Montelukast Use and the Risk of Neuropsychiatric Adverse Events in Children

To evaluate the potential association between montelukast use and the risk of neuropsychiatric adverse events in children and adolescents.This nationwide, register-based cohort study in Sweden included 74 291 children aged 6 to 17 years who were new users of either montelukast (n = 26 462) or long-acting β-agonists (LABAs) (n = 47 829) between January 2007 and November 2021. The mean age of the participants was 12.3 years.Researchers conducted an active-comparator, new-user cohort study comparing children initiating montelukast with those initiating LABA. Data were sourced from Swedish national registers. The primary outcome was a composite of any neuropsychiatric adverse event, which included secondary outcomes such as anxiety, depression, sleep-related disorders, suicidal actions, and others, identified through diagnosis codes and prescription drugs that were dispensed. The analysis used pooled logistic regression to estimate hazard ratios (HRs), with statistical adjustments made to reduce potential confounding and selection bias.During a mean follow-up of 5.8 months, there was no significant difference in the risk of neuropsychiatric adverse events between the 2 groups. The incidence rate of any neuropsychiatric adverse event was 2.39 per 100 patient-years for montelukast users and 2.41 per 100 patient-years for LABA users. The adjusted hazard ratio (HR) for the primary outcome was 0.99 (95% CI, 0.84–1.16). Analyses of specific secondary outcomes also showed no substantial differences in risk, including for anxiety (HR, 0.79), depression (HR, 1.16), sleep-related disorders (HR, 0.93), and suicide and suicidal actions (HR, 1.31). Findings remained consistent across various subgroup and sensitivity analyses.In this large, nationwide study, the use of montelukast was not associated with an increased risk of neuropsychiatric adverse events in children and adolescents when compared with the use of LABAs. The authors suggest these findings can inform the clinical management of asthma and allergic rhinitis in this population.This was a large-scale observational study addressing ongoing safety concerns about montelukast, particularly following the 2020 Food and Drug Administration boxed warning. The use of an active-comparator design with new users of LABAs is a significant strength, as it helps minimize confounding by indication that can affect studies on this topic. The comprehensive data from Swedish national registries allow for a large, unselected cohort, enhancing the generalizability of the results. The study’s finding of no increased risk adds to other studies that found similar findings. However, this is still a cohort study and not a randomized controlled trial, and many neuropsychiatric or behavioral adverse events may not have been documented by diagnostic codes. Furthermore, in a manufacturer-led post hoc analysis of montelukast clinical trials, the risk of behavior-related adverse experiences was analyzed using data from 35 and 11 placebo-controlled trials in adults and children (11 673 patients) who received montelukast; it evaluated odds ratios (ORs) of behavior-related adverse experiences vs placebo and found an OR of 2.17 (95% CI, 0.71-7.89) for children aged 12 to 17 years. There is still need for appropriate counseling and close observation in patients prescribed montelukast, but adverse effects should not be exaggerated.