10th June 2019, Dr Chee L Khoo
Children with moderate to severe asthma often needs more than the usual bronchodilators. Even the newer long acting beta agonists (LABA) or long acting muscarinic antagonists (LAMA) may not be enough to control the symptoms and reduce exacerbations and inhaled corticosteroids (ICS) are often needed. But we are careful to keep the total daily dose of corticosteroids to a minimum. This is when a leukotriene receptor antagonist (LTRA) like montelukast is used as an adjunct to ICS.
The possible link between LTRAs and neuropsychiatric events were first raised in The Individual Case Safety Reports and adverse drug reaction reports to the World Health Organization’s VigiBase and Sweden’s SWEDIS (1,2). In 2009, the US FDA issued safety alerts and required manufacturers of leukotriene-modifying agents including montelukast (Singulair®), zafirlukast (Accolate®) and zileuton (Zyflo® or ZyfloCR®) to include suicide and neuropsychiatric events as a precaution in the drug label (3).
The most commonly reported neuropsychiatric events included depression, anxiety, sleep disturbance, aggression/agitation, suicidal ideation, suicide attempts, and/or suicide. From 1998 to 2009 there were 838 suicide-related adverse events associated with leukotrienes reported to the FDA, of which all but five involved montelukast. To date, the safety alerts are based primarily on case reports. Well conducted, comparative, observational studies of this link are still limited.
In a recent matched, nested case–control study, 898 children aged 5-18 years old with asthma who was prescribed an asthma maintenance medication and suffered their first neuropsychiatric event were identified from a cohort of children from Ontario, Canada (4). These cases were matched with 3497 controls with asthma.
Children with asthma who experienced a new-onset neuropsychiatric event had nearly twice the odds of having been prescribed montelukast in the year before their event. Most of the events were anxiety (48%) and/or sleep disturbance (26%). Almost half (42%) of the events occurred within the first 90 days of the prescription while 22% occurred between 90-180 days of the prescription. New onset neuropsychiatric events occurred more often in the youngest and oldest.
Cases with neuropsychiatric events had significantly more ED visits and hospitalisation for asthma in the 12 months leading up to the events. They were also more likely to have been prescribed systemic steroids (41% vs 14%) and greater number of other preventative asthma medications.
This study is not the only study reporting the link. In another nested case–control study of children with asthma in Quebec, Canada, individuals on montelukast had significantly greater risk of neuropsychiatric adverse drug reactions than those on inhaled corticosteroids (5). Two earlier nested case–control studies found no association between montelukast and neuropsychiatric events or suicide attempts (6,7). Both used US health insurance claims databases. One study used suicide as the primary outcome while the other used a broad, non-specific definition of neuropsychiatric events.
The human brain does not have leukotriene receptors. It has been postulated that montelukast increases blood-brain permeability and inhibits the production of serotonin and noradrenalin. Another reason cited for the higher incidence of agitation in children was that these children have more energy because their symptoms of asthma are being tempered by montelukast and parents may interpret this as abnormal behaviour or aggression.
The adverse events generally resolve when montelukast therapy was discontinued (8). These recent reports call for increased awareness among prescribers and continued monitoring of europsychiatric adverse events. Clinicians should be aware of the potential risks of montelukast, as it may influence their prescribing practices and clinical follow-up visits. Perhaps, parents should also be made aware of these potential adverse events when these agents are initiated.
References
- Aldea Perona A, Garcıa-Saiz M, Sanz AE. Psychiatric Disorders and Montelukast in Children: A Disproportionality Analysis of the VigiBase. Drug Saf 2016;39:69-78.
- Wallerstedt SM, Brunl€of G, Sundstr€om A, Eriksson AL. Montelukast and psychiatric disorders in children. Pharmacoepidemiol Drug Saf 2009;18: 858-64.
- US Food and Drug Administration. Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and ZyfloCR). https://wayback.archive-it.org/7993/20170111080414/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm165489.htm; August 28, 2009. Accessed March 6, 2019.
- Dresden Glockler-Lauf, Yaron Finkelstein, Jingqin Zhu, Laura Y. Feldman. Montelukast and Neuropsychiatric Events in Children with Asthma: A Nested Case–Control Study J Pediatr 2019;209:176-82).
- Benard B, Bastien V, Vinet B, Yang R, Krajinovic M, Ducharme FM. Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice. Eur Respir J 2017;50:1700148.
- Ali MM, O’Brien CE, Cleves MA, Martin BC. Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case–control study. Pharmacoepidemiol Drug Saf 2015;24:435-45.
- Schumock GT, Stayner LT, Valuck RJ, Joo MJ, Gibbons RD, Lee TA. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol 2012;130:368-75.
- Calapai G, Casciaro M, Miroddi M, Calapai F, Navarra M, Gangemi S. Montelukast-induced adverse drug reactions: a review of case reports in the literature. Pharmacology 2014;94:60-70.