Sleep Medicine

A heart rate–profiling algorithm shows promise at distinguishing differences in heart rate patterns during sleep between people with depression and healthy controls, research shows.

The algorithm was modeled using machine learning based on 1,203 polysomnograms from either people with depression or healthy controls, according to Mysa Saad, of the sleep research unit of the Royal’s Institute of Mental Health Research in Ottawa, and associates. That final algorithm was then tested on a new sample of 174 individuals (87 controls, 87 with depression) to categorize each person as either depressed or not depressed. This result was compared with medical record diagnoses. The study was published in BMC Psychiatry.

Compared with the control group, patients in the depression group slept 30.6 minutes less, had significantly longer sleep and REM onset latency, and had a lower amount of REM sleep as a percentage of total sleep time and in overall time. The algorithm incorrectly identified 15 patients with depression as being in the control group, and incorrectly identified 20 controls as having depression. The overall accuracy was 79.9%, with a sensitivity of 82.8% and a specificity of 77%.

“In addition to providing an improved biological underpinning for the diagnosis of depression, this [tool] could possibly offer supplemental information to psychiatric clinical assessment, and objective measures for early screening. Moreover, the use of distinct physiological variables as biomarkers of depression may help emphasize the interactions between mental and physical health. This may contribute to reducing the stigma associated with depression, lifting some social barriers to accessing psychiatric treatment, and allowing for more holistic patient care,” the investigators concluded.

Medibio provided partial funding for the salaries of research assistants; no other conflicts of interest were reported.

[email protected]

SOURCE: Saad M et al. BMC Psychiatry. 2019 Jun 7. doi: 10.1186/s12888-019-2152-1.

A heart rate–profiling algorithm shows promise at distinguishing differences in heart rate patterns during sleep between people with depression and healthy controls, research shows.

The algorithm was modeled using machine learning based on 1,203 polysomnograms from either people with depression or healthy controls, according to Mysa Saad, of the sleep research unit of the Royal’s Institute of Mental Health Research in Ottawa, and associates. That final algorithm was then tested on a new sample of 174 individuals (87 controls, 87 with depression) to categorize each person as either depressed or not depressed. This result was compared with medical record diagnoses. The study was published in BMC Psychiatry.

Compared with the control group, patients in the depression group slept 30.6 minutes less, had significantly longer sleep and REM onset latency, and had a lower amount of REM sleep as a percentage of total sleep time and in overall time. The algorithm incorrectly identified 15 patients with depression as being in the control group, and incorrectly identified 20 controls as having depression. The overall accuracy was 79.9%, with a sensitivity of 82.8% and a specificity of 77%.

“In addition to providing an improved biological underpinning for the diagnosis of depression, this [tool] could possibly offer supplemental information to psychiatric clinical assessment, and objective measures for early screening. Moreover, the use of distinct physiological variables as biomarkers of depression may help emphasize the interactions between mental and physical health. This may contribute to reducing the stigma associated with depression, lifting some social barriers to accessing psychiatric treatment, and allowing for more holistic patient care,” the investigators concluded.

Medibio provided partial funding for the salaries of research assistants; no other conflicts of interest were reported.

[email protected]

SOURCE: Saad M et al. BMC Psychiatry. 2019 Jun 7. doi: 10.1186/s12888-019-2152-1.

A heart rate–profiling algorithm shows promise at distinguishing differences in heart rate patterns during sleep between people with depression and healthy controls, research shows.

The algorithm was modeled using machine learning based on 1,203 polysomnograms from either people with depression or healthy controls, according to Mysa Saad, of the sleep research unit of the Royal’s Institute of Mental Health Research in Ottawa, and associates. That final algorithm was then tested on a new sample of 174 individuals (87 controls, 87 with depression) to categorize each person as either depressed or not depressed. This result was compared with medical record diagnoses. The study was published in BMC Psychiatry.

Compared with the control group, patients in the depression group slept 30.6 minutes less, had significantly longer sleep and REM onset latency, and had a lower amount of REM sleep as a percentage of total sleep time and in overall time. The algorithm incorrectly identified 15 patients with depression as being in the control group, and incorrectly identified 20 controls as having depression. The overall accuracy was 79.9%, with a sensitivity of 82.8% and a specificity of 77%.

“In addition to providing an improved biological underpinning for the diagnosis of depression, this [tool] could possibly offer supplemental information to psychiatric clinical assessment, and objective measures for early screening. Moreover, the use of distinct physiological variables as biomarkers of depression may help emphasize the interactions between mental and physical health. This may contribute to reducing the stigma associated with depression, lifting some social barriers to accessing psychiatric treatment, and allowing for more holistic patient care,” the investigators concluded.

Medibio provided partial funding for the salaries of research assistants; no other conflicts of interest were reported.

[email protected]

SOURCE: Saad M et al. BMC Psychiatry. 2019 Jun 7. doi: 10.1186/s12888-019-2152-1.

The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].

The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].

The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Blood oxygen levels drop during sleep, but how much and when that happens is mainly hereditary? Now researchers from Brigham and Women’s Hospital and Case Western Reserve University are getting closer to finding the genetic reasons for the fluctuations, which could help people with sleep apnea and other lung illnesses.

In their study, funded by the National Heart, Lung, and Blood Institute (NHLBI), the researchers analyzed whole genome sequence data from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. They also incorporated results for family-based linkage analysis, which maps genes with hereditary traits to their location in the genome.

The researchers identified 57 genetic variations of DLC1, a gene consistently associated with average arterial oxyhemoglobin saturation during sleep. The variants explain almost 1% of the variability in the oxygen levels in European Americans. That is high for complex genetic phenotypes, the researchers say. Of the 57 variants, 51 influence and regulate human lung fibroblast cells.

 “This study highlights the advantage of using family data in searching for rare variants,” says James Kiley, PhD, director of the Division of Lung Diseases at NHLBI. “It showed that, when guided by family linkage data, whole genome sequence analysis can identify rare variants that signal disease risks, even with a small sample. In this case, the initial discovery was done with fewer than 500 samples.”

Blood oxygen levels drop during sleep, but how much and when that happens is mainly hereditary? Now researchers from Brigham and Women’s Hospital and Case Western Reserve University are getting closer to finding the genetic reasons for the fluctuations, which could help people with sleep apnea and other lung illnesses.

In their study, funded by the National Heart, Lung, and Blood Institute (NHLBI), the researchers analyzed whole genome sequence data from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. They also incorporated results for family-based linkage analysis, which maps genes with hereditary traits to their location in the genome.

The researchers identified 57 genetic variations of DLC1, a gene consistently associated with average arterial oxyhemoglobin saturation during sleep. The variants explain almost 1% of the variability in the oxygen levels in European Americans. That is high for complex genetic phenotypes, the researchers say. Of the 57 variants, 51 influence and regulate human lung fibroblast cells.

 “This study highlights the advantage of using family data in searching for rare variants,” says James Kiley, PhD, director of the Division of Lung Diseases at NHLBI. “It showed that, when guided by family linkage data, whole genome sequence analysis can identify rare variants that signal disease risks, even with a small sample. In this case, the initial discovery was done with fewer than 500 samples.”

Blood oxygen levels drop during sleep, but how much and when that happens is mainly hereditary? Now researchers from Brigham and Women’s Hospital and Case Western Reserve University are getting closer to finding the genetic reasons for the fluctuations, which could help people with sleep apnea and other lung illnesses.

In their study, funded by the National Heart, Lung, and Blood Institute (NHLBI), the researchers analyzed whole genome sequence data from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. They also incorporated results for family-based linkage analysis, which maps genes with hereditary traits to their location in the genome.

The researchers identified 57 genetic variations of DLC1, a gene consistently associated with average arterial oxyhemoglobin saturation during sleep. The variants explain almost 1% of the variability in the oxygen levels in European Americans. That is high for complex genetic phenotypes, the researchers say. Of the 57 variants, 51 influence and regulate human lung fibroblast cells.

 “This study highlights the advantage of using family data in searching for rare variants,” says James Kiley, PhD, director of the Division of Lung Diseases at NHLBI. “It showed that, when guided by family linkage data, whole genome sequence analysis can identify rare variants that signal disease risks, even with a small sample. In this case, the initial discovery was done with fewer than 500 samples.”

NEW ORLEANS – Social media and electronics aren’t the only barriers to a good night’s sleep for teens, according to Adiaha I. A. Spinks-Franklin, MD, MPH, a pediatrician at Texas Children’s Hospital in Houston.

junpinzon/Thinkstock

Another half-dozen “sleep enemies” interfere with adolescents’ sleep and can contribute to insomnia or other sleep disorders, she told attendees at the annual meeting of the American Academy of Pediatrics.

Knowing what normal sleep physiology looks like in youth and understanding the most common sleep enemies and sleep-behavior problems can help you use effective interventions to help your patients get the sleep they need, she said.

Infants need the most sleep, about 12-16 hours each 24-hour period, including naps, for those aged 4-12 months. As they grow into toddlerhood and preschool age, children gradually need less: Children aged 1-2 years need 11-14 hours and children aged 3-5 years need 10-13 hours, including naps. By the time children are in school, ages 6-12, they should have dropped their naps and need 9-12 hours a night.

Parents may expect teens can get by with only as much sleep as adults need, but teens actually need 8-10 hours of sleep a night, and many don’t get that much. In fact, 75% of high school seniors get less than 8 hours of sleep a day and live with a chronic sleep debt, Dr. Spinks-Franklin said.

Although social media use and electronics in the bedroom – TVs, computers, cell phones, and video games – can certainly contribute to inadequate sleep, a heavy academic load and extracurricular activities can be just as problematic, Dr. Spinks-Franklin said. Teens who work after school also may have difficulty getting enough sleep, especially if they also have to balance a heavier academic load or even one or two extracurricular activities.

Socializing with friends also can interfere with sleep, especially when get-togethers run late; drinking caffeinated drinks in the afternoon onward can make it difficult for adolescents to get the sleep they need as well. Less-modifiable contributors to too little sleep are stress and early school start times, Dr. Spinks-Franklin said.

The two most common sleep problems seen in teens are insomnia and delayed sleep phase syndrome. Addressing these is important because the effects of chronic insufficient sleep can have far-reaching consequences. Obesity and related chronic health conditions are associated with inadequate sleep, as are poor academic performance, poor judgment, poor executive functioning, and mental health disorders like depression.

Short-term effects of insufficient sleep also can be problematic and can exacerbate existing sleep problems, such as sleeping in on the weekends to “catch up” on sleep or drinking more caffeine to try to stay awake during the day. Increased caffeine intake can interfere with non-REM deep sleep, Dr. Spinks-Franklin said, and therefore reduce the quality of sleep even if the person gets the total hours they need.

Insomnia in adolescents

Insomnia can refer to difficulty falling asleep, staying asleep, sleeping for long enough, or getting enough sleep in one period of time even when the opportunity is there. Some people may have no trouble falling asleep, but they wake up too early – before they have had gotten the sleep they need – and cannot return to sleep.

To be insomnia, the problem must occur “despite having enough time available for sleep,” Dr. Spinks-Franklin said. “Patient who restrict the amount of time for sleep due to work or social commitments may have trouble sleeping and daytime sleepiness but do not have insomnia.”

Daytime impairment also is part of the American Academy of Sleep Medicine’s definition of insomnia. The rare teen who doesn’t need as much sleep as average and functions without difficulty during the day does not necessarily have insomnia.

But the impairment may not necessarily just be fatigue or sleepiness. In fact, many of the symptoms are the same as those seen with ADHD.

Daytime consequences of insomnia can include the following:

• Depression, feeling sad or “blue,” or emotional hypersensitivity.
• Mood swings, crankiness, or irritability.
• Difficulty concentrating or paying attention, poor memory, mind wandering, or even inability to sit still.
• Job or school problems, such as not being able to finish homework, not finishing tasks they start, or forgetfulness.
• Difficulty in social situations, such as discomfort with others or problems with friends.
• Daytime sleepiness, even when unable to actually take a nap.
• Behavioral problems, such as hyperactivity, impulsivity, or aggression.
• Frequent mistakes, especially at work, at school, or while driving (often “errors of omission,” such as not seeing a street sign or not hearing an instruction).
• Lower levels of motivation or initiative, feeling less energetic.
• Excessive worry about sleep.

Evaluation of insomnia can be framed with “the three-factor model,” which includes predisposing factors, precipitating factors, and perpetuating factors.

Predisposing factors – those that indicate a person already may be at risk for insomnia – include potential genetic influences as well as their typical response to stress. “Do they sleep more or less?” Dr. Spinks-Franklin said. Even teens predisposed to insomnia may not develop it, however, without a precipitating trigger.

These triggers could include stress, anxiety, poor initial sleep hygiene that becomes a pattern, dietary intake or behaviors (such as drinking caffeine or eating too much or too late in the evening), changes to their schedule, or side effects of medications.

Once insomnia begins, various factors can then perpetuate the cycle, including some of those that triggered it, such as anxiety or a school or work schedule. Sometimes it can be difficult to pinpoint the factor prolonging insomnia, such as the unconscious reward of going to work or school late with few or no consequences.

Delayed sleep phase syndrome

Delayed sleep phase syndrome occurs when someone has a delayed onset of melatonin secretion that pushes back the time when they can fall asleep. Melatonin is the neurotransmitter produced by the pineal gland that signals the start of nighttime. Although it has a hereditary component, delayed sleep phase syndrome also can result from a pattern of poor sleep onset and sleeping in on the weekends.

Dr. Spinks-Franklin described the typical cycle: A teen doesn’t go to sleep until after midnight and then wants to sleep in later in the morning. Because they have to wake up early for school, they sleep in on the weekends to try to regain the sleep they lost. Sleeping in pushes their circadian rhythm even later, perpetuating the problem.

Interventions for sleep disorders

The recommended treatment for insomnia is cognitive-behavior therapy for insomnia, for which strong evidence exists. Before seeking cognitive-behavior therapy, however, families can work to improve sleep hygiene and reduce stimuli that contribute to insomnia.

Teens should avoid screens for at least 1 hour before bedtime and avoid caffeine and exercise for at least 4 hours before going to bed. They also need to develop a schedule with a consistent bedtime and wake-up time, including on the weekends. They should avoid sleeping in on the weekends or taking naps during the day, Dr. Spinks-Franklin said.

Delayed sleep phase syndrome is more resistant to treatment and has a high recurrence rate, she said, and it requires commitment from the parent and their child to address it successfully. Teens with this condition also can start with sleep hygiene practices: a consistent wake-up time that they maintain on the weekends and no daytime naps. Phototherapy in the morning can be added to hopefully induce an earlier onset of melatonin release in the evening.

The next step is making changes to the youth’s schedule, particularly evening and/or weekend activities. They can try to gradually advance their biological clock by changing their sleep schedule.

Dr. Spinks-Franklin also briefly addressed the use of over-the-counter melatonin supplements for treating sleep problems. Melatonin can be effective for treating insomnia by improving sleep onset and sleep quality, particularly in children and teens with autism spectrum disorder or ADHD.

Dr. Spinks-Franklin had no disclosures, and her presentation used no outside funding.

NEW ORLEANS – Social media and electronics aren’t the only barriers to a good night’s sleep for teens, according to Adiaha I. A. Spinks-Franklin, MD, MPH, a pediatrician at Texas Children’s Hospital in Houston.

junpinzon/Thinkstock

Another half-dozen “sleep enemies” interfere with adolescents’ sleep and can contribute to insomnia or other sleep disorders, she told attendees at the annual meeting of the American Academy of Pediatrics.

Knowing what normal sleep physiology looks like in youth and understanding the most common sleep enemies and sleep-behavior problems can help you use effective interventions to help your patients get the sleep they need, she said.

Infants need the most sleep, about 12-16 hours each 24-hour period, including naps, for those aged 4-12 months. As they grow into toddlerhood and preschool age, children gradually need less: Children aged 1-2 years need 11-14 hours and children aged 3-5 years need 10-13 hours, including naps. By the time children are in school, ages 6-12, they should have dropped their naps and need 9-12 hours a night.

Parents may expect teens can get by with only as much sleep as adults need, but teens actually need 8-10 hours of sleep a night, and many don’t get that much. In fact, 75% of high school seniors get less than 8 hours of sleep a day and live with a chronic sleep debt, Dr. Spinks-Franklin said.

Although social media use and electronics in the bedroom – TVs, computers, cell phones, and video games – can certainly contribute to inadequate sleep, a heavy academic load and extracurricular activities can be just as problematic, Dr. Spinks-Franklin said. Teens who work after school also may have difficulty getting enough sleep, especially if they also have to balance a heavier academic load or even one or two extracurricular activities.

Socializing with friends also can interfere with sleep, especially when get-togethers run late; drinking caffeinated drinks in the afternoon onward can make it difficult for adolescents to get the sleep they need as well. Less-modifiable contributors to too little sleep are stress and early school start times, Dr. Spinks-Franklin said.

The two most common sleep problems seen in teens are insomnia and delayed sleep phase syndrome. Addressing these is important because the effects of chronic insufficient sleep can have far-reaching consequences. Obesity and related chronic health conditions are associated with inadequate sleep, as are poor academic performance, poor judgment, poor executive functioning, and mental health disorders like depression.

Short-term effects of insufficient sleep also can be problematic and can exacerbate existing sleep problems, such as sleeping in on the weekends to “catch up” on sleep or drinking more caffeine to try to stay awake during the day. Increased caffeine intake can interfere with non-REM deep sleep, Dr. Spinks-Franklin said, and therefore reduce the quality of sleep even if the person gets the total hours they need.

Insomnia in adolescents

Insomnia can refer to difficulty falling asleep, staying asleep, sleeping for long enough, or getting enough sleep in one period of time even when the opportunity is there. Some people may have no trouble falling asleep, but they wake up too early – before they have had gotten the sleep they need – and cannot return to sleep.

To be insomnia, the problem must occur “despite having enough time available for sleep,” Dr. Spinks-Franklin said. “Patient who restrict the amount of time for sleep due to work or social commitments may have trouble sleeping and daytime sleepiness but do not have insomnia.”

Daytime impairment also is part of the American Academy of Sleep Medicine’s definition of insomnia. The rare teen who doesn’t need as much sleep as average and functions without difficulty during the day does not necessarily have insomnia.

But the impairment may not necessarily just be fatigue or sleepiness. In fact, many of the symptoms are the same as those seen with ADHD.

Daytime consequences of insomnia can include the following:

• Depression, feeling sad or “blue,” or emotional hypersensitivity.
• Mood swings, crankiness, or irritability.
• Difficulty concentrating or paying attention, poor memory, mind wandering, or even inability to sit still.
• Job or school problems, such as not being able to finish homework, not finishing tasks they start, or forgetfulness.
• Difficulty in social situations, such as discomfort with others or problems with friends.
• Daytime sleepiness, even when unable to actually take a nap.
• Behavioral problems, such as hyperactivity, impulsivity, or aggression.
• Frequent mistakes, especially at work, at school, or while driving (often “errors of omission,” such as not seeing a street sign or not hearing an instruction).
• Lower levels of motivation or initiative, feeling less energetic.
• Excessive worry about sleep.

Evaluation of insomnia can be framed with “the three-factor model,” which includes predisposing factors, precipitating factors, and perpetuating factors.

Predisposing factors – those that indicate a person already may be at risk for insomnia – include potential genetic influences as well as their typical response to stress. “Do they sleep more or less?” Dr. Spinks-Franklin said. Even teens predisposed to insomnia may not develop it, however, without a precipitating trigger.

These triggers could include stress, anxiety, poor initial sleep hygiene that becomes a pattern, dietary intake or behaviors (such as drinking caffeine or eating too much or too late in the evening), changes to their schedule, or side effects of medications.

Once insomnia begins, various factors can then perpetuate the cycle, including some of those that triggered it, such as anxiety or a school or work schedule. Sometimes it can be difficult to pinpoint the factor prolonging insomnia, such as the unconscious reward of going to work or school late with few or no consequences.

Delayed sleep phase syndrome

Delayed sleep phase syndrome occurs when someone has a delayed onset of melatonin secretion that pushes back the time when they can fall asleep. Melatonin is the neurotransmitter produced by the pineal gland that signals the start of nighttime. Although it has a hereditary component, delayed sleep phase syndrome also can result from a pattern of poor sleep onset and sleeping in on the weekends.

Dr. Spinks-Franklin described the typical cycle: A teen doesn’t go to sleep until after midnight and then wants to sleep in later in the morning. Because they have to wake up early for school, they sleep in on the weekends to try to regain the sleep they lost. Sleeping in pushes their circadian rhythm even later, perpetuating the problem.

Interventions for sleep disorders

The recommended treatment for insomnia is cognitive-behavior therapy for insomnia, for which strong evidence exists. Before seeking cognitive-behavior therapy, however, families can work to improve sleep hygiene and reduce stimuli that contribute to insomnia.

Teens should avoid screens for at least 1 hour before bedtime and avoid caffeine and exercise for at least 4 hours before going to bed. They also need to develop a schedule with a consistent bedtime and wake-up time, including on the weekends. They should avoid sleeping in on the weekends or taking naps during the day, Dr. Spinks-Franklin said.

Delayed sleep phase syndrome is more resistant to treatment and has a high recurrence rate, she said, and it requires commitment from the parent and their child to address it successfully. Teens with this condition also can start with sleep hygiene practices: a consistent wake-up time that they maintain on the weekends and no daytime naps. Phototherapy in the morning can be added to hopefully induce an earlier onset of melatonin release in the evening.

The next step is making changes to the youth’s schedule, particularly evening and/or weekend activities. They can try to gradually advance their biological clock by changing their sleep schedule.

Dr. Spinks-Franklin also briefly addressed the use of over-the-counter melatonin supplements for treating sleep problems. Melatonin can be effective for treating insomnia by improving sleep onset and sleep quality, particularly in children and teens with autism spectrum disorder or ADHD.

Dr. Spinks-Franklin had no disclosures, and her presentation used no outside funding.

NEW ORLEANS – Social media and electronics aren’t the only barriers to a good night’s sleep for teens, according to Adiaha I. A. Spinks-Franklin, MD, MPH, a pediatrician at Texas Children’s Hospital in Houston.

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Another half-dozen “sleep enemies” interfere with adolescents’ sleep and can contribute to insomnia or other sleep disorders, she told attendees at the annual meeting of the American Academy of Pediatrics.

Knowing what normal sleep physiology looks like in youth and understanding the most common sleep enemies and sleep-behavior problems can help you use effective interventions to help your patients get the sleep they need, she said.

Infants need the most sleep, about 12-16 hours each 24-hour period, including naps, for those aged 4-12 months. As they grow into toddlerhood and preschool age, children gradually need less: Children aged 1-2 years need 11-14 hours and children aged 3-5 years need 10-13 hours, including naps. By the time children are in school, ages 6-12, they should have dropped their naps and need 9-12 hours a night.

Parents may expect teens can get by with only as much sleep as adults need, but teens actually need 8-10 hours of sleep a night, and many don’t get that much. In fact, 75% of high school seniors get less than 8 hours of sleep a day and live with a chronic sleep debt, Dr. Spinks-Franklin said.

Although social media use and electronics in the bedroom – TVs, computers, cell phones, and video games – can certainly contribute to inadequate sleep, a heavy academic load and extracurricular activities can be just as problematic, Dr. Spinks-Franklin said. Teens who work after school also may have difficulty getting enough sleep, especially if they also have to balance a heavier academic load or even one or two extracurricular activities.

Socializing with friends also can interfere with sleep, especially when get-togethers run late; drinking caffeinated drinks in the afternoon onward can make it difficult for adolescents to get the sleep they need as well. Less-modifiable contributors to too little sleep are stress and early school start times, Dr. Spinks-Franklin said.

The two most common sleep problems seen in teens are insomnia and delayed sleep phase syndrome. Addressing these is important because the effects of chronic insufficient sleep can have far-reaching consequences. Obesity and related chronic health conditions are associated with inadequate sleep, as are poor academic performance, poor judgment, poor executive functioning, and mental health disorders like depression.

Short-term effects of insufficient sleep also can be problematic and can exacerbate existing sleep problems, such as sleeping in on the weekends to “catch up” on sleep or drinking more caffeine to try to stay awake during the day. Increased caffeine intake can interfere with non-REM deep sleep, Dr. Spinks-Franklin said, and therefore reduce the quality of sleep even if the person gets the total hours they need.

Insomnia in adolescents

Insomnia can refer to difficulty falling asleep, staying asleep, sleeping for long enough, or getting enough sleep in one period of time even when the opportunity is there. Some people may have no trouble falling asleep, but they wake up too early – before they have had gotten the sleep they need – and cannot return to sleep.

To be insomnia, the problem must occur “despite having enough time available for sleep,” Dr. Spinks-Franklin said. “Patient who restrict the amount of time for sleep due to work or social commitments may have trouble sleeping and daytime sleepiness but do not have insomnia.”

Daytime impairment also is part of the American Academy of Sleep Medicine’s definition of insomnia. The rare teen who doesn’t need as much sleep as average and functions without difficulty during the day does not necessarily have insomnia.

But the impairment may not necessarily just be fatigue or sleepiness. In fact, many of the symptoms are the same as those seen with ADHD.

Daytime consequences of insomnia can include the following:

• Depression, feeling sad or “blue,” or emotional hypersensitivity.
• Mood swings, crankiness, or irritability.
• Difficulty concentrating or paying attention, poor memory, mind wandering, or even inability to sit still.
• Job or school problems, such as not being able to finish homework, not finishing tasks they start, or forgetfulness.
• Difficulty in social situations, such as discomfort with others or problems with friends.
• Daytime sleepiness, even when unable to actually take a nap.
• Behavioral problems, such as hyperactivity, impulsivity, or aggression.
• Frequent mistakes, especially at work, at school, or while driving (often “errors of omission,” such as not seeing a street sign or not hearing an instruction).
• Lower levels of motivation or initiative, feeling less energetic.
• Excessive worry about sleep.

Evaluation of insomnia can be framed with “the three-factor model,” which includes predisposing factors, precipitating factors, and perpetuating factors.

Predisposing factors – those that indicate a person already may be at risk for insomnia – include potential genetic influences as well as their typical response to stress. “Do they sleep more or less?” Dr. Spinks-Franklin said. Even teens predisposed to insomnia may not develop it, however, without a precipitating trigger.

These triggers could include stress, anxiety, poor initial sleep hygiene that becomes a pattern, dietary intake or behaviors (such as drinking caffeine or eating too much or too late in the evening), changes to their schedule, or side effects of medications.

Once insomnia begins, various factors can then perpetuate the cycle, including some of those that triggered it, such as anxiety or a school or work schedule. Sometimes it can be difficult to pinpoint the factor prolonging insomnia, such as the unconscious reward of going to work or school late with few or no consequences.

Delayed sleep phase syndrome

Delayed sleep phase syndrome occurs when someone has a delayed onset of melatonin secretion that pushes back the time when they can fall asleep. Melatonin is the neurotransmitter produced by the pineal gland that signals the start of nighttime. Although it has a hereditary component, delayed sleep phase syndrome also can result from a pattern of poor sleep onset and sleeping in on the weekends.

Dr. Spinks-Franklin described the typical cycle: A teen doesn’t go to sleep until after midnight and then wants to sleep in later in the morning. Because they have to wake up early for school, they sleep in on the weekends to try to regain the sleep they lost. Sleeping in pushes their circadian rhythm even later, perpetuating the problem.

Interventions for sleep disorders

The recommended treatment for insomnia is cognitive-behavior therapy for insomnia, for which strong evidence exists. Before seeking cognitive-behavior therapy, however, families can work to improve sleep hygiene and reduce stimuli that contribute to insomnia.

Teens should avoid screens for at least 1 hour before bedtime and avoid caffeine and exercise for at least 4 hours before going to bed. They also need to develop a schedule with a consistent bedtime and wake-up time, including on the weekends. They should avoid sleeping in on the weekends or taking naps during the day, Dr. Spinks-Franklin said.

Delayed sleep phase syndrome is more resistant to treatment and has a high recurrence rate, she said, and it requires commitment from the parent and their child to address it successfully. Teens with this condition also can start with sleep hygiene practices: a consistent wake-up time that they maintain on the weekends and no daytime naps. Phototherapy in the morning can be added to hopefully induce an earlier onset of melatonin release in the evening.

The next step is making changes to the youth’s schedule, particularly evening and/or weekend activities. They can try to gradually advance their biological clock by changing their sleep schedule.

Dr. Spinks-Franklin also briefly addressed the use of over-the-counter melatonin supplements for treating sleep problems. Melatonin can be effective for treating insomnia by improving sleep onset and sleep quality, particularly in children and teens with autism spectrum disorder or ADHD.

Dr. Spinks-Franklin had no disclosures, and her presentation used no outside funding.

The conventional approach to treat hypoventilation has been to use noninvasive ventilation (NIV), while continuous positive airway pressure (CPAP) that does not augment alveolar ventilation improves gas exchange by maintaining upper airway patency and increasing functional residual capacity. Why, then, are we debating the use of CPAP vs NIV in the treatment of obesity hypoventilation syndrome (OHS)? To understand this rationale, it is important to first review the pathophysiology of OHS.

The hallmark of OHS is resting daytime awake arterial PaCO₂of 45 mm Hg or greater in an obese patient (BMI > 30 kg/m²) in absence of any other identifiable cause. To recognize why only some but not all obese subjects develop OHS, it is important to understand the different components of pathophysiology that contribute to hypoventilation: (1) obesity-related reduction in functional residual capacity and lung compliance with resultant increase in work of breathing; (2) central hypoventilation related to leptin resistance and reduction in respiratory drive with REM hypoventilation; and (3) upper airway obstruction caused by upper airway fat deposition along with low FRC contributing to pharyngeal airway narrowing and increased airway collapsibility (Masa JF, et al. Eur Respir Rev. 2019; 28:180097).

CPAP vs NIV for OHS

Let us examine some of the studies that have compared the short-term efficacy of CPAP vs NIV in patients with OHS. In a small randomized controlled trial (RCT), the effectiveness of CPAP and NIV was compared in 36 patients with OHS (Piper AJ, et al. Thorax. 2008;63:395). Reduction in PaCO₂ at 3 months was similar between the two groups. However, patients with persistent nocturnal desaturation despite optimal CPAP were excluded from the study. In another RCT of 60 patients with OHS who were either in stable condition or after an episode of acute on chronic hypercapnic respiratory failure, the use of CPAP or NIV showed similar improvements at 3 months in daytime PaCO₂, quality of life, and sleep parameters (Howard ME, et al. Thorax. 2017;72:437).

In one of the largest randomized control trials, the Spanish Pickwick study randomized 221 patients with OHS and AHI >30/h to NIV, CPAP, and lifestyle modification (Masa JF, et al. Am J Respir Crit Care Med. 2015:192:86). PAP therapy included NIV that consisted of in-lab titration with bilevel PAP therapy targeted to tidal volume 5-6 mL/kg of actual body weight or CPAP. Life style modification served as the control group. Primary outcome was the change in PaCO₂ at 2 months. Secondary outcomes were symptoms, HRQOL, polysomnographic parameters, spirometry, and 6-min walk distance (6 MWD). Mean AHI was 69/h, and mean PAP settings for NIV and CPAP were 20/7.7 cm and 11 cm H₂O, respectively. NIV provided the greatest improvement in PaCO₂ and serum HCO₃ as compared with control group but not relative to CPAP group. CPAP improved PaCO₂ as compared with control group only after adjustment of PAP use. Spirometry and 6 MWD and some HRQOL measures improved slightly more with NIV as compared to CPAP. Improvement in symptoms and polysomnographic parameters was similar between the two groups.

In another related study by the same group (Masa JF, et al. Thorax. 2016;71:899), 86 patients with OHS and mild OSA (AHI <30/h), were randomized to NIV and lifestyle modification. Mean AHI was 14/h and mean baseline PaCO₂ was 49 +/-4 mm Hg. The NIV group with mean PAP adherence at 6 hours showed greater improvement in PaCO₂ as compared with lifestyle modification (6 mm vs 2.8 mm Hg). They concluded that NIV was better than lifestyle modification in patients with OHS and mild OSA.

To determine the long-term clinical effectiveness of CPAP vs NIV, patients in the Pickwick study, who were initially assigned to either CPAP or NIV treatment group, were continued on their respective treatments, while subjects in the control group were again randomized at 2 months to either CPAP or NIV (Masa JF, et al. Lancet. 2019;393:1721). All subjects (CPAP n=107; NIV n=97) were followed for a minimum of 3 years. CPAP and NIV settings (pressure-targeted to desired tidal volume) were determined by in-lab titration without transcutaneous CO₂ monitor, and daytime adjustment of PAP to improve oxygen saturation. Primary outcome was the number of hospitalization days per year. Mean CPAP was 10.7 cm H₂O pressure and NIV 19.7/8.18 cm H₂O pressure with an average respiratory rate of 14/min. Median PAP use and adherence > 4 h, respectively, were similar between the two groups (CPAP 6.0 h, adherence > 4 h 67% vs NIV 6.0/h, adherence >4 h 61%). Median duration of follow-up was 5.44 years (IOR 4.45-6.37 years) for both groups. Mean hospitalization days per patient-year were similar between the two groups (CPAP 1.63 vs NIV 1.44 days; adj RR 0.78, 95% CI 0.34-1.77; p=0.561). Overall mortality, adverse cardiovascular events, and arterial blood gas parameters were similar between the two groups, suggesting equal efficacy of CPAP and NIV in this group of stable patients with OHS with an AHI >30/h. Given the low complexity and cost of CPAP vs NIV, the authors concluded that CPAP may be the preferred PAP treatment modality until more studies are available.

An accompanying editorial (Murphy PB, et al. Lancet. 2019; 393:1674), discussed that since this study was powered for superiority as opposed to noninferiority of NIV (20% reduction in hospitalization with NIV when compared with CPAP), superiority could not be shown, due to the low event rate for hospitalization (NIV 1.44 days vs CPAP 1.63 days). It is also possible optimum NIV titration may not have been determined since TCO₂ was not used. Furthermore, since this study was done only in patients with OHS and AHI >30/h, these results may not be applicable to patients with OHS and low AHI < 30/h that are more likely to have central hypoventilation and comorbidities, and this group may benefit from NIV as compared with CPAP.

Novel modes of bi-level PAP therapy

There are limited data on the use of the new bi-level PAP modalities, such as volume-targeted pressure support ventilation (PS) with fixed or auto-EPAP. The use of intelligent volume-assured pressure support ventilation (iVAPS) vs standard fixed pressure support ventilation in select OHS patients (n=18) showed equivalent control of chronic respiratory failure with no worsening of sleep quality and better PAP adherence (Kelly JL, et al. Respirology. 2014;19:596). In another small randomized, double-blind, crossover study, done on two consecutive nights in 11 patients with OHS, the use of auto-adjusting EPAP was noninferior to fixed EPAP (10.8 cm vs 11.8 cm H₂O pressure), with no differences in sleep quality and patient preference (McArdle N. Sleep. 2017;40:1). Although the data are limited, these small studies suggest the use of new PAP modalities, such as variable PS to deliver target volumes and auto EPAP could offer the potential to initiate bi-level PAP therapy in outpatients without the in-lab titration. More studies are needed before bi-level PAP therapy can be safely initiated in outpatients with OHS.

Summary

In summary, how can we utilize the most effective PAP therapy for patients with OHS? Can we use a phenotype-dependent approach to PAP treatment options? The answer is probably yes. Recently published ATS Clinical Practice Guideline (Am J Respir Crit Care Med. 2019;200:e6-e24) suggests the use of PAP therapy for stable ambulatory patients with OHS as compared with no PAP therapy, and patients with OHS with AHI >30/h (approximately 70% of the OHS patients) can be initially started on CPAP instead of NIV. Patients who have persistent nocturnal desaturation despite optimum CPAP can be switched to NIV. On the other hand, data are limited on the use of CPAP in patients with OHS with AHI <30/h, and these patients can be started on NIV. PAP adherence >5-6 h, and weight loss using a multidisciplinary approach should be encouraged for all patients with OHS.

Dr. Dewan is Professor and Program Director, Sleep Medicine; Division of Pulmonary, Critical Care and Sleep Medicine; Chief, Pulmonary Section VA Medical Center; Creighton University, Omaha, Nebraska.

The conventional approach to treat hypoventilation has been to use noninvasive ventilation (NIV), while continuous positive airway pressure (CPAP) that does not augment alveolar ventilation improves gas exchange by maintaining upper airway patency and increasing functional residual capacity. Why, then, are we debating the use of CPAP vs NIV in the treatment of obesity hypoventilation syndrome (OHS)? To understand this rationale, it is important to first review the pathophysiology of OHS.

The hallmark of OHS is resting daytime awake arterial PaCO₂of 45 mm Hg or greater in an obese patient (BMI > 30 kg/m²) in absence of any other identifiable cause. To recognize why only some but not all obese subjects develop OHS, it is important to understand the different components of pathophysiology that contribute to hypoventilation: (1) obesity-related reduction in functional residual capacity and lung compliance with resultant increase in work of breathing; (2) central hypoventilation related to leptin resistance and reduction in respiratory drive with REM hypoventilation; and (3) upper airway obstruction caused by upper airway fat deposition along with low FRC contributing to pharyngeal airway narrowing and increased airway collapsibility (Masa JF, et al. Eur Respir Rev. 2019; 28:180097).

CPAP vs NIV for OHS

Let us examine some of the studies that have compared the short-term efficacy of CPAP vs NIV in patients with OHS. In a small randomized controlled trial (RCT), the effectiveness of CPAP and NIV was compared in 36 patients with OHS (Piper AJ, et al. Thorax. 2008;63:395). Reduction in PaCO₂ at 3 months was similar between the two groups. However, patients with persistent nocturnal desaturation despite optimal CPAP were excluded from the study. In another RCT of 60 patients with OHS who were either in stable condition or after an episode of acute on chronic hypercapnic respiratory failure, the use of CPAP or NIV showed similar improvements at 3 months in daytime PaCO₂, quality of life, and sleep parameters (Howard ME, et al. Thorax. 2017;72:437).

In one of the largest randomized control trials, the Spanish Pickwick study randomized 221 patients with OHS and AHI >30/h to NIV, CPAP, and lifestyle modification (Masa JF, et al. Am J Respir Crit Care Med. 2015:192:86). PAP therapy included NIV that consisted of in-lab titration with bilevel PAP therapy targeted to tidal volume 5-6 mL/kg of actual body weight or CPAP. Life style modification served as the control group. Primary outcome was the change in PaCO₂ at 2 months. Secondary outcomes were symptoms, HRQOL, polysomnographic parameters, spirometry, and 6-min walk distance (6 MWD). Mean AHI was 69/h, and mean PAP settings for NIV and CPAP were 20/7.7 cm and 11 cm H₂O, respectively. NIV provided the greatest improvement in PaCO₂ and serum HCO₃ as compared with control group but not relative to CPAP group. CPAP improved PaCO₂ as compared with control group only after adjustment of PAP use. Spirometry and 6 MWD and some HRQOL measures improved slightly more with NIV as compared to CPAP. Improvement in symptoms and polysomnographic parameters was similar between the two groups.

In another related study by the same group (Masa JF, et al. Thorax. 2016;71:899), 86 patients with OHS and mild OSA (AHI <30/h), were randomized to NIV and lifestyle modification. Mean AHI was 14/h and mean baseline PaCO₂ was 49 +/-4 mm Hg. The NIV group with mean PAP adherence at 6 hours showed greater improvement in PaCO₂ as compared with lifestyle modification (6 mm vs 2.8 mm Hg). They concluded that NIV was better than lifestyle modification in patients with OHS and mild OSA.

To determine the long-term clinical effectiveness of CPAP vs NIV, patients in the Pickwick study, who were initially assigned to either CPAP or NIV treatment group, were continued on their respective treatments, while subjects in the control group were again randomized at 2 months to either CPAP or NIV (Masa JF, et al. Lancet. 2019;393:1721). All subjects (CPAP n=107; NIV n=97) were followed for a minimum of 3 years. CPAP and NIV settings (pressure-targeted to desired tidal volume) were determined by in-lab titration without transcutaneous CO₂ monitor, and daytime adjustment of PAP to improve oxygen saturation. Primary outcome was the number of hospitalization days per year. Mean CPAP was 10.7 cm H₂O pressure and NIV 19.7/8.18 cm H₂O pressure with an average respiratory rate of 14/min. Median PAP use and adherence > 4 h, respectively, were similar between the two groups (CPAP 6.0 h, adherence > 4 h 67% vs NIV 6.0/h, adherence >4 h 61%). Median duration of follow-up was 5.44 years (IOR 4.45-6.37 years) for both groups. Mean hospitalization days per patient-year were similar between the two groups (CPAP 1.63 vs NIV 1.44 days; adj RR 0.78, 95% CI 0.34-1.77; p=0.561). Overall mortality, adverse cardiovascular events, and arterial blood gas parameters were similar between the two groups, suggesting equal efficacy of CPAP and NIV in this group of stable patients with OHS with an AHI >30/h. Given the low complexity and cost of CPAP vs NIV, the authors concluded that CPAP may be the preferred PAP treatment modality until more studies are available.

An accompanying editorial (Murphy PB, et al. Lancet. 2019; 393:1674), discussed that since this study was powered for superiority as opposed to noninferiority of NIV (20% reduction in hospitalization with NIV when compared with CPAP), superiority could not be shown, due to the low event rate for hospitalization (NIV 1.44 days vs CPAP 1.63 days). It is also possible optimum NIV titration may not have been determined since TCO₂ was not used. Furthermore, since this study was done only in patients with OHS and AHI >30/h, these results may not be applicable to patients with OHS and low AHI < 30/h that are more likely to have central hypoventilation and comorbidities, and this group may benefit from NIV as compared with CPAP.

Novel modes of bi-level PAP therapy

There are limited data on the use of the new bi-level PAP modalities, such as volume-targeted pressure support ventilation (PS) with fixed or auto-EPAP. The use of intelligent volume-assured pressure support ventilation (iVAPS) vs standard fixed pressure support ventilation in select OHS patients (n=18) showed equivalent control of chronic respiratory failure with no worsening of sleep quality and better PAP adherence (Kelly JL, et al. Respirology. 2014;19:596). In another small randomized, double-blind, crossover study, done on two consecutive nights in 11 patients with OHS, the use of auto-adjusting EPAP was noninferior to fixed EPAP (10.8 cm vs 11.8 cm H₂O pressure), with no differences in sleep quality and patient preference (McArdle N. Sleep. 2017;40:1). Although the data are limited, these small studies suggest the use of new PAP modalities, such as variable PS to deliver target volumes and auto EPAP could offer the potential to initiate bi-level PAP therapy in outpatients without the in-lab titration. More studies are needed before bi-level PAP therapy can be safely initiated in outpatients with OHS.

Summary

In summary, how can we utilize the most effective PAP therapy for patients with OHS? Can we use a phenotype-dependent approach to PAP treatment options? The answer is probably yes. Recently published ATS Clinical Practice Guideline (Am J Respir Crit Care Med. 2019;200:e6-e24) suggests the use of PAP therapy for stable ambulatory patients with OHS as compared with no PAP therapy, and patients with OHS with AHI >30/h (approximately 70% of the OHS patients) can be initially started on CPAP instead of NIV. Patients who have persistent nocturnal desaturation despite optimum CPAP can be switched to NIV. On the other hand, data are limited on the use of CPAP in patients with OHS with AHI <30/h, and these patients can be started on NIV. PAP adherence >5-6 h, and weight loss using a multidisciplinary approach should be encouraged for all patients with OHS.

Dr. Dewan is Professor and Program Director, Sleep Medicine; Division of Pulmonary, Critical Care and Sleep Medicine; Chief, Pulmonary Section VA Medical Center; Creighton University, Omaha, Nebraska.

The conventional approach to treat hypoventilation has been to use noninvasive ventilation (NIV), while continuous positive airway pressure (CPAP) that does not augment alveolar ventilation improves gas exchange by maintaining upper airway patency and increasing functional residual capacity. Why, then, are we debating the use of CPAP vs NIV in the treatment of obesity hypoventilation syndrome (OHS)? To understand this rationale, it is important to first review the pathophysiology of OHS.

The hallmark of OHS is resting daytime awake arterial PaCO₂of 45 mm Hg or greater in an obese patient (BMI > 30 kg/m²) in absence of any other identifiable cause. To recognize why only some but not all obese subjects develop OHS, it is important to understand the different components of pathophysiology that contribute to hypoventilation: (1) obesity-related reduction in functional residual capacity and lung compliance with resultant increase in work of breathing; (2) central hypoventilation related to leptin resistance and reduction in respiratory drive with REM hypoventilation; and (3) upper airway obstruction caused by upper airway fat deposition along with low FRC contributing to pharyngeal airway narrowing and increased airway collapsibility (Masa JF, et al. Eur Respir Rev. 2019; 28:180097).

CPAP vs NIV for OHS

Let us examine some of the studies that have compared the short-term efficacy of CPAP vs NIV in patients with OHS. In a small randomized controlled trial (RCT), the effectiveness of CPAP and NIV was compared in 36 patients with OHS (Piper AJ, et al. Thorax. 2008;63:395). Reduction in PaCO₂ at 3 months was similar between the two groups. However, patients with persistent nocturnal desaturation despite optimal CPAP were excluded from the study. In another RCT of 60 patients with OHS who were either in stable condition or after an episode of acute on chronic hypercapnic respiratory failure, the use of CPAP or NIV showed similar improvements at 3 months in daytime PaCO₂, quality of life, and sleep parameters (Howard ME, et al. Thorax. 2017;72:437).

In one of the largest randomized control trials, the Spanish Pickwick study randomized 221 patients with OHS and AHI >30/h to NIV, CPAP, and lifestyle modification (Masa JF, et al. Am J Respir Crit Care Med. 2015:192:86). PAP therapy included NIV that consisted of in-lab titration with bilevel PAP therapy targeted to tidal volume 5-6 mL/kg of actual body weight or CPAP. Life style modification served as the control group. Primary outcome was the change in PaCO₂ at 2 months. Secondary outcomes were symptoms, HRQOL, polysomnographic parameters, spirometry, and 6-min walk distance (6 MWD). Mean AHI was 69/h, and mean PAP settings for NIV and CPAP were 20/7.7 cm and 11 cm H₂O, respectively. NIV provided the greatest improvement in PaCO₂ and serum HCO₃ as compared with control group but not relative to CPAP group. CPAP improved PaCO₂ as compared with control group only after adjustment of PAP use. Spirometry and 6 MWD and some HRQOL measures improved slightly more with NIV as compared to CPAP. Improvement in symptoms and polysomnographic parameters was similar between the two groups.

In another related study by the same group (Masa JF, et al. Thorax. 2016;71:899), 86 patients with OHS and mild OSA (AHI <30/h), were randomized to NIV and lifestyle modification. Mean AHI was 14/h and mean baseline PaCO₂ was 49 +/-4 mm Hg. The NIV group with mean PAP adherence at 6 hours showed greater improvement in PaCO₂ as compared with lifestyle modification (6 mm vs 2.8 mm Hg). They concluded that NIV was better than lifestyle modification in patients with OHS and mild OSA.

To determine the long-term clinical effectiveness of CPAP vs NIV, patients in the Pickwick study, who were initially assigned to either CPAP or NIV treatment group, were continued on their respective treatments, while subjects in the control group were again randomized at 2 months to either CPAP or NIV (Masa JF, et al. Lancet. 2019;393:1721). All subjects (CPAP n=107; NIV n=97) were followed for a minimum of 3 years. CPAP and NIV settings (pressure-targeted to desired tidal volume) were determined by in-lab titration without transcutaneous CO₂ monitor, and daytime adjustment of PAP to improve oxygen saturation. Primary outcome was the number of hospitalization days per year. Mean CPAP was 10.7 cm H₂O pressure and NIV 19.7/8.18 cm H₂O pressure with an average respiratory rate of 14/min. Median PAP use and adherence > 4 h, respectively, were similar between the two groups (CPAP 6.0 h, adherence > 4 h 67% vs NIV 6.0/h, adherence >4 h 61%). Median duration of follow-up was 5.44 years (IOR 4.45-6.37 years) for both groups. Mean hospitalization days per patient-year were similar between the two groups (CPAP 1.63 vs NIV 1.44 days; adj RR 0.78, 95% CI 0.34-1.77; p=0.561). Overall mortality, adverse cardiovascular events, and arterial blood gas parameters were similar between the two groups, suggesting equal efficacy of CPAP and NIV in this group of stable patients with OHS with an AHI >30/h. Given the low complexity and cost of CPAP vs NIV, the authors concluded that CPAP may be the preferred PAP treatment modality until more studies are available.

An accompanying editorial (Murphy PB, et al. Lancet. 2019; 393:1674), discussed that since this study was powered for superiority as opposed to noninferiority of NIV (20% reduction in hospitalization with NIV when compared with CPAP), superiority could not be shown, due to the low event rate for hospitalization (NIV 1.44 days vs CPAP 1.63 days). It is also possible optimum NIV titration may not have been determined since TCO₂ was not used. Furthermore, since this study was done only in patients with OHS and AHI >30/h, these results may not be applicable to patients with OHS and low AHI < 30/h that are more likely to have central hypoventilation and comorbidities, and this group may benefit from NIV as compared with CPAP.

Novel modes of bi-level PAP therapy

There are limited data on the use of the new bi-level PAP modalities, such as volume-targeted pressure support ventilation (PS) with fixed or auto-EPAP. The use of intelligent volume-assured pressure support ventilation (iVAPS) vs standard fixed pressure support ventilation in select OHS patients (n=18) showed equivalent control of chronic respiratory failure with no worsening of sleep quality and better PAP adherence (Kelly JL, et al. Respirology. 2014;19:596). In another small randomized, double-blind, crossover study, done on two consecutive nights in 11 patients with OHS, the use of auto-adjusting EPAP was noninferior to fixed EPAP (10.8 cm vs 11.8 cm H₂O pressure), with no differences in sleep quality and patient preference (McArdle N. Sleep. 2017;40:1). Although the data are limited, these small studies suggest the use of new PAP modalities, such as variable PS to deliver target volumes and auto EPAP could offer the potential to initiate bi-level PAP therapy in outpatients without the in-lab titration. More studies are needed before bi-level PAP therapy can be safely initiated in outpatients with OHS.

Summary

In summary, how can we utilize the most effective PAP therapy for patients with OHS? Can we use a phenotype-dependent approach to PAP treatment options? The answer is probably yes. Recently published ATS Clinical Practice Guideline (Am J Respir Crit Care Med. 2019;200:e6-e24) suggests the use of PAP therapy for stable ambulatory patients with OHS as compared with no PAP therapy, and patients with OHS with AHI >30/h (approximately 70% of the OHS patients) can be initially started on CPAP instead of NIV. Patients who have persistent nocturnal desaturation despite optimum CPAP can be switched to NIV. On the other hand, data are limited on the use of CPAP in patients with OHS with AHI <30/h, and these patients can be started on NIV. PAP adherence >5-6 h, and weight loss using a multidisciplinary approach should be encouraged for all patients with OHS.

Dr. Dewan is Professor and Program Director, Sleep Medicine; Division of Pulmonary, Critical Care and Sleep Medicine; Chief, Pulmonary Section VA Medical Center; Creighton University, Omaha, Nebraska.

COPENHAGEN – Sleep spindle density is diminished in euthymic patients with bipolar disorder, suggesting that this sleep architecture abnormality might offer potential for early differentiation of bipolar from unipolar depression, Philipp S. Ritter, MD, said at the annual congress of the European College of Neuropsychopharmacology.

Bruce Jancin/MDedge News

“Hopefully in the future our finding, if replicated, might have clinical utility. It might be a kind of soft biomarker that could be used in early detection, or, in people having their first depressive episode, you could perhaps use this to risk-stratify. And if you see there’s a great reduction in spindle density then a patient might have a higher likelihood of a bipolar disorder, so you might not want to treat with antidepressants that have a high switch rate,” explained Dr. Ritter, a psychiatrist at Technical University of Dresden (Germany).

Sleep spindles are a specific sleep architecture formation evident on the sleep EEG. They are sudden high-amplitude bursts occurring in stage N2 sleep. They are thought to be associated with sensory gating and memory processes. Other investigators have repeatedly demonstrated that patients with schizophrenia, as well as their asymptomatic first-degree relatives, have a reduced density of fast spindles greater than 13 Hz, compared with the general population. In contrast, patients with unipolar depression do not display this polysomnographic abnormality.

These findings prompted Dr. Ritter and his coinvestigators to conduct an all-night polysomnographic study in 24 euthymic patients with bipolar disorder and 25 healthy controls. The bipolar patients demonstrated a reduced density and mean frequency of fast sleep spindles, but not slow spindles (Acta Psychiatr Scand. 2018 Aug;138[2]:163-72).

These sleep spindle findings implicate thalamic dysfunction as a potential neurobiologic mechanism in bipolar disorder, since spindles are generated in the thalamus and spun off in thalamocortical feedback loops, Dr. Ritter observed.
 

Which came first: the chicken (bipolar disorder) or the egg (sleep disturbance)?

Sleep problems are a prominent issue in patients with bipolar disorder, even when they are euthymic.

“Anybody who deals with bipolar patients knows that sleep is a constant issue. You are always talking to your patients about their sleep. They’re sleeping too much, or not enough, or they’re sleeping just about right but it’s unsatisfactory. They do not sleep well. And if there’s something that disrupts their sleep, it can precipitate episodes,” Dr. Ritter said.

He wondered whether sleep problems are an intrinsic part of the bipolar illness, or a byproduct of the stress of having a severe mental disorder, perhaps a medication side effect, or whether the disordered sleep actually precedes the clinical expression of the mood disorder. So he and his coinvestigators turned to a Munich-based cohort sample of 3,021 adolescents and young adults assessed via the standardized Composite International Diagnostic Interview four times during 10 years of prospective follow-up.

Among 1,943 participants in the epidemiologic study who were free of major mental disorders at entry, the presence of sleep disturbance at baseline as quantified using the Symptom Checklist-90-Revised doubled the risk of developing bipolar disorder within the next 10 years. After the researchers controlled for potential confounders, including parental mood disorder, gender, age, and a history of alcohol or cannabis dependence, poor sleep quality at baseline remained independently associated with a 1.75-fold increased chance of subsequently developing bipolar disorder (J Psychiatr Res. 2015 Sep;68:76-82).

“This is a little bit higher, actually, than the odds ratio usually found for depressive disorders,” said Dr. Ritter.

“A different and perhaps more helpful way to think about it is to say good sleep is a resilience factor and puts you at lower risk of developing bipolar disorder,” he added.

Dr. Ritter reported having no financial conflicts regarding these studies.

[email protected]

COPENHAGEN – Sleep spindle density is diminished in euthymic patients with bipolar disorder, suggesting that this sleep architecture abnormality might offer potential for early differentiation of bipolar from unipolar depression, Philipp S. Ritter, MD, said at the annual congress of the European College of Neuropsychopharmacology.

Bruce Jancin/MDedge News

“Hopefully in the future our finding, if replicated, might have clinical utility. It might be a kind of soft biomarker that could be used in early detection, or, in people having their first depressive episode, you could perhaps use this to risk-stratify. And if you see there’s a great reduction in spindle density then a patient might have a higher likelihood of a bipolar disorder, so you might not want to treat with antidepressants that have a high switch rate,” explained Dr. Ritter, a psychiatrist at Technical University of Dresden (Germany).

Sleep spindles are a specific sleep architecture formation evident on the sleep EEG. They are sudden high-amplitude bursts occurring in stage N2 sleep. They are thought to be associated with sensory gating and memory processes. Other investigators have repeatedly demonstrated that patients with schizophrenia, as well as their asymptomatic first-degree relatives, have a reduced density of fast spindles greater than 13 Hz, compared with the general population. In contrast, patients with unipolar depression do not display this polysomnographic abnormality.

These findings prompted Dr. Ritter and his coinvestigators to conduct an all-night polysomnographic study in 24 euthymic patients with bipolar disorder and 25 healthy controls. The bipolar patients demonstrated a reduced density and mean frequency of fast sleep spindles, but not slow spindles (Acta Psychiatr Scand. 2018 Aug;138[2]:163-72).

These sleep spindle findings implicate thalamic dysfunction as a potential neurobiologic mechanism in bipolar disorder, since spindles are generated in the thalamus and spun off in thalamocortical feedback loops, Dr. Ritter observed.
 

Which came first: the chicken (bipolar disorder) or the egg (sleep disturbance)?

Sleep problems are a prominent issue in patients with bipolar disorder, even when they are euthymic.

“Anybody who deals with bipolar patients knows that sleep is a constant issue. You are always talking to your patients about their sleep. They’re sleeping too much, or not enough, or they’re sleeping just about right but it’s unsatisfactory. They do not sleep well. And if there’s something that disrupts their sleep, it can precipitate episodes,” Dr. Ritter said.

He wondered whether sleep problems are an intrinsic part of the bipolar illness, or a byproduct of the stress of having a severe mental disorder, perhaps a medication side effect, or whether the disordered sleep actually precedes the clinical expression of the mood disorder. So he and his coinvestigators turned to a Munich-based cohort sample of 3,021 adolescents and young adults assessed via the standardized Composite International Diagnostic Interview four times during 10 years of prospective follow-up.

Among 1,943 participants in the epidemiologic study who were free of major mental disorders at entry, the presence of sleep disturbance at baseline as quantified using the Symptom Checklist-90-Revised doubled the risk of developing bipolar disorder within the next 10 years. After the researchers controlled for potential confounders, including parental mood disorder, gender, age, and a history of alcohol or cannabis dependence, poor sleep quality at baseline remained independently associated with a 1.75-fold increased chance of subsequently developing bipolar disorder (J Psychiatr Res. 2015 Sep;68:76-82).

“This is a little bit higher, actually, than the odds ratio usually found for depressive disorders,” said Dr. Ritter.

“A different and perhaps more helpful way to think about it is to say good sleep is a resilience factor and puts you at lower risk of developing bipolar disorder,” he added.

Dr. Ritter reported having no financial conflicts regarding these studies.

[email protected]

COPENHAGEN – Sleep spindle density is diminished in euthymic patients with bipolar disorder, suggesting that this sleep architecture abnormality might offer potential for early differentiation of bipolar from unipolar depression, Philipp S. Ritter, MD, said at the annual congress of the European College of Neuropsychopharmacology.

Bruce Jancin/MDedge News

“Hopefully in the future our finding, if replicated, might have clinical utility. It might be a kind of soft biomarker that could be used in early detection, or, in people having their first depressive episode, you could perhaps use this to risk-stratify. And if you see there’s a great reduction in spindle density then a patient might have a higher likelihood of a bipolar disorder, so you might not want to treat with antidepressants that have a high switch rate,” explained Dr. Ritter, a psychiatrist at Technical University of Dresden (Germany).

Sleep spindles are a specific sleep architecture formation evident on the sleep EEG. They are sudden high-amplitude bursts occurring in stage N2 sleep. They are thought to be associated with sensory gating and memory processes. Other investigators have repeatedly demonstrated that patients with schizophrenia, as well as their asymptomatic first-degree relatives, have a reduced density of fast spindles greater than 13 Hz, compared with the general population. In contrast, patients with unipolar depression do not display this polysomnographic abnormality.

These findings prompted Dr. Ritter and his coinvestigators to conduct an all-night polysomnographic study in 24 euthymic patients with bipolar disorder and 25 healthy controls. The bipolar patients demonstrated a reduced density and mean frequency of fast sleep spindles, but not slow spindles (Acta Psychiatr Scand. 2018 Aug;138[2]:163-72).

These sleep spindle findings implicate thalamic dysfunction as a potential neurobiologic mechanism in bipolar disorder, since spindles are generated in the thalamus and spun off in thalamocortical feedback loops, Dr. Ritter observed.
 

Which came first: the chicken (bipolar disorder) or the egg (sleep disturbance)?

Sleep problems are a prominent issue in patients with bipolar disorder, even when they are euthymic.

“Anybody who deals with bipolar patients knows that sleep is a constant issue. You are always talking to your patients about their sleep. They’re sleeping too much, or not enough, or they’re sleeping just about right but it’s unsatisfactory. They do not sleep well. And if there’s something that disrupts their sleep, it can precipitate episodes,” Dr. Ritter said.

He wondered whether sleep problems are an intrinsic part of the bipolar illness, or a byproduct of the stress of having a severe mental disorder, perhaps a medication side effect, or whether the disordered sleep actually precedes the clinical expression of the mood disorder. So he and his coinvestigators turned to a Munich-based cohort sample of 3,021 adolescents and young adults assessed via the standardized Composite International Diagnostic Interview four times during 10 years of prospective follow-up.

Among 1,943 participants in the epidemiologic study who were free of major mental disorders at entry, the presence of sleep disturbance at baseline as quantified using the Symptom Checklist-90-Revised doubled the risk of developing bipolar disorder within the next 10 years. After the researchers controlled for potential confounders, including parental mood disorder, gender, age, and a history of alcohol or cannabis dependence, poor sleep quality at baseline remained independently associated with a 1.75-fold increased chance of subsequently developing bipolar disorder (J Psychiatr Res. 2015 Sep;68:76-82).

“This is a little bit higher, actually, than the odds ratio usually found for depressive disorders,” said Dr. Ritter.

“A different and perhaps more helpful way to think about it is to say good sleep is a resilience factor and puts you at lower risk of developing bipolar disorder,” he added.

Dr. Ritter reported having no financial conflicts regarding these studies.

[email protected]

COPENHAGEN – The traditional treatment paradigm for patients with comorbid depression and insomnia has been to focus on the depression in expectation that the sleep problems will fade away with the depressive symptoms.

Big mistake, Kerstin Blom, PhD, said during the annual congress of the European College of Neuropsychopharmacology.

That treatment strategy is insufficient, because untreated insomnia seldom improves. It hinders recovery from depression, increases the risk of new depressive episodes, and causes continued suffering because of poor sleep, asserted Dr. Blom, a clinical psychologist and researcher at the Internet Psychiatry Clinic at the Karolinska Institute in Stockholm.

She presented highlights of a series of three randomized, controlled trials for which she was first author. The take-home message: Insomnia with comorbid depression is not merely a symptom of depression; it requires specific treatment.

“Insomnia needs to be treated according to guidelines – that is, with cognitive-behavioral therapy – when it’s comorbid with depression,” she declared. “Insomnia therapy also treats comorbid depression, but it’s not so much the other way around. There are some effects on insomnia when you treat depression, but they’re not very large.”

The first study in her series included 43 adults with psychiatrist-diagnosed comorbid insomnia and major depression who were randomized to an 8-week course of psychologist-guided, Internet-delivered cognitive-behavioral therapy (ICBT) for one disorder or the other. At 6- and 12-month follow-up, patients who received ICBT for insomnia had significantly greater improvement in their insomnia as measured by the self-rated Insomnia Severity Index than did those who got ICBT for depression, while both forms of treatment were similarly effective in reducing depression severity as reflected in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (Sleep. 2015 Feb 1;38[2]:267-77).

At 3-year follow-up, the beneficial impact of ICBT for insomnia remained strong, with recipients reporting less need for additional sleep treatment and less use of sleep medication than did the patients who got ICBT for depression. Both groups were left with mild depression, pointing to the need to develop a combined form of CBT that would simultaneously address both disorders in patients with comorbid depression and insomnia (Sleep. 2017 Aug 1;40[8]. doi. 10.1093/sleep/zsx108).

The Swedish investigators went on to create a 9-week course of psychologist-guided combination ICBT for both insomnia and depression. Then they randomized 126 dual-diagnosis patients to that treatment program or to therapist-guided ICBT for depression plus a placebo sleep intervention, which included education about sleep hygiene, stress management, and use of a sleep diary. At 6 months of follow-up, the dual-target ICBT group had a significantly greater reduction in Insomnia Severity Index scores than those who got ICBT for depression plus placebo. No between-group difference were found in the reduction in MADRS scores.

“This means treating patients with insomnia therapy was as effective for the treatment of depression as was depression therapy,” Dr. Blom observed. Follow-up out to 36 months is ongoing.

The third study included 148 nondepressed adults with insomnia who were randomized to the 8-week ICBT insomnia intervention or an active control treatment, which again included patient education, stress management, and a sleep diary. At 6 months, the active CBT-insomnia group had significantly lower Insomnia Severity Index scores than controls. However, at 12 and 36 months, the control group caught up, and there was no longer a between-group difference, with 74% of participants no longer meeting diagnostic criteria for insomnia at 36 months. The explanation for the catch-up? The control group used significantly more hypnotic sleep medications and more frequently sought additional insomnia treatments, including yoga and mindfulness, outside of the study setting during follow-up (Sleep. 2016 Jun 1;39[6]:1267-74).

It was Dr. Blom’s intent to also use this randomized, controlled trials to test the hypothesis that improving insomnia in nondepressed patients prevents future episodes of depression. She was thwarted in this attempt.

“After they got our low-intensity control version of a sleep intervention, they went out and got more treatment and that seems to have helped them, which is great,” Dr. Blom said. “But it sort of ruined our prediction study.”

However, in a post hoc analysis, study participants who were poor sleepers at 12 months had significantly more depressive symptoms at 36 months than did those with improved sleep at 12 months. The effect size was quite large, with a between-group 5.5-point difference in MADRS scores at 36 months in a study population that was nondepressed at baseline.

“So improved sleep may prevent depression long term,” Dr. Blom said. “The jury is still out on that one.”

She reported having no financial conflicts regarding her studies, which were supported by government research funding.

[email protected]

COPENHAGEN – The traditional treatment paradigm for patients with comorbid depression and insomnia has been to focus on the depression in expectation that the sleep problems will fade away with the depressive symptoms.

Big mistake, Kerstin Blom, PhD, said during the annual congress of the European College of Neuropsychopharmacology.

That treatment strategy is insufficient, because untreated insomnia seldom improves. It hinders recovery from depression, increases the risk of new depressive episodes, and causes continued suffering because of poor sleep, asserted Dr. Blom, a clinical psychologist and researcher at the Internet Psychiatry Clinic at the Karolinska Institute in Stockholm.

She presented highlights of a series of three randomized, controlled trials for which she was first author. The take-home message: Insomnia with comorbid depression is not merely a symptom of depression; it requires specific treatment.

“Insomnia needs to be treated according to guidelines – that is, with cognitive-behavioral therapy – when it’s comorbid with depression,” she declared. “Insomnia therapy also treats comorbid depression, but it’s not so much the other way around. There are some effects on insomnia when you treat depression, but they’re not very large.”

The first study in her series included 43 adults with psychiatrist-diagnosed comorbid insomnia and major depression who were randomized to an 8-week course of psychologist-guided, Internet-delivered cognitive-behavioral therapy (ICBT) for one disorder or the other. At 6- and 12-month follow-up, patients who received ICBT for insomnia had significantly greater improvement in their insomnia as measured by the self-rated Insomnia Severity Index than did those who got ICBT for depression, while both forms of treatment were similarly effective in reducing depression severity as reflected in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (Sleep. 2015 Feb 1;38[2]:267-77).

At 3-year follow-up, the beneficial impact of ICBT for insomnia remained strong, with recipients reporting less need for additional sleep treatment and less use of sleep medication than did the patients who got ICBT for depression. Both groups were left with mild depression, pointing to the need to develop a combined form of CBT that would simultaneously address both disorders in patients with comorbid depression and insomnia (Sleep. 2017 Aug 1;40[8]. doi. 10.1093/sleep/zsx108).

The Swedish investigators went on to create a 9-week course of psychologist-guided combination ICBT for both insomnia and depression. Then they randomized 126 dual-diagnosis patients to that treatment program or to therapist-guided ICBT for depression plus a placebo sleep intervention, which included education about sleep hygiene, stress management, and use of a sleep diary. At 6 months of follow-up, the dual-target ICBT group had a significantly greater reduction in Insomnia Severity Index scores than those who got ICBT for depression plus placebo. No between-group difference were found in the reduction in MADRS scores.

“This means treating patients with insomnia therapy was as effective for the treatment of depression as was depression therapy,” Dr. Blom observed. Follow-up out to 36 months is ongoing.

The third study included 148 nondepressed adults with insomnia who were randomized to the 8-week ICBT insomnia intervention or an active control treatment, which again included patient education, stress management, and a sleep diary. At 6 months, the active CBT-insomnia group had significantly lower Insomnia Severity Index scores than controls. However, at 12 and 36 months, the control group caught up, and there was no longer a between-group difference, with 74% of participants no longer meeting diagnostic criteria for insomnia at 36 months. The explanation for the catch-up? The control group used significantly more hypnotic sleep medications and more frequently sought additional insomnia treatments, including yoga and mindfulness, outside of the study setting during follow-up (Sleep. 2016 Jun 1;39[6]:1267-74).

It was Dr. Blom’s intent to also use this randomized, controlled trials to test the hypothesis that improving insomnia in nondepressed patients prevents future episodes of depression. She was thwarted in this attempt.

“After they got our low-intensity control version of a sleep intervention, they went out and got more treatment and that seems to have helped them, which is great,” Dr. Blom said. “But it sort of ruined our prediction study.”

However, in a post hoc analysis, study participants who were poor sleepers at 12 months had significantly more depressive symptoms at 36 months than did those with improved sleep at 12 months. The effect size was quite large, with a between-group 5.5-point difference in MADRS scores at 36 months in a study population that was nondepressed at baseline.

“So improved sleep may prevent depression long term,” Dr. Blom said. “The jury is still out on that one.”

She reported having no financial conflicts regarding her studies, which were supported by government research funding.

[email protected]

COPENHAGEN – The traditional treatment paradigm for patients with comorbid depression and insomnia has been to focus on the depression in expectation that the sleep problems will fade away with the depressive symptoms.

Big mistake, Kerstin Blom, PhD, said during the annual congress of the European College of Neuropsychopharmacology.

That treatment strategy is insufficient, because untreated insomnia seldom improves. It hinders recovery from depression, increases the risk of new depressive episodes, and causes continued suffering because of poor sleep, asserted Dr. Blom, a clinical psychologist and researcher at the Internet Psychiatry Clinic at the Karolinska Institute in Stockholm.

She presented highlights of a series of three randomized, controlled trials for which she was first author. The take-home message: Insomnia with comorbid depression is not merely a symptom of depression; it requires specific treatment.

“Insomnia needs to be treated according to guidelines – that is, with cognitive-behavioral therapy – when it’s comorbid with depression,” she declared. “Insomnia therapy also treats comorbid depression, but it’s not so much the other way around. There are some effects on insomnia when you treat depression, but they’re not very large.”

The first study in her series included 43 adults with psychiatrist-diagnosed comorbid insomnia and major depression who were randomized to an 8-week course of psychologist-guided, Internet-delivered cognitive-behavioral therapy (ICBT) for one disorder or the other. At 6- and 12-month follow-up, patients who received ICBT for insomnia had significantly greater improvement in their insomnia as measured by the self-rated Insomnia Severity Index than did those who got ICBT for depression, while both forms of treatment were similarly effective in reducing depression severity as reflected in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (Sleep. 2015 Feb 1;38[2]:267-77).

At 3-year follow-up, the beneficial impact of ICBT for insomnia remained strong, with recipients reporting less need for additional sleep treatment and less use of sleep medication than did the patients who got ICBT for depression. Both groups were left with mild depression, pointing to the need to develop a combined form of CBT that would simultaneously address both disorders in patients with comorbid depression and insomnia (Sleep. 2017 Aug 1;40[8]. doi. 10.1093/sleep/zsx108).

The Swedish investigators went on to create a 9-week course of psychologist-guided combination ICBT for both insomnia and depression. Then they randomized 126 dual-diagnosis patients to that treatment program or to therapist-guided ICBT for depression plus a placebo sleep intervention, which included education about sleep hygiene, stress management, and use of a sleep diary. At 6 months of follow-up, the dual-target ICBT group had a significantly greater reduction in Insomnia Severity Index scores than those who got ICBT for depression plus placebo. No between-group difference were found in the reduction in MADRS scores.

“This means treating patients with insomnia therapy was as effective for the treatment of depression as was depression therapy,” Dr. Blom observed. Follow-up out to 36 months is ongoing.

The third study included 148 nondepressed adults with insomnia who were randomized to the 8-week ICBT insomnia intervention or an active control treatment, which again included patient education, stress management, and a sleep diary. At 6 months, the active CBT-insomnia group had significantly lower Insomnia Severity Index scores than controls. However, at 12 and 36 months, the control group caught up, and there was no longer a between-group difference, with 74% of participants no longer meeting diagnostic criteria for insomnia at 36 months. The explanation for the catch-up? The control group used significantly more hypnotic sleep medications and more frequently sought additional insomnia treatments, including yoga and mindfulness, outside of the study setting during follow-up (Sleep. 2016 Jun 1;39[6]:1267-74).

It was Dr. Blom’s intent to also use this randomized, controlled trials to test the hypothesis that improving insomnia in nondepressed patients prevents future episodes of depression. She was thwarted in this attempt.

“After they got our low-intensity control version of a sleep intervention, they went out and got more treatment and that seems to have helped them, which is great,” Dr. Blom said. “But it sort of ruined our prediction study.”

However, in a post hoc analysis, study participants who were poor sleepers at 12 months had significantly more depressive symptoms at 36 months than did those with improved sleep at 12 months. The effect size was quite large, with a between-group 5.5-point difference in MADRS scores at 36 months in a study population that was nondepressed at baseline.

“So improved sleep may prevent depression long term,” Dr. Blom said. “The jury is still out on that one.”

She reported having no financial conflicts regarding her studies, which were supported by government research funding.

[email protected]