Depression constitutes a primary contributor to the global burden of disease stemming from psychiatric disorders due to its high prevalence, substantial disease burden, elevated suicide rates, and increased mortality, making it a significant global public health concern (1–3). Furthermore, depression is associated with various serious illnesses, including cardiovascular diseases, stroke, Alzheimer’s disease, cancer, and diabetes, collectively contributing to increased mortality rates among patients with depression (4–7). Therefore, identifying and addressing modifiable risk factors is crucial to extending the life expectancy of patients with depression.

During the COVID-19 pandemic in 2020, increased SARS-CoV-2 infection rates and reduced human mobility led to a significant rise in depression prevalence. Concurrently, elevated levels of the Systemic Immune-Inflammation Index (SII) were noted in COVID-19 patients (8, 9), suggesting inflammation as a potential shared pathophysiological mechanism between COVID-19 and depression. Previous studies have emphasized the critical roles of chronic inflammation and cell-mediated immune activation in depression pathogenesis (10, 11). Furthermore, large-scale cohort studies based on UK Biobank data have revealed that chronic inflammatory states play a key role in the complex associations between depression, various diseases, and mortality rates (12). Previous studies have confirmed that systemic inflammatory markers, such as SII and Systemic Inflammation Response Index (SIRI), are associated with increased risk of multiple diseases, including depression (13–15). However, research on the association between systemic inflammatory markers and mortality risk in patients with depression is limited. In addition, dietary patterns and components, as modifiable lifestyle factors, have been demonstrated to regulate systemic inflammation levels and influence the onset and progression of diseases. For instance, the Mediterranean diet (rich in fruits, vegetables, olive oil, whole grains, etc.) is associated with lower inflammation levels and prevention of cardiovascular disease (CVD) and metabolic syndrome (16–18). In contrast, the Western diet (high in red meat, high-fat dairy products, refined grains, etc.) is linked to higher inflammation levels, hyperlipidemia, CVD, metabolic syndrome, and cancer development (19–21). Additionally, specific nutrients, including carbohydrates, polyunsaturated fatty acids, and vitamins C/D/E, are associated with lower inflammation levels (22–24). Researchers at the University of South Carolina developed the Dietary Inflammatory Index (DII) by integrating cell culture, animal studies, and epidemiological research to assess the overall inflammatory potential of diets, and found that this index correlates with levels of inflammation (25, 26).

The aforementioned studies indicate that inflammation is not only associated with depression but also linked to an increased risk of mortality in depression patients. As a modifiable lifestyle factor, the DII can improve systemic inflammation levels in depression patients. However, the interplay between DII, systemic inflammatory markers, and depression mortality risk remains underexplored. Further investigation in this area is crucial for improving patient outcomes through dietary interventions. This study aims to explore the associations between DII, systemic inflammatory markers, and depression mortality risk using data from the National Health and Nutrition Examination Survey (NHANES) and the National Death Index (NDI) from 2005 to 2018.

This study conducted a prospective cohort study on adult Americans with depression to explore the associations of DII, SII, and SIRI with all-cause and CVD mortality risks. Based on quartile categorization of SII/SIRI, the highest quartile of SII was significantly associated with CVD mortality risk, whereas the highest quartile of SIRI was significantly associated with both all-cause and CVD mortality risks. Further analysis revealed that ln SII/SIRI remained significantly associated with all-cause and CVD mortality risks across all models, even after excluding cardiovascular diseases and cancer. This finding has not received adequate attention in previous studies.

In contrast, Zhang et al. (30) analyzed NHANES data from 2007 to 2018 and found a significant positive association between the highest quartile of DII and both all-cause and CVD mortality risks among non-cancer depressive patients, whereas no significant association with all-cause mortality risk was observed among depressive patients with combined cancer. Our results indicate that, after adjusting for covariates, the highest quartile of DII is significantly associated with cancer-specific mortality risk among depressive patients. However, using RCS categorization, DII ≥ 1.62 was found to be significantly associated with all-cause and CVD mortality risks. A meta-analysis demonstrated that dietary patterns can significantly improve inflammatory biomarkers (31). Similarly, our study found that after adjusting for covariates, DII was not significantly associated with the highest quartiles of SII/SIRI, but showed significant associations with SII (continuous variable) and ln SII. Through RCS analysis, we identified a beneficial DII threshold of 1.62. When ln SII/SIRI was included as a covariate, DII ≥ 1.62 was significantly associated with all-cause and CVD mortality risks in depressed patients. Additionally, ln SII was found to mediate the relationship between DII and all-cause and CVD mortality risks, with this mediation effect exhibiting gender differences. However, after excluding patients who died within 12 months of follow-up, and those with CVD and cancer, the association with CVD mortality risk was no longer significant. This study also identified a significant linear dose–response relationship between DII and all-cause mortality risk. Previous research on DII and average annual weight change has reported a similar linear relationship (32). Zhang’s et al. (30) study found that the median DII for the most pro-inflammatory quartile was 2.1 and 2.2. In contrast, our study’s median DII was 1.62, and 1.58 after adjusting for confounding factors, reflecting a potential inflammatory dietary pattern among U.S. adults with depression. Modifying dietary patterns may help prevent the overall health decline following depression.

Systemic chronic inflammation is increasingly recognized as a crucial factor in the development and exacerbation of chronic diseases. A large-scale community cohort study based on the UK Biobank revealed that the primary pathways to depression-related mortality involve three disease clusters: cardiometabolic diseases, chronic inflammatory diseases, and tobacco-related diseases (12). The exploration of the relationship between mood disorders and the immune system began over two decades ago. Numerous clinical and epidemiological studies have since shown that chronic inflammation is prevalent among depression patients, potentially contributing to poor treatment response and prognosis (33–37). With the advancement of RNA sequencing technology, researchers have identified genetic variations and gene expression pathways related to inflammation in the pathogenesis of depression. Polymorphisms in genes such as IL-1β, IL-6, IL-10, TNF, MCP1/CCL2, CRP, and phospholipase A2 are among the most consistently observed findings in major depressive disorder (38). Currently, there are no large-scale clinical trials specifically investigating anti-inflammatory treatments for depression. Immune-mediated dysfunctions exhibit stage-specific characteristics, but studies have indicated significant anti-inflammatory properties and alleviation of depressive symptoms with vitamin D, selective serotonin reuptake inhibitors, and non-steroidal anti-inflammatory drugs (39–41). This suggests a potential cumulative effect between inflammation levels and depressive symptoms.

An elevated neutrophil-to-lymphocyte ratio (NLR) indicates an imbalance between innate and adaptive immune cells. Research has shown that chronic stress can lead to increased NLR, a finding confirmed in both animal models and human studies (42, 43). Neutrophils, in response to persistent stimuli, undergo a series of reactions culminating in the formation of neutrophil extracellular traps (NET). NETs serve as a bridge linking inflammation, innate immunity, oxidative stress, and cardiovascular diseases (44). Additionally, through platelet–neutrophil interactions, NET formation significantly contributes to the progression of atherosclerosis and plays a crucial role in acute coronary syndrome among patients with depression (45). These interactions localize platelets to inflammation sites, enhance reactive oxygen species production, promote thrombosis, and activate neutrophils, a key step in NET release (46, 47). Moreover, the differentiation of monocytes into macrophages or dendritic cells plays a crucial role in the progression of atherosclerosis (48). In patients with depression, activated monocytes release elevated levels of IL-6, exacerbating this process (49). Chronic inflammation not only raises the risk of CVD mortality but also heightens suicide risk among depressed individuals. A genome-wide association study based on the UK Biobank identified a link between IL-6 signaling and suicidal tendencies (34). Additionally, chronic inflammatory conditions such as asthma, osteoarthritis, and other inflammatory arthritides can further elevate mortality risk in depressed patients (12).

From a biological perspective, while extensive research has demonstrated the detrimental effects of inflammation, it is inherently a protective mechanism in the body, employed to fend off invasive harmful substances (50). This study observed a linear relationship between the DII and all-cause mortality risk in depressed patients, as demonstrated through RCS and sensitivity analyses. This linearity simplifies the interpretation of DII’s significance, highlighting its association with positive health outcomes and facilitating behavioral changes when necessary. Previous research has indicated that a DII < 2.74 can reduce depression risk (51). Our findings suggest that a DII < 1.57–1.62 can lower all-cause mortality risk in depressed patients, indicating a certain tolerance to pro-inflammatory diets among U.S. adults with depression. In multiple linear regression analyses, DII consistently exhibited a significant positive correlation with both SII and ln SII. Additionally, correlation analysis revealed significant associations between DII and various blood cell counts (Supplementary Table S14). These findings align with previous research (52), including 10 survey cycles of the NHANES study, which demonstrated a significant positive linear relationship between DII and SII (53). The positive correlation between DII and inflammatory markers suggests that dietary modifications could help reduce chronic inflammation in the body. Previous studies have shown that adherence to prudent, Mediterranean, or other anti-inflammatory diets can effectively lower levels of inflammatory markers in humans (54, 55). This study also found that a DII ≥1.62 not only directly increased the all-cause mortality risk in patients with depression but also indirectly influenced this risk through ln SII, with a more pronounced mediation effect in males (increased PM). Additionally, females had significantly higher weighted DII (1.64 ± 0.04) and SII (595.84 ± 9.29) compared to males (0.84 ± 0.05; 546.56 ± 8.08; p < 0.001). Mediation analysis by gender revealed an increased ADE in females across all groups. Women are at a higher risk of developing depression compared to men (56, 57), potentially due to their greater susceptibility to inflammation-induced emotional and behavioral changes (58). Conversely, depression has a more pronounced impact on mortality in men, possibly related to sex differences in telomere (59, 60). Diets with high DII may accelerate telomere shortening, which is associated with increased mortality risk (61, 62). Women generally have longer telomeres than men; although estrogen is pro-inflammatory, its response elements in the telomerase catalytic subunit promoter enhance telomerase production and activity (63–65). In addition, depression itself increases mortality rates not only due to the heightened risk of comorbid conditions like asthma and inflammatory arthritis but also from non-natural causes and medication-related risks (12, 66, 67). By comprehensively assessing dietary habits and systemic inflammation markers, early identification of health risks in depressed patients can inform tailored dietary interventions. Such interventions hold potential to enhance overall prognosis among adult depression patients in the United States.

This study has several limitations. Firstly, only 28 food parameters were used to construct the DII score, as data for the remaining 17 were unavailable. Nevertheless, the DII score remains valid when calculated with fewer than 30 nutritional parameters (68, 69). Secondly, although the data on depression and diet were validated and based on repeated measures, the use of self-reported 24-h dietary recalls and the PHQ-9 for DII and depression scores may introduce recall bias. However, the validated and repeated nature of these records helps mitigate this concern. Thirdly, despite employing inverse probability weighting and mediation analysis, the cross-sectional design of the data may limit causal inference. Future research should undertake further field intervention studies to provide stronger evidence regarding the relationship between DII and mortality risk in patients with depression.