Association and mechanism of montelukast on depression: A combination of clinical and network pharmacology study

Post-marketing surveillance found montelukast use was associated with an increased risk of depression. However, results of observational studies are inconsistent. This study aimed to assess whether montelukast exposure is associated with depression and elucidate the possible molecular mechanism. We conducted a cross-sectional study of 9508 adults from the National Health and Nutrition Examination Survey (NHANES) 2007–2016. Multivariable regression was used to evaluate the association between montelukast exposure and depression. Network pharmacology was conducted to identify the mechanisms of montelukast on depression. Montelukast exposure had a higher prevalence of depression (37.4 %). In a multivariable logistic regression model adjusted for sociodemographic, behavioural, and health characteristics, montelukast exposure was associated with depression (odds ratio [OR]: 1.61; confidence interval [CI]: 1.18–2.19). Network pharmacology was identified 69 key targets of montelukast on depression. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested montelukast mainly works through multiple pathways in endocrine resistance, chemical carcinogenesis-receptor activation, estrogen signaling pathway, etc. Cross-sectional data. The study implies a potential positive association between long-term montelukast exposure and depression through multi-faceted mechanisms. It is suggested that attention be given to the possibility of depression in patients undergoing prolonged montelukast therapy. •Montelukast exposure linked to higher depression prevalence (37.4%).•Montelukast use associated with increased depression risk (OR, 1.61; 95% CI, 1.18-2.19).•Montelukast exposure linked to depression via multi-target mechanisms.