Background

Depression, a mental health condition that impacts the well-being of over 300 million individuals globally [1], has emerged as the leading contributor to disability-adjusted life years among mental disorders [2]. Accumulating evidence suggests that depression is associated with a heightened risk of multiple detrimental health outcomes, including all-cause and cancer mortality, as well as cardiovascular disease morbidity and mortality [3, 4]. However, traditional therapies for depression (e.g., medication) are costly and of limited efficacy [5]. Hence, identifying cost-effective strategies to prevent depression is paramount.

Physical health has garnered growing attention as a modifiable protective factor for depression. Whilst research has reported that low grip strength is a significant risk factor for new-onset depression [1], the role of lung function, which is recognized as an inexpensive, non-invasive, and modifiable indicator for assessing physical fitness, in preventing depression remains poorly understood. A review involving 1,161,632 subjects has shed light on the advantages of maintaining moderate or high levels of pulmonary fitness in the prevention of depression [6]. However, it remains unclear whether poor lung function, as measured by forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), is a direct risk factor for depression. Previous evidence on this topic has primarily focused on either the impact of lung diseases on depression or examined associations in the opposite direction [7, 1: Tables S5-S8). Stratification analysis discovered that detrimental effects of impaired lung function were stronger among individuals who were older, less educated, non-employed, living in areas with high TDI, and current or former smokers (Pfor interaction < 0.05) (Additional file 1: Fig. S1).

Fig. 2
figure 2

Restricted cubic spline analyses for the association of FVC (% predicted) and FEV1 (% predicted) with incident depression

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Table 2 Association between lung function and risk of incident depression
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Although impaired lung function was substantially associated with all selected biomarkers except monocyte percentage, hematocrit percentage, urea, and ALT, only some of them were significant predictors of depression risk, such as leukocyte count, neutrophil count and percentage, lymphocyte count and percentage, CRP, platelet count, erythrocyte count, RBC distribution width, hemoglobin concentration, cystatin C, urate, ALP, AST, GGT, TBIL, TP, and ALB (FDR < 0.05) (Additional file 1: Table S9). Hence, these biomarkers may serve as potential mediators from impaired lung function to incident depression. Additionally, lung function was significantly associated with most metabolites, but none of these metabolites were statistically associated with depression risk (Additional file 1: Table S10). Therefore, no metabolites are available as potential mediators of the association between impaired lung function and incident depression.

Figure 3 exhibits the PM of these potential mediators that were simultaneously associated with both lung function and incident depression. We observed significant mediating effects of inflammation, suggesting that impaired lung function might increase the risk of depression through the induction of inflammatory dysregulation (FDR < 0.05). Neutrophil count and CRP might explain 5.5% (95% CI = 3.2–9.8%) and 2.9% (1.0–5.8%) of the association, respectively. Markers related to erythrocytes and renal function might partially account for the increased risk of depression caused by impaired lung function. The overall effect of low lung function leading to an increased risk of depression might be partially explained by biomarkers related to liver function, with PM (95% CI) ranging from 0.4 (0.1–0.8%) to 5.9% (3.5–9.7%).

Fig. 3
figure 3

Association of lung function with incident depression mediated by biomarkers

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Discussion

Based on a large prospective cohort with a median follow-up of exceeding 13 years, our findings indicated that participants with impaired lung function had a higher risk of depression, independent of confounders including sociodemographic, lifestyle, environment, and comorbidities. The nonlinear dose-response curves revealed that the risk of new-onset depression was steeper at low lung function. Four biomarker pathways, including inflammation, erythrocytes, liver, and renal function, but not metabolite pathways, might partially mediate the association between impaired lung function and incident depression.

Supporting our findings, prior studies have documented a negative association between lung function and depression, but mostly using small samples, cross-sectional designs, or implemented in susceptible populations. A cross-sectional study from the National Health and Nutrition Examination Survey (NHANES) revealed a significant negative FVC-depression association [40, 41]. For instance, a cohort study involving more than 370,000 participants revealed a significant association between liver function markers, such as ALT, TBIL, ALB, TP, GGT, and ALP, and an elevated risk of lung disease [13]. Also, a MR study supported a causal relationship between lung diseases and renal function [14]. Remarkably, the relationship between liver and renal dysfunction and depression has been well established [40, 41].

The main strength of this study was the comprehensive examination of the prospective lung function-depression association and the preliminary exploration of the underlying biological mechanisms of the association. Other strengths comprised large sample sizes, long follow-up, sufficient adjustment for confounders, reliable methods for assessing lung function, and identification of depression from multiple sources including clinical diagnosis.

Several limitations should be considered. First, the participants in the cohort were overwhelmingly white, limiting the extrapolation of our findings. Second, most of the confounders are self-reported, which can introduce recall bias. Third, we did not find any statistical association between metabolites and incident depression cases, which may be due to the low rate of incident depression. Fourth, the methods we used to identify cases of depression may have insufficient power in identifying mild cases, which could lead to misclassification bias and thus obscure the associations found by the study. Nevertheless, sensitivity analyses after excluding possible cases of mild depression additionally identified by PHQ-2 at baseline did not substantially change the robustness of the associations. Fifth, although the UK Biobank cohort has a “healthy volunteer” bias that may affect the representativeness of our findings [42], the associations of risk factors in the cohort have been demonstrated to be similar to those found in the representative cohort [42]. Sixth, although we excluded the participants with a history of depression at baseline, the age of onset of depression is usually earlier than the lower age limit (37 years) of the UK Biobank sample, so caution is necessary in applying our findings to a younger population. Seventh, despite our efforts to control for a range of confounders, residual confounding may still exist. Eighth, the inherent nature of observational studies precludes us from drawing causal inferences. Further MR or clinical trials are warranted to confirm causality. Additionally, the mediation analysis method used in this study could only assess one mediator at a time to explore the single pathway of mediating mechanisms for associations between lung function and incident depression. Multiple pathways adopting serial mediation or structural equation model are needed in further studies. Finally, longitudinal mediation analyses necessitate a clear temporal relationship between variables, but the exposure and mediators in the present study were measured at the same time point due to data availability constraints. Nonetheless, the previously proposed lung-brain-axis hypothesis, which suggests that impaired lung function can affect brain structure via the blood pathway, may theoretically support the temporal relationship between the exposures and mediators in our study [43]. Caution is warranted in interpreting the mediation results, and future studies with well-defined temporal relationships are required to validate the mediating role of these markers.

Conclusions

Based on a large-scale prospective cohort, the study revealed that impaired lung function was associated with an increased risk of develo** depression. Regular screening of lung function in routine practice has the potential to facilitate the identification of at-risk populations and the development of personalized interventions, yielding profound clinical and public health implications. Additionally, our findings underscored that the biomarkers involving systemic inflammation, erythrocytes, and liver and renal function may partially mediate this association, but these mediation findings should be interpreted with caution due to potential temporal ambiguity. Further studies with repeatedly measured data are warranted to replicate our mediation findings.