Brian Lund, PharmD, Research Investigator at the Iowa, City, IA, Iowa City Veterans Affairs Health Care System

IOWA, CITY, IA — Montelukast, a prescription drug used to treat and prevent asthma, can affect antidepressant effectiveness, and initiating the asthma medication in patients already receiving antidepressant maintenance therapy is associated with an increased risk for treatment failure, according to a new study.

The study, published in the Journal of Psychosomatic Research, examined two objectives, whether existing montelukast therapy was associated with acute antidepressant treatment failure and whether montelukast initiation was associated with depression relapse during maintenance antidepressant therapy, compared to inhaled corticosteroid use.1

Study participants were patients receiving care in the VHA for both asthma and depression from 2007 to 2019. The study used national administrative healthcare data from the VA Corporate Data Warehouse. For the study’s first objective, the researchers examined data from 12,109 patients who initiated an antidepressant after receiving montelukast or inhaled corticosteroid for six months. For the study’s second objective, the researchers examined data from 14,673 patients who initiated montelukast or inhaled corticosteroid after receiving stable antidepressant monotherapy for six months. Inhaled corticosteroids were the reference comparison group.

While implicated in causing depression, no previous studies have examined the impact of montelukast on antidepressant effectiveness, the study reports. Pharmacoepidemiologic studies have explored the relationship between montelukast and the onset of neuropsychiatric events such as depression, but they don’t directly address many important clinical issues, including whether montelukast impacts the effectiveness of antidepressant therapy. Previous studies have limited usefulness in helping healthcare providers and patients make key decisions related to depression pharmacotherapy. The researchers studied two separate objectives to fill this knowledge gap.

One key decision is whether existing montelukast therapy should be reevaluated and potentially discontinued when patients require initiation of pharmacologic treatment for depression. To inform this decision, the first objective examined whether existing montelukast therapy in patients with asthma increased the likelihood of acute antidepressant treatment failure, in comparison with existing therapy with inhaled corticosteroid. Due to concerns of depression relapse, a second key decision is whether montelukast initiation should be avoided in patients requiring a change in their asthma regimen but are currently receiving stable antidepressant maintenance therapy. To inform this decision, objective two selected patients with asthma receiving stable antidepressant monotherapy for at least six months, who then initiated either montelukast or an inhaled corticosteroid.

Antidepressant Dose Increase

“Our study had two main objectives and associated findings. First, we found no evidence that concurrent use of montelukast at the time of antidepressant initiation was associated with a greater likelihood of antidepressant treatment failure during acute treatment,” Brian Lund, PharmD, a research investigator at the Iowa, City, IA, Iowa City Veterans Affairs Health Care System, told U.S. Medicine. “Second, we found some evidence that initiating montelukast in patients receiving antidepressant maintenance therapy was associated with an increased risk for treatment failure, as evidenced by an increased risk of requiring an antidepressant dose increase, switching to another antidepressant, or addition of an augmenting agent, particularly within the first 45 days following initiation.”

For the first objective, the 12,109 patients selected for analysis included 2,943 patients receiving montelukast and 9,166 receiving an inhaled corticosteroid. Patients were majority white, majority male and 45 years of age or older. Those receiving montelukast were significantly younger and more likely to be female. Of the 2,943 patients receiving existing montelukast therapy at the time of index antidepressant initiation, 628 (21.3%) had evidence of acute antidepressant treatment failure, defined as initiation of a new antidepressant or augmenting agent within 180 days following index. In contrast, 2,044 (22.3%) patients receiving an inhaled corticosteroid experienced acute antidepressant treatment failure. Failure rates were not significantly different between the montelukast and inhaled corticosteroid groups.

For the second objective, the 14,673 patients selected for analysis included 1,182 patients receiving montelukast and 13,491 receiving an inhaled corticosteroid. Patients receiving montelukast were significantly younger, more likely to be female, and less likely to be white. Of the 1,182 patients who initiated montelukast while receiving stable antidepressant therapy, 288 (24.4%) had evidence of depression relapse, defined as dose increase of an existing antidepressant, initiation of a new antidepressant or initiation of an augmenting agent within 180 days. In contrast, 3,027 (22.4%) patients experienced depression relapse in the inhaled corticosteroid group. Within the 90-day follow-up period, 180 (15.2%) patients in the montelukast group and 1,801 (13.3%) in the inhaled corticosteroid group met criteria for depression relapse. This difference was statistically significant after adjustment for confounding factors.

The study found that discontinuation of existing montelukast therapy is unnecessary when initiating antidepressants. However, potential evidence for depression relapse following the initiation of montelukast warrants additional investigation.

Montelukast, a leukotriene receptor antagonist, is indicated for the prevention and chronic treatment of asthma, prevention of exercise-induced bronchoconstriction and relief of symptoms of allergic rhinitis in children and adults. The U.S. Food & Drug Administration (FDA) updated montelukast product labeling in 2008 to include risk information concerning neuropsychiatric events, in response to spontaneously reported adverse events following its 1998 market approval. This alert was elevated to a boxed warning in March 2020, largely due to continued reporting of severe events, including suicide. Potential biological mechanisms for montelukast contributing to neuropsychiatric events are not well understood.

“The FDA warning for neuropsychiatric adverse events is based on relatively sparse data, and the surveillance study the FDA commissioned to specifically examine this issue using the Sentinel program failed to demonstrate any evidence of increased risk for depression or suicide associated with montelukast,” Lund explained in an email. “Importantly, the warning does not provide any direct evidence or guidance for managing either clinical scenario examined in this study. First, should preexisting montelukast therapy be discontinued in patients requiring initiation of antidepressant therapy? Our study found no evidence this is necessary. Second, can the initiation of montelukast increase risk for relapse/recurrence in patients receiving stable antidepressant maintenance therapy? In this case, we did find an increased risk associated with montelukast, approximately 50% within the first 45 days following montelukast initiation.”

Lund notes that more studies are needed before making suggestions to health care providers on how they should treat patients.

“This is the first study to examine this question and further research is needed to confirm or reject this observation before any strong recommendations can be made,” Lund wrote in an email. “Patients and prescribers should be aware of this potential risk, and closer monitoring for the return of depression symptoms in the first one to three months following montelukast initiation may be warranted.”

A Food and Drug Administration (FDA) safety communication in 2020 said the agency was strengthening existing warnings about serious behavior and mood-related changes with montelukast, an asthma and allergy medication which is sold under the brand name Singulair and as generics), which is a prescription medicine for asthma and allergy.

“We are taking this action after a review of available information led us to reevaluate the benefits and risks of montelukast use,” the FDA said. “Montelukast prescribing information already includes warnings about mental health side effects, including suicidal thoughts or actions; however, many healthcare professionals and patients/caregivers are not aware of the risk. We decided a stronger warning is needed after conducting an extensive review of available information and convening a panel of outside experts, and therefore determined that a Boxed Warning was appropriate.”

The agency added, “Because of the risk of mental health side effects, the benefits of montelukast may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with other medicines.”


  1. Chung H, Hanken K, Gerke AK, Lund BC. Montelukast and risk for antidepressant treatment failure. J Psychosom Res. 2023 Jan;164:111075. doi: 10.1016/j.jpsychores.2022.111075. Epub 2022 Nov 9. PMID: 36368225.