By Dr. Larry Chiaramonte
It was one of those headlines that really get me: “Asthma drug Singulair linked to suicidal thoughts in young people”. I don’t mean to pick on Australia, but as elsewhere, their headline writers have so sense of proportion when it comes to public health risks. The nation’s “medicine watchdog” Therapeutic Goods Administration (TGA) recorded 58 adverse affects associated with 20,000 children and teenagers who took the drug between 2000 and 2013, including “five reports of suicidal ideation, five reports of depression, and five reports of agitation.” The numbers, they caution, could be higher, but they are limited by doctor reporting. This is a country with over 400 actual asthma deaths per year, which is a much higher rate than the United States, although it is less than half the peak figure of 964 recorded in 1989. Deaths of children under 15, however, rose from seven in 2005 to 17 in 2009.
Merck, which brought Singulair—montelukast–to market (although it is now also made generically) lists psychiatric symptoms among the side effects, and the FDA has been warning about them since 2009. Doesn’t it stand to reason that a drug that acts on the immune system to block production of a powerful mediator—leukotrienes–could also have a dramatic effect on psychology and behavior in some?
Singulair has a significant place in the pharmacopeia of asthma treatment. We use it in our book as an example of how a drug can burst on the scene as an apparent panacea, only to recede into the medicine cabinet as its limitations emerge in a wider patient population:
“There’s a big difference between 5,000–10,000 patients and the hundreds of thousands who will get the drug after its release. The drug may be ineffective or may have bad side effects for a statistically insignificant number of people in a trial, but even if it’s just one percent, when 100,000 people are taking it, that leaves 1,000 who need something else. For those people, the new miracle drug is no miracle at all. And over a period of time, its shortcomings are likely to become magnified. Every time referrals to our offices dry up from one doctor or another, it usually coincides with some new drug release, but over time, new patients start to trickle in as the miracle starts to wear off.
“This was certainly the case with a drug called Singulair, which pediatricians loved because it could be taken orally—you sometimes have to hold a kid down to teach him to use an inhaler—and because it had no steroids. But while a useful drug, its great wave of popularity crested as it showed its limitations; it was not the panacea it first appeared to be. Many patients still needed the combination of treatments allergists offer.”
Obviously, side effects also show up in a population of millions. As I have written before, mental health should always be a concern with asthma treatment or with any other chronic disease. Apart from both body and brain chemistry, there are tangible effects on family chemistry. How parents relate to their children and how children relate to one another come into play. By all means, doctors, be on the lookout for suicidal ideation, but don’t stop there. Patient and family mental health should be a routine part of asthma treatment.
Thank you so much for this enlightening and thought-provoking post on Singulair, Dr. Chiaramonte. While the risk seems small across the large swath of people taking the drug, side-effects on a person’s mood are indeed serious and alarming. I so very much appreciate that as a physician, you are on the look-out for rare, but serious side-effects that may be tricky to trace back to an asthma drug of all things.
Through the lens of a neuroscientist, this post was very intriguing scientifically. One of the emerging things in neuroscience within the last ~10 years is the discovery of many traditionally immune system molecules, showing up to have vital roles in the central nervous system (brain/spinal cord)! The dogma used to be that the immune system cells didn’t really have access to the brain/spinal cord under normal conditions. Here is a nice lay summary of some emerging brain/immune system interactions that flies in the face of historical dogma. http://www.scientificamerican.com/article.cfm?id=are-immune-system-molecules-build-brains
From the sounds of it, the active ingredient in Singulair, montelukast, must be having some effect on the central nervous system in the cases where the drug adversely affects mood. The big question to address, in my mind, surrounds the blood-brain barrier (BBB). Access of things in the blood – many bodily signaling chemicals, white blood cells, drugs we take, etc – is tightly regulated. Under normal circumstances the central nervous system will not have access to random things floating around in the blood for very good reason (major exceptions are very small molecules and fat-loving molecules, hence why drugs like alcohol and the THC in marijuana have such a major effect on our brains/behavior!). Mucking with the CNS is bad since it controls just about every bodily system. This is why the BBB is so crucial and likely why nature gave us the BBB in the first place. It is also the reason why designing drugs to treat brain disorders is so challenging! Things that need to get across the barrier and into the brain/spinal cord, will often have specific gates where access to the brain/spinal cord is granted (the blood sugar – glucose – is one prime example). It makes me wonder if in cases where Singulair results in such adverse side-effects the blood-brain barrier is breaking down? From what I can find, there is little evidence that montelukast crosses the BBB under normal circumstances. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020829s051_020830s052_021409s028lbl.pdf
If indeed montelukast does get across the BBB and has a direct effect in some individuals, I would expect to find the specific leukotriene receptors in areas of the brain that are crucial for mood. (The identified pharmacological role of montelukast is to inhibit a receptor sub-type for leukotrienes, which are pro-inflammatory molecules). A major caveat is that indirect effects are always a possibility to consider. All-in-all, these side-effects highlight just how complicated biology really is, and how much more we still have to learn. Thanks again for a great post!
I can’t remember the specifics, but we discontinued Singulair for my daughter, because of behavioral side effects. It took me a long time to even convince myself to try it, given what I had read about potential side effects, and then when I finally tried it out, I was not happy, at all, with the marked effect on her mood.
She’s now on Qvar, and seems to be doing fine with that.