Montelukast and the risk of neuropsychiatric effects: what the science says

EDITORIAL NOTE

This article was originally published in the past and has been updated according to scientific and divulgative criteria. It contains a review of the available evidence on montelukast and possible neuropsychiatric effects. The purpose is informative: it does not replace the advice of your treating physician. For personal therapeutic decisions, always consult a healthcare professional.

IN BRIEF

• Montelukast is an antileukotriene used for asthma and allergic rhinitis; reports of mood disorders, abnormal sleep, agitation, and, in rare cases, suicidal thoughts have been reported.
• Regulatory agencies have strengthened warnings, and in 2020, the FDA introduced a boxed warning for neuropsychiatric risks.
• Epidemiological evidence is heterogeneous: some observational studies and spontaneous reports suggest an association; investigations of large databases do not always confirm a clear increase in risk compared to other treatments.
• The absolute risk stated in the analyses is low, but the presence of serious reports necessitates caution, information, and monitoring, especially in children and young people.

MAIN SECTION

Abstract: what does science say?

Montelukast is a leukotriene receptor antagonist used for asthma and allergic rhinitis. Over the past two decades, reports of neuropsychiatric events (sleep disturbances, anxiety, irritability, depression, suicidal ideation) associated with its use have emerged. The evidence includes case series, reporting analyses, large cohort observational studies, and systematic reviews; the results are not uniform: some investigations show an increased relative risk for specific reactions, while others do not show significant differences compared to comparators such as inhaled steroids. Interpretation is complicated by confounding factors (underlying respiratory disease, psychiatric comorbidities, concomitant drug use) and by methodological limitations inherent in observational studies. In practical terms, the reported absolute risk is low, but there are repeated signals that have led to regulatory measures and the recommendation to inform and monitor the patient. In the absence of definitive experimental proof of causality, it is necessary to evaluate benefits and risks on a case-by-case basis and maintain active surveillance for neuropsychiatric symptoms.

What the literature shows: context and key terms

Montelukast was introduced as a symptomatic treatment for asthma and allergic rhinitis. The first reports of behavioral and mood changes date back to the early 2000s, and since then, clinical observations and pharmacovigilance studies have accumulated. The available research is observational (cohort, case-control, case-crossover), analyses of spontaneous reports, and systematic reviews. This methodological framework means that most evidence can indicate associations but rarely offers incontrovertible causal proof. Risk assessment requires distinguishing between spontaneous reports—important for early signal detection—and controlled studies designed to quantify relative and absolute risk in comparable populations. Furthermore, conditions such as asthma and allergy themselves can be associated with mood swings and sleep disturbances, complicating the interpretation of studies.

What does science say? Updated summary

In recent years, regulatory authorities have revised the montelukast label in response to reports: the U.S. Food and Drug Administration (FDA) has included strengthened warnings and, in 2020, a boxed warning for neuropsychiatric risks, limiting the use of montelukast for allergic rhinitis to cases where alternatives are not adequate [1]. Reviews and meta-analyses have highlighted conflicting results: some analyses of large databases have not found a consistent increase in suicide or self-harm compared to appropriate comparators [2][3], while more recent observational studies and pharmacovigilance analyses have found associations with mood changes and other neuropsychiatric events, especially in pediatric and adolescent age groups [4][5][6][7]. Some clinical and pharmacological investigations propose plausible biological hypotheses (e.g., brain penetration of the drug or modulation of inflammatory pathways that interfere with neurophysiology), but these remain largely theoretical and unproven in large-scale experimental studies [10]. In summary: there are repeated signals of possible neuropsychiatric events related to montelukast use, but the literature is heterogeneous; for this reason, the benefit-risk assessment must be individual and based on updated information and careful monitoring.

What it means in practice

For patients, families, and healthcare professionals, the practical implications are clear: information and monitoring. Health authorities recommend that prescribers of montelukast inform the patient or caregivers about possible sleep disturbances, mood changes, agitation, or suicidal ideation, and that they evaluate the appropriateness of treatment for non-serious indications (e.g., allergic rhinitis when alternatives are available) [1]. Observational studies indicate that signals appear in a small number of subjects but can manifest at any age and even in people without a known psychiatric history [2][6][7]. It is prudent that, after starting treatment, the doctor explicitly asks the patient or caregiver about the appearance of emotional or behavioral symptoms within the first few weeks and at regular intervals [2][3]. In cases where significant psychological symptoms appear, clinical re-evaluation and assessment by a specialist are indicated; discontinuation of the drug is a clinical decision that should be made with the doctor, evaluating the severity of symptoms and the respiratory benefit obtained [1][4]. These recommendations are not absolute prescriptions but practical guidelines based on an individual benefit-risk ratio.

Key points to remember

• Montelukast is effective in some respiratory conditions, but it is not without adverse effects; neuropsychiatric reports exist and are documented.
• The absolute risk is low in the available series, but the consequences can be serious for individual patients.
• Evidence is conflicting: large population studies sometimes do not show an excess of suicide, while other studies and reviews document associations with neuropsychiatric symptoms.
• It is essential to inform patients and caregivers and regularly monitor for any behavioral or mood changes.

Limitations of the evidence

The literature on montelukast and neuropsychiatric events has substantial limitations. First, much data comes from spontaneous reports and observational studies, which are subject to reporting bias and confounding (e.g., asthma severity, comorbidities, use of oral corticosteroids). Second, the definition of outcomes varies between studies: some use hospital diagnostic codes, others self-reported outcomes or prescriptions for psychiatric drugs, making it difficult to compare results. Third, the absence of randomization does not allow for establishing causality; the discordant results between studies on different databases underscore the need for cautious interpretation. Fourth, the proposed biological mechanisms are plausible but not yet proven in conclusive experimental studies. Finally, population variability (age, psychiatric history, healthcare context) limits the generalizability of the results: what is observed in one national cohort may not be replicated in another context.

Editorial conclusion

Montelukast remains a useful drug in specific respiratory conditions, but the available reports and studies require caution. It is not possible today to affirm a certain causal relationship with suicide or other neuropsychiatric events, but the presence of repeated signals has led to regulatory restrictions and a clear recommendation: inform, monitor, and re-evaluate use on a case-by-case basis. For healthcare professionals, the priority is to communicate potential effects clearly and without alarmism; for patients and families, it is important to know what to observe and when to seek help. Future research should aim for better-controlled studies and investigations into biological mechanisms that can clarify if and how montelukast affects behavior and mood.

Editorial note

This piece has been updated for informational purposes, including references to studies and regulatory documents. The content is not intended to replace individual medical advice. For specific questions, consult your doctor or a specialist.

SCIENTIFIC RESEARCH

1. Food and Drug Administration (FDA) - Drug Safety Communication: FDA requires boxed warning about serious mental health side effects for montelukast. https://www.fda.gov/...
2. Ekhart C, van Hunsel F, Sellick V, de Vries T. Neuropsychiatric reactions with the use of montelukast. BMJ. 2022. https://doi.org/10.1136/bmj-2021-067554
3. Gibson GA, Wise RP, et al. Risk of Psychiatric Adverse Events Among Montelukast Users (FDA Sentinel analysis). J Allergy Clin Immunol Pract. 2020. https://doi.org/10.1016/j.jaip.2020.07.052
4. National study on large cohorts: Psychiatric adverse effects of montelukast – nationwide cohort study. J Allergy Clin Immunol In Practice. 2023. https://doi.org/10.1016/j.jaip.2023.03.010
5. Lo et al. Neuropsychiatric events associated with montelukast in patients with asthma: a systematic review. European Respiratory Review. 2023. https://doi.org/10.1183/16000617.0079-2023
6. Risk of neuropsychiatric adverse events associated with montelukast use in children and adolescents: a population-based case-crossover study. BMJ Paediatrics Open. 2024. https://doi.org/10.1136/bmjpo-2023-002483
7. Montelukast and Neuropsychiatric Events in Children with Asthma: A Nested Case-Control Study. J Pediatr. 2019. https://doi.org/10.1016/j.jpeds.2019.02.009
8. Montelukast and neuropsychiatric events – a sequence symmetry analysis. Journal of Asthma. 2021. https://doi.org/10.1080/02770903.2021.2018705
9. Rate of suicide in patients taking montelukast. Pharmacotherapy. 2009. https://doi.org/10.1592/phco.29.2.165
10. Association and mechanism of montelukast on depression: a combination of clinical and network pharmacology study. Journal of Affective Disorders. 2024. https://doi.org/10.1016/j.jad.2024.05.130