Study: Montelukast not associated with neuropsychiatric events in children
Key takeaways:
- There were no differences in mental health outcomes between montelukast and long-acting beta-agonists.
- Psychiatric events rose over time, likely due to increased screening, diagnoses and awareness.
Montelukast does not appear to increase the risk for neuropsychiatric adverse events in children and adolescents, according to a study published in JAMA Pediatrics.
Montelukast is a leukotriene receptor commonly used to treat asthma and allergic rhinitis. Starting in 2008, reports emerged about a possible association between montelukast use and neuropsychiatric events like depression, anxiety and suicide, which prompted the FDA to require a boxed warning in 2020 and advise against prescribing it for mild asthma and allergy symptoms.
“Since the signal emerged, several studies have been conducted to evaluate it,” Viktor Wintzell, PhD, a researcher in the division of clinical epidemiology at Karolinska Institutet’s Department of Medicine in Stockholm, Sweden, and colleagues wrote. “The available evidence on this safety concern is inconclusive, and the data among children are particularly heterogeneous.”
Wintzell and colleagues tracked neuropsychiatric outcomes for 74,291 children aged 6 to 17 years (47.7% girls; mean age, 12.3 years; standard deviation, 3.3 years) who used montelukast or long-acting beta-agonists (LABAs) in Sweden from Jan. 1, 2007, to Nov. 30, 2021. The cohort study compared 26,462 children taking montelukast with 47,829 taking LABAs.
Overall, the researchers reported 310 children from the montelukast group and 566 from the LABA group who experienced neuropsychiatric events up to 1 year after starting medication. This equated to a weighted incidence rate of 2.39 events per 100 patient-years for montelukast and 2.41 per 100 patient-years for LABAs. The weighted analysis showed no significant difference in the incidence of adverse events between the two medications.
Additionally, Wintzell and colleagues did not find significant differences in the risk for specific outcomes, including anxiety, depression, sleep disruptions, suicide or attempted suicide, disrupted control of activity, attention and behavior, confusion or psychotic symptoms.
The researchers noted that the incidence of primary outcomes for both drugs increased from 1.69 per 100 patient-years between 2007 and 2011 to 3.03 per 100 patient-years between 2017 and 2021. They hypothesized that the increase was due to changes in screening, diagnosis and awareness of mental health issues.
“Suspected neuropsychiatric adverse effects of montelukast have been a major concern for patients, clinicians and regulators,” Wintzell and colleagues wrote. “However, there is still a lack of observational studies confirming the signal; in particular, the need for pediatric evidence has been emphasized.”
“In this nationwide cohort study of children and adolescents, we found no support for an association between montelukast and the risk of neuropsychiatric adverse events,” they wrote.
Healio asked the FDA if it would reconsider the black box warning for montelukast based on the findings. In return, we received a comment about the communications pause issued by HHS to the nation’s various health agencies, including the FDA.
Perspective
Back to TopNiels Rutjes, MD and Susanne Vijverberg, PhD
Montelukast is a leukotriene receptor antagonist. The drug is used as an add-on controller medication in pediatric asthma management. In contrast to most other asthma medications, it is available in both tablet and granule forms instead of inhaler medication. It can be used as add-on therapy when other controller medications, such as inhaled corticosteroids and LABAs, are insufficient, or when inhaled corticosteroids are deemed undesirable because of severe adverse effects.
Despite the widespread use of montelukast, parents and users have regularly reported neuropsychiatric side effects, including mood changes, depression, anxiety and sleep disturbances including vivid dreams and nightmares, raising severe concerns among clinicians worldwide. This has been evidenced by both case reports and pharmacovigilance studies. However, observational studies have shown conflicting evidence regarding the risk of such adverse effects in the pediatric population, which may be partly due to heterogeneity in study design and study outcomes. In March 2020, the FDA issued a black box warning for montelukast, and the Global Initiative for Asthma 2024 guidelines have been updated to advise patients and caregivers about potential neuropsychiatric effects.
The study by Wintzell and colleagues presents the findings of a Swedish nationwide register-based cohort study. This large observational study included over 74,000 children, more than 26,000 of whom used montelukast. The investigators did not observe an increased risk for neuropsychiatric side effects associated with montelukast use when compared with LABA users. These results are reassuring, particularly as they suggest that montelukast, when used appropriately, does not pose a heightened risk of neuropsychiatric complications in the pediatric population compared with LABAs.
It is essential, however, to note that although this study adds valuable evidence to the ongoing debate, individual predispositions to neuropsychiatric reactions may still exist. As such, health care providers should remain vigilant and monitor for any potential behavioral or psychological changes in pediatric patients using montelukast. This is especially true in light of the heterogeneous nature of drug responses, which can vary between individuals. Therefore, although the findings of this large study are reassuring, clinical awareness and ongoing surveillance remain key to ensuring patient safety and optimizing asthma management.
References:
Global Initiative for Asthma. 2024 GINA main report. https://ginasthma.org/2024-report/. Published May 22, 2024. Accessed Jan. 28, 2024.
Kim JW, et al. BMJ Paediatr Open. 2024;doi:10.1136/bmjpo-2023-002483.
Lo CWH, et al. Eur Respir Rev. 2023;doi:10.1183/16000617.0079-2023.
Paljarvi T, et al. Thorax. 2024;doi:10.1136/thorax-2024-221590.
Zschocke A, et al. Wien Klin Wochenschr. 2021;doi:10.1007/s00508-021-01981-1.
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