, we examined the actions of green tea based on the CE/TA ratio, which is the difference between its major components. This study has the following limitations: One is that there may be differences in CE/TA ratios for depressed mood between mice and humans. Another is the limitation of the CE/TA ratio in clinical trials. It is necessary to study green tea with CE/TA ratios other than the CE/TA ratio of 4 to 5 examined in this study. Further studies using green teas with different CE/TA ratios are needed, but the results suggest that consuming green tea with a CE/TA ratio of 4 to 5 improves depressed-like moods; the type of tea corresponding to this is sencha.