In this nationally representative sample of US adults with depression, we found that overall dietary antioxidant intake significantly reduced the risk of all-cause and cancer mortality after adjusting for a wide range of potential confounders. To the best of our knowledge, this is the first study to report the associations of overall dietary antioxidant intake, evaluated by two dietary antioxidant indices, with the risk of all-cause and cause-specific mortality risk among adults with depression.
The associations between individual antioxidants and mortality have been extensively studied in previous studies, but the results were not entirely consistent (REF). For example, Agudo et al reported that higher intakes of vitamin A and C were significantly associated with a lower risk of all-cause mortality in a large prospective Spain cohort study with 41,358 subjects. A 10-year follow-up randomized nutrition intervention trial has also found the beneficial effects of vitamin A, E, and selenium on reducing total and cancer mortality. But Stepaniak et al did not find the significant associations between antioxidant intakes and mortality. Consistent with the above studies, we also found depressed adults with the highest intake of vitamin A and E had significantly lower risk of all-cause mortality, 38% and 36% respectively. Until now, the majority of antioxidants-mortality reported associations just focused on isolated individual nutrients. There is compelling evidence that the impact of food on health is influenced not only by individual nutrients but also by their interactions and synergies[33, 34]. Methods evaluating dietary overall antioxidant quality to investigate diet-disease associations may be more important and explicable than focusing on a single antioxidant[35, 36]. But it is spares that data pertains to the potential health benefits of overall antioxidant consumption on mortality among depressed adults. In this study, we found that overall antioxidant intake seems to have a stronger and more pronounced protective effect on mortality than individual antioxidants, and the depressed adults in the highest DAQs and DAI category had significantly lower risk of all-cause mortality, 47% and 46% respectively. Our findings provide potential evidence for the importance of comprehensive, rather than only single antioxidant intake in lowering mortality risk among depressed patients.
Depressed patients had more years of potential life loss (YPLL) and longer disability-adjusted life years (DALYs), compared with the general population[5, 37]. Moreover, patients with depression often had an unbalanced nutritional status owing to unhealthy lifestyles, non-compliance with dietary recommendations, and emotional eating[38, 39]. Emotional eating is the tendency to eat in response to negative emotions and is particularly associated with sweets and high-fat food intake, but not with fruits and vegetables[40]. Similarly, we compared the antioxidant intake among 3051 adults with depression and 3051 age- and sex-matched controls without depression in the present study, and the results illustrated that all antioxidant intakes were significantly lower in adults with depression than in those without (eTable 6 in the Supplement). However, limited evidence was available on the relationship between antioxidant and long-term health outcomes among depressed adults who had elevated death risk and poor antioxidant status. In the present study, we filled these research gaps and found the holistic intakes of vitamin A, C, E, zinc, selenium, and magnesium significantly reduced the risk of all-cause and cancer mortality among people with depression.
In addition, we also examined the cross-sectional association between overall antioxidant intake and depressive symptom severity, evaluated by the PHQ-9 score at baseline in the present study. Our result suggested that the combined intake of dietary antioxidants was negatively associated with depression severity, and the depression scores in the highest DAQs and DAI tertile were decreased by 0.87 and 0.60, respectively. Future studies, including larger longitudinal studies and clinical trials, are needed to replicate these findings. Thus, a comprehensive intake of foods rich in antioxidants such as fruits, vegetables, legumes, wholegrain cereals, nuts, and seeds should be recommended in the daily diet of depressed patients to improve depression symptoms and prevent premature death[41]. In subgroup analysis, we observed significant interactions between the overall dietary antioxidant intake and the predefined risk factors on mortality. Both DAQs and DAI showed a stronger negative association with mortality among overweight/obese participants, may be partly due to that they had higher oxidative stress level, and intake or supplementation with exogenous antioxidants appears to have a more prominently beneficial effect in people with high levels of innate reactive oxygen species (ROS)[42, 43]. The results were materially altered after we excluded the participants who died within 2 years and who self-reported cancer and CVD diseases at baseline in sensitivity analyses that illustrated the robustness of our results.
The potential beneficial effect of overall antioxidant intake on mortality may be partially due to its anti-inflammatory and antioxidant properties. Over the past decades, oxidative stress (OS) has been recognized as a key risk factor for depression, cancer, and death[44, 45]. Preclinical and clinical studies have shown that increased production of reactive oxygen species (ROS) and failure of antioxidant defense systems are responsible for structural changes in the brain [46, 47]. Along with increased OS, activation of pro-inflammatory signaling pathways is also involved in the pathogenesis of depression[48]. Some proinflammatory cytokines, such as IL-1β, IL-2, and TNF-α, may induce central nervous inflammation through oxidation and nitrosation stress (O&NS) pathways and thus induce depressive behavior[49, 50]. Meanwhile, ROS are involved in modulating various stages of tumor development, including transformation to malignant cells, tumor cell proliferation, invasion, and metastasis, playing an important role in cancer. However, antioxidants terminate these oxidative and inflammatory responses by scavenging free radical intermediates as well as by being oxidized themselves[51–53]. Previous randomized controlled trials indicated that antioxidant supplementation significantly improved oxidative stress and inflammatory markers [54–56]. Moreover, a study of 3853 Chinese women reported that both DAQs and DAI were inversely associated with levels of IL-1β and TNF-α [22], providing evidence for the biological mechanism of our study.
Strengths and Limitations
The strengths of the present study included prospective study design, primary focused on depressed people, use of individual as well as overall antioxidant indicators and consideration of a variety of important confounding factors. The relatively large sample size of depressed population which allows us to conduct stratified and sensitivity analyses. Moreover, the use of a nationally representative sample of US depressive adults, which increases the generalizability of our findings.
Our study also has several limitations. First, self-reported dietary intake is typically overestimated by report bias, and this may lead to an overestimation of the beneficial effects of antioxidants. Second, although the PHQ-9 is already a validated instrument to assess depressive symptoms, it cannot be used to clinically diagnose depressive disorders. Third, dietary habits change over time, and dietary information only at baseline without tracking the trajectory of change may not be representative of the long-term average exposure. Forth, death outcomes are determined by linking to the National Death Index using a probability matching method, which may lead to misclassification