Delirium is the most common psychiatric syndrome observed in hospitalized older adults after acute illness or surgery, defined by an acute decline and fluctuation of attention, cognitive function, and disturbance of consciousness (Wilson et al., 2020). The incidence ranges from 11 % to 51 %, depending on the setting or patient population (Gibb et al., 2020). Delirium is associated with a prolonged length of hospital stay, higher morbidity and mortality, cognitive decline, dementia, and poorer overall outcomes. The lack of effective treatments calls for the identification of modifiable risk factors and prevention strategies (Mattison, 2020; Marcantonio, 2017; Gleason et al., 2015).

Major depression (MD) is common in the elderly, with an overall 12-month prevalence of approximately 6 %, although there is considerable variation across countries (McCarron et al., 2021; Malhi and Mann, 2018). In observational studies, MD is a well-recognized risk factor for delirium, with risk in some studies having increased by two to three times (O'Sullivan et al., 2014; Oldham et al., 2019). Although delirium and depression frequently co-exist, observational studies cannot provide direct evidence of causality. The observational correlation between depression and delirium may indicate a predisposition to comorbidity in patients who share risk factors for neuropsychiatric disorders or simply reflect a lack of phenomenological precision that occurs with syndromal diagnoses. These previous studies controlled for various confounding factors; however, residual confounding is still inevitable. Therefore, genetic evidence for the potential role of antidepressant therapy in reducing the risk of delirium is lacking in large, population-based studies.

Mendelian randomization (MR) uses data from genetic studies to estimate the unconfounded relationships between exposures and outcomes (Emdin et al., 2019) Confounding factors are mitigated due to random assortment of genetic variants during meiosis. The MR method also prevents reverse causality, as genetic variants are fixed at conception and are unaffected by the disease process. If genetically predicted levels of a risk factor are associated with a disease outcome, then it is possible that the association between the risk factor and outcome has a causal basis (Bowden and Holmes, 2019). Here, we conducted a two-sample MR analysis based on summary data from large-scale genome-wide association studies (GWASs) to investigate the causal effect of MD on delirium.