Depression and anxiety are common mental disorders. According to the World Health Organization, the estimated number of people globally who have depression and anxiety has increased by 18.4% and 14.9%, respectively, over the last ten years, totaling more than 300 million and 250 million, respectively [1
]. Women are more likely to have mental disorders than men [1
]. Large fluctuations of the serum estrogen level in the premenstrual, postpartum, and perimenopausal periods contribute to mood changes [2
]. An increased risk for mental disorders, including depression, is observed during the menopause transition [4
]; additionally, the early menopause transition and early menopause are significant risks for depression, which indicates that a short duration of exposure to endogenous estrogens can increase the risk for late-life depression [6
]. Estrogen plays neuroprotective, anti-depressive, and anti-anxiety roles via the regulation of serotonergic and noradrenergic systems [8
]; however, the associations between psychological symptoms and absolute serum sex hormone levels are inconsistent [3
]. Additionally, several reports have demonstrated the beneficial effects of hormone replacement therapy (HRT) on mood symptoms [10
], while a randomized controlled trial covering a wide age range of postmenopausal women failed to show the effects of HRT on depressive disorders [13
Furthermore, as there are increasing concerns about the side effects of HRT associated with cardiovascular diseases and hormone-sensitive cancers, such as breast, endometrial, and ovarian cancer, expectations for a complementary form of therapy are growing. Several reports have shown the association between specific nutrients, such as thiamine, folate, vitamin B6 and B12, zinc, and iron, and mental health [14
]; however, the psychological effects of dietary intake of various nutrients remain largely unknown, especially in peri- and postmenopausal women. This study thus investigated the associations between anxiety/depressive symptoms and dietary consumption of nutrients in Japanese middle-aged and elderly women.
The participants’ (n
= 289) mean age was 52.0 ± 6.9 years. The prevalence of mild, moderate, and severe anxiety was 54.0%, 28.7%, and 17.3%, respectively, and that of depression was 61.6%, 25.6%, and 12.8%, respectively. The participants’ background characteristics are shown in Table 1
and Table 2
. The participants with severe anxiety/depressive symptoms had a low quality of life according to the assessment using the MHR-QOL and were less frequently engaged in exercise. Moreover, the participants with severe depressive symptoms were younger than those with mild symptoms. There was no significant difference in body composition or the physical fitness test between the three severity groups.
First, we assessed the daily intake of 43 nutrients; then, we investigated the nutritional intake, which differed significantly between the three anxiety/depression severity groups. The intake of 10 and 22 nutrients showed significant differences between the three groups of anxiety and depression severity, respectively (Table 3
and Table S3
). Similarly, the background factors related to the severity of anxiety and depressive symptoms were investigated. The factors that were significantly related to anxiety were insomnia and depression scores, while the factors associated with depression were life satisfaction, social involvement, and anxiety scores. Next, to identify the independent variables among these nutrients related to the severity of anxiety/depressive symptoms, a stepwise regression analysis was performed after eliminating multicollinearity. We found that the severity of both anxiety and depressive symptoms was only significantly associated with the intake of vitamin B6. Finally, a multivariate logistic regression analysis was performed to identify the independent relationships between the daily intake of vitamin B6 and moderate-to-severe anxiety/depressive symptoms. After adjusting for age, menopausal status (model 2), and background factors that were significantly related to the severity of anxiety/depressive symptoms (model 3), the intake of vitamin B6 was significantly associated with moderate-to-severe depression (model 2: adjusted odds ratio (AOR) per 10 μg/MJ in vitamin B6 intake = 0.91, 95% confidence interval (CI) = 0.85–0.97; model 3: AOR = 0.89, 95% CI = 0.80–0.99), while there was no significant relationship between the intake of vitamin B6 and the severity of anxiety after adjusting for the background variables (AOR = 0.97, 95% CI = 0.90–1.04; Table 4
In our cross-sectional analysis, the severity of depressive symptoms was significantly inversely associated with the dietary intake of vitamin B6 in Japanese middle-aged and elderly women. Vitamin B6, which comprises six chemical compounds (pyridoxine, pyridoxamine, pyridoxal, and their phosphorylated derivatives pyridoxine 5′-phosphate, pyridoxamine 5′-phosphate, and pyridoxal 5′-phosphate (PLP)), is richly contained in red pepper, garlic, nuts, fish, and meats. PLP, the most active form, serves as an enzymatic cofactor in more than 140 different biochemical reactions, such as those involving amino acids, neurotransmitters, heme biosynthesis, fatty acid metabolism, and glycogen breakdown [27
It is well known that neurotransmitters, such as serotonin, dopamine, norepinephrine, γ-aminobutyric acid, and glutamate, play a critical role in the development of psychiatric disorders, and their receptors could be potential therapeutic targets for the treatment of psychoneurological symptoms. Abundant reports have shown that the dysregulation of monoamine systems contributes to anxiety and depressive disorders [29
]. Serotonin is synthesized from tryptophan by PLP-dependent dopa decarboxylase, and dopamine and norepinephrine production are also required for the catalysis of PLP-dependent dopa decarboxylase. Decreased vitamin B6 (PLP) could be associated with monoamine depletion and impaired neurotransmission. Furthermore, the kynurenine pathway involving two PLP-dependent enzymes, which is a major tryptophan metabolic pathway, is associated with depression [31
]. The disturbance of the balance between the neuroprotection and neurotoxicity of kynurenine pathway metabolites—i.e., kynurenines, such as kynurenic acid and quinolinic acid—plays a key role in the development of depression [32
]. It is supposed that PLP-dependent kynureninase is more sensitive to PLP deficiency than is the PLP-dependent kynurenine aminotransferase; thus, PLP deficiency reduces kynureninase activity first [33
]. Therefore, kynurenic acid, 3-hydroxykynurenine, and xanthurenic acid could increase, although, the changes in the plasma and urinary levels of kynurenines via vitamin B6 depletion are inconsistent [33
]. Kynurenic acid inhibits N-methyl-D-aspartate receptors and alfa-acetylcholine receptors in the central nervous system [36
], leading to a decline in the extracellular levels of acetylcholine, glutamate, and dopamine. Additionally, 3-hydroxykynurenine, which is a redox-active metabolite, is neurotoxic through generating reactive oxygen species and eventually induces apoptosis [38
], while xanthurenic acid acts as a metabolic glutamate 2/3 receptor agonist, which could improve positive and negative symptoms in schizophrenia [39
]. Vitamin B6 depletion might cause a dysregulated neurotransmitter system and neural dysfunction through imbalances of tryptophan metabolites via kynurenine.
There are several reports on the association between vitamin B6 and depression. Hvas and colleagues showed that low plasma levels of PLP were related to depressive symptoms in 140 study participants [40
]. A seven-year longitudinal study of 3503 adults aged ≥65 years demonstrated that a higher total intake of vitamin B6 (dietary and supplementary intake) was related to a lower likelihood of depression [41
]. Moreover, a higher dietary intake of vitamin B6 was associated with a lower incidence of depression among women in a three-year longitudinal study of 1793 adults aged ≥68 years [42
]. Additionally, a few systematic reviews of the effects on mood of vitamin B6 alone, or a combinative intervention of vitamins and minerals, such as folate, vitamin B12, vitamin C, vitamin D, magnesium, calcium, and iron, on mood supported the idea that supplementation with B6 vitamins could relieve mood symptoms. For example, Williams and colleagues reported the beneficial effects of vitamin B6 supplementation on depression among premenopausal women [43
]. Young and colleagues also revealed that the supplementation of B vitamins might alleviate mood symptoms in healthy adults and adults at risk for mental disorders [44
In contrast, several randomized controlled trials failed to find significant effects due to a combinative intervention of B vitamins, including vitamin B6, on mood symptoms [45
]. In the current study, the mean daily vitamin B6 intake was smaller than the recommended dietary allowance only in the severe depressive group [48
], which might affect our results. Further studies should be conducted to determine the exact effects of vitamin B6 as an independent treatment.
The major limitations of our study were the relatively small sample size and uncertain causal relationship owing to its cross-sectional nature. It may not be appropriate to generalize our findings to a wider population. We did not investigate the serum levels of vitamin B6, although we estimated the daily intake of vitamin B6 using the BDHQ. Therefore, it was uncertain whether the severity of depression was related to serum vitamin B6 levels. Furthermore, the BDHQ, which is a method based on food recall to determine the frequency of food eaten, provided information only for the 61 listed foods and beverages. In addition, a potential contributor to mood, namely, the use of dietary supplements, was not assessed. The use of dietary supplements, such as vitamins (B1, B2, B6, C, and E) and minerals (calcium and iron), has been estimated at only 7.7% in Japanese women [49
]. Nevertheless, the dietary intake in this study did not represent the total nutrient intake.
Nonetheless, our study has several strengths and novel features. As many as 43 nutrients and various background factors, including physical and psychological health status, life satisfaction, and social involvement, were analyzed simultaneously. Therefore, we found that the intake of vitamin B6 was independently associated with the severity of depressive symptoms. To the best of our knowledge, this is the first report on the relationship between the intake of vitamin B6 and depressive symptoms as a result of an analysis of various nutrients.
In conclusion, moderate-to-severe depressive symptoms were associated with a lower dietary intake of vitamin B6 in Japanese middle-aged and elderly women. A higher intake of vitamin B6 could help relieve depressive symptoms in this population.