Montelukast Induces Depressive‐Like Behaviour in ICR Young Mice Through Oxidative Stress and Inflammatory Response

ABSTRACT Background In response to the US Food and Drug Administration's black box warning highlighting the neuropsychiatric risks associated with montelukast, the mechanisms underlying these psychiatric adverse effects, particularly depression in paediatric populations, have remained poorly understood. Methods To address this, we examined whether montelukast induces depression‐like behaviours in an animal model and investigated the potential mechanisms. Young ICR mice were administered montelukast continuously for 28 days, and depression‐like behaviours were assessed using the open field test (OFT), tail suspension test (TST), and forced swim test (FST). Oxidative stress and inflammatory markers were analysed via RT‐qPCR, biochemical assays and western blot. Results Our results revealed that 24 h post‐montelukast administration, cysteinyl leukotriene receptor 1 and malondialdehyde (MDA) levels were significantly upregulated in the hippocampus, while glutathione (GSH), glutathione peroxidase 4 (GPx4), superoxide dismutase 2 (SOD2) and catalase (CAT) levels were downregulated. After 28 days of treatment, MDA levels remained elevated, and GSH, GPx4, SOD2 and CAT levels were further reduced. Additionally, hippocampal interleukin‐1β and serum corticosterone levels were increased, whereas hippocampal glucocorticoid receptor expression was decreased. Conclusions These findings collectively demonstrate that montelukast induces depression‐like behaviours in young ICR mice through mechanisms involving enhanced oxidative stress and inflammatory responses.