Sepsis, arising from a dysregulated host response to severe infection, can result in multiple organ dysfunction (1). Sepsis has high morbidity and mortality, with approximately 1.75 million cases reported in the United States in 2014 (2), and an estimated 48.9 million cases worldwide in 2017, leading to 11 million deaths (3), making it the third leading cause of hospital deaths (4). Since sepsis imposes a huge economic burden on human health, identifying sepsis risk factors and reducing its incidence and associated mortality rates is vital. Despite deeply insights into sepsis’ pathophysiology, there remains limited knowledge about its associated risk factors.

SMI (severe mental illness) is a category of psychotic disorders that affect individual cognition, emotions, and behavioral functions, significantly impacting a person’s daily life, including social, occupational, and familial functioning. It lasts for a long time, is severe, and requires long-term professional treatment and support. SMI includes, but is not limited to, major depression, schizophrenia, and bipolar disorders. Individuals with SMI are prone to suffer from physical illness (5) such as diabetes (6) and cardiovascular disease (7). Some studies have indicated that individuals with SMI face an elevated risk of infections. Seminog OO et al. showed that SMI is a risk factor for pneumococcal disease (8). A nationwide, population-based, cross-sectional research indicated that individuals with SMI also had an elevated risk of HIV (human immunodeficiency virus), HBV (hepatitis B), and HCV (hepatitis C) (9). Furthermore, schizophrenia is associated with an increased risk of acute respiratory failure and mechanical ventilation (10). Additionally, the incidence of tuberculosis is higher in individuals with schizophrenia compared to the general population (11). A prospective population-based study showed that depression was associated with many types of infections including hepatitis, respiratory and urogenital infection (12).

Although SMI is substantiated to increase the risk of some types of infections, the association between SMI and sepsis or sepsis mortality is limited. In a prospective population-based study, Andersson NW found that depression elevated the risk of sepsis (12). The mortality in patients with SMI is significantly higher than in the general population (13). A systematic review and meta-analysis showed that patients with schizophrenia suffered an average of 14.5 years of potential life lost (14). However, when it comes to sepsis mortality, the association between SMI and sepsis mortality is controversial (15, 16). Additionally, the causal association between SMI and sepsis or sepsis mortality is restricted to traditional observational studies, in which confounding biases could not be entirely excluded. MR (mendelian randomization) can minimize confounding biases and overcome the limitations of traditional observational studies. Thus, we performed MR to better establish the causality between SMI and sepsis.

Our study aimed to investigate the causal relationships between SMI and sepsis or sepsis mortality using MR techniques. SMI includes major depression and schizophrenia. We hypothesized that there would be a directional causal effect between SMI and sepsis or sepsis mortality.

We investigated the causal connections between SMI and the risk of sepsis or sepsis mortality by MR analysis in individuals of European ancestry. Our findings suggest that genetically predicted major depression is suggestively associated with an elevated risk of sepsis, however, no evidence was found to endorse an association between schizophrenia and sepsis. Furthermore, we observed no distinct link between SMI and sepsis mortality.

Observational studies have also reported an association between major depression and sepsis. Askim et al. identified that severe depression was linked to a moderate increase in sepsis risk among the general population reporting anxiety and depression symptoms, even after controlling for BMI, lifestyle, and comorbidities factors (19). In a Danish nationwide cohort study, patients with depression exhibited a more than twofold higher risk of sepsis diagnosed according to the International Classification of Diseases (12). In a study involving community-dwelling individuals in the United States, the connection between psychological distress and an elevated long-term sepsis risk could be partially attributed to depression (20). Whereas the mechanism underlying the causal association between depression and the heightened sepsis risk remains unclear.

The change in the immune system in individuals with depression may elucidate the increased sepsis risk (19). There is evidence showing that patients with major depression have increased proinflammatory cytokines (21). Interleukin-6 (22) and CRP (C-reactive protein) (23, 24) levels are strongly increased in patients with depressive disorders. Levine J et al. reported that individuals with depression exhibited higher CSF (Cerebrospinal Fluid) levels of IL-1β (25). In addition to the innate immune response, Miller AH et al. reminded us that adaptive immune responses, especially T cell responses, also contribute to depression. The author demonstrated that reductions in the quantity and efficacy of pertinent T cell subsets might play a direct role in the onset and persistence of depression (26–28). Another research also found that an increased level of soluble interleukin-2 receptor, indicating T cell activation, in individuals with depression (29). Furthermore, the alteration of the immune system in depressed individuals is partly similar to sepsis patients. Sepsis is characterized by a destructive balance of the immune system (30). In sepsis, hyperinflammation is primarily instigated by neutrophils and cytokines, which are part of the protective innate immune (31). Anti-inflammation reactions are triggered to regulate hyperinflammation, but they often lead to sustained immunosuppression (32). Immunosuppression is marked by a reduction in immune cells, such as CD4+ and CD8+ T cells, natural killer cells, and B cells (33–35). Thus, the change in the immune system in individuals with depression could contribute to the risk of sepsis.

Conversely, some studies have demonstrated that inflammation may elevate the risk of major depression, and pro-inflammatory cytokines can influence the brain, initiating the onset of depression (36, 37). In clinical settings, psychiatric impairments were observed in some sepsis patients, even after recovery from sepsis. The main psychiatric impairments include PTSD (posttraumatic stress disorder), cognitive impairment, and depression (38). Therefore, we further explored whether reverse causality existed between them. We conducted MR analyses using major depression as the outcome and sepsis as the exposure to assess reverse causation and found no association. The observations in clinical settings were not consistent with MR analysis, which may result from differences in race and sample. In addition, some biases in observational study cannot be excluded, more comprehensive and larger studies are needed.

Schizophrenia is also an SMI. In contrast to major depression, MR analysis indicated no evidence of schizophrenia being a risk factor for sepsis. However, some observational studies have shown an association between them. Daumit GL revealed that patients with schizophrenia had a minimum of twice the adjusted odds for intensive care unit admission and death due to respiratory failure or sepsis during hospitalization (39). Tokuda Y found that sepsis (7.3%) ranked as one of the primary causes of death in acute care hospitalizations among patients with schizophrenia (40). MR results in our study were inconsistent with observational studies, which may be explained by the administration of clozapine in schizophrenic patients. Clozapine is the only medication licensed for treatment-resistant schizophrenia. Ponsford M reported that the use of clozapine substantially decreased immunoglobulin levels, potentially contributing to higher rates of pneumonia and mortality related to sepsis (41). A case report showed that a schizophrenia patient who received clozapine for 4 weeks was diagnosed with clozapine-induced pancytopenia complicated by severe sepsis (42). In the future, it may be more accurate to evaluate the causal association between schizophrenia and sepsis after eliminating the confounding factor of clozapine. For example, patients treated with clozapine could be excluded.

Regarding sepsis mortality as the outcome, there was no causal link between SMI and sepsis mortality in our study. There were few studies related to sepsis mortality in patients with SMI, and the studies showed conflicting results. Two cohort studies in Denmark reported that people with SMI (schizophrenia, unipolar depression and bipolar affective disorder) have elevated mortality in the 30 days after sepsis (15, 43). On the contrary, Oud L reported that mental illness was linked to a markedly lower risk of short-term mortality in sepsis (44). Furthermore, a nationwide, population-based cohort study indicated an enhanced outcome in septic shock for individuals with SMI compared to those without, even when accounting for social disadvantages and comorbidities in physical health (16). Thus, the association between SMI and sepsis mortality need more large clinical trials.

Our study suggests that major depression is a risk factor for sepsis incidence. This finding can serve as a reminder for clinicians to consider the possibility of subsequent infection and sepsis in depressive patients, which may help reduce the incidence of sepsis in individuals with depression. Our study results are technically credible. MR analysis is more reliable method for evaluating causal associations than traditional observational studies. To obtain a robust MR estimate, the F statistics of instrumental variables in our study exceeded 100, which is larger than the typically used value of 10. We also excluded SNPs correlated with outcomes and addressed directional pleiotropy and heterogeneity. It’s noteworthy that all participants in our study were of European ancestry, which minimized population admixture.

Nevertheless, our study is subject to several limitations. Firstly, our results are confined to individuals of European descent, the study lacks ancestral and cultural diversity. Secondly, when performing power calculations for MR analysis between major depression and sepsis (http://cnsgenom-ics.com/shiny/mRnd/), the power was calculated to be 0.68, slightly lower than the typically used value of 0.8. Thirdly, our results were based solely on publicly available GWAS data. A more comprehensive clinical investigation may lead to more compelling conclusion.

Our investigation suggests that genetically predicted major depression is suggestively linked with an elevated risk of sepsis in individuals of European ancestry. This finding can serve as a reminder for clinicians to consider the possibility of subsequent infection and sepsis in depressive patients, potentially contributing to a reduction in sepsis incidence among individuals with depression.

All data are publicly available. Further inquiries can be directed to the corresponding authors.

RY: Visualization, Writing – original draft. HX: Formal analysis, Writing – original draft. TZ: Writing – review & editing, Conceptualization, Writing – original draft.