Obstructive sleep apnea (OSA) has long faced a shortcoming of reliable therapeutic options. The first-line treatment, continuous positive airway pressure (CPAP), has poor long-term compliance, with adherence rates of 50% or less. Second-line therapies, such as mandibular advancement splints and upper airway surgery, are not predictably effective. 

Recent advances in OSA pathogenesis using upper airway and respiratory phenotyping techniques have unlocked new approaches for targeted treatment. Investigators have identified 4 key causes of OSA, a heterogenous disorder involving both anatomical and nonanatomical factors. The primary cause: an impaired anatomy or narrow or collapsible upper airway. The 3 main nonanatomical contributors: impaired upper airway dilator muscle function, a low respiratory arousal threshold, and unstable respiratory control (high loop gain). 

Despite the advances, there remains a great need for additional tools to identify and focus on the 4 phenotypic causes of sleep apnea in patients in the clinical setting, but the existing framework holds promise. Each phenotype is a potential therapeutic target, and these prospective pharmacotherapies will be a major advance for the field.1 

To provide more insight into the latest knowledge regarding sleep apnea phenotyping and its role in the development of targeted pharmacotherapies, NeurologyLive™ sat down with Danny Eckert, PhD, principal research scientist at Neuroscience Research Australia and an associate professor of medicine at the University of New South Wales in Sydney, Australia, at the 24th Congress of the European Sleep Research Society in Basel, Switzerland. 

Q: Could you describe OSA pathophysiology? 

For a long time, we’ve been trying to come up with a pharmacotherapy to treat this very common disorder, but unfortunately, despite multiple attempts, we have not yet succeeded. It’s an exciting time in the field, because we now have not only identified new therapeutic targets for the reasons people get sleep apnea but also unlocked new therapeutic targets for pharmacotherapies. There are 4 main causes of sleep apnea: the anatomy, or how collapsible the upper airway is—from the back the throat to the back of the nose—as well as 3 nonanatomical causes. These include how well the muscles around the throat are able to open the airway during sleep, a muscle trait. The next is how easily a person sleeps, or what we call arousal threshold, and the fourth point is what we call respiratory control or loop gain. The latter 3—the nonanatomical ones— are quite recent in terms of our knowledge, and these are all novel therapeutic targets. 

We’ve identified these 4 main reasons people get sleep apnea (see FIGURE). We’ve always known that it’s an anatomical issue. Crowded or narrow airways, whether due to obesity or skeletal issues, can be a main driver of sleep apnea, but now we know about these other 3 causes and how the muscles respond. One-third of all people are not able to activate their muscles during sleep, which further progresses the condition for those with sleep apnea. A third of people also have problems with how easily they wake up—they’re light sleepers, if you like, or have what we call a low arousal threshold. The remaining cause is respiratory control; some people are just too sensitive to carbon dioxide during sleep, and that causes all sorts of problems in terms of cyclic breathing and feeds into sleep apnea. Those latter 3 nonanatomical causes really have opened new targets for pharmacological therapy for this common disorder. 

Q: What treatment options are available for reducing OSA severity? 

If I start with the control of breathing trait, oxygen therapy, a nonpharmacologic intervention can reduce the unstable control of breathing in people that have that issue. A drug called acetazolamide, which is a common generic agent that people take to reduce mountain sickness when they go to high altitudes, can also help sleep apnea in certain people. 

Other drugs can stabilize sleep or promote sleep, if you like— common hypnotics; sleeping pills; things like zolpidem, zopiclone, trazodone, and temazepam. These agents can actually promote sleep. We used to think that was really bad for those with sleep apnea and would actually make them worse, but a lot of work that we and others have done in the past 10 years or so has shown that certain sleeping pills can promote breathing stability and, in fact, reduce sleep apnea in certain people who have the problem of waking up too easily, which contributes to their sleep apnea. For others, however, using these agents can worsen the problem, so it really does involve a targeted approach of giving it to the right patients. 

The other main trait that we’ve long tried to target involves the muscles. We used to think that serotonin was a really important driver of pharyngeal muscle control, and it turned out that a lot of that knowledge was based on really reduced preparations in animal models where there were a lot of anesthetic agents on board. When we did those human studies, it turned out that the endogenous serotonin was really playing a minor role. We now know from more detailed animal studies and freely behaving animals—work from Richard Horner’s lab and others in Toronto—that these cholinergic and muscarinic processes are really important in mediating pharyngeal muscle control. A body of work that is trying to use agents for those particular targets is showing some exciting results in the proof-of-concept work in terms of reducing sleep apnea severity. 

Q: What role does phenotyping play in sleep apnea? 

The main therapy for sleep apnea, continuous positive airway pressure (CPAP) therapy, that opens up the airway, with that, it really doesn’t matter why you get your sleep apnea, if you can tolerate the therapy it will keep your airway open and stabilize breathing during sleep. The problem is that half or more of patients that try that therapy are unable to tolerate it and others are unwilling to even try it. We hope that phenotyping—and by phenotyping, I mean understanding those specific 4 causes on a per-patient basis—will help us knew exactly why each individual is getting their sleep apnea. We could then target each of the individual specific problem with an individualized therapy. We’ve developed quite complex techniques to measure those in the research lab, and our next challenge is to roll those out into the clinic and simplify them. We’re having some progress in obtaining that goal, which will really be necessary in terms of rolling out targeted or precision medicine for sleep apnea. 

Q: How is phenotyping making an impact on these patients in the clinic? 

Recognition and awareness that most patients have 1 or more nonanatomical contributors to their sleep apnea is changing the way clinicians evaluate their patients and is beginning to inform treatment decisions. This is especially true for those who do not respond to traditional therapies. For example, there is greater recognition that a key reason many patients do not respond to second-line therapies that target the anatomical problem, such as mandibular advancement therapy and upper airway surgery, involves residual issues with unstable control of breathing—high loop gain—which these therapies do not address. 

Q: What aspect of this area most excites you right now? 

Because of this new framework and understanding of why people get their sleep apnea, it really is an exciting time for the field. These new potential pharmacotherapies will be a major advance, and we’re all very hopeful that this approach will help many patients. 

Q: What’s next? 

We currently do not have simple, accurate tools to estimate the 4 phenotypic causes of sleep apnea in individual patients in the clinical setting. These tools are essential for making targeted therapy for sleep apnea a reality. Exciting work is under way in this area, but these new techniques have yet to translate to the clinic. There is also a need to develop therapies that target the nonanatomical phenotypes and to combine them with existing second-line anatomical therapies [eg, mandibular advancement therapy and upper airway surgery] to achieve therapeutic efficacy for the many patients who have an incomplete response to existing second-line monotherapies. 
REFERENCE 
1. Eckert DJ. Phenotypic approaches to obstructive sleep apnoea – new pathways for targeted therapy. Sleep Med Rev. 2018;37:45–59.
doi: 10.1016/j.smrv.2016.12.003.