US FDA finds widely used asthma drug impacts the brain

By Dan Levine and Sheila Dang

(Reuters) - U.S. government researchers have found that a widely prescribed asthma drug originally sold by Merck & Co may be linked to serious mental health problems for some patients, according to a scientific presentation reviewed by Reuters.

The researchers found that the drug, sold under the brand name Singulair and generically as montelukast, attaches to multiple brain receptors critical to psychiatric functioning.

Singulair was a blockbuster product for Merck after its launch in 1998, offering relief in a pill as an alternative to an inhaler. In early advertising, the company said the side effects were so benign that they were "similar to a sugar pill," while the label said any distribution in the brain was "minimal." Generic versions are still prescribed to millions of adults and children every year.

But by 2019, thousands of reports of neuropsychiatric episodes, including dozens of suicides, in patients prescribed the drug had piled up on internet forums and in the U.S. Food and Drug Administration’s tracking system. Such “adverse event” reports do not prove a causal link between a medicine and a side effect, but are used by the FDA to determine whether more study of a drug’s risks are warranted.

After years of analysis, the reports and new scientific research led the FDA in 2020 to add a "black box" warning to the montelukast prescribing label, flagging serious mental health risks like suicidal thinking or actions. 

The agency also convened a group of internal experts around the same time to look into why the drug might trigger neuropsychiatric side effects.

The results of the group's work, which are preliminary and have not been previously reported or released publicly, were presented to a limited audience at the American College of Toxicology meeting in Austin, Texas on Wednesday.

Jessica Oliphant, a deputy director at FDA's National Center for Toxicological Research, said at the event that laboratory tests showed "significant binding" of montelukast to multiple receptors found in the brain. 

The FDA also confirmed earlier scientific research showing montelukast penetrates the brains of rats. More study is needed about how the drug accumulates in the nervous system, Oliphant said. "These data indicate that montelukast is highest in brain regions known to be involved in (psychiatric effects),” she said. 

The FDA said it does not plan to update the drug label based on data from the presentation.

'SOMETHING THAT'S CONCERNING'

The behavior of montelukast appears similar to other drugs known to have neuropsychiatric effects, such as the antipsychotic risperidone, according to FDA slides reviewed by Reuters. The FDA has cautioned that its studies are ongoing, and results have not been finalized.

When the FDA added the black box, it cited research from Julia Marschallinger and Ludwig Aigner at Austria's Institute of Molecular Regenerative Medicine.

The two scientists told Reuters on Thursday the new data showed significant quantities of montelukast present in the brain. The receptors involved play a role in governing mood, impulse control, cognition and sleep, among other functions, they said.

The research does not show whether that binding mechanism leads directly to harmful effects in individual patients, or who is particularly at risk, the two scientists said. However, Marschallinger said the new data bolsters reports from people who reported suffering side effects. 

"It's definitely doing something that's concerning," she said. 

A Merck representative did not respond to questions. Organon, a Merck spinoff that now markets Singulair, said in a statement it is confident in the drug's safety profile. 

"The product label for Singulair contains appropriate information regarding Singulair benefits, risks and reported adverse reactions," the company said.

Reuters reported last year that the FDA had received thousands of reports of patients, including many children, experiencing depression, suicidal thoughts and behaviors, or other psychiatric problems after they began using montelukast.

By 2019, the FDA tallied 82 suicides linked to Singulair and its generic versions reported to its adverse-event database since 1998. At least 31 of those reports involved someone age 19 or younger.

Robert England's 22-year old son Nick killed himself in 2017 less than two weeks after starting montelukast. England recalls that his son had trouble sleeping before he died, and said he was completely healthy and had no mental health problems prior to taking the drug.

"He was on that medication for just days, literally just days," England said. "It completely changed the trajectory of our lives."

The Reuters report also detailed lawsuits alleging that Merck knew from its early research that the drug could impact the brain and minimized the potential for psychiatric problems in statements to regulators. Many of those lawsuits are still pending.

(Reporting by Dan Levine in New York and Sheila Dang in Austin, Texas; Editing by Michele Gershberg and Bill Berkrot)