Richard K. Bogan, MD, FCCP, FAASM, and Asim Roy, MD, provide an overview of the pathophysiology of narcolepsy and the role of orexin in regulating the sleep/wakefulness cycle.
Richard K. Bogan, MD, FCCP, FAASM: Welcome to this Psychiatric Times® presentation titled “Case-Based Insights Into the Management of Narcolepsy.” I’m Dr Richard Bogan. I’m the medical director of Bogan Sleep Consultants in Columbia, South Carolina. I’m also an associate clinical professor at the University of South Carolina School of Medicine, in Columbia, as well as the Medical University of South Carolina in Charleston. I’m joined by Dr Asim Roy. He’s the medical director of the Ohio Sleep Medicine Institute in New Albany, Ohio. Our discussion will focus on the practical considerations and clinical management of narcolepsy by reviewing the treatment landscape and discussing patient cases. Let’s begin. Welcome, Asim.
Asim Roy, MD: Thank you for having me. I’m looking forward to our discussion.
Richard K. Bogan, MD, FCCP, FAASM: Likewise. I know you have a lot of clinical experience in this arena. We’ve both had a chance to see patients over the years. First, narcolepsy is this window into sleep-wake processes because the brain wants a stabilized state. We should be awake during the day and asleep at night. For us to live and survive, these are very important biological processes. Narcolepsy is a window into that. I’d love for you to explore the pathophysiology. What happens in patients with narcolepsy? Why are they sleepy, and why do they have these REM [rapid eye movement] dissociative symptoms?
Asim Roy, MD: This is a great area of focus and understanding that we’ve evolved over the last 15 to 20 years as we’ve learned more about the neuropeptides that are involved in the sleep-wake process. Narcolepsy type 1 is where we have the most well-defined path of physiology. When we start talking about type 2 narcolepsy, narcolepsy without cataplexy, or idiopathic hypersomnia, we’re more in the nebulous region and not clear on the path to physiology. Type 1 is the most pure in terms of understanding the physiology that’s going on. What most likely happens is this autoimmune process attacks this area within the brain. Within the hypothalamus, specifically the lateral hypothalamus, a group of neurons make a specific neuropeptide called orexin or hypocretin, which are interchangeable names. Most drugs were starting to target these areas, and some of the newer insomnia drugs target orexin as well.
What we know about orexin has been described in numerous publications, including some good Nature articles. The idea is that orexin is the backbone of the sleep-wake system and promotes wakefulness throughout the day. The way I describe it to patients is that it’s like a light switch. On means awake, and off means asleep. In orexin, when it’s working properly and you’re making enough of it, keeps the switch on throughout the day. When you go to bed, orexin decreases at night, and the switch can turn off and sleep-promoting neurons can take over. That’s the way I perceive it. With type 1 narcolepsy we know this autoimmune process damages these neurons—at least 80% or more of those cells get damaged, and these individuals no longer make orexin. That light switch now doesn’t have anything stabilizing it. The brain can go between wake and sleep continuously throughout a 24-7 period. What are your thoughts?
Richard K. Bogan, MD, FCCP, FAASM: They oscillate back and forth because they have state instability. It’s also useful to think that in terms of orexin, it stimulates other regions of the brain downstream. Other neurons, when they get excited, release these monoaminergic amines dopamine, norepinephrine, acetylcholine, histamine, and serotonin. The brain has redundancy to stay awake. We’re committed to staying awake during the daytime to protect ourselves, get food, reproduce, and do all the things we need to do to survive. Orexin is pivotal to a stabilizing state. As you said, we have this redundancy. When you have this deficiency of orexin, we have state instability.
It’s interesting to think about this because normally we have state stability. We’re making orexin and downstream histamine, dopamine, and norepinephrine to keep us awake. At night, when the orexin levels drop and the sleep and the circuit lights up, we go into a deep sleep. Our brain actually shrinks, and we get rid of adenosine through lymphatics and other things. Then we have a dreaming period toward the end of that. It takes about 60 minutes for us to dream. We use this as part of our diagnostic criteria, both historically and when we do diagnostic studies, because we can see this when we do nap studies. I tell my patients all the time that we do a sleep study at night to see how your brain organizes your sleep. Interestingly, many patients with narcolepsy have disrupted sleep, and they have REM-related symptoms. But in the daytime, we’re going to do a series of nap studies where we isolate the brain by putting you in a dark room, with the lights out and no sensory input. Then we can see what your brain does during the day. If you’re making orexin, you should stay awake.
Transcript Edited for Clarity