NEW DRUG FOR INSOMNIA

Story first appeared on WSJ.com.
For those who have trouble sleeping, there may soon be new ways to summon the sandman.
Several pharmaceutical companies are working on new approaches to treat insomnia. The compounds are meant to work differently than current leading sleep aids such as Ambien and Lunesta, which, while generally safe, can have troubling side effects because they act on many areas of the brain. By contrast, many of the drugs being developed target particular systems responsible for sleep and wakefulness. The hope is that they will have fewer side effects and less potential for addiction and cognition problems the next day.
New drugs are in the works to treat insomnia, which affects 10% to 30% of Americans (and more women than men).
About 30% of American adults have insomnia symptoms each year, scientific studies estimate. Some 10% of the population has chronic insomnia, which is generally defined as having difficulty sleeping at least three times a week for a month or more. Chronic insomnia sufferers also feel tired, cranky or foggy-headed during the day.
Insomnia comes in various forms. Some people have a tough time falling asleep and others wake in the middle of the night and have trouble getting back to sleep. Some people rise for the day too early. Insomnia can increase the risk for other conditions, including heart disease, diabetes and depression.
Merck & Co. is investigating a compound that inhibits the action of orexin receptors, which in turn interferes with the activity of orexin, a chemical in the brain that produces alertness. The company hopes to file for Food and Drug Administration approval by next year. Last fall, Somaxon Pharamaceuticals Inc. launched Silenor, a drug that blocks histamine receptors, which are important in regulating wakefulness. Neurim Pharmaceuticals Ltd. is seeking FDA approval of Circadin, a prescription form of the sleep-promoting hormone melatonin. The drug, which delivers melatonin in a prolonged-release formulation, is already available in Europe, Asia and the Middle East. Other research efforts are targeting specific serotonin receptors, a move that could promote deeper stages of sleep. There is also growing interest in a form of cognitive behavioral therapy that treats insomnia.
Lights Out
The most popular prescription drugs to help with sleep, such as Ambien CR and Lunesta, work on a neurotransmitter known as GABA that is found throughout the brain. Several new, more targeted, approaches are in the works or have recently been approved, including:
• A drug that inhibits the action of orexin receptors, which in turn interferes with the activity of orexin, a chemical in the brain that produces wakefulness.
• Compounds that work on serotonin, a neurotransmitter related to alertness.
• Prescription melatonin, which bathes the brain in the sleep-inducing hormone.
• A drug that blocks histamine receptors, which are important in regulating wakefulness.
Some companies have halted work on new insomnia drugs. GlaxoSmithKline PLC and Actelion Ltd. in January said they discontinued development of an orexin-receptor antagonist, citing safety concerns. Glaxo didn't elaborate, but said at the time that it had conducted additional clinical studies in part to assess the drug's tolerability profile. In 2009,Sanofi-Aventis shelved its plan to develop eplivanserin, a serotonin antagonist. The company's announcement said it had received an FDA request for additional information regarding benefit-risk, but didn't give specifics. And last week, the FDA denied Transcept Pharmaceuticals Inc. approval of a form of zolpidem, the generic form of Ambien, that patients could dissolve under the tongue if they wake up in the middle of the night and have trouble getting back to sleep. The FDA cited concerns that residual amounts of the drug in a patient's body could be unsafe if the person were to drive the next day.
Americans spent about $2 billion on prescription sleep drugs in 2010, according to IMS Health, which tracks pharmaceutical sales. Although the number of prescriptions written rose 23% to about 60 million last year from 48.9 million in 2006, total dollar sales slid as cheaper generic versions of drugs like Ambien have entered the market. Sales of prescription sleeping pills were $3.6 billion in 2006. Beyond that, doctors say many people self-treat their insomnia with alcohol or over-the-counter medications, including Tylenol PM and Benadryl, which usually contain some form of an antihistamine.
The most common sleep-aid drugs, called benzodiazepine receptor agonists, alter the activity of gamma-aminobutyric acid (GABA), a neurotransmitter that is thought to facilitate sleep. These are sedatives that slow the brain down and put it to sleep. GABA is found throughout the brain and doesn't affect only sleep.
The GABA drugs are effective, doctors say, but can come with significant side effects including daytime drowsiness, sometimes called the hangover effect, and memory and balance problems. They can be dangerous when combined with other sedatives, notably alcohol, and there are some concerns that the medications can be addictive and abused. The drugs also can cause people to engage in strange nocturnal activities—eating, sex and driving—that they don't recall the next day. Often you get the story that it worked for a few weeks, then it stopped working and the patient has to take more.
Drug companies say they expect the compounds being developed will have fewer side effects, be less addictive and interact less with alcohol. They say early clinical trials have so far supported those hypotheses, although evidence is preliminary.
In a phase IIb clinical trial of Merck's new orexin drug, the most common side effects included dizziness, vivid dreams and drowsiness. Somaxon's Silenor, approved for use by those who have trouble staying asleep at night, can cause drowsiness, the company said. The company says that, unlike Silenor, antihistamines like Benadryl don't strongly hit the specific histamine receptor that is closely associated with sleep. The active ingredient in Silenor, doxepin, has been used for years in higher doses as an antidepressant.
Studies show that cognitive behavioral therapy for insomnia, known as CBT-I, can be as effective as medication for treating chronic insomnia. The Veterans Health Administration launched a program last year to train clinicians to deliver CBT-I to veterans, and so far more than 140 clinicians have been trained. CBT-I typically includes sleep restriction, or limiting the amount of time patients spend in bed when they're unable to sleep, and stimulus control, which means keeping the bedroom off-limits for such things as TVs and computers. There are patients who literally move their entire house into their bedroom, which then becomes associated with a host of distractions instead of sleep. Patients are also taught sleep hygiene - avoiding caffeine and alcohol and sleeping in a cool, dark room, for example.
Nearly everyone experiences a few nights of tossing and turning here and there, what is known as transient insomnia. To prevent it from mushrooming into a chronic problem, try to tough it out. That means no napping or going to sleep earlier the next night. And if you do conk out and end up taking a nap try to balance the books by going to bed even later than usual the next night.
Many medical conditions can contribute to insomnia including depression, sleep apnea, heart failure, arthritis and chronic pain. There is mounting evidence that a predisposition to insomnia may be partly genetic as well.
Stress, alcohol and caffeine use and menopause can also fuel insomnia. Sleeping pills are not an alternative to taking a look at your life and figuring out why you're having a sleeping problem.

Sleep Deprived? Your Reaction could be Genetic

LA Times

You and your co-worker have been burning the midnight oil for a week to complete a project, and your abbreviated sleep schedule has you feeling like a zombie. Your co-worker, by contrast, bounces through the workday looking and acting none the worse for wear. There are drugs that can do this, you tell yourself, but your co-worker waves off the suggestion. “I’ve always been able to get by with less sleep,”  she says.

Is she just more disciplined than you are? Did she train herself to “need” less sleep? Is she just saying that to make you feel like a slug? While you may too tired to decide, a study published this week in the journal Neurology supplies the likely answer: It’s in her genes. And your exhaustion is in yours, as well.

The Neurology study, conducted at University of Pennsylvania School of Medicine, found evidence that “interindividual differences” in the way we fall asleep, stay asleep and cope with sleep shortage can be predicted reliably by whether or not we have inherited an allele called DBQ1*0602.
You may very well be one of the more than one-in-four people who are positive for the DBQ1*0602 allele, which happens to be a genetic marker for narcolepsy--a sleep disorder that causes sufferers to fall deeply asleep during the day with little warning. Most narcoleptics have this genetic peculiarity, although being DBQ1*0602-positive is no assurance you’ll be narcoleptic. Compared to those without this allele, someone who’s positive for this allele is likely to fall fitfully into sleep even when she’s exhausted; break free from sleep’s hold several times a night, and feel miserably sleepy when he hasn’t gotten enough shut-eye.

That resilient co-worker, by contrast, appears to be in the genetic majority: DBQ1*0602-negative. Faced with the prospect of less sleep, her body and brain settle into sleep more quickly, slide seamlessly into deep sleep, and stay under until she has to wake up.

After putting 129 healthy adults through a five-night ordeal of partial sleep deprivation (four hours per night), the authors of the Neurology study found no actual differences in cognitive performance between those who were positive and those who were negative for the allele: the differences were in how sleepy and fatigued individuals in the two groups felt after five nights of abbreviated sleep.

In a world where sleep is in chronically short supply, this kind of research is of considerable interest to employers. In lines of work where hours can be long, sleep is had in short bursts, and alertness is non-negotiable—e.g. fighting wars, tending to the sick, driving trucks and flying commercial aircraft—finding people who can function well on little sleep is essential. As research refines how our genes influence our sleeping patterns, some ethicists worry research like this will be used to weed out those who genes predispose them to tolerate sleep deprivation poorly. (The Genetic Information Nondiscrimination Act—GINA—made law in 2008 makes such actions illegal. But that legal protection can potentially be short-circuited by arguments about public safety or national security.)

Namni Goel, the author of the Neurology study published this week, says that using such research to weed out employees who feel miserable when sleep deprived “would be a negative outcome.” She’d rather people use such information to help themselves function optimally: if they know they’re genetically vulnerable to sleep deprivation, they should have a cup of coffee or take a nap when they’ve failed get enough nighttime sleep, said Goel.

Dreams Can Help with Learning

BBC News

Napping after learning something new could help you commit it to memory - as long as you dream, scientists say.

They found people who dream about a new task perform it better on waking than those who do not sleep or do not dream.

Volunteers were asked to learn the layout of a 3D computer maze so they could find their way within the virtual space several hours later.

Those allowed to take a nap and who also remembered dreaming of the task, found their way to a landmark quicker.

The researchers think the dreams are a sign that unconscious parts of the brain are working hard to process information about the task.

Dr Robert Stickgold of Harvard Medical School, one of the authors of the paper, said dreams may be a marker that the brain is working on the same problem at many levels.

He said: "The dreams might reflect the brain's attempt to find associations for the memories that could make them more useful in the future."

Study tips

Co-author Dr Erin Wamsley said the study suggests our non-conscious brain works on the things that it deems are most important.

"Every day we are gathering and encountering tremendous amounts of information and new experiences," she said.

"It would seem that our dreams are asking the question, 'How do I use this information to inform my life?"

The research, published in the academic journal Cell Biology, could have practical implications.

The scientists say there may be ways to take advantage of this phenomenon for improving learning and memory.

For example, students might be better studying hard before bedtime, or taking a nap after a period of afternoon study.

In Sleepless Nights, A Hope for Treating Depression

NY Times

 

Is there anything good about insomnia? Could there possibly be any upside to a long, torturous sleepless night?

To answer the question, let’s look at another condition entirely.

Postpartum depression affects between 5 percent and 25 percent of new mothers.  Symptoms — including sadness, fatigue, appetite changes, crying, anxiety and irritability — usually occur in the first few months after child birth.  There is a simple way to alleviate postpartum depression in just a few hours: sleep deprivation.

If a depressed mother stays up all night, or even the last half of the night, it is likely that by morning the depression will lift.  Although this sounds too good to be true, it has been well documented in over 1,700 patients in more than 75 published papers during the last 40 years.[1]  Sleep deprivation used as a treatment for depression is efficacious and robust: it works quickly, is relatively easy to administer, inexpensive, relatively safe and it also alleviates other types of clinical depression. Sleep deprivation can elevate your mood even if you are not depressed, and can induce euphoria. This throws a new light on insomnia.

This remarkable result is not well known outside a small circle of sleep researchers for three good reasons.  First, sleep deprivation is not as convenient as taking a pill.  Second, prolonged sleep deprivation is not exactly a desirable state; it leads to cognitive defects, such as reduced working memory and impaired decision making.  Finally, depression recurs after the mother, inevitably, succumbs to sleep, even for a short nap.  Nonetheless this is an incredibly important observation; it shows that depression can be rapidly reversed and suggests that something is happening in the sleeping brain to bring on episodes of depression.  All this offers hope that studying sleep deprivation may lead to new, unique and rapid treatments for depression.

Neuroscientists have been trying to solve this puzzle.  The first hint of what may be happening during sleep came from J. Christian Gillin, a former colleague of mine at the University of California at San Diego and the San Diego Veterans Affairs Medical Center. Using imaging, he found that a small area of the cerebral cortex in the front of the brain  — the anterior cingulate cortex — which was consistently overactive in depressed patients, quieted to normal levels of activity after the patients were deprived of sleep. And when the patients were allowed to sleep, the activity in this area returned to the elevated levels.

Helen Mayberg at Emory University has shown that electrical stimulation of the anterior cingulate cortex, which disrupts normal activity, also reduces depression.  Some patients reported feeling immediate relief and calm after the procedure.

This tells us where in the cortex to look, but we also need to understand the changes that occur in the cortex during sleep. As you fall asleep, neurons in the brain stem that project throughout the cortex and keep it activated stop firing. The reduced stimulation from the brain stem disconnects the cortex from sensory input and there is a major shift in the pattern of electrical activity in the cortex. During the early part of the night the cortex is in a state of slow-wave sleep punctuated by brief periods of rapid-eye movement sleep (REM), which become more frequent and longer lasting toward early morning.

One major class of antidepressants, tricyclics, blocks REM sleep, which suggests that sleep deprivation may work against depression the same way. This is consistent with the tendency for depressed individuals to sleep longer than they do when they feel normal. Additional support for this hypothesis comes from genetic studies of families with short REM latency — the tendency to enter REM early in the sleep cycle. This condition disrupts slow wave sleep and extends REM sleep. The risk of depression is much greater if you come from a family with this genetic background. While this is a rare genetic defect that can only account for a small fraction of all depressed patients, these special cases give us valuable clues to conditions that predispose some people to clinical depression.

Despite all we have learned about the brain and sleep states, we still do not have a smoking gun to pinpoint what goes wrong when a mother suffers from postpartum depression, or why sleep deprivation lifts her mood. But what we do know is intriguing and this is driving research that could lead someday to rapid and effective ways to treat depression.

This is exciting news for researchers, and for the millions who suffer from debilitating mood disorders. Insomniacs, though, are unlikely to welcome yet another lost night of sleep, or to be cheered by the notion that a good slumber the night before could have made them feel even worse.

Footnote: [1] J. Christian Gillin, Monte Buchsbaum, Joseph Wu, Camellia Clark, William Bunney Jr., Sleep deprivation as a model experimental antidepressant treatment: Findings from functional brain imaging, Depression and Anxiety 14 (1), 37-49, 2001

U.S. Health Survey: Too Few Exercising, Too Many Smoking

USA Today

This is not a nation of teetotalers or regular exercisers, new government data show.

The National Health Interview Survey, based on telephone interviews with 79,000 adults over three years, has found:

•61% of people in the USA drink alcohol. These are adults who have had at least 12 drinks in their lifetime and at least one drink in the past year.

•31% of people do enough regular leisure-time physical activity to get health benefits — that is, moderate exercise for 30 minutes five times a week or vigorous activity for 20 minutes three times a week.

•40% do no regular leisure-time physical activity.

•20% smoke.

•21% are former smokers.

•58.5% have never smoked cigarettes. That is, they have never smoked or smoked fewer than 100 cigarettes in their entire life.

"There has been no progress at all in increasing physical activity since we started doing this report in 1997," says Charlotte Schoenborn, a health statistician with the National Center for Health Statistics, part of the Centers for Disease Control and Prevention. About 40% of respondents were doing nothing then, the same as now, Schoenborn says.

"We are a long way from where the health experts want us to be with smoking — one in five is way above national health goals," Schoenborn says.

Education makes a difference. The survey found that adults who had higher levels of education were less likely to be smoking, were more active in their leisure time, were less likely to be obese and were less likely to sleep as little as six hours or less in the past 24 hours.

Overall, "having higher levels of education or greater economic resources tends to increase the likelihood of having healthier behaviors," Schoenborn says.

In addition, Schoenborn says, "married adults tend to have healthier behaviors overall than people who are divorced, separated or widowed."

Survey Sheds Light on U.S. Bedtime Routines

CNN

Your racial and ethnic background can shape many aspects of your life: the type of food you eat, where you live, and your political views.

Now a new survey suggests that how you sleep and what you do before you hit the hay -- whether it's watch TV, pray, or have sex -- varies by ethnic group as well.

In the survey, the first of its kind, a representative sample of more than 1,000 whites, African Americans, Asians, and Hispanics ages 25 to 60 were asked about their sleep and bedtime routines. While their answers revealed plenty of differences between groups, they also showed that we have something in common: Most of us aren't sleeping well.

In each group, roughly six out of 10 people reported that they don't get a good night's sleep every night or almost every night, according to the survey, which was conducted by the National Sleep Foundation, a nonprofit organization based in Washington, D.C.

"A significant proportion of all ethnic groups are experiencing sleepiness that impacts their day to day living," says Thomas J.Balkin, Ph.D., chairman of the National Sleep Foundation. "Sleepiness impacts every aspect of our lives, so for those people who are not getting a good night's sleep, getting better sleep will make you sharper in the boardroom, give you a better quality of life, and [make] the sun seem a whole lot brighter."

Across the board, a lack of sleep appears to be affecting people's lives and relationships.

Roughly one in four people in each ethnic group said that they missed work or a family function because they were too sleepy, and a similar proportion said they were too exhausted to have sex on a regular basis.

The survey results offered a peek inside the bedrooms of Americans, and how we spend our time before drifting off.

For instance, 75 percent of African Americans reported watching television routinely in the hour before going to bed, compared with 64 percent of whites.

Only 52 percent of Asians said they watched TV before bed almost every night, but they were far more likely to use a computer or surf the Web before bed; more than half said they did so almost every night, compared with about 20 percent in the other groups.



Sexual activity also varied among the groups. Ten percent of African Americans and Hispanics reported having sex almost every night, compared with 4 percent of whites and 1 percent of Asians.

African Americans, meanwhile, were far more likely than other groups to pray before bedtime almost every night of the week.

Who -- or what -- Americans sleep with also appears to vary by ethnicity. Nine out of 10 whites who are married or "partnered" sleep with their significant others, a slightly higher rate than that among African Americans.

But three-quarters and two-thirds of Hispanics and Asians, respectively, said that they don't sleep with their partner. Those groups, however, were more likely to share a bedroom with their children.

"Asians tend to sleep with children in their beds and that could have an impact on sleep quality because anything that disrupts sleep like a dog or kid in the bed can negatively impact sleep and the restorative value of that sleep," Balkin says. Whites were more likely to sleep with their pets than other ethnic groups, the poll showed.

Although each group reported getting between six and seven hours of sleep on the average weekday (or other workday), the amount of sleep did vary significantly. African Americans got the least (about 6.25 hours), and whites got the most (just under seven hours).

With numbers like these, it's not surprising that relatively few of the survey respondents reported consistently getting a good night's sleep. "Most people require seven to nine hours of sleep to feel rested," says Balkin. "The first step is to become aware of the problem, and then make more time for sleep and engage in practices that promote good, healthy sleep."

According to Balkin, good sleep hygiene includes going to bed and waking up at the same time each day (ideally without an alarm clock); using the bedroom only for sleep and sex; abstaining from nicotine, caffeine, or alcohol after 2 p.m.; and avoiding stressful tasks right before bed.

"If you try all these tips and are still not getting enough sleep or are still sleepy, you may have a problem that requires a greater level of intervention, such as medication or light therapy, which can help re-train or reset your body's internal clock," he adds.

The rate of diagnosed sleep disorders differs among the groups, the survey found. Whites were more likely to have been diagnosed with insomnia, while African Americans were more likely to have sleep apnea, a breathing problem that causes people to wake up frequently.

What else is keeping us awake at night? Roughly 20 percent of whites, African Americans, and Hispanics said that financial problems were causing them to lose sleep at night, compared to just 9 percent of Asians. More so than other groups, Hispanics also worried about health-related concerns.

Priyanka Yadav, D.O., a sleep medicine specialist at Somerset Medical Center in Somerville, New Jersey, says that the survey's findings suggest that she and other experts in the field need to tailor their treatment to different ethnicities.

While Asians reported the fewest sleep problems and were among the least likely to use sleeping aids (such as medication), for instance, they were also least likely to bring up sleep problems with their doctors.

"Now that I know this, if I had an Asian patient, I would ask them about their sleep to get the dialogue started," says Yadav.

"It is really important to realize how ethnicities view sleep, so we can better target our treatment recommendations," she adds.

In the end, the racial and ethnic differences in the survey may be less important than the fact that so many people struggle to get a good night's, suggests Mark W. Mahowald, M.D., the director of the Minnesota Regional Sleep Disorders Center.

"There are ethnic and cultural differences and socioeconomic factors that play a role in how much sleep everyone gets, but a significant percent of the adult population is sleep deprived," he says. "The main consequence of this is impaired performance in the workplace, in the classroom, and behind the wheel, followed by irritability."

People with busy schedules often cut back on sleep to make time for other things, Mahowald adds. But, he says, "Sleep is non-negotiable and is as important as diet and exercise to our overall well-being."