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Importance: Spontaneous reports have indicated that montelukast increases the risk of neuropsychiatric adverse events, and the US Food and Drug Administration added a boxed warning about these risks in 2020. However, the potential mechanism is not well understood, and the observational evidence is scarce, particularly in children.

Objective: To assess the potential association between the use of montelukast and the risk of neuropsychiatric adverse events in children and adolescents.

Design, Setting, and Participants: This nationwide register-based cohort study used data from Sweden from January 1, 2007, to November 30, 2021. Participants included children aged 6 to 17 years who used montelukast and long-acting β-agonists (LABA). Data analysis was performed from December 2023 to April 2024.

Exposure: Montelukast vs LABA.

Main Outcomes and Measures: The primary outcome, any neuropsychiatric adverse event, was a composite of secondary outcomes, including anxiety; depression; sleep-related disorders; suicide and suicidal actions; disrupted control of activity, attention, and behavior; and confusion and psychotic-like symptoms. Outcomes were defined on the basis of diagnosis codes and dispensings of prescription drugs for specific neuropsychiatric symptoms. Patients were followed up from drug initiation to discontinuation, and treatment and censoring weights were used to adjust for potential confounding on baseline and selection bias from informative censoring. Pooled logistic regression was used to estimate hazard ratios (HRs).

Results: The final cohort included 74 291 children (mean [SD] age, 12.3 [3.3] years; 35446 female [47.7%]); 26462 used montelukast and 47829 used LABA. During a mean (SD) follow-up of 5.8 (3.2) months, 310 neuropsychiatric adverse events in the montelukast patients and 566 events in the LABA patients were identified. In the weighted cohort, the incidence rates of neuropsychiatric adverse events were 2.39 per 100 patient-years among the montelukast users and 2.41 per 100 patient-years among the LABA users. This translated to a weighted HR of 0.99 (95% CI, 0.84-1.16). No substantial differences were observed between the montelukast and LABA patients when analyzing the risk of specific neuropsychiatric adverse events: the HRs were 0.79 (95% CI, 0.54-1.14) for anxiety; 1.16 (95% CI, 0.70-1.95) for depression; 0.93 (95% CI, 0.76-1.13) for sleep-related disorders; 1.31 (95% CI, 0.64-2.69) for suicide and suicidal actions; 1.27 (95% CI, 0.84-1.90) for disrupted control of activity, attention, and behavior; and 0.51 (95% CI, 0.05-5.53) for confusion and psychotic-like symptoms. The risk of the primary outcome was consistent over subgroups and a range of sensitivity analyses.

Conclusions and Relevance: In this large study of children and adolescents based on data from routine clinical practice, there was no association between use of montelukast and the risk of neuropsychiatric adverse events. In aggregation with other robust observational studies, these results can inform the management of asthma and allergic rhinitis in this patient group.