Sedating Antidepressants for Insomnia?

Antidepressants have been prescribed as de facto sleeping pills for over 3 decades now. This used to bother me. Most antidepressants have not been tested on people with simple insomnia and shown to improve their sleep.

These days I see things differently.

Can antidepressants help you sleep?Antidepressants have been prescribed as de facto sleeping pills for over 3 decades now. This used to bother me. Most antidepressants have not been tested on people with simple insomnia and shown to improve sleep.

In contrast, sleeping pills approved for the treatment of insomnia have been tested on insomniacs in clinical trials and shown to work. Why would a doctor prescribe a drug that hasn’t been held to the same standard? It looked like a cop-out to me.

These days I see things differently. Not because the pharmaceutical companies have suddenly come forward with proof that sedating antidepressants improve the sleep of people with insomnia in the absence of depression. (One such drug, low-dose doxepin, a tricyclic antidepressant, has been tested and approved for insomnia. Details are below.)

I’ve changed my mind for a personal reason: about 9 months ago, I was persuaded to start taking a low dose of a tricyclic antidepressant for a stomach problem I have. As a result, I can now eat small portions of many foods that were off-limits to me for 5 or 6 years.

Do I care that nortriptyline has never been tested and approved for the treatment of functional dyspepsia? No. Eating is believing. And now I’m willing to accept the idea that low-dose antidepressants might be a reasonable solution to the sleep problems of insomniacs who say they need medication to get a decent night’s sleep. Here’s some general information about sedating antidepressants and details about those frequently prescribed for people with insomnia.

Sedating Antidepressants

Doctors like antidepressants in part because of what they’re not. Most sleeping pills on the market today—zolpidem (Ambien), eszopiclone (Lunesta), and suvorexant (Belsomra), for example—are Schedule IV drugs, meaning that they’re believed to have some potential for abuse and dependence. Nightly users of these drugs may also develop tolerance to them and find they no longer work.

In contrast, antidepressants are unscheduled drugs not known to foster dependency or abuse. They’re considered relatively safe for long-term use. If you find one that helps you manage your insomnia, your doctor will probably be happy to prescribe it indefinitely.

The downside of many sedating antidepressants is that they have side effects at the high doses typically prescribed for people with depression. Drowsiness, increased susceptibility to falls, cognitive impairment, weight gain, dry mouth, constipation, difficulty with urination, and fine tremor are adverse effects noted by significant numbers of users. In the absence of formal testing, it’s hard to predict how frequently these adverse effects would occur at the low doses prescribed for people with insomnia.

Doxepin (Silenor)

As mentioned above, this is the only antidepressant approved for the treatment of insomnia. Doxepin at doses prescribed for depression (over 75 mg) acts on several neurotransmitter systems. At the low dose typically prescribed for insomnia (less than 10 mg), its sole appreciable effect is to block secretion of histamine, a neurotransmitter associated with wakefulness.

Strengths and weaknesses, per a review of randomized placebo-controlled trials:

  • Doxepin is better than placebo at keeping people sleeping through the night, extending sleep time, and improving sleep efficiency. The higher the dose, the more marked are the effects.
  • Doxepin does not help with sleep initiation. Headache and grogginess are possible side effects.

Trazodone (Desyrel)

Trazodone is the sedating antidepressant most commonly prescribed for people diagnosed with insomnia in the United States. At the low dose typically prescribed for sleep (50 mg), its blockade of histamine, serotonin, and alpha-1 receptors likely gives this drug its sedative effects. Trazodone’s popularity as a hypnotic is based on little hard evidence. No long-term studies of the drug’s efficacy as a hypnotic exist. This is unfortunate because it’s generally used as a maintenance treatment for people with insomnia.

Short-term trials obtained the following results:

  • In a large, 2-week trial comparing 50 mg trazodone with 10 mg zolpidem and placebo, trazodone in the first week reduced wakefulness at night and improved total sleep time and sleep quality. The drug performed no better than placebo in the second week.
  • In a small week-long trial of 50 mg of trazodone conducted to assess the drug’s side effects, investigators found that compared with placebo, trazodone cut down on nighttime awakenings and stage 1 sleep (the lightest stage). On day 7 only, subjects got more deep sleep and experienced less sleepiness the following day. However, taking the drug also led to “small but significant impairments of short-term memory, verbal learning, equilibrium, and arm muscle endurance across time points.” How likely these side effects would be to occur with long-term use is unknown.

Mirtazapine (Remeron)

Mirtazapine is a tetracyclic antidepressant also used for insomnia. This drug has never been tested on people with simple insomnia. But in 15 to 45-mg doses, it’s been found to have sedative effects in people with depression and insomnia. This is likely due to the drug’s blockade of histamine and serotonin receptors.

Strengths and weaknesses, per short- and long-term trials conducted on people with depression and insomnia (most of these trials did not have a placebo or FDA-approved control) :

  • Mirtazapine helps with falling asleep and staying asleep and may improve sleep quality.
  • Mirtazapine may potentially cause weight gain. Other common side effects include daytime drowsiness or dizziness and dry mouth.

According to a review article in the Journal of the American Pharmacists Association, “Lower doses (e.g., 7.5–15 mg) of mirtazapine may actually provide more sedation when compared with higher doses, as higher doses . . . [may blunt] the drug’s sedative effect.”

Amitriptyline (Elavil)

Amitriptyline is a tricyclic antidepressant that is sometimes prescribed in low doses (5–25 mg) for people with insomnia and other chronic health conditions. No clinical trials of the drug’s efficacy as a treatment for insomnia have ever been conducted. But studies conducted on people with depression and healthy individuals have found that amitriptyline has sedative effects.

Common side effects are daytime drowsiness, dry mouth, and urinary problems.

The Take-Away

The point of this blog is not to suggest that sedating antidepressants are a good solution to the sleep problems of everyone with persistent insomnia. My point is that these drugs may be a viable option for people who haven’t found relief through other means.

If you’ve tried an antidepressant for sleep, what was your experience like?

OTC Sleep Aids: A Risky Business

Many of us assume that over-the-counter drugs are safer than prescription drugs.

Yet the long-term effects of any drug can remain unknown for decades, and now researchers have found a correlation between long-term and/or high-dose use of OTC sleep aids and dementia.

Over-the-counter sleeping pills may not be as safe as we thinkSome insomniacs are leery of prescription sleeping pills but feel OK about sleep aids sold at the drugstore.

“I’m not really looking for medical intervention,” said Dale, a marketing manager who spoke to me about his insomnia as I was conducting interviews for my book. “I’m absolutely not interested in anything strong. But if it’s sold over the counter and I can take a half dose of it, that’s fine.”

Many of us assume that over-the-counter drugs are safer than prescription drugs. Yet the long-term effects of any drug can remain unknown for decades, and now researchers have found a correlation between long-term and/or high-dose use of OTC sleep aids and dementia.

Which Drugs Are Involved?

These drugs are called anticholinergics, among them the first-generation antihistamines that are now marketed as sleep aids. The active ingredient in these sleep aids is diphenhydramine or doxylamine. Here’s a list of common brand names:

  • Benadryl
  • Sominex
  • ZzzQuil
  • Tylenol PM
  • Excedrin PM
  • Nytol
  • Unisom
  • Store brands containing diphenhydramine and doxylamine.

Anticholinergic drugs block the action of acetylcholine, a neurotransmitter that plays an important role in waking us up and keeping us vigilant. When we’re awake, acetylcholine neurons are active in several areas of the brain. But the brains of people with Alzheimer’s disease show a marked reduction of acetylcholine and acetylcholine-secreting nerve cells. Other common anticholinergic medications include tricyclic antidepressants such as doxepin (Sinequan) and antimuscarinic drugs for bladder control such as oxybutynin (Ditropan).

Gist of the Study

Investigators at the University of Washington began tracking the medical records of 3,434 healthy 65-year-olds to see if anticholinergic medications increased their risk of developing dementia. About 23 percent of these older adults went on to develop dementia over a 7-year period.

Compared with people who did not take anticholinergic drugs, people taking at least 4 mg of diphenhydramine daily (1 capsule of Benadryl or ZzzQuil contains 25 mg of diphenhydramine), 10 mg of doxepin daily, and 5mg of oxybutynin for more than 3 years had a small increased risk of developing dementia. The risk increased in a linear fashion with higher doses and longer use.

Results in Perspective

This is not the first study to link dementia to the use of anticholinergic drugs. Researchers in Australia found that taking more anticholinergic medications was associated with greater risk of hospitalization for confusion or dementia. Researchers in Spain have concluded that long-term use of anticholinergic drugs “may generate a worsening of cognitive functions” and can also “initiate signs of dementia.”

None of the studies show that the relationship between anticholinergics and dementia is causal. Yet they do suggest that frequent use of OTC sleep aids may not be as harmless as many insomniacs suppose.

So what to do? Several prescription sleeping pills have also been connected to an increased risk of dementia, and a small body of research suggests that poor sleep may itself be a factor in the development of cognitive impairment. Now is the time to check into drug-free treatments for insomnia and be more sparing in the use of sleep meds, whether they’re handed over by a pharmacist or you can buy them right off the shelf.

 

For Sounder Sleep, Adjust Your Meds

Do you take medication for a chronic health condition? That drug may be disturbing your sleep.

Working with a doctor to adjust the dose or time you take it—or replace it with a similar drug that does not stimulate the central nervous system—may be all you need to hold insomnia at bay.

Which drugs can interfere with sleep? Here are a few most widely prescribed.

insomnia can be caused by daily medicationsDo you take medication for a chronic health condition? That drug may be disturbing your sleep.

Working with a doctor to adjust the dose or time you take it—or replace it with a similar drug that does not stimulate the central nervous system—may be all you need to hold insomnia at bay.

Which drugs can interfere with sleep? You’ll find a complete list in the 2010 edition of Principles and Practice of Sleep Medicine. Following are a few most widely prescribed.

Cardiovascular and Cholesterol-Lowering Drugs

Cardiovascular agents (for high blood pressure, heart disease, and kidney disease) and cholesterol-lowering drugs were the two most common types of drugs prescribed in 2007-2010, according to a CDC report released in May. Some may disrupt your sleep:

  • Beta Blockers, aimed at lowering blood pressure and reducing the risk of repeated heart attacks, are used by many adults. Metoprolol, for example, was the fourth most prescribed medication in the US last year, according to data from IMS Health. Yet metoprolol and other fat-soluble beta blockers—such as propranolol and pindolol—have caused insomnia and nightmares in some users, as well as reductions in REM sleep. Beta blockers also decrease the release of melatonin, which might disturb the continuity of your sleep.
  • Statins are widely prescribed to lower cholesterol and prevent heart attacks and strokes. Simvastatin, for example, was the fifth most prescribed medication in the US last year. Clinical trials of simvastatin and similar drugs—atorvastatin, lovastatin and pravastatin—have generally failed to show that these drugs impair sleep. But anecdotal reports suggest they cause insomnia and nightmares in some users.

Antidepressants

The CDC cites antidepressants as another commonly used type of medication. About 10.6 percent of Americans aged 18-64 years report using them, as do 13.7 Americans aged 65 and above. The antidepressant duloxetine (Cymbalta) was the fifth highest selling drug in 2013.

Some antidepressants are sedating (trazodone, nefazodone, and doxepin, for example). Others tend to be arousing (desipramine, nortriptyline, and protriptyline) and may disrupt sleep. But some antidepressants are neither fish nor fowl, and their effects on sleep are harder to predict:

  • Selective serotonin reuptake inhibitors (SSRIs) cause insomnia in some people and daytime sedation in others. Fluoxetine (Prozac) reportedly caused insomnia in 10 to 17 percent of users and daytime sedation in 5 to 21 percent.
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs) also cause insomnia in some people and daytime sedation in others. Duloxetine, for example, caused insomnia in 10 to 18 percent of users and daytime sedation in 8 to 13 percent.

See your doctor if you’re wondering whether a drug you take is contributing to your insomnia. Small adjustments in timing or dosage may be all it takes to put you on track to sounder sleep.

Please share questions or comments about drugs you take and their effects on your sleep.

Insomnia in the Middle of the Night

Does your sleep problem involve waking up in the middle of the night once or several times and then trouble falling back to sleep? Sleep maintenance insomnia is actually the most common form of insomnia, and it’s more common as people age. Here’s a quick review of the possible causes and what can be done.

sleep-maintenance-insomniaDoes your sleep problem involve waking up in the middle of the night once or several times and then trouble falling back to sleep? Sleep maintenance insomnia is actually the most common form of insomnia, and it’s more common as people age. Here’s a quick review of the possible causes and what can be done.

Having to pay a bathroom call at night will of course wake you up. Anything you can do cut down on the need to do that—eating an earlier dinner, drinking less in the evening, changing the time you take a medication (with an OK from the doctor)—will help. Other possible reasons for unwanted wake-ups include:

  • Age-related degeneration of neurons connected with the body clock. This results in weaker circadian rhythms, declining levels of melatonin (a hormone helpful to sleep), and more frequent shifts between sleep and waking.
  • Health problems involving chronic pain.
  • A higher rate of “cyclic alternating patterns”—repetitive brainwave patterns that occur during non-REM, or quiet, sleep, which cause your sleep to become less stable.

Reducing Nighttime Wake-ups

I’ll start by describing a behavioral strategy that may be helpful and then move on to medication.

  • Consolidate your sleep by reducing your time in bed. This is one key aim of Sleep Restriction Therapy, which I’ve blogged about many times. Simply delay your bedtime for an hour or more while continuing to get up at the same time every morning. Research suggests that the increased sleep pressure that builds up when you postpone bedtime will cut down on wake-ups at night. This strategy is known to work for adults of all ages.
  • If you suspect that a lack of melatonin is involved, you could ask your doctor about testing for melatonin deficiency (blood, urine, or saliva tests will work). You could also buy a test kit online, collect a sample and send it away to a lab yourself (I don’t, however, have information on the reliability of these labs). If your middle-of-the-night wake-ups are related to a melatonin deficiency, my blog on Melatonin Replacement Therapy describes the treatment options that exist–none perfect.

Prescription Medication

Many doctors frown on the nightly use of hypnotics. Although the FDA has approved a few of them for use without short-term restriction (Lunesta and Ambien CR, for example), concerns about side effects and the potential of these sleeping pills to cause drowsiness in the morning make physicians leery of prescribing them. This is especially true for older patients, whose bodies process drugs more slowly and who are thus more likely to experience unwanted effects.

As occurred in the 1980s and 1990s, physicians are now prescribing more sedating antidepressants and antipsychotics for patients with sleep maintenance insomnia. (Unfortunately, there have been few controlled studies assessing the efficacy of these drugs for insomnia.) Here are some examples:

  • Silenor. This low-dose formulation of doxepin is the single antidepressant drug that has been approved by the FDA for the treatment of sleep maintenance insomnia. Controlled studies have shown that it cuts down on nighttime wake-ups. The brand-name drug is expensive; generic doxepin is chemically identical and will work just as well . . . if it does work.
  • Trazodone. This sedating antidepressant was the best-selling drug for insomnia until the turn of the 21st century (and may now enjoy renewed popularity). The few short-term studies of the drug as a treatment for insomnia suggest that low doses (100 mg or less) cut down on wake time in the middle of the night. See my blog on trazodone for details.
  • Seroquel and Klonopin. See my blog on Off-Label Meds for Insomnia for information on these drugs. Here I’ll offer an addendum: the fact that these drugs are now available as generics (and therefore inexpensive) makes it unlikely that they’ll ever be tested for efficacy in treating insomnia. They may be effective for sleep maintenance insomnia—but any evidence now is based on observation only.

One last note on medication for middle-of-the-night awakeners: The sleeping pill zaleplon (a.k.a. Sonata) has not been approved for use in the middle of the night. But it has a very short half-life (1 hour) and tests are under way to evaluate the safety of middle-of-the-night dosing. A new study shows that while Ambien CR taken at bedtime interfered with the consolidation of memories at night, 10 mg of zaleplon taken in the middle of the night did not. Other studies have shown no residual grogginess in insomniacs at 4 hours after taking zaleplon. The drug may be an option for those looking to get back to sleep more quickly.

If you have sleep maintenance insomnia, what strategies and medications have you tried, and have they worked?

The Insomnia-Depression Connection Writ Large

Insomnia doesn’t often get front-page coverage, but it did on Tuesday. Benedict Carey of The New York Times reported on a study of people under treatment for depression. The results showed that nearly twice as many subjects were cured of depression when—in addition to taking an antidepressant or a pill placebo—they received cognitive-behavioral therapy (CBT) for insomnia.

It’s time to reassess the relationship between insomnia and depression.

Depression responds to treatment with cognitive behavioral therapy for insomniaInsomnia doesn’t often get front-page coverage, but it did on Tuesday. Benedict Carey of The New York Times reported on a study of people under treatment for depression. The results showed that nearly twice as many subjects were cured of depression when—in addition to taking an antidepressant or a pill placebo—they received cognitive-behavioral therapy (CBT) for insomnia.

It’s time to reassess the relationship between insomnia and depression. Sleep researchers in recent years have noted that the two disorders share biological turf. Compared with people who are healthy, those with insomnia and those with depression tend to get less deep sleep—the type of sleep associated with feelings of restoration. Elevated levels of cortisol, a stress hormone, and interleukin-6, a protein that stimulates the immune response, are also common to people in both groups.

Conventional Thinking About Depression and Sleep

Yet for hundreds of years, insomnia has been viewed as merely a symptom of depression. Just as in the fifteenth and sixteenth centuries sleeplessness was seen as a symptom of melancholia, so insomnia is still regarded by many psychotherapists as a symptom of depression. Treat the depression, the thinking goes, and the insomnia will disappear.

But this strategy does not always work, the authors of the current study concluded in an earlier study published in 2007, which I blogged about in September. Antidepressants may clear up depression, but insomnia often persists.

People I interviewed for The Savvy Insomniac (where I explore insomnia-related disorders and CBT at length) told stories of frustration as they looked for solutions to depression and insomnia. Laura, for example, had trouble sleeping long before she developed depression. Yet when she took her complaints to the doctor, all the doctor did was prescribe an antidepressant. The depression cleared up but the insomnia continued, and her doctor had nothing to suggest.

“Over the years,” Laura said, “they always assumed my insomnia was a symptom of depression rather than seeing it as separate. They don’t even consider the possibility that they’re exclusive with respect to each other.”

A New Perspective

New research is suggesting that insomnia may be a kind of way station to depression, and if results of the current study are confirmed by others soon to follow, they’ll really upset the apple cart. Not only may it be the case that CBT for insomnia helps clear up depression-related sleep problems. It may also true that supplementing traditional depression therapy with CBT for insomnia doubles the chance of recovery from depression.

Now put that in your pipe and smoke it.

If you’ve struggled with depression and insomnia, what treatments have you tried, and have they worked?

Off-Label Meds for Insomnia

Post-marketing tests now show that Ambien and Lunesta, the most popular sleeping pills today, are not as benign as they once were believed to be. Are we moving into a period similar to that which occurred in the 1980s, when physicians moved away from prescribing sleeping pills for people with insomnia and prescribed off-label medications instead?

dont-knowIn 1999, during a terrible bout of insomnia, I went to see a sleep specialist. A friend had told me that Klonopin (a.k.a. clonazepam) got rid of her insomnia and convinced me that I should try it myself. What was there to lose?

“Klonopin!” the doctor exclaimed at my suggestion. “That’s an antipsychotic.” (Clonazepam is now more often classified as an antianxiety medication.) “Your symptoms don’t warrant that. Take Ambien as needed, and don’t worry about taking a second pill if you wake up in the middle of the night.”

Fast forward to last month, when I went in to my primary care doctor for a routine physical and asked for a refill of Ambien, which I take occasionally.

“I’m not sure about the Ambien,” the doctor said. “It’s a bad drug. There’s a new story about it coming out everyday. How about trying clonazepam instead? I didn’t use to prescribe anything at all to patients with sleep problems. But now I’ve got patients using clonazepam daily and I’m not seeing any harmful effects.”

Déjà Vu

I’m reminded of events that occurred in the early 1980s, when the then-popular sleeping pill Halcion made its dramatic fall from grace. Higher dosages of the drug came to be associated with depression, suicidal thoughts, and violent behavior, and Upjohn, the drug’s maker, was accused of withholding information about these side effects from the FDA. So powerful was this sleeping pill believed to be that a handful of Americans were actually absolved of murder when their lawyers used what came to be known as “the Halcion defense” in court. (“The drug made me do it.”)

One result was that many doctors stopped prescribing sleeping pills for people with insomnia and started prescribing antidepressants like trazodone and amitriptyline instead. These antidepressants had not been tested and found to be effective for insomnia. But they were known to have sedating properties and believed to be safer than sleeping pills (never mind side effects like daytime fogginess, cardiovascular complications and erectile dysfunction in men). Did they work and were they tolerable? Insomniacs I interviewed for my book gave very mixed reviews.

History Repeats Itself

Post-marketing tests now show that Ambien and Lunesta, the most popular sleeping pills today, are not as benign as they once were believed to be. (See my blogs about Ambien for details.)

Now I hear of people taking drugs like clonazepam and Seroquel (quetiapine), an atypical antipsychotic, for help with sleep. These drugs have not been approved for the treatment of insomnia, but testimonials suggest that doctors are prescribing them, and insomniacs writing on Drugs.com give them fairly high marks (9.1 out of 10 and 8.3 out of 10, respectively).

I don’t have a problem with doctors prescribing medications off label if there’s hard evidence that they work. But where is that evidence? In Pubmed I can’t find a single study assessing the safety and efficacy of clonazepam for insomnia. The few tests assessing the efficacy of quetiapine are inconclusive, according to a meta-analysis published in 2012. Another meta-analysis concludes that safety concerns outweigh benefits.

Does it make sense to replace sleeping pills with known benefits and side effects with drugs whose efficacy and safety for insomnia is untested?

This is not a rhetorical question. I’d like to hear your thoughts.

A New Look at Trazodone for Sleep

Trazodone has never been approved for the treatment of insomnia. Yet it rose to the top of the bestseller charts as a medication for sleeplessness in the 1990s and enjoys great popularity still. Here’s one explanation for its appeal.

It’s been a stretch for me to accept that trazodone, a sedating antidepressant, is such a popular treatment for insomnia. Clinical trials have never shown it helps put people to sleep or keeps them sleeping longer. And even at low doses (50 mg.), the drug is known to produce cognitive and motor impairments the following day.* Trazodone has never been approved for the treatment of insomnia, yet it rose to the top of the bestseller charts as a medication for sleeplessness in the 1990s and enjoys great popularity still.

Trazodone

Confession: this is the sort of knotty paradox that keeps me awake at night.

Now, I have insomniac friends who swear by trazodone, and I know they’re not delusional. They use low-dose trazodone because it works for them, and they don’t need to understand why.

But I’m a stickler for evidence, and this gap between subjective experience and objective proof is a real sore point. So imagine my thrill at finding a paper that explains why it might be that trazodone works.

Trazodone and REM Sleep

The traditional view of insomnia holds that it’s basically a problem of non-REM (or quiet) sleep. Insomniacs may not be getting the same percent of deep sleep as good sleepers, or the problem may be in how deep sleep is discharged. Deep sleep is the restorative stuff, the kind that “knits up the raveled sleeve of care.” Alternatively, the quality of non-REM sleep may be compromised by lots of high-frequency brain activity that enables you to sense things even while you’re asleep.

But for insomniacs who struggle with frequent awakenings in the middle of the night, the problem may in fact be occurring during REM (or active) sleep, when you’re dreaming. A new analysis shows that percent-wise, people with sleep maintenance insomnia get less REM sleep and awaken more often during REM sleep than good sleepers. The hypothesis is that these insomniacs may be suffering from “REM sleep instability.”**

Despite its otherwise underwhelming characteristics as a sleep medication, trazodone does cut down on nighttime awakenings and make sleep feel easier. Unlike most other antidepressants, the drug does not suppress REM sleep. So as a sleeping pill, trazodone may have a claim to legitimacy after all.

Perhaps you’re one who knew it all along, but I was a skeptic, and this bit of news has done wonders for my sleep!

Effects of Trazodone

** REM Sleep Instability