Insomnia and Comorbidity: High Risk with Poor Outcomes

Narrator Introduction:
This is ReachMD! This Prova Education activity is titled Insomnia and Comorbidity: High Risk with Poor Outcomes. It is supported by an independent medical educational grant from Merck.
The following is a live lecture recorded at “From Guidelines to Practice: Managing Challenging Cases in Primary Care” in Pasadena, California.
Prior to beginning the activity, please be sure to review the faculty disclosure statements, as well as the Learning Objectives.
Your presenter is Dr. Larry Culpepper, professor of Medicine of Family Practice at Boston University.

Dr. Culpepper:
I really want to take you through an understanding of sleep, what it is, and I'm going to answer a question for you that, or at least partly answer a question, that has puzzled us for ages, which is why do we sleep? What's the purpose of sleep? So, I'll get to that at the end. Who's heard of glymphatics? We're also going to look at three cases, particularly looking at the intersection of insomnia and comorbid medical sleep. So, I'm going to take three cases; one focused on cardiovascular, another on diabetes, and a third on depression, and really look at the interaction of insomnia and those chronic conditions and then think about how that might influence a choice of treatment.

So, if you've got a patient with a chronic medical condition sitting in front of you, what's the likelihood that they have insomnia? Well, that's the red bars here, and they often are complaining about musculoskeletal, but look at the frequency of cardiovascular disease which may be silent. So, think about that. The other, flipping that, if you have a patient with a medical condition in front of you, what's the likelihood that they have insomnia? And that's the bars in blue. What we see here is not only is insomnia very frequently but so is severe insomnia. So, that's key in terms of what we see in practice. The number of conditions, as we go up the four, it more than doubles from just one condition up to about 40% almost. So, that also helps us recognize it. Patients with chronic insomnia often don't complain, it's just there lot in life and they let it be.

I want to give you a conceptual approach to insomnia in your practice. How do we best conceptualize this? Well, what we know is that a large part of it runs in families. So 40 to about 60% of patients with chronic insomnia have a considerable hereditable influence on that. When we look at mechanism, we find autonomic and CNS arousal. Hyperarousal is a very common final pathway. We have whole brain metabolism increase, both sleep and awake, and we also see cortisol and corticotropin increases. Another way of looking at it, these interact as a sleep/wake regulation imbalance. What we now understand is we have two systems in the brain. One basically increases the sleep drive throughout the day. There are a number of chemicals that accumulate in the brain and result in us becoming drowsy. The other is a drive to stay awake. The reticular activating system is a key component of that and that's driving the brain to stay alert, stay awake, stay oriented to the environment, stay safe, process things and interact. What happens is that drive is on a circadian rhythm. So, in the evening, that drive decreases allowing the sleep pressure, which is increased throughout the day, to take over and puts us to sleep. So, that can be out of balance, it can be uncoordinated, and it may be that it is a failure of the wake-promoting drive to decrease in the evening. So, that's conceptually very important as we approach treatment.

Here are some of the pathways around arousal. This is all fairly new. It was only about the late 1990s that orexin was identified, first time in the brain, and it turns out to be a key component, a key driver, of the arousal system. In what we find is that arousal system involves a number of brain areas, I'm not going to go through them, but they keep the cortex aroused and alert. But they also interconnect with the hypothalamic and basal ganglia systems involved in energy, the hypothalamic pituitary axis, nucleus accumbens and reward motivation, and cognition. We have this understanding now that it is really important around arousal and probably the best approach is to think of insomnia as having a significant component of dysfunction in the arousal system. Now, when we evaluate a patient, is the duration of sleep important? Well, it actually turns out to be quite important. When we put patients in the sleep lab and objectively observe their total sleep time in terms of EEG and so forth, it often is somewhat out of sync with their perception. You know, they report the next day of how much they slept and when you have objective short sleep, that is a real marker for genetic predisposition, it tends to be unremitting and chronic and it goes along very much with basal brain activity we see; glucose, cortisol, and ACTH levels altered. So they've got normal sleep duration in the lab, but they are complaining of insomnia. Well, that act tends to be more influenced in terms of our higher cognitive processes. You know, we're not thinking we're not feeling this well, you know, we're not imbalanced in terms of a cognitive emotional state, but it doesn't have the marked impact on our basic body systems that the objective for sleep has.

When I approach a patient, I want to diagnosis insomnia, but I also want to keep in mind my assessment. So, I want to know is it acute or is it chronic? Were there any precipitating events? Is it nightly, intermittently? Is it only during the work week? Is it only on the weekends? When you're in the night, is it onset problems that just can't turn the mind off and go to sleep or is it early morning awakening? I wake up too early and just can't stay asleep and I don't feel rested. How severe is it? We don't have a sleep lab to put them in, but certainly we can get a sense of severity in terms of self-report and then, importantly, what's the impact on function? Other things we want to think about are expectations, preferences, what medical comorbidities and medications might be an influence? Are they getting up to urinate? Patients get up to urinate and they go back to bed and they go back to sleep. A patient that gets up to urinate and then stays awake for an hour, that is insomnia. They are not the same and certainly we want to look at other things. When we approach treatment, certainly the base that we start from is sleep hygiene, education, CBT-I which we may not be able to get formally but we can certainly use some of its principles in terms of helping a patient approach their sleep problem, and exercise which is a critical component. The key with exercise is moderate exercise but four to five hours before they go to bed at least and the reason for that is you want core body temperature to come back down because a cool environment and a cool core body temperature is very helpful in getting a patient to sleep. We then have a number of nonspecific treatments; the benzos, the non-benzodiazepines, they tend to act on GABA which is throughout the CNS and is a suppressant. We also have specific agents, melatonin, histamine antagonists, and orexin antagonist that target that awakening system and are the specific brain centers involved in regulating sleep.

Now CBT works and it works well and it has a lasting influence. If you look here, this is a comparison of CBT and pharmacotherapy and combination therapy and what you see is CBT takes awhile often for it to kick in. If you look long-term it actually increases where as pharmacotherapy will often take effect early but then you get rebound insomnia, which is not rebound from the medication, it's just the insomnia that comes back if you've only treated it with pharmacotherapy. So, oftentimes we may use both. We may use pharmacotherapy short-term to get the patient to sleep while CBT is helping them adjust their approaches in life to decrease their insomnia. Mechanisms again, when we look at the hypnotics of the benzos and non-benzos, what we find is they don't inhibit GABA, they use GABA which is an inhibitory agent and the key issue is half-life. That is a broad, broad effect on the brain; it's taking a sledgehammer to the entire brain, but it works and patients know it. It hits their brain and they turn off, so a lot of patients really like that effect. It's an issue as you move patients off of these agents onto something else that you've got to explain that to them. A problem is, is also has some cognitive effects, particularly if it lasts into the next day. I'll come back at the end of the talk to talk about some further worrisome issues. Melatonin works. It is not used very often, but what we find is after three to four weeks it really kicks in for some patients, and particularly if patients have circadian problems it may be useful. It certainly is benign in terms of side effects. The antidepressants; we really have two in this class, trazodone, which we often use off-label, and one that I'll show you in a minute that actually has an FDA indication but there are other ways to get it. So, trazodone certainly, H1 antihistamine at the low dose is key and also has the Alpha-1 antagonist effect; that might be useful for nightmares and PTSD. It does have six to eight hours of half-life so it does last through the night and you can see the comparison here to other agents. The problem is we don't have studies on this that go beyond about two weeks, so we're not real certain if this preparation really has a long-term effect on sleep. Doxepin low dose is a pure H1 antihistamine. We think of it as an SSRI and, in 1982, it was one of the major branded antidepressants but it was very sedating. What we find is at 3 to 6 mg it is very effective for insomnia, particularly for sleep maintenance and insomnia and keeping people asleep throughout the night and into the next morning. There is also no head-to-head comparison in the literature between the 3 to 6 mg branded approach and the 10 mg dose, so I will leave that for your consideration. Orexin antagonists are fairly new and there is one on the market now. There are a number of these in development that you are going to see coming out over the next few years I expect. What they do is very specifically affect the sleep mechanisms. These are really the most directly affected at targeting the sleep control mechanism. So suvorexin suppresses, inhibits orexin and, in doing so, it inhibits the alerting system in the brain. It's very specific to the sleep system. It doesn't change your sleep profile, so if we look at REM sleep and we look at different stages of sleep, they all increase as patients improve their insomnia.
Let's look at the first patient, a cardiovascular patient. This is a 39-year-old accountant. Think about it, he is doing your taxes, okay? Approach it from that perspective. He comes in for a hypertension follow-up, not for insomnia, but for a hypertension follow-up. You can see he's had borderline elevated hypertension for a number of years, he has been on benazepril with good control in the past, but recently it's not been keeping his blood pressure in shape. He's got some stressors in his life and, in reviewing it, he also reports that, yes, he's having more difficulty sleeping. He goes to bed at 11:00 and gets up at 6:30, that's seven-and-a-half hours potential sleep. It takes him an hour to get to sleep, that's down to six-and-a-half hours and now he is often waking up at 5:00 a.m. He's not able to stay asleep throughout the night and he doesn't feel good the next day, it's really having an effect. He's having difficulty focusing and concentrating on your taxes. Think of that. But it has only been going on for a few months and that's key. This is acute onset. There are stressors involved. Now how does that connect to his blood pressure? You know, he came in for his blood pressure check. This is the, oh by the way can you help with my sleep presentation, and if you look at family history, yeah, he's got some red flags in terms of cardiovascular. You can see his basic indicators; he does have some arterial narrowing and he is borderline overweight/obese. So, how is insomnia associated with hypertension? Well, this is a cross-sectional study not cause and effect. I'm going to explain it now and we're going to see it again later.

In Pennsylvania, they had a grant; they went out and got a little bit less than 2,000 randomly selected adults. They put them in the sleep lab, you know you'd have to do something to convince me to go into a sleep lab for a couple of nights, and they looked for insomnia. When they compared those with insomnia on history of greater than a year, what they found is this increase, cross-sectional increase, in hypertension based on the objective duration of their sleep. You can see a fivefold increase in hypertension and those that were sleeping less than five hours. That's after we adjust for the conditions over in the text error box. Last, but still significant, three-and-a-half fold increase in those with five to six hours. But does it contribute to the development of hypertension? Here is an interesting study is a U.S. military study, so more men, but both genders, and they did long-term follow-up enrolling people starting in 1998. They excluded those in the analysis with chronic insomnia at onset and they also had a group that did not have hypertension, did not have insomnia, and then they followed them for years. What they found is that those that developed insomnia over time were twice as likely to go on and develop hypertension. So, 46 per 1,000 that controls per 10,000 developed hypertension. The insomnia group more than doubled that. Here we see really a pretty strong signal of cause and effect. There are other studies that document this. Most everybody that is studied it's a very consistent finding.

Let's go beyond hypertension. How about cardiovascular risk? These are all national registry studies. Taiwan, Sweden, Norway; they all have national registries so they can track their entire population over years and these are prospected follow-up studies that are done that way. They are not randomized, they're not controlled, but they are an entire population followed over time. What they find is these marked increases in those with insomnia followed over time, what we find is that acute MIs go up by 70%, stroke goes up by 80 to 90%, first cardiovascular events under that is men and women (both genders) go up 30 to 40%. When we look at congestive heart failure, this is another national study; I think this was in Stockholm but I'm not sure. What we find is that the number of insomnia symptoms as that increases your likelihood of then going on later to develop congestive heart failure also increases. So, clear signal is not just hypertension, it's cardiovascular.

How about contributing mortality, cardiovascular mortality? There are a number of studies here, health professional studies, this is you and I, large, federally-funded study, this was reported in circulation a couple of years ago, It enrolled U.S. men and followed them. Those with difficulty initiating and reporting nonrestorative sleep had a 55% increase in total mortality per year over the follow-up and, specifically, cardiovascular mortality increased by about 30%. You can see other initiating only, maintaining only, early morning awakening had lesser effects, but still considerable. When that study is thrown in to meta analysis with 12 other studies, what we find is a very consistent effect. There is really no inconsistency in the data around insomnia contributing to cardiovascular disease.

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Moving to treatment. The first thing is do no harm and what we find is that a big impact on whether beta blockers get into the brain. When we get down to the beta selective and then to atenolol and bisoprolol, which do not cross the blood brain barriers because they're low lipidicity as well, they have marked decrease likelihood of contributing to new insomnia. So, use that as you think about a beta blocker in cardiovascular disease. How about if we treat insomnia, is it going to help blood pressure? Is it going to help this gentleman? Well, here we see it. So, a hypnotic actually does decrease both diastolic and systolic blood pressure and it's particularly impactful when the insomnia improves. This is certainly encouraging. This is a busy slide. Let me talk you through it.

The bottom bullets; the risk score, eight biomarkers. Here you see lipids, triglycerides, C-reactive protein, hemoglobin A1c, fibrinogen, glucose and insulin. Those are individual ones. High risk was considered if four or more of those were abnormal and these are all non-pharmacological interventions. CBT, tai-chi versus a controlled sleep. What we find is the percent remaining in the high-risk category, so the percent of patients that continue to have four or more abnormal biomarkers; if their sleep improves, so that's the light gray, they have a marked decrease, they go from 70% with four or more biomarkers down to only 30%, at four months and a significant further increase by 16 months. That's just looking at sleep quality. If sleep quality improves, our biomarkers improve. Then looking at the specific interventions, CBT doesn't have as good an effect early on, but at four months it kicks in and then in 16 months it kicks in even more. Tai-chi has a modest effect and not long-term. So, critical to consider treatment in terms of lowering the biomarkers as well as cardiovascular disease.

Let's come back to this 39-year-old. We assess him, he's got a recent onset, it's frequent, he's having onset and early morning awakening and he's got some recent stressors. He is down in a pretty significant range; severity is five to six hours subjectively and he would like medication. That's a preference; he just doesn't have time for the CBT. So, if we approach him in terms of treatment, it's new insomnia to him so sleep hygiene is going to be pretty important to think through. Getting him to exercise can be very helpful, it's very augmenting in terms of sleep, moderate use of alcohol and calories, particularly later in the evening is critical. The old idea of "hey, I'll have a glass of wine and it'll put me to sleep," it will put you to sleep but three or four hours later it's going to wake you up and that's the problem, particularly when he has early onset. So, that's certainly something to emphasize. Explain catastrophizing, "oh my god I'm not asleep, I'm going to mess up tomorrow, I just gotta get to sleep." That type of catastrophizing sets in for a lot of patients and is one of the foci of CBT, so explaining to him that, yes, you're going to feel drowsy, but, objectively, your performance doesn't decrease that much with just one night of lost sleep, it's really the chronic cumulative effect that is critical. Epworth Sleepiness Scale, you may not have seen it, but Google it; it's a simple chart, few questions that really helps you gauge the severity of a sleep problem. It's things like how long does it take you to fall asleep if you're just sitting in a quiet room reading or do you fall asleep watching TV, or do you fall asleep at the red light as you drive home? That's kind of a red flag for severe insomnia. So, it's useful. A sleep diary may be helpful. I use these both to find out more about it myself but also to get patients involved in thinking about their sleep. In terms of treatment, I want something short-term so this might be a place where I might use a short-term benzodiazepine. I also might use doxepin since it does have a good impact in terms of the early awakening which the non-benzodiapines is problematic in terms of half-life having something that stays effective six to eight hours into the night but doesn't wipe out the next morning in terms of alertness.

Let's move to diabetes. A 34-year-old, sixth grade teacher comes in with a family history of diabetes that is a little worrisome, overweight, and finds herself irritable. She wants to lose weight. She is concerned about the diabetes. She is tired all the time and you can see her baseline insomnia on the physical findings there. Getting a further sleep history, she goes to bed a little bit before 11:00 and alarm is set at 6:00, seven hours and change in terms of possible sleep, but she takes an hour to get to sleep, so that's down to six hours or so and then she wakes and stays awake for at least an hour. We're down into that five hour range and it's been chronic since college. She has just sort of accepted this, it's just her lot in life, but it really is dragging her down at this point. On the weekends, she does compensate but that by itself is not adequate. She has a bunch of things that go through her head and help her stay awake. Just looking at snoring, there's no report of snoring or apneic events by bed partners, so we're thinking of another potential diagnosis and she's used a bunch of things, none of them have ever really helped with. So, again, is it associated? Well, this same cross-sectional study, the Pennsylvania random sample of population, and here we see the onset ratio for diabetes. So, objective sleep markedly increases, a threefold increase, in your likelihood of having diabetes. This is cross-sectional not cause and effect. When we look at the health professional study, what we find is our diet goes down. We don't sleep well, we don't eat well. Lifestyle intervention advice is helpful, but this just is the impact that we worsen our diets is just behavioral. That active duty military study, again, it doesn't matter how you slice or dice the population, if you develop chronic insomnia, you're very likely to go on and develop diabetes. It showed more than twofold increase, it doesn't matter if you look by age or obese or not obese, chronic insomnia precedes and leads to the development of diabetes. When we look at mechanisms, well, insulin resistance is altered for the worst in those with insomnia, particularly if they have daytime sleepiness which is a good indicator of severity. When a Japanese company looked at their annual checkup data, what they found was the difficulty maintaining asleep and early morning awakening markedly increased diabetes, in the range of two, four, almost a sevenfold increase in diabetes, particularly markers of chronic. Yes, it's an impact. When we look at that study in terms of the eight biomarkers, we look at them now but thinking with diabetes in mind, we've got hemoglobin A1c, we've got insulin and glucose, and so forth, again, improving sleep quality decreases biomarkers for both cardiovascular and diabetes, and CBT is effective; it is effective at four months, and is more effective at 16 months. Tai-chi has some effect and just a sleep education had adversely no effect.

Back to our 34-year-old school teacher. She's got chronic insomnia that's been part of her life since college. She has just accepted it, so she doesn't complain of it. She complains of being tired but not "I can't sleep." Most nights onset is in the middle of the night so she needs something to start, to keep her asleep. She is sleeping okay once she gets into five/six but it's significant. She doesn't have anything that's waking her up at night and it's certainly having an impact. She really doesn't have any strong preference. She is not exercising so that's something we're going to kick in. So, reviewing sleep hygiene, she has probably seen this on the web already, but that's critical, focusing on the exercise. If you're tired, you don't want to go out and exercise. It's that catch-22. Getting them over the hump, a little motivation. Just start out five minutes more walking, let's move it up to ten minutes, 15 minutes can be very helpful. Education, again, it's catastrophizing. Sleepiness scale or sleep diary may be helpful in terms of letting her monitor her sleep as well as you. Here's a patient with chronic insomnia. I don't want to put her on a benzo. She has tried the OTCs and has already encountered the side effects. Diphenhydramine; the problem with it is it's still in your brain 16 hours later knocking you out the next day when you're trying to be alert and active. So, it’s a big downfall. It also has a number of side effects.

We're coming back now to what's the best treatment approach. , I would be looking in chronic insomnia at something that is going to be targeting specific sleep mechanisms. We've got the sense she wakes up, she keeps alert, and she keeps thinking. She is not turning her brain off at night. So, she needs something to dampen the awakening drive and that's where suvorexant, doxepin, as FDA-indicated treatments may be effective. Trazodone, if you look at the American College of Physicians recommendations, they basically diss trazodone as a sleep intervention, they certainly don't use it first line. But doxepin and trazodone both affect H1, both are antihistaminic. Suvorexant here is probably the most specific again. So, in a chronic patient where they may need chronic treatment, this is certainly something to consider, and I definitely would want to get her in to a CBT-like intervention if possible.

Let's move on to the third case. Now we're changing models. So, we've had cardiovascular, diabetes, and now depression. These often times coalesce in single patients and I totally acknowledge that. This 55-year-old house painter says "my life's turning gray again." He's had multiple episodes of depression, and it's back, and he doesn't like it. No real new stressors and that's very frequent. The initial episodes of depression often occur in the early 20s, late 20s, 30s, in response to significant stress or significant loss, but as the episodes accumulate and if you follow patients with an initial episode of depression, for five years roughly 50 to 60% have had a recurrence. If you follow them after 15 years, 85% have had recurrent episodes. So, patients with depression, it really is a recurrent illness. The initial ones often due to stressors but as you get further out; third, fourth event, they just come autonomous. It is just often and out of the blue, not precipitated by stress. But, insomnia and sleep problems may be interactive with onset. So, he's been on escitalopram maintenance therapy and he is noticing his flags for depression; that's why he is in your office, which is decreased innervation, energy, he is a-motivated in terms of motivation, has trouble concentrating and focusing. He is painting your kitchen and the lines are getting wavy because he's just not keeping his focus on it, and he's having difficulty sleeping again. He has found that's a real concern because that often is part of the problem. We see here that he is really getting down in that five to six-hour range of sleep and it's persistent. This is part of his routine. He gets insomnia and he gets depressed.

Further assessment is chronic recurrent with depressive episodes. Most nights five hours of sleep, middle of the night and early awakening. That's often a very common pattern with depression. I get to sleep but then wake up and can't get back to sleep, decreased energy and so forth. He's tried his wife's alprazolam, it worked, and he liked it. He wants some for himself. He is willing to take your advice and he's got really no nocturnal concerns and doesn't exercise regularly. Which of the following psychiatric disorders was insomnia most likely to increase the incidents of in patients at risk over a three-and-a-half period follow-up time. Major depression, any anxiety state, drug abuse dependency or alcohol abuse and dependency. So, which of those was insomnia most likely to increase the incidents of in a three-and-a-half year follow-up study?

Okay, major depression, and then we see the rest of those. I think we will see more data on that. So, this is looking at the study. Three-and-a-half year follow-up, no psychiatric disorder at baseline, insomnia at baseline, and what we see is from those that continued not to have insomnia only 5% of them became depressed and that bumps up to a sixfold increase up to 31%. It does increase the others; it's just not as much as major depression. That's key in terms of the interaction. Who develops insomnia, in relation to their mental health history? Starting from a mental health perspective, who is most likely to develop insomnia? And what we see, this was a study of New Zealanders, about 1,000 New Zealanders born in 1972, 1973, and they're still being followed. So, this is a long-term follow-up starting at birth. People like New Zealand, they don't leave, so 95% retention rate, pretty amazing. What we find is when we look at insomnia at age 35 and then look back at psychiatric histories that have been assessed repeatedly in this population over time starting at age five, what we find is that patients that develop insomnia, those at high-risk of insomnia, had family histories of depression and anxiety and had lifelong episodes of depression and anxiety, particularly beginning in childhood. Depression and anxiety tends to lead to chronic insomnia. This is another study, this is looking at teenagers. So, 13 to 16-year-olds, probably the best study in this area, and what we find is that there is a lot of interaction between insomnia precipitating psychiatric conditions and vice versa. But, overall, as we look over the lifespan is anxiety disorders, which tend to be fairly chronic, often precede the insomnia. They very likely contribute to the insomnia, but they precede the insomnia. Anxiety first, then insomnia, then depression, and then insomnia and depression bounce back and forth. Anxiety frequently is a constant in these people's lives. There's certainly interaction among these and anxiety may be an early precipitant. Does insomnia alter the course of depression? What we find is that those with persistent insomnia, those that continue to have sleep difficulty were much more likely to remain depressed, and then it was both sleep latency, not being able to get to sleep or just plain old garden variety insomnia that increased the likelihood of not remitting to treatment with depression.

Looking at the impairment what we find is depressed patients or anxious patients that also had insomnia, you're going to see them in the office a lot more commonly; two to three times more visits to us and the insomnia may still be hidden or we may just consider it part of the depression, but it's a comorbid condition. It needs to be focused on separately in addition to the depression, and it certainly has its impairment in terms of work and activity. The key here is that you need to treat both. There have been a number of studies now that show that if you start, if you have a depressed patient, and they have insomnia, and that should be part of the baseline assessment, if you treat both of them from the get go, so you start treatment for both, at the same time, and you look down the line, in terms of the depression status, three months later, six months later, they're more likely to be in remission from depression than if you take a consecutive approach. Okay, they're depressed, insomnia may be part of it, and I'll treat the depression. You treat the depression, you look later, three, six weeks later, and their insomnia is persisting, and the depression is really not improving like you want, so now you add treatment for insomnia. Long-term, they don't end up having as good a result as those when you treat both to start. So, consider them comorbid. The old concept of primary insomnia and secondary insomnia were abolished. That is outdated. The latest DSM-5 and the latest insomnia guidelines around diagnosis and treatment categories, the sleep specialists, they eliminate primary insomnia from their vocabulary and secondary insomnia. They basically say they are comorbid, they're comorbid conditions, and they need to be treated at the same time. You get better outcomes. Same with pain, if you treat both depression and pain at the same time and pain, insomnia, and depression often go together. It is very useful to treat all of them from the start.
When we look at treatment of depression what we find is that very frequently patients do continue to have insomnia even if their depression improves, and this is in both patients with pharmacotherapy or CBT. Treating depression alone does not treat insomnia and it needs to be treated. When we look at choice of antidepressant, we certainly do know that there are sedating antidepressants, but the way we assess that is daytime somnolence and certainly paroxetine will cause daytime somnolence and mirtazapine at low doses will cause daytime somnolence. Sometimes we use that to help patients get sleep, but what we find is that they're really overall, when you through the number studies into a meta analysis, there's no systematic effect on insomnia as opposed to daytime somnolence. Not a big issue there. Zolpidem certainly improves the insomnia but it really doesn't augment the antidepressant effect. So, again, you have to treat both, you can't treat one and expect it to help with the other.

When we look at suicidality, something to be concerned about with depression, what we find is patients with sedative hypnotic use have a significant increase after adjusting for our insomnia. This is certainly an issue to consider in terms of hypnotics and non-benzodiazepine use in depressed patients. Something to think about. Suicidality, we don't have completed suicide, but certainly this is suicidality. Let's go back to our 55-year-old house painter. He's got chronic insomnia and it's a co-traveler with his depression. When they're both active, it's particularly bad. It's onset, it's the middle of the night, there's early morning awakening, he does have the impact in at five hours; now, his depression is already doubling his likelihood of diabetes and cardiovascular disease and other chronic conditions. Throw insomnia on top of that and he is at marked risk for increase in those chronic conditions. He has tried OTCs, tossed them out; he likes his wife's alprazolam, and doesn't have any concerns. He is not exercising regularly, and so, again, encourage exercise. It's very helpful in terms of augmenting sleep. Again, standard recommendations in terms of objective scales that can help you and the patient monitor their sleep issues. This is, again, a patient I would stay away from benzos on. So, he wants a benzo, I don't want him on a benzo. Again, suvorexant, doxepin; they're both going to help with the early morning awakening. They are both very helpful at that range. They don't have the marked knockout effect that the benzos have, which he really liked, in terms of onset, but they are effective at onset. I find that the antihistaminics tend to decrease, particularly their onset effect, with time. There is an accommodation to that to development of tolerance in terms of putting the patients to sleep at the beginning of the night, but the early morning awakening effect does continue long-term. Doxepin certainly would be a reasonable recommendation for him. Suvorexant, again, because of the chronic nature of his condition and the specific targeting would be very useful, and, again, I would emphasize it has a much more gentle, totally different effect in terms of putting people to sleep. They can take a half-hour or so before bedtime and it does significantly cut down on onset insomnia. It doesn't have the psychic knockout effect that the benzos have. But, he wants his wife's med. He liked that regular med, it worked.

What else can you throw in? A family history of Alzheimer's disease…aha! What do we know about dementia and hypnotics? Now, I'd emphasize this is mainly data on the traditional benzos, not the non-benzos, so we really don't have an answer to this question or on the non-benzos. There's still difficulty in terms of understanding the interaction of anxiety disorders and the brain changes due to those; the insomnia and the benzos. We haven't teased that apart, but what we find is that adjusting for chronic conditions, the benzos, particularly the long-acting ones at high dose, are the ones to be of concern. Those have significant increase in association with later onset of dementia.

Now, remember I asked you about glymphatics. This is an article in 2013 science magazine. This has already moved up to the top 1% of referenced articles in science and the science literature. This is a major breakthrough. I wouldn't be surprised if we don't see a Nobel Prize coming out of this. What they describe is a new system that we did not know about in the brain, which is when we sleep, the space around arterials increases significantly. That leads to a major way by which the brain washes itself out of amyloids and other waste products. There's only about a 5% flow when you're awake. That increases by 60% during sleep. There's a lot of work going on this, but this may well explain why it's so important and why everybody that's got a brain, and all animals that have got brains, sleep. It may be the way our brain empties itself of waste products including amyloid. So, this now is a major consideration in terms of the value of sleep. It goes along with the idea of objective sleep, duration being important, critical. The brain does not have a lymphatic system, well, no, it doesn't, but it empties itself of waste by what's called a glymphatic system, this opening of the space around arterials sort of the arterial glia neuron structure to allow it to flush out the brain. Critical, critical new finding that you'll see a lot more of. We explained that to him and he's quite happy now to take suvorexant, particularly given the chronicity of his condition and its effect, and we explained again that the onset of action isn't going to be the same as what he expected with benzos.

In summary, chronic condition is not a wastebasket diagnosis, it's not a nuisance diagnose, it may be key to helping your patients with chronic disease obtain adequate control of their chronic diseases and decrease progression. Particularly important is significant insomnia, particularly if it's objective and you can often see that just with the hours that they report being in bed and not being awake. Treating it is something to think about doing coterminous with the treatment of those conditions. It's a comorbidity; it's not a primary or secondary thing. Pharmacotherapy, you need to select pharmacotherapy in keeping with the chronicity and pattern of insomnia and the expected duration of treatment. If you're using it like in our very first case, for a short-term insomnia problem, hopefully we can quickly get that patient back to sleeping well, that's where a non-benzo hypnotic might be valuable. Other than that, I would tend to stay away from those.

Let me stop there.

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