Depression is associated with higher all-cause mortality rates.

Depression is one of the world’s most serious mental health problems (1). It has become a major disease that has the same adverse consequences on health and society as diabetes and hypertension. Depression not only causes psychological deterioration in daily life activities (2) but also negatively affects mood, cognition, somatic symptoms, feelings, thinking, and behaviors (3). It is also associated with physical changes such as weight loss, dullness of the eyes, loss of appetite, and marked fatigue (4). Moreover, according to World Health Organization (WHO) statistics, there are approximately 322 million patients with depression worldwide, and the incidence of depression is constantly increasing. A meta-analysis demonstrated a strong correlation between depression and an increased risk of death during the follow-up period (5). Depression has been shown to increase mortality among patients in different countries (6–8). In addition, depression leads to high rates of associated disability, making it one of the leading causes of the global burden of disability (4). In the US, depression may cause a 52% (5) increased risk of death. Fabiano et al., in their two recent meta-analyses, looked at how exercise affects suicide attempts or the risk of death; in their conclusion, they showed that exercise reduces people’s suicide attempts (9). Depression is also a prevalent risk factor for cardiovascular disease (10) and is independently associated with increased cardiovascular disease and mortality (11, 12). Depression combined with hypertension creates a toxic combination, leading to an increased risk of all-cause mortality (13). In addition, depression causes an annual economic burden of approximately $118 billion (14) and a considerable financial burden on health care (15). The global burden of disease is expected to be the leading cause of depression (16). Therefore, the prevention and treatment of depression remain public health priorities.

For people with mild to moderate or severe depression, the efficacy of drug therapy may be limited (17). The success rates of antidepressant medications and psychotherapy are approximately 72 and 50% (18, 19), respectively; only 10–25% of patients are affected to receive treatment for depressive symptoms, as medication can be costly and of limited efficacy for the majority of people with depression, with more than 75% of people in low- and middle-income countries not receiving treatment (20). Moreover, only approximately 30% of those treated respond to initial treatment. Given the high disease burden and societal costs, research studies must focus on alternative therapies and improving treatment outcomes (21). Physical activity (PA) is capable of producing multiple benefits, including psychological well-being. To achieve practical health benefits, the WHO recommends that all adults perform 150–300 min of moderate-intensity physical activity, 75–150 min of vigorous-intensity physical activity, or some equivalent combination of moderate-intensity and vigorous-intensity aerobic physical activity per week (22). As an effective treatment strategy for depression (23), PA has been shown to reduce symptoms of depression and can be a valuable addition to medications and psychotherapy (24). A meta-analysis found that physical activity reduces the risk of depression, offering significant benefits even at levels below the recommended amount; however, additional benefits diminish at higher activity volumes (25). PA interventions are virtually free of side effects and high costs associated with antidepressant medications and psychotherapy (26). PA combats depression through dual mechanisms: biologically by improving neuroplasticity, reducing inflammation and oxidative stress, and regulating the hypothalamic–pituitary–adrenal (HPA) axis, and psychologically by boosting self-esteem, social support, and self-efficacy (27). Additionally, PA reduces mortality risk by enhancing cardiorespiratory fitness (VO₂ max), preventing chronic diseases (e.g., type-2 diabetes [T2D] and cardiovascular diseases [CVD]), and activating survival pathways (e.g., AMPK/PGC-1α-mediated mitochondrial biogenesis, BDNF-dependent neuroprotection) (28). As an increasing number of people have a strong interest and expectation in the role of PA as a substitute for drugs (29), it may become a beneficial measure to reduce the risk of death in patients with depression with “the lowest cost and good effect.”

However, the majority of the of the published articles have focused on examining the effects of PA in terms of the prevalence of depression. Although PA has been shown to reduce mortality in different populations (30–33), there are still few studies on the association between PA and the risk of death in patients with depression. Therefore, this study utilizes on the NHANES database, which provides a nationally representative sample, to analyze the relationship between PA and the risk of death in patients with depression through a prospective cohort study. We hypothesize that achieving the recommended levels of PA can reduce mortality in depressed patients.

We used data from studies based on the publicly available U.S. National Health and Nutrition Examination Survey (NHANES: 2005–2018) population. National Health and Nutrition Examination Survey (NHANES), and their survival status was correlated with the U.S. National Death Index (NDI) database through the subject’s common serial number (SEQN). The analytic sample excluded individuals aged below 20 years who were not depressed and who did not have physical activity response data. All studies were approved by the institutional review boards of their coordinating agencies and adhered to the principles outlined in the Declaration of Helsinki.

Among these screened subjects, an association analysis was conducted between physical activity and mortality to evaluate the impact of physical activity on mortality risk. The study revealed that, as long as sufficient physical activity is carried out, regardless of the amount of physical activity, the mortality risk of depressed patients can be reduced compared with that of the group lacking physical activity. Moreover, the proportion of leisure physical activities is negatively correlated with the risk of patient mortality. Even for depressed patients with stroke or heart disease, engaging in physical activity can reduce the risk of death.

This study found that sufficient physical activity significantly reduces mortality among individuals with depression. With an estimated 322 million people affected by depression worldwide, these findings highlight the vital role of PA in clinical and public health strategies to prevent deaths. Unhealthy behaviors such as being sedentary and physical inactivity are associated with a significantly increased risk of developing depression (38). The 2018 PA Guidelines (39) state that physical inactivity is one of the leading threats to human life and health, leading to increased depressive symptoms and an elevated risk of death (40). Physical activity is an intervention that can be effective in reducing the risk of death in patients with clinical depression (41). A growing number of articles and evidence suggest that a certain level of PA has a protective role in treating depression and reducing all-cause mortality. PA is the basis of primary prevention of depression and plays an important role in every age and stage of depression, especially with regard to depression in the older adult population (42). There is an inverse linear relationship between PA and the severity of depression (43). The majority of the studies, which are consistent with the results of this study, have shown that sufficient PA can reduce the risk of death in depressed patients compared with a lack of PA. Still, the discussion of whether different amounts of PA can improve depressive symptoms and reduce the risk of death is controversial. Studies have consistently shown that performing a small amount of PA has a better antidepressant effect when the frequency of exercise is appropriate (44). With respect to PA intervention as a complementary treatment for depressed patients, different levels of PA have different effects on depression (41, 45). For people who do not engage in physical activity, even at levels below those public health recommendations, the prevalence of depression decreases, as well as improvement in depressive symptoms. The benefits do not increase significantly with excessive levels of physical activity, and additional benefits are limited (25). Several experiments have shown that patients with depression can experience greater and better therapeutic effects when they undergo moderate-intensity physical activity experiments under the guidance of an exercise specialist (46); There may be an independent correlation between the level of PA and all-cause mortality in depressed patients (47). Increased exercise activity is inversely associated with the risk of illness and the incidence of depression (47). Trivedi and coworkers used two different doses, one being the upper limit of public health recommendations, and compared it with the lower limit of public health recommendations. The median adherence rate to low doses was significantly better than that to high doses. One study for major depression suggested that the high-dose group may have better cyclic relief for all men and women without a family history of mental illness. In addition, some Mendelian randomization studies validated a causal relationship between physical activity and depression (48, 49). However, exercise therapy dosage should be judged on an individual basis, and perhaps for some people, low-dose exercise may lead to better results instead (50). In addition to demonstrating the benefits of sufficient PA in reducing the risk of death in depressed patients, in the present study, different amounts of PA were found to reduce the risk of death, and a PAV of 600–1,199 MET-min/week may be sufficient to reduce the risk of death in depressed patients. In addition, the optimal amount of PA to reduce the risk of death occurring at ≥9,000 MET-min/week may be due to bias caused by the small sample size. In addition, it is possible that excessive amounts of PA may increase the risk of sports injuries and mental stress (51, 52). Only a few studies have explored the relationship between PA and mortality in individuals with depression. Murri et al. reviewed the mechanisms underlying the potential protective effects of PA on cardiovascular mortality in patients with depression (53). Luo et al. found that MVPA, but not LPA, reduced the risk of mortality associated with mood disorders, including depression (54). Expanding on this, the present study further investigates the association between PA volume and purpose with mortality in patients with depression. PA may reduce the mortality of patients with depression through physiological and psychological pathways (27). Biologically, it enhances neuroplasticity, reduces inflammation and oxidative stress, and regulates the HPA axis (27). Psychologically, it promotes self-esteem, strengthens social support, and enhances self-efficacy (27).

There is evidence that PA for different purposes influences the relationship between PA and depression (55). Leisure PA interventions appear to be best suited to improving levels of depression (56), reducing patients’ risk of all-cause mortality. This article follows the WHO classification of PA into three categories for different purposes (leisure time, work, and transport trips). It concludes that people with depression can try to engage in leisure-based PA. White et al. reported that excessive work-related PA was associated with increased levels of depression, whereas leisure-type PA led to decreased levels of depression (57). The majority of the work and transport categories are designed to achieve PA and serve as external motivators. To a certain extent, excessive PA produces positive benefits to reduce mortality risk. Still, excessive PA, instead, causes some physical and mental stress (51, 52), resulting in the same high mortality risk as a lack of PA. In contrast, activities performed during leisure time are more likely to be seen as self-directed, enjoyable tasks (57). According to self-determination theory, autonomous motivation related to PA is more likely to produce psychological satisfaction (autonomy, competence, and relatedness), which, in turn, supports mental health (58). The RCS graphs in the article indicate a tendency to increase the risk of death after a certain amount of physical activity has been exceeded, followed by a decrease in risk when engaging in more physical activity. However, if recreational physical activity is performed consistently, it may have a better positive effect.

In previous findings, BMI was found to be positively correlated with levels of depression, which increased as BMI increased (59). In particular, when depressed patients have physical inactivity and unhealthy eating habits leading to weight gain and a high BMI (60), the risk of death is significantly greater. Thus, in contrast, having a normal BMI and engaging in sufficient PA have positive effects on improving depressive symptoms and reducing the risk of death. Depression is a significant public health problem in older adults compared with middle-aged adults (61). There is a huge impact on mortality when it is comorbid with chronic diseases (62). Chronic diseases such as hypertension place a higher burden on depressed patients, which in turn leads to lifestyle changes such as PA deficiency, increasing the risk of eventual mortality (63). Another example is low cardiorespiratory fitness (CRF), which is an indicator of physical inactivity (23). In other meta-analyses, CRF was found to be negatively correlated with depression severity in depressed patients (64), and performing sufficient PA can increase CRF levels in patients, which is beneficial to the physical and mental health of depressed patients and prolongs survival time. The above extensive literature shows that depressed patients have an exponentially increased risk of death when accompanied by chronic diseases such as cardiovascular disease, cancer, and diabetes (65). In addition, sufficient PA can reduce depressive symptoms, increase CRF, increase muscle strength, and sustainably lower blood pressure (40), which indirectly reduces the associated risk of death to some extent.

This study underscores the crucial role of PA in reducing mortality among individuals with depression, highlighting its potential as a non-pharmacological intervention. The findings demonstrate that various intensities of PA contribute to lowering depression-related mortality. Clinical guidelines should incorporate PA recommendations tailored to individual needs, with a minimum of 600–1,199 MET-min per week to effectively reduce the risk of death. Mental health professionals and primary care providers should integrate PA counseling into routine care for individuals with depression, ensuring they have access to appropriate exercise programs. Public health policies should prioritize PA promotion through initiatives such as community-based exercise programs, workplace wellness strategies, and insurance coverage for PA-based treatments. These combined efforts can contribute to a more comprehensive and effective approach to addressing depression and its associated challenges.

This study showed that sufficient PA can significantly reduce all-cause mortality in patients with depression, with three main findings: (1) PAV between 600–1,199 MET-min/week are associated with a reduced risk of mortality; (2) Leisure-time PA demonstrates a dose-dependent inverse correlation with mortality, proving more beneficial than work- or transport-related activities; and (3) The protective effects of PA persist even in depressed patients with comorbidities such as stroke or heart disease. These findings reinforce the role of PA as a non-pharmacological intervention and highlight the need for clinical guidelines to prioritize leisure-time PA. However, this study has some limitations, including self-reported PA data, potential unmeasured confounders, and the absence of longitudinal depression tracking. Future research should use accelerometer-based PA measurements, monitor depression dynamics, and conduct randomized trials to optimize PA prescriptions. This study underscores the need to integrate tailored PA interventions into global depression management to reduce premature mortality in this vulnerable population.