In April 2020, the U.S. Food and Drug Administration (FDA) has raised serious concerns about the safety of montelukast — the popular brand-name drug Singulair used by children and adults in preventive and chronic asthma therapy, to prevent exercise-induced bronchoconstriction (EIB), and to manage symptoms of seasonal and persistent allergic rhinitis. The regulator believes that physicians and patients underestimate the risks posed by montelukast associated with adverse mental health reactions, including suicidal thoughts or behaviors.
The existence of a certain probability of developing neuropsychiatric disorders outweighs the benefits that montelukast can provide. And so the FDA insists that physicians should be more restrained and cautious about prescribing treatment with montelukast. This is especially true if the symptoms are mild and the disease itself is amenable to therapy with other drugs.
For example, in the case of allergic rhinitis, also known as hay fever, montelukast should be reserved as a backup medication, prescribed only after other drugs have failed or if they are intolerant. Among the wide range of these are the antihistamines loratadine, fexofenadine, cetirizine, levocetirizine, diphenhydramine, and the steroidal intranasal sprays fluticasone, triamcinolone, budesonide. Allergen-specific immunotherapy should also not be forgotten.
In most cases, mental health symptoms have been noted during therapy with montelukast and they resolved after discontinuation of the drug. However, there have been documented cases of neuropsychiatric disorders that manifested themselves or persisted even after withdrawal of montelukast. All of the above is true for patients both with a history of mental illness and without prior mental disorders.
The problems of montelukast related to its negative effects on the mind first came to light back in 2008. And now, due to the continuing increase in the number of cases of neuropsychiatric disorders, we can safely say that there is a direct link with the use of montelukast.
Montelukast should be stopped immediately if there is any change in behavior or mood. Such signal changes include:
- agitation, including aggressive behavior or hostility
- attention problems
- bad or vivid dreams
- disorientation or confusion
- feeling anxious
- memory problems
- obsessive-compulsive symptoms
- suicidal thoughts and actions
- tremor or shakiness
- trouble sleeping
- uncontrolled muscle movements.
By the way, patients taking drugs from the same class of antileukotrienes as montelukast — zafirlukast and zileuton — also experience adverse reactions in the form of neuropsychiatric disorders.
The FDA has conducted a thorough investigation of the safety of montelukast. They evaluated trends in the FDA Adverse Event Reporting System (FAERS) by reviewing reports of neuropsychiatric events during the administration of montelukast. An observational study of data collected in the Sentinel System, which tracks the safety of drugs, vaccines, and medical products, was also performed. In addition, the results of observational studies and animal trials published in the scientific literature were reviewed.
For example, the FAERS database from February 1998 to May 2019 found 82 cases of completed suicides associated with montelukast: many reports stated the occurrence of concomitant neuropsychiatric symptoms prior to the suicide. The statistics are as follows:
- 45 suicides were committed by patients over 17 years of age, 19 were 17 years of age or younger, and no age information was provided for the remaining 18.
- For more than half of the cases (n=48/82), no comprehensive data set was available that would allow a thorough evaluation of the relationship between montelukast and the occurrence of a suicidal event. This included such key information as time elapsed before completed suicide; use of other medications; past and present comorbid conditions, including psychiatric disorders; degree of pharmacological control of asthma; and presence of other risk factors for suicide.
- The remaining 34 cases were more fully documented and reported additional risk factors relevant to suicide, such as medication use or comorbidities that were associated with increased odds of self-harm or developing behavioral disorders. In 6 cases, facts were reported that the health care provider was not specifically aware of the possibility of neuropsychiatric side effects from the use of montelukast.
The Sentinel System, from January 2010 to September 2015, outlined the following picture with the hypothesis of an increased risk of inpatient or outpatient treatment for depressive disorder and self-harm or suicide associated with montelukast prescriptions — compared to inhaled corticosteroids (ICS). The data covered 457,000 patients aged 6 years and older:
- The risk difference for hospitalization for depressive disorder was not significant among those receiving montelukast or ICS (hazard ratio [HR] 1.06 [95% CI: 0.90–1.24]). There was no significant risk among men, women, patients 12 years of age or older, or patients with a history of mental illness.
- Administration of montelukast was significantly associated with decreased risk of outpatient treatment for depressive disorder (HR 0.91 [95% CI: 0.89–0.93]). There was a decreased risk among patients with a history of mental illness, patients ages 12–17 years and ages 18 years or older, men and women.
- Montelukast therapy was not associated with risks of self-harm (HR 0.92 [95% CI: 0.69–1.21]) or modified self-harm (HR 0.81 [95% CI: 0.63–1.05]).
- Four cases of suicide were recorded (two each in the montelukast and ICS groups) among patients over 18 years of age and with a history of mental illness.
It should be understood that the data collected by Sentinel System are characterized by certain limitations. Thus, the study relied only on the clinical outcomes according to which patients sought medical care as recorded in their medical records. In other words, it did not assess the entire spectrum of neuropsychiatric events or events whose resolution did not require medical intervention, but only the discontinuation of montelukast. Again, after the 2008 change in the drug’s prescribing information, patients may have become more aware of the risks of adverse neuropsychiatric events and therefore monitored their onset in a timely fashion by withdrawing from montelukast. Finally, the study is not tailored to patients’ socioeconomic status, although a review of the literature found no evidence that montelukast and ICS are prescribed disproportionately on this measure. It is possible, however, that higher-income individuals are more likely to see physicians during asthma therapy and therefore find themselves in an increased follow-up group for the manifestation of neuropsychiatric events.
Animal studies have shown that montelukast can act directly on brain cells. Orally administered montelukast was found in the brain tissue and cerebrospinal fluid of rodents, thus confirming that it can pass the blood-brain barrier.
Montelukast: Mechanism of Action
Leukotrienes (LT) are a family of inflammatory mediators that are products of the metabolism of arachidonic and eicosapentaenoic acids and that are released by various cell types, including mast cells, eosinophils, and basophils. Leukotrienes are responsible for regulating immune responses. Their cellular excretion often accompanies the release of histamine and prostaglandins, which also act as inflammatory mediators.
A key function of leukotriene D4 (LTD4), which belongs to the so-called cysteinyl leukotrienes, is to induce contraction of the smooth muscles, leading to constriction of the bronchi and blood vessels, as well as increased microvascular permeability and mucus secretion. The role of leukotriene E4 (LTE4), which acts as a stable variant of LTD4, is generally the same.
Montelukast is a highly selective leukotriene receptor antagonist (LTRA) that binds with high affinity to cysteinyl leukotriene receptor 1 (CYSLTR1). When montelukast binds to CYSLTR1, whose ligands are LTD4 and LTE4 and which is expressed by airway cells, including macrophages and smooth muscle cells, the physiological leukotriene effects are suppressed without any agonist activity. In the case of asthma, such inhibition is reflected by the inhibition of pathophysiological effects associated with airway edema, smooth muscle contraction, and altered cellular activity during the inflammatory process. In allergic rhinitis, CYSLTR1 is released from the nasal mucosa after allergen exposure, and therefore its suppression eliminates the signs and symptoms of the disease.
Singulair (montelukast). Prescribing information. U.S. [PDF]
List of Brand Names of Montelukast
Montelukast, being more than a popular drug, is available for sale in all countries of the world. In the United States, the patent protection of montelukast expired in August 2012. For reference purposes, we have prepared a list of brand names of montelukast. And it turned out to be huge (almost 400 trademarks)!